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    Clinical Trial Results:
    A randomized, open-label, multicenter, controlled, parallel arm, phase III study assessing the efficacy and safety of AOP2014 vs. Hydroxyurea in patients with Polycythemia Vera

    Summary
    EudraCT number
    2012-005259-18
    Trial protocol
    HU   CZ   IT   SK   AT   BG   DE   PL   ES   BE  
    Global end of trial date
    08 Apr 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Mar 2018
    First version publication date
    11 Mar 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PROUD-PV
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AOP Orphan Pharmaceuticals AG
    Sponsor organisation address
    Wilhelminenstrasse 91/II f/B4, Vienna, Austria, 1160
    Public contact
    Head of Clinical Operations, AOP Orphan Pharmaceuticals AG, 43 015037224446, michael.zoerer@aoporphan.com
    Scientific contact
    Head of Clinical Operations, AOP Orphan Pharmaceuticals AG, 43 015037224446, michael.zoerer@aoporphan.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
    24 Jan 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Apr 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of AOP2014 vs. Hydroxyurea in terms of disease response rate in both Hydroxyurea naïve and currently treated patients, diagnosed with Polycythemia Vera.
    Protection of trial subjects
    An independent DMC was established that reviewed accumulated data on safety as well as efficacy in an open-label manner in regular intervals. Following the meetings the DMC advised the sponsor in writing on outcomes and findings of the meeting. Per the signed DMC charter the DMC took responsibility for continued safety as well as efficacy oversight.
    Background therapy
    Low dose aspirin (acetylsalicylic acid) (100 mg/day) was given to patients in both groups, during the 12 months of study treatment, unless contraindicated.
    Evidence for comparator
    Hydroxyurea is an established first-line treatment option currently approved in several European countries for Polycythemia Vera (PV) patients requiring a cytoreductive therapy. Clinical trials have shown that Hydroxyurea is an effective drug for preventing thrombosis in PV compared to phlebotomy. Major concerns of a long term treatment with Hydroxyurea is development of intolerance or resistance in a significant proportion of patients, and its potential leukemogenic risk, based on the mechanism of action.
    Actual start date of recruitment
    17 Sep 2013
    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
    Slovakia: 10
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Austria: 19
    Country: Number of subjects enrolled
    Bulgaria: 45
    Country: Number of subjects enrolled
    Czech Republic: 27
    Country: Number of subjects enrolled
    Poland: 28
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Hungary: 35
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Russian Federation: 33
    Country: Number of subjects enrolled
    Ukraine: 30
    Country: Number of subjects enrolled
    Romania: 9
    Worldwide total number of subjects
    257
    EEA total number of subjects
    194
    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)
    177
    From 65 to 84 years
    79
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    Patients meeting the inclusion criteria were contacted and asked for their interest in participating in the study. All patients who agreed to participate in the study provided written informed consent before any study specific assessments or procedures were performed.

    Pre-assignment
    Screening details
    Patients diagnosed with Polycythemia Vera, either Hydroxyurea naïve or currently being treated with Hydroxyurea, and fulfilling other eligibility criteria were randomized. Patients considered for study entry, but who failed to meet one or more of the eligibility criteria, were reported in the eCRF detailing the reason for ineligibility.

    Period 1
    Period 1 title
    Enrollment period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    AOP2014
    Arm description
    Patients planned to be treated with AOP2014
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Hydroxyurea
    Arm description
    Patients planned to be treated with Hydroxyurea
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    AOP2014 Hydroxyurea
    Started
    127
    130
    Completed
    127
    127
    Not completed
    0
    3
         Consent withdrawn by subject
    -
    3
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    AOP2014
    Arm description
    Patients treated with AOP2014. During the initial treatment phase (first 12 weeks following randomization), the dose of AOP2014 was adjusted to the dose which delivered the optimal disease response.
    Arm type
    Experimental

    Investigational medicinal product name
    AOP2014
    Investigational medicinal product code
    AOP2014
    Other name
    Peg-P-IFN-α-2b
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    AOP2014 was administered at the starting dose of 100 µg every 2 weeks for up to 12 months of treatment. During the initial treatment phase (first 12 weeks following randomization), the dose of AOP2014 was adjusted to the dose which delivered the optimal disease response (Hematocrit [Hct] <45%, platelets <400 x 109/L and leukocytes <10 x 109/L). If no complete response was achieved, patients were treated at the individual highest tolerable dose, which had been achieved and kept during the maintenance treatment phase.

    Investigational medicinal product name
    Hydroxyurea
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    For the patients concurrently receiving Hydroxyurea at the time of screening but randomized to AOP2014 was the initial phase of the trial (up to week 12) a transition from Hydroxyurea to AOP2014. Hydroxyurea dose was decreased every two weeks and discontinued after week 12.

    Arm title
    Hydroxyurea
    Arm description
    Patients treated with Hydroxyurea. During the initial treatment phase (first 12 weeks following randomization), the dose of Hydroxyurea was adjusted to the dose which delivered the optimal disease response.
    Arm type
    Active comparator

    Investigational medicinal product name
    Hydroxyurea
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Hydroxyurea was administered per os at the starting dose of 500 mg daily for up to 12 months of treatment. During the initial treatment phase (first 12 weeks following randomization), the dose of Hydroxyurea was adjusted to the dose which delivered the optimal disease response (Hematocrit [Hct] <45%, platelets <400 x 109/L and leukocytes <10 x 109/L). If no complete response was achieved, patients were treated at the individual highest tolerable dose, which had been achieved and kept during the maintenance treatment phase.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: No analysis was done on all enrolled patients, full analysis set (e.g. patients who started treatment) was used.
    Number of subjects in period 2 [2]
    AOP2014 Hydroxyurea
    Started
    127
    127
    Week 12 Assesment visit
    125
    122
    Completed
    106
    111
    Not completed
    21
    16
         Positive/Elevated TPOab
    -
    2
         Lack of efficacy
    -
    2
         Non-compliance with the protocol
    -
    3
         Adverse event, non-fatal
    11
    3
         Consent withdrawn by subject
    6
    5
         Administrative reasons
    4
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Three subjects were enrolled and randomized, but never received the treatment as they withdrew their consent before first administration.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AOP2014
    Reporting group description
    Patients treated with AOP2014. During the initial treatment phase (first 12 weeks following randomization), the dose of AOP2014 was adjusted to the dose which delivered the optimal disease response.

    Reporting group title
    Hydroxyurea
    Reporting group description
    Patients treated with Hydroxyurea. During the initial treatment phase (first 12 weeks following randomization), the dose of Hydroxyurea was adjusted to the dose which delivered the optimal disease response.

    Reporting group values
    AOP2014 Hydroxyurea Total
    Number of subjects
    127 127 254
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    90 84 174
        From 65-84 years
    36 43 79
        85 years and over
    1 0 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    58.5 ± 10.81 57.9 ± 13.1 -
    Gender categorical
    Units: Subjects
        Female
    68 67 135
        Male
    59 60 119
    Race
    Units: Subjects
        White
    127 127 254
    Durration of Polycythemia Vera
    Units: month(s)
        arithmetic mean (standard deviation)
    12.6 ± 24.7 15.7 ± 25.65 -
    Subject analysis sets

    Subject analysis set title
    AOP2014 PPS
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Per Protocol Set (PPS) consisted of patients included in the Full Analysis Set who completed a certain pre-specified minimal exposure to the treatment regimen, had all measurements needed for assessment of the primary endpoint available and did not violate the study protocol in major concerns. The PPS was used for efficacy sensitivity analysis.

    Subject analysis set title
    Hydroxyurea PPS
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Per Protocol Set (PPS) consisted of patients included in the Full Analysis Set who completed a certain pre-specified minimal exposure to the treatment regimen, had all measurements needed for assessment of the primary endpoint available and did not violate the study protocol in major concerns. The PPS was used for efficacy sensitivity analysis.

    Subject analysis sets values
    AOP2014 PPS Hydroxyurea PPS
    Number of subjects
    115
    114
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    84
    74
        From 65-84 years
    30
    40
        85 years and over
    1
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    58 ± 10.67
    58.4 ± 13.09
    Gender categorical
    Units: Subjects
        Female
    60
    59
        Male
    55
    55
    Race
    Units: Subjects
        White
    115
    114
    Durration of Polycythemia Vera
    Units: month(s)
        arithmetic mean (standard deviation)
    12.6 ± 25.56
    14.9 ± 24.52

    End points

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    End points reporting groups
    Reporting group title
    AOP2014
    Reporting group description
    Patients planned to be treated with AOP2014

    Reporting group title
    Hydroxyurea
    Reporting group description
    Patients planned to be treated with Hydroxyurea
    Reporting group title
    AOP2014
    Reporting group description
    Patients treated with AOP2014. During the initial treatment phase (first 12 weeks following randomization), the dose of AOP2014 was adjusted to the dose which delivered the optimal disease response.

    Reporting group title
    Hydroxyurea
    Reporting group description
    Patients treated with Hydroxyurea. During the initial treatment phase (first 12 weeks following randomization), the dose of Hydroxyurea was adjusted to the dose which delivered the optimal disease response.

    Subject analysis set title
    AOP2014 PPS
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Per Protocol Set (PPS) consisted of patients included in the Full Analysis Set who completed a certain pre-specified minimal exposure to the treatment regimen, had all measurements needed for assessment of the primary endpoint available and did not violate the study protocol in major concerns. The PPS was used for efficacy sensitivity analysis.

    Subject analysis set title
    Hydroxyurea PPS
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Per Protocol Set (PPS) consisted of patients included in the Full Analysis Set who completed a certain pre-specified minimal exposure to the treatment regimen, had all measurements needed for assessment of the primary endpoint available and did not violate the study protocol in major concerns. The PPS was used for efficacy sensitivity analysis.

    Primary: Disease response rate

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    End point title
    Disease response rate
    End point description
    The disease response rate was defined by the rate of patients who met all criteria after 12 months of AOP2014 or Hydroxyurea treatment: • Haematocrit < 45% without phlebotomy (at least 3 month since last phlebotomy) • Platelets < 400 x 109/L • Leukocytes < 10 x 109/L • Spleen size normality defined as spleen length ≤ 12cm for females/≤ 13 cm for males (by imaging) Patients who discontinued the study were considered as non-responders.
    End point type
    Primary
    End point timeframe
    The disease response rate at 12 months of treatment (Week 52 assessment visit).
    End point values
    AOP2014 Hydroxyurea AOP2014 PPS Hydroxyurea PPS
    Number of subjects analysed
    122
    123
    115
    114
    Units: subjects
        Responder
    26
    34
    26
    33
        Non-responder
    96
    89
    89
    81
    Statistical analysis title
    Evaluation of non-inferiority, full analysis set
    Statistical analysis description
    The analysis of the primary efficacy endpoint was defined as disease response rate after one year, testing non-inferiority of AOP2014 to Hydroxyurea using a weighted Cochran-Mantel-Haenszel method (adjusted for the stratification groups) to calculate the confidence interval.
    Comparison groups
    Hydroxyurea v AOP2014
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    P-value
    = 0.2233 [2]
    Method
    Wald test
    Parameter type
    Difference in percentages
    Point estimate
    -6.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.23
         upper limit
    4.09
    Notes
    [1] - Non-inferiority is concluded if the lower limit of the 95% two-sided CI of the Mantel-Haenszel common estimate of response rate differdifference exceeds -10.5% for the Full Analysis Set and the Per Protocol Analysis Set.
    [2] - The Wald test for testing the non-inferiority of AOP2014 versus Hydroxyurea was not adjusted for the stratification groups.
    Statistical analysis title
    Evaluation of non-inferiority, per-protocol set
    Statistical analysis description
    The analysis of the primary efficacy endpoint was defined as disease response rate after one year, testing non-inferiority of AOP2014 to Hydroxyurea using a weighted Cochran-Mantel-Haenszel method (adjusted for the stratification groups) to calculate the confidence interval.
    Comparison groups
    Hydroxyurea PPS v AOP2014 PPS
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    P-value
    = 0.2353 [4]
    Method
    Wald test
    Parameter type
    Difference in percentages
    Point estimate
    -6.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.49
         upper limit
    4.92
    Notes
    [3] - Non-inferiority is concluded if the lower limit of the 95% two-sided CI of the Mantel-Haenszel common estimate of response rate differdifference exceeds -10.5% for the Full Analysis Set and the Per Protocol Analysis Set.
    [4] - The Wald test for testing the non-inferiority of AOP2014 versus Hydroxyurea was not adjusted for the stratification groups.

    Secondary: Complete haematological response

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    End point title
    Complete haematological response
    End point description
    The disease response (without spleen size normality) i.e. the complete haematological response was defined as: • Haematocrit < 45% without phlebotomy (at least 3 month since last phlebotomy) • Platelets < 400 x 109/L • Leukocytes < 10 x 109/L
    End point type
    Secondary
    End point timeframe
    Complete haematological response at 12 months of treatment (Week 52 assessment visit).
    End point values
    AOP2014 Hydroxyurea AOP2014 PPS Hydroxyurea PPS
    Number of subjects analysed
    123
    125
    113
    114
    Units: subjects
        Responder
    53
    57
    50
    53
        Non-responder
    70
    68
    63
    61
    Statistical analysis title
    Evaluation of non-inferiority, full analysis set
    Statistical analysis description
    Complete haematological response after one year, testing non-inferiority of AOP2014 to Hydroxyurea using a weighted Cochran-Mantel-Haenszel method (adjusted for the stratification groups) to calculate the confidence interval.
    Comparison groups
    AOP2014 v Hydroxyurea
    Number of subjects included in analysis
    248
    Analysis specification
    Post-hoc
    Analysis type
    non-inferiority [5]
    P-value
    = 0.0028 [6]
    Method
    Wald test
    Parameter type
    Difference in percentages
    Point estimate
    -3.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.55
         upper limit
    9.52
    Notes
    [5] - Non-inferiority is concluded if the lower limit of the 95% two-sided CI of the Mantel-Haenszel common estimate of response rate difference exceeds – 20.0% for the Full Analysis Set and the Per Protocol Analysis Set.
    [6] - The Wald test for testing the non-inferiority of AOP2014 versus Hydroxyurea was not adjusted for the stratification groups.
    Statistical analysis title
    Evaluation of non-inferiority, per-protocol set
    Statistical analysis description
    Complete haematological response after one year, testing non-inferiority of AOP2014 to Hydroxyurea using a weighted Cochran-Mantel-Haenszel method (adjusted for the stratification groups) to calculate the confidence interval.
    Comparison groups
    AOP2014 PPS v Hydroxyurea PPS
    Number of subjects included in analysis
    227
    Analysis specification
    Post-hoc
    Analysis type
    non-inferiority [7]
    P-value
    = 0.0036 [8]
    Method
    Wald test
    Parameter type
    Difference in percentages
    Point estimate
    -2.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.76
         upper limit
    10.49
    Notes
    [7] - Non-inferiority is concluded if the lower limit of the 95% two-sided CI of the Mantel-Haenszel common estimate of response rate difference exceeds – 20.0% for the Full Analysis Set and the Per Protocol Analysis Set.
    [8] - The Wald test for testing the non-inferiority of AOP2014 versus Hydroxyurea was not adjusted for the stratification groups.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first study treatment administration onwards through the observational phase until the last safety follow-up visit.
    Adverse event reporting additional description
    Subjects were queried about adverse events at each visit (approximately every two weeks).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Hydroxyurea
    Reporting group description
    Patients treated with Hydroxyurea

    Reporting group title
    AOP2014
    Reporting group description
    Patients treated with AOP2014

    Serious adverse events
    Hydroxyurea AOP2014
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 127 (8.66%)
    14 / 127 (11.02%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (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 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Aortic valve replacement
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid endarterectomy
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst excision
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glioblastoma
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Spermatocytic seminoma
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         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
    Multi-organ failure
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         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 polyp
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subcutaneous haematoma
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhagic transformation stroke
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (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
    Appendicitis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         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: 0%
    Non-serious adverse events
    Hydroxyurea AOP2014
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    111 / 127 (87.40%)
    100 / 127 (78.74%)
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Contrast media reaction
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 127 (0.79%)
         occurrences all number
    2
    1
    Foot fracture
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Gastrointestinal disorder postoperative
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Forearm fracture
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Ligament sprain
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Limb injury
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Overdose
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Subcutaneous haematoma
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Thermal burn
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Traumatic haematoma
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 127 (0.79%)
    9 / 127 (7.09%)
         occurrences all number
    1
    10
    Anti-thyroid antibody positive
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 127 (0.79%)
    8 / 127 (6.30%)
         occurrences all number
    1
    9
    Blood bilirubin increased
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Blood fibrinogen decreased
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Blood glucose increased
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Blood iron decreased
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    2
    Blood potassium decreased
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Blood potassium increased
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Blood pressure abnormal
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Blood pressure systolic increased
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    2
    Blood uric acid increased
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 127 (1.57%)
         occurrences all number
    1
    2
    Blood urea increased
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Body temperature decreased
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Body temperature increased
         subjects affected / exposed
    1 / 127 (0.79%)
    3 / 127 (2.36%)
         occurrences all number
    1
    3
    Ejection fraction decreased
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    2
    Electrocardiogram PR prolongation
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 127 (0.79%)
    18 / 127 (14.17%)
         occurrences all number
    1
    24
    Electrocardiogram QT interval abnormal
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Haematocrit decreased
         subjects affected / exposed
    4 / 127 (3.15%)
    0 / 127 (0.00%)
         occurrences all number
    5
    0
    Haematocrit increased
         subjects affected / exposed
    1 / 127 (0.79%)
    6 / 127 (4.72%)
         occurrences all number
    1
    10
    Haemoglobin decreased
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 127 (0.00%)
    7 / 127 (5.51%)
         occurrences all number
    0
    9
    Mean cell volume increased
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Nitrite urine present
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Platelet count decreased
         subjects affected / exposed
    8 / 127 (6.30%)
    2 / 127 (1.57%)
         occurrences all number
    14
    2
    Platelet count increased
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Transferrin decreased
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Visual acuity tests abnormal
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    2
    White blood cell count decreased
         subjects affected / exposed
    4 / 127 (3.15%)
    3 / 127 (2.36%)
         occurrences all number
    8
    8
    White blood cell count increased
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    White blood cells urine positive
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Aortic valve calcification
         subjects affected / exposed
    3 / 127 (2.36%)
    0 / 127 (0.00%)
         occurrences all number
    3
    0
    Arrhythmia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Atrial fibrillation
         subjects affected / exposed
    2 / 127 (1.57%)
    2 / 127 (1.57%)
         occurrences all number
    10
    2
    Atrial flutter
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Bradycardia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Bundle branch block left
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Cardiac failure
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Cyanosis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Dilatation ventricular
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Intracardiac thrombus
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Mitral valve calcification
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Palpitations
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 127 (1.57%)
         occurrences all number
    1
    3
    Mitral valve incompetence
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 127 (0.79%)
         occurrences all number
    2
    1
    Sinus tachycardia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Sinoatrial block
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    1 / 127 (0.79%)
    3 / 127 (2.36%)
         occurrences all number
    2
    3
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Congenital, familial and genetic disorders
    Cataract congenital
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Marfan's syndrome
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    31 / 127 (24.41%)
    8 / 127 (6.30%)
         occurrences all number
    50
    9
    Granulocytopenia
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Cytopenia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Leukopenia
         subjects affected / exposed
    27 / 127 (21.26%)
    11 / 127 (8.66%)
         occurrences all number
    53
    27
    Neutropenia
         subjects affected / exposed
    5 / 127 (3.94%)
    2 / 127 (1.57%)
         occurrences all number
    11
    2
    Lymphadenopathy
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Polycythaemia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Splenic infarction
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Splenomegaly
         subjects affected / exposed
    3 / 127 (2.36%)
    5 / 127 (3.94%)
         occurrences all number
    3
    5
    Thrombocytopenia
         subjects affected / exposed
    36 / 127 (28.35%)
    19 / 127 (14.96%)
         occurrences all number
    99
    35
    Thrombocytosis
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Dizziness
         subjects affected / exposed
    10 / 127 (7.87%)
    12 / 127 (9.45%)
         occurrences all number
    14
    15
    Dysgeusia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Head discomfort
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Hypoaesthesia
         subjects affected / exposed
    0 / 127 (0.00%)
    3 / 127 (2.36%)
         occurrences all number
    0
    5
    Headache
         subjects affected / exposed
    11 / 127 (8.66%)
    12 / 127 (9.45%)
         occurrences all number
    16
    26
    Intercostal neuralgia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Migraine
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Migraine with aura
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Neuralgia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia
         subjects affected / exposed
    4 / 127 (3.15%)
    0 / 127 (0.00%)
         occurrences all number
    4
    0
    Peripheral nerve lesion
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Sciatica
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Radiculopathy
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Sinus headache
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Somnolence
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    2
    Trigeminal neuritis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Age-related macular degeneration
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Asthenopia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Blepharitis
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Blepharochalasis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Cataract
         subjects affected / exposed
    3 / 127 (2.36%)
    6 / 127 (4.72%)
         occurrences all number
    3
    6
    Chalazion
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Corneal opacity
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Diabetic retinopathy
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Dry eye
         subjects affected / exposed
    2 / 127 (1.57%)
    4 / 127 (3.15%)
         occurrences all number
    2
    4
    Eye inflammation
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Eye pain
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Eye irritation
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Keratopathy
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Myopia
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Maculopathy
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Posterior capsule opacification
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Presbyopia
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    2
    Retinopathy
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 127 (1.57%)
         occurrences all number
    1
    2
    Retinopathy hypertensive
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Visual acuity reduced
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    2
    Vision blurred
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Ear discomfort
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Tinnitus
         subjects affected / exposed
    0 / 127 (0.00%)
    3 / 127 (2.36%)
         occurrences all number
    0
    8
    Vertigo
         subjects affected / exposed
    7 / 127 (5.51%)
    4 / 127 (3.15%)
         occurrences all number
    7
    4
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Abdominal distension
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    2
    1
    Abdominal pain
         subjects affected / exposed
    7 / 127 (5.51%)
    7 / 127 (5.51%)
         occurrences all number
    11
    7
    Abdominal pain upper
         subjects affected / exposed
    6 / 127 (4.72%)
    2 / 127 (1.57%)
         occurrences all number
    11
    3
    Aphthous ulcer
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Abdominal wall disorder
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Burning mouth syndrome
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    6 / 127 (4.72%)
    3 / 127 (2.36%)
         occurrences all number
    6
    5
    Diarrhoea
         subjects affected / exposed
    10 / 127 (7.87%)
    8 / 127 (6.30%)
         occurrences all number
    20
    15
    Dry mouth
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Diverticulum intestinal
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Epigastric discomfort
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Flatulence
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Gastric disorder
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    2
    1
    Gastritis
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    2
    Gastrointestinal pain
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Gingival pain
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Gingival bleeding
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 127 (0.79%)
         occurrences all number
    2
    1
    Haematemesis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Oesophagitis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    15 / 127 (11.81%)
    3 / 127 (2.36%)
         occurrences all number
    19
    4
    Paraesthesia oral
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Reflux gastritis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Stomatitis
         subjects affected / exposed
    2 / 127 (1.57%)
    2 / 127 (1.57%)
         occurrences all number
    5
    2
    Vomiting
         subjects affected / exposed
    5 / 127 (3.94%)
    3 / 127 (2.36%)
         occurrences all number
    6
    3
    Truncus coeliacus thrombosis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Dysuria
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Leukocyturia
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Micturition urgency
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Nephrolithiasis
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Nephroptosis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Nocturia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Pyelocaliectasis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Renal cyst
         subjects affected / exposed
    2 / 127 (1.57%)
    2 / 127 (1.57%)
         occurrences all number
    2
    2
    Renal colic
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 127 (0.00%)
    6 / 127 (4.72%)
         occurrences all number
    0
    9
    Blood blister
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Dermatitis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Dry skin
         subjects affected / exposed
    4 / 127 (3.15%)
    0 / 127 (0.00%)
         occurrences all number
    4
    0
    Eczema
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    6
    Erythema
         subjects affected / exposed
    1 / 127 (0.79%)
    3 / 127 (2.36%)
         occurrences all number
    1
    4
    Hyperhidrosis
         subjects affected / exposed
    0 / 127 (0.00%)
    3 / 127 (2.36%)
         occurrences all number
    0
    3
    Night sweats
         subjects affected / exposed
    3 / 127 (2.36%)
    2 / 127 (1.57%)
         occurrences all number
    3
    2
    Photosensitivity reaction
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    8 / 127 (6.30%)
    10 / 127 (7.87%)
         occurrences all number
    9
    41
    Pruritus generalised
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    2
    Psoriasis
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    2
    Rash
         subjects affected / exposed
    4 / 127 (3.15%)
    3 / 127 (2.36%)
         occurrences all number
    5
    3
    Rash erythematous
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Rosacea
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Skin exfoliation
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Skin ulcer
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Xeroderma
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 127 (3.15%)
    12 / 127 (9.45%)
         occurrences all number
    5
    24
    Back pain
         subjects affected / exposed
    4 / 127 (3.15%)
    9 / 127 (7.09%)
         occurrences all number
    5
    9
    Arthritis reactive
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    2
    Bone pain
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 127 (1.57%)
         occurrences all number
    1
    2
    Gouty arthritis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Groin pain
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Joint swelling
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 127 (0.79%)
    3 / 127 (2.36%)
         occurrences all number
    1
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 127 (0.79%)
    3 / 127 (2.36%)
         occurrences all number
    1
    8
    Musculoskeletal pain
         subjects affected / exposed
    0 / 127 (0.00%)
    5 / 127 (3.94%)
         occurrences all number
    0
    14
    Myalgia
         subjects affected / exposed
    3 / 127 (2.36%)
    11 / 127 (8.66%)
         occurrences all number
    3
    13
    Neck pain
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    2
    Osteoarthritis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Osteochondrosis
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Osteoporosis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    3 / 127 (2.36%)
    9 / 127 (7.09%)
         occurrences all number
    3
    12
    Spinal pain
         subjects affected / exposed
    2 / 127 (1.57%)
    3 / 127 (2.36%)
         occurrences all number
    2
    3
    Tendonitis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Autoimmune thyroiditis
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Hyperthyroidism
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Hypothyroidism
         subjects affected / exposed
    1 / 127 (0.79%)
    3 / 127 (2.36%)
         occurrences all number
    1
    3
    Thyroiditis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Decreased appetite
         subjects affected / exposed
    0 / 127 (0.00%)
    3 / 127 (2.36%)
         occurrences all number
    0
    3
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Gout
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    2
    Hypocalcaemia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    2
    Hypoglycaemia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Iron deficiency
         subjects affected / exposed
    4 / 127 (3.15%)
    5 / 127 (3.94%)
         occurrences all number
    5
    7
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Alveolar osteitis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Bronchitis
         subjects affected / exposed
    6 / 127 (4.72%)
    3 / 127 (2.36%)
         occurrences all number
    6
    3
    Conjunctivitis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Cystitis
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 127 (1.57%)
         occurrences all number
    1
    2
    Erysipelas
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Folliculitis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Fungal infection
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Fungal skin infection
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    3
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Infection
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    10 / 127 (7.87%)
    2 / 127 (1.57%)
         occurrences all number
    10
    2
    Laryngitis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Lyme disease
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    8 / 127 (6.30%)
    4 / 127 (3.15%)
         occurrences all number
    10
    8
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Onychomycosis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Oral herpes
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 127 (0.79%)
         occurrences all number
    3
    1
    Oral infection
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Paronychia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    3 / 127 (2.36%)
    2 / 127 (1.57%)
         occurrences all number
    3
    2
    Rhinitis
         subjects affected / exposed
    2 / 127 (1.57%)
    3 / 127 (2.36%)
         occurrences all number
    3
    3
    Sinusitis
         subjects affected / exposed
    3 / 127 (2.36%)
    1 / 127 (0.79%)
         occurrences all number
    4
    1
    Tonsillitis
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    2
    Tooth infection
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 127 (3.94%)
    5 / 127 (3.94%)
         occurrences all number
    6
    7
    Urinary tract infection
         subjects affected / exposed
    5 / 127 (3.94%)
    4 / 127 (3.15%)
         occurrences all number
    6
    5
    Viral infection
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Viraemia
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Blood pressure fluctuation
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Circulatory collapse
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Erythromelalgia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Femoral artery occlusion
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Haematoma
         subjects affected / exposed
    3 / 127 (2.36%)
    1 / 127 (0.79%)
         occurrences all number
    4
    1
    Hypertension
         subjects affected / exposed
    7 / 127 (5.51%)
    4 / 127 (3.15%)
         occurrences all number
    7
    5
    Hypertensive crisis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Hypotension
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Peripheral circulatory failure
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Peripheral coldness
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Phlebitis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Raynaud's phenomenon
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Subclavian steal syndrome
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Varicose vein
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Vascular pain
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Surgical and medical procedures
    Cataract operation
         subjects affected / exposed
    3 / 127 (2.36%)
    0 / 127 (0.00%)
         occurrences all number
    3
    0
    Endocervical curettage
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Eye operation
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Intraocular lens implant
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Maxillofacial operation
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Ovarian cystectomy
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Tooth extraction
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adrenal adenoma
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Angiolipoma
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Benign neoplasm of thyroid gland
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Blepharal papilloma
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Fibrous histiocytoma
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Primary myelofibrosis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Seasonal allergy
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Social circumstances
    Stress at work
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 127 (3.94%)
    7 / 127 (5.51%)
         occurrences all number
    7
    14
    Axillary pain
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Chest pain
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 127 (1.57%)
         occurrences all number
    1
    2
    Chills
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Drug intolerance
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    17 / 127 (13.39%)
    16 / 127 (12.60%)
         occurrences all number
    21
    43
    Feeling cold
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    3
    0
    Impaired healing
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    2
    Inflammation
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Influenza like illness
         subjects affected / exposed
    2 / 127 (1.57%)
    7 / 127 (5.51%)
         occurrences all number
    2
    7
    Injection site erythema
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Injection site pain
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    2
    Injection site pruritus
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    2
    Mucosal inflammation
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 127 (1.57%)
         occurrences all number
    2
    2
    Oedema peripheral
         subjects affected / exposed
    1 / 127 (0.79%)
    3 / 127 (2.36%)
         occurrences all number
    1
    3
    Pain
         subjects affected / exposed
    4 / 127 (3.15%)
    1 / 127 (0.79%)
         occurrences all number
    5
    1
    Pyrexia
         subjects affected / exposed
    2 / 127 (1.57%)
    7 / 127 (5.51%)
         occurrences all number
    3
    11
    Puncture site pain
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Sensation of foreign body
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Soft tissue inflammation
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Agitation
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Anxiety
         subjects affected / exposed
    3 / 127 (2.36%)
    4 / 127 (3.15%)
         occurrences all number
    3
    4
    Anxiety disorder
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Apathy
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Depressed mood
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Depression
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 127 (1.57%)
         occurrences all number
    1
    2
    Emotional distress
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Hallucination
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    5 / 127 (3.94%)
    4 / 127 (3.15%)
         occurrences all number
    7
    4
    Mood altered
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Mood swings
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    2
    Nervousness
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Panic attack
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Restlessness
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    2
    Sleep disorder
         subjects affected / exposed
    1 / 127 (0.79%)
    3 / 127 (2.36%)
         occurrences all number
    1
    3
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Breast pain
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Endometrial dysplasia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Erectile dysfunction
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Fibrocystic breast disease
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Metrorrhagia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Ovarian cyst
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Uterine cervical erosion
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 127 (3.94%)
    7 / 127 (5.51%)
         occurrences all number
    6
    7
    Dyspnoea
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 127 (1.57%)
         occurrences all number
    0
    2
    Epistaxis
         subjects affected / exposed
    2 / 127 (1.57%)
    2 / 127 (1.57%)
         occurrences all number
    2
    3
    Increased bronchial secretion
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 127 (2.36%)
    3 / 127 (2.36%)
         occurrences all number
    3
    5
    Pneumonitis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Pulmonary hypertension
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Rhinitis allergic
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 127 (0.00%)
         occurrences all number
    2
    0
    Sneezing
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Throat irritation
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Cholelithiasis
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 127 (0.79%)
         occurrences all number
    1
    1
    Gallbladder disorder
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Hepatic cyst
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 127 (0.79%)
         occurrences all number
    0
    1
    Hepatic steatosis
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 127 (1.57%)
         occurrences all number
    1
    2
    Hepatomegaly
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 127 (0.00%)
         occurrences all number
    1
    0
    Liver disorder
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 127 (1.57%)
         occurrences all number
    1
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Feb 2014
    Following the discussions with the U.S. FDA, the secondary endpoint "Durable disease response" was added. The amended study protocol states that the endpoint "Durable disease response" was to be analysed as the primary one for study submission in the U.S.; however, for study submission in Europe the primary endpoint "disease response at 12 months" remained unchanged. In order to avoid confusion, a separate US Specific SAP was written for submission in the U.S. All endpoints as per study protocol were included in both SAPs (for the European and for the U.S submission). The statistical methods and sample size justification are consistent in both SAPs. In addition, the power calculation for "Durable disease response" is presented in the separate US specific SAP.
    12 Feb 2016
    According to EMA advice letter dated 12-Feb-2016, the protocol ammendment was added on 15-Jun-2016. Primary objective was changed from “To demonstrate superiority of AOP2014 vs. Hydroxyurea in terms of disease response rate in both Hydroxyurea naïve and currently treated patients, diagnosed with Polycythemia Vera.” to “To demonstrate non-inferiority of AOP2014 vs. Hydroxyurea in terms of disease response rate in both Hydroxyurea naïve and currently treated patients, diagnosed with Polycythemia Vera.”

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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