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    Clinical Trial Results:
    A Phase 2, Exploratory, Placebo-Controlled, Multicenter, Double-Blind Evaluation of the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Effects of Five Dose Regimens of Aes-103 Given for 28 Days to Subjects with Stable Sickle Cell Disease

    Summary
    EudraCT number
    		 2013-001534-18
    Trial protocol
    		 GB  
    Global end of trial date
    16 Mar 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Mar 2016
    First version publication date
    19 Mar 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Aes-103-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01987908
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Baxalta US Inc.
    Sponsor organisation address
    One Baxter Way, Westlake Village, United States, CA 91362-3811
    Public contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
    Sponsor organisation name
    Baxalta Innovations GmbH
    Sponsor organisation address
    Industriestrasse 67, Vienna, Austria, 1221
    Public contact
    Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.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
    03 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Mar 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Mar 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the safety and PK profile of five dosing regimens of Aes-103 (1000 mg four times a day [q.i.d.] in Cohort A and up to four higher or lower dosing regimens in Cohort B) for up to 28 days in adult subjects with stable sickle cell disease compared with subjects receiving placebo.
    Protection of trial subjects
    The study was performed in accordance with Good Clinical Practice (GCP), the ethical principles that have their origin in the Declaration of Helsinki, Title 21 of the Code of Federal Regulations Parts 50 (Protection of Human Subjects), 56 (Institutional Review Boards), and 312 (Investigational New Drug Application), and International Conference on Harmonisation E6 (Guideline for Good Clinical Practice).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Dec 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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)
    23
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Enrollment was conducted at 6 clinical sites in the United Kingdom.

    Pre-assignment
    Screening details
    		 Of 35 enrolled subjects, 12 were screen failures. Of 23 subjects who started the 2-week, single-blind, outpatient, placebo lead-in period (where all subjects received placebo treatment to obtain stable baseline values and to screen out subjects who did not tolerate placebo or were not compliant with study procedures), 9 subjects were discontinued.

    Pre-assignment period milestones
    Number of subjects started
    		 23
    Number of subjects completed
    		 14

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Adverse event, non-fatal: 2
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Reason: Number of subjects
    		 Physician decision: 2
    Reason: Number of subjects
    		 Study termination by Sponsor: 4
    Period 1
    Period 1 title
    Double-Blind Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    To maintain blinding of the subjects and the clinical team, the unblinded pharmacist consulted the randomization sequence and dispensed the appropriate blinded bottles of solutions containing study drug or placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Study Drug
    Arm description
    		 Subjects randomized 3:1 to receive 4 times daily dosing of 1,000 mg of Aes-103 or placebo for 28 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aes-103
    Investigational medicinal product code
    Other name
    5-hydroxymethyl furfural (5-HMF)
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    liquid oral formulation

    Arm title
    		 Placebo
    Arm description
    		 Subjects randomized 3:1 to receive 4 times daily dosing of 1,000 mg of Aes-103 or placebo for 28 days
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    liquid oral formulation

    Number of subjects in period 1 [1]
    		Study Drug Placebo
    Started
    11
    3
    Completed
    10
    2
    Not completed
    1
    1
         Adverse event, non-fatal
    1
    1
    Notes
    [1] - 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: Of 35 enrolled subjects, 12 were screen failures. Of 23 subjects who started the 2-week, single-blind, outpatient, placebo lead-in period (where all subjects received placebo treatment to obtain stable baseline values and to screen out subjects who did not tolerate placebo or were not compliant with study procedures), 9 subjects were discontinued.
    Period 2
    Period 2 title
    Post-Treatment Observation Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Subjects received double-blind treatment during the 28-day treatment period.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Study Drug
    Arm description
    		 In the double-blind treatment period, subjects were randomized 3:1 to receive 4 times daily dosing of 1,000 mg of Aes-103 or placebo for 28 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aes-103
    Investigational medicinal product code
    Other name
    5-hydroxymethyl furfural (5-HMF)
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    liquid oral formulation

    Arm title
    		 Placebo
    Arm description
    		 In the double-blind treatment period, subjects were randomized 3:1 to receive 4 times daily dosing of 1,000 mg of Aes-103 or placebo for 28 days
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    liquid oral formulation

    Number of subjects in period 2
    		Study Drug Placebo
    Started
    10
    2
    Completed
    7
    2
    Not completed
    3
    0
         Bad veins
    1
    -
         Study withheld by the sponsor
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double-Blind Treatment Period
    Reporting group description
    		 Treatment (Cohort A)

    Reporting group values
    		 Double-Blind Treatment Period Total
    Number of subjects
    		 14 14
    Age categorical
    Units: Subjects
        85 years and over
    		 0 0
        From 65-84 years
    		 0 0
        Adults (18-64 years)
    		 14 14
        Adolescents (12-17 years)
    		 0 0
        Children (2-11 years)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        In utero
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 28 ( 6 ) -
    Gender categorical
    Units:
        Female
    		 8 8
        Male
    		 6 6
    Subject analysis sets

    Subject analysis set title
    Double-blind treatment (n=14)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects treated in the double-blind treatment period (ie, randomized to study drug or placebo), Day 1 to Day 28

    Subject analysis set title
    Treatment: Study Drug (n=11)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Double-blind treatment period: 1000 mg of study drug QID (every 6 hours)

    Subject analysis set title
    Treatment: Placebo (n=3)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Double-blind treatment period: 1000 mg of placebo QID (every 6 hours)

    Subject analysis set title
    Placebo lead-in period (n=23)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who received at least 1 dose of placebo in the lead-in period, ie, prior to the double-blind treatment period, Day -14 to Day -1

    Subject analysis set title
    Post-treatment observation period (n=12)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who completed the double-blind treatment period and entered the post-treatment observation period, Day 29 to Day 49

    Subject analysis sets values
    		 Double-blind treatment (n=14) Treatment: Study Drug (n=11) Treatment: Placebo (n=3) Placebo lead-in period (n=23) Post-treatment observation period (n=12)
    Number of subjects
    14
    11
    3
    23
    12
    Age categorical
    Units: Subjects
        85 years and over
    0
    0
    0
    0
        From 65-84 years
    0
    0
    0
    0
        Adults (18-64 years)
    14
    11
    3
    23
        Adolescents (12-17 years)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        In utero
    0
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    28 ( 6 )
    29 ( 6 )
    25 ( 3 )
    28 ( 7 )
    28 ( 7 )
    Gender categorical
    Units:
        Female
    8
    8
    0
    13
        Male
    6
    3
    3
    10

    End points

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    End points reporting groups
    Reporting group title
    Study Drug
    Reporting group description
    		 Subjects randomized 3:1 to receive 4 times daily dosing of 1,000 mg of Aes-103 or placebo for 28 days

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects randomized 3:1 to receive 4 times daily dosing of 1,000 mg of Aes-103 or placebo for 28 days
    Reporting group title
    Study Drug
    Reporting group description
    		 In the double-blind treatment period, subjects were randomized 3:1 to receive 4 times daily dosing of 1,000 mg of Aes-103 or placebo for 28 days

    Reporting group title
    Placebo
    Reporting group description
    		 In the double-blind treatment period, subjects were randomized 3:1 to receive 4 times daily dosing of 1,000 mg of Aes-103 or placebo for 28 days

    Subject analysis set title
    Double-blind treatment (n=14)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects treated in the double-blind treatment period (ie, randomized to study drug or placebo), Day 1 to Day 28

    Subject analysis set title
    Treatment: Study Drug (n=11)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Double-blind treatment period: 1000 mg of study drug QID (every 6 hours)

    Subject analysis set title
    Treatment: Placebo (n=3)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Double-blind treatment period: 1000 mg of placebo QID (every 6 hours)

    Subject analysis set title
    Placebo lead-in period (n=23)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who received at least 1 dose of placebo in the lead-in period, ie, prior to the double-blind treatment period, Day -14 to Day -1

    Subject analysis set title
    Post-treatment observation period (n=12)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who completed the double-blind treatment period and entered the post-treatment observation period, Day 29 to Day 49

    Primary: Frequency and severity of adverse events, including sickle-cell specific symptoms, during the double-blind treatment period (Day 1 to Day 28)

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    End point title
    		 Frequency and severity of adverse events, including sickle-cell specific symptoms, during the double-blind treatment period (Day 1 to Day 28) [1]
    End point description
    Measurement of spontaneously reported adverse events during the double-blind treatment period. Sickle-cell specific symptoms included the development of new skin ulcers, hospitalization or ambulatory acute care, intravenous analgesics visit for pain episodes (ie, sickle-cell disease related pain), acute chest syndrome, priapism, and stroke.
    End point type
    Primary
    End point timeframe
    28 days
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, descriptive statistics were collected for this endpoint.
    End point values
    		 Study Drug Placebo Double-blind treatment (n=14)
    Number of subjects analysed
    11
    3
    14
    Units: subjects
        Treatment-emergent AEs
    9
    3
    12
        Related AEs
    8
    2
    10
        Serious AEs
    0
    0
    0
        Severe AEs
    0
    0
    0
        AEs leading to discontinuation
    1
    1
    2
        AEs leading to death
    0
    0
    0
        Sickle-cell specific complications
    4
    1
    5
    No statistical analyses for this end point

    Primary: Frequency and severity of adverse events, including sickle-cell specific symptoms, during the placebo lead-in period (Day -14 to Day -1)

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    End point title
    		 Frequency and severity of adverse events, including sickle-cell specific symptoms, during the placebo lead-in period (Day -14 to Day -1) [2]
    End point description
    Measurement of spontaneously reported adverse events during the placebo lead-in period.
    End point type
    Primary
    End point timeframe
    14 days
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, descriptive statistics were collected for this endpoint.
    End point values
    		 Placebo lead-in period (n=23)
    Number of subjects analysed
    23
    Units: subjects
        Treatment-emergent AEs
    21
        Related AEs
    12
        Serious AEs
    2
        Severe AEs
    2
        AEs leading to discontinuation
    2
        AEs leading to death
    0
        Sickle-cell specific complications
    2
    No statistical analyses for this end point

    Primary: Frequency and severity of adverse events, including sickle-cell specific symptoms, during the post-treatment observation period (Day 29 to Day 49)

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    End point title
    		 Frequency and severity of adverse events, including sickle-cell specific symptoms, during the post-treatment observation period (Day 29 to Day 49) [3]
    End point description
    Measurement of spontaneously reported adverse events during the post-treatment observation period.
    End point type
    Primary
    End point timeframe
    21 days
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, descriptive statistics were collected for this endpoint.
    End point values
    		 Study Drug Placebo Post-treatment observation period (n=12)
    Number of subjects analysed
    10
    2
    12
    Units: subjects
        Treatment-emergent AEs
    4
    0
    4
        Related AEs
    2
    0
    2
        Serious AEs
    1
    0
    1
        Severe AEs
    1
    0
    1
        AEs leading to discontinuation
    0
    0
    0
        AEs leading to death
    0
    0
    0
        Sickle-cell specific complications
    1
    0
    1
    No statistical analyses for this end point

    Primary: Sickle-Cell Disease-Related Symptoms

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    End point title
    		 Sickle-Cell Disease-Related Symptoms [4]
    End point description
    End point type
    Primary
    End point timeframe
    Throughout study, total of approximately 9 weeks
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, descriptive statistics were collected for this endpoint.
    End point values
    		 Treatment: Study Drug (n=11) Treatment: Placebo (n=3)
    Number of subjects analysed
    11
    3
    Units: subjects
        Abdominal Pain - Sickle Pain
    1
    0
        Exacerbation of Sickle Cell (SC) Disease Pain
    1
    0
        SC Disease Related Pain
    3
    0
        SC Pain
    3
    1
        SC-nonspecific: Back Pain
    1
    0
        SC-nonspecific: Body Pain
    1
    0
        SC-nonspecific: Headache
    5
    1
        SC-nonspecific: Migraine
    1
    0
        SC-nonspecific: T Wave inversion
    1
    0
        SC-nonspecific: Transaminitis
    0
    1
    No statistical analyses for this end point

    Secondary: Resting oxygen saturation as measured by oximetry (SpO2) - Change from baseline

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    End point title
    		 Resting oxygen saturation as measured by oximetry (SpO2) - Change from baseline
    End point description
    A measure of the amount of oxygen in the blood. Oxygen saturation was determined by pulse oximetry. A pulse oximeter was placed over a nail polish-free finger nail to determine peripheral oxygen saturation (SpO2). Baseline was defined as the most recent value obtained prior to the start of dosing on Day 1 of the double-blind dosing period. A mean change from baseline >0 indicates an increase in oxygen saturation, a mean change <0 indicates a decrease in oxygen saturation.
    End point type
    Secondary
    End point timeframe
    Measured prior to, during and after the end of dosing in the double-blind treatment period, ie, at baseline, Day 4, Day 7, Day 14, Day 28.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    11
    3
    Units: Percent
    arithmetic mean (standard deviation)
        Day 4
    0 ( 2 )
    4 ( 5 )
        Day 7
    0 ( 2 )
    -4 ( 8 )
        Day 14
    0 ( 2 )
    8 ( 10 )
        Day 28
    0 ( 3 )
    6 ( 8 )
    No statistical analyses for this end point

    Secondary: Oxygen binding p50/p20 value - Change from baseline

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    End point title
    		 Oxygen binding p50/p20 value - Change from baseline
    End point description
    A measure of the ability of hemoglobin to bind oxygen. The p50 is the oxygen level at which 50% of the hemoglobin contains oxygen. The p20 is the oxygen level at which 20% of the hemoglobin contains oxygen. Baseline is defined as the most recent value obtained prior to start of dosing on Day 1 of the double-blind dosing period.
    End point type
    Secondary
    End point timeframe
    7 days
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    11
    3
    Units: Percent
    arithmetic mean (standard deviation)
        Day 1
    0 ( 0.2 )
    0 ( 0.2 )
        Day 4
    0 ( 0.1 )
    0.1 ( 0.1 )
        Day 7
    0 ( 0.2 )
    0 ( 0.1 )
    No statistical analyses for this end point

    Secondary: Plasma erythropoietin (EPO) levels - Change from baseline

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    End point title
    		 Plasma erythropoietin (EPO) levels - Change from baseline
    End point description
    Erythropoietin (EPO) is a hormone produced by the kidney that promotes the formation of red blood cells by the bone marrow. EPO can be detected and measured in the blood.
    End point type
    Secondary
    End point timeframe
    Measured at baseline and at Day 28
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    8
    2
    Units: U/L
        arithmetic mean (standard deviation)
    -5.9 ( 50.3 )
    -15.1 ( 20.4 )
    No statistical analyses for this end point

    Secondary: Hematocrit levels - Change from baseline

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    End point title
    		 Hematocrit levels - Change from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Measured prior to, during and after the end of dosing in the double-blind treatment period, ie, at baseline, Day 1, Day 4, Day 7, Day 14, Day 28.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    11 [5]
    3 [6]
    Units: L/L
    arithmetic mean (standard deviation)
        Day 1
    0.006 ( 0.011 )
    -0.002 ( 0.007 )
        Day 7
    0.007 ( 0.013 )
    0.02 ( 0.01 )
        Day 14
    0.003 ( 0.013 )
    -0.006 ( 0.015 )
        Day 28
    0.011 ( 0.012 )
    0.006 ( 0.007 )
    Notes
    [5] - Day 1: n=11, Day 7: n=9, Day 14: n=8, Day 28: n=8
    [6] - Day 1: n=3, Day 7: n=3, Day 14: n=2, Day 28: n=2
    No statistical analyses for this end point

    Secondary: Lactate dehydrogenase (LDH) levels - Change from baseline

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    End point title
    		 Lactate dehydrogenase (LDH) levels - Change from baseline
    End point description
    LDH levels were measured as a biomarker for intravascular hemolysis. The results are based on the LDH Total measurement.
    End point type
    Secondary
    End point timeframe
    Measured prior to, during and after the end of dosing in the double-blind treatment period, ie, at baseline, Day 1, Day 7, Day 14, Day 28.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    11 [7]
    3 [8]
    Units: U/L
    arithmetic mean (standard deviation)
        Day 1
    60 ( 107 )
    0 ( 197 )
        Day 7
    71 ( 101 )
    -6 ( 167 )
        Day 14
    4 ( 100 )
    689 ( 1142 )
        Day 28
    29 ( 110 )
    -69 ( 91 )
    Notes
    [7] - Day 1: n=11, Day 7: n=9, Day 14: n=8, Day 28: n=8
    [8] - Day 1: n=3, Day 7: n=3, Day 14: n=2; Day 28: n=2
    No statistical analyses for this end point

    Secondary: Hemoglobin levels - Change from baseline

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    End point title
    		 Hemoglobin levels - Change from baseline
    End point description
    A clinical laboratory endpoint that reflects the amount of red blood cells present in the blood.
    End point type
    Secondary
    End point timeframe
    Measured prior to, during and after the end of dosing in the double-blind treatment period, ie, at baseline, Day 1, Day 4, Day 7, Day 14, Day 28.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    11 [9]
    3 [10]
    Units: g/L
    arithmetic mean (standard deviation)
        Day 1
    0 ( 5 )
    -3 ( 7 )
        Day 4
    1 ( 7 )
    3 ( 3 )
        Day 7
    -1 ( 5 )
    3 ( 2 )
        Day 14
    -2 ( 5 )
    -6 ( 1 )
        Day 28
    0 ( 4 )
    -2 ( 5 )
    Notes
    [9] - Day 1: n=11, Day 4: n=10, Day 7: n=10, Day 14: n=8, Day 28: n=10
    [10] - Day 1: n=3, Day 4: n=3, Day 7: n=3, Day 14: n=2, Day 28: n=2
    No statistical analyses for this end point

    Secondary: Direct bilirubin - Change from baseline

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    End point title
    		 Direct bilirubin - Change from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Measured prior to, during and after the end of dosing in the double-blind treatment period, ie, at baseline, Day 1, Day 4, Day 7, Day 14, Day 28.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    11 [11]
    3 [12]
    Units: µmol/L
    arithmetic mean (standard deviation)
        Day 1
    0 ( 0 )
    0 ( 0 )
        Day 4
    0 ( 0 )
    0 ( 0 )
        Day 7
    0 ( 0 )
    0 ( 0 )
        Day 14
    0 ( 0 )
    0 ( 0 )
        Day 28
    0 ( 0 )
    0 ( 0 )
    Notes
    [11] - Day 1: n=11, Day 4: n=10, Day 7: n=10, Day 14: n=8, Day 28: n=10
    [12] - Day 1: n=3, Day 4: n=3, Day 7: n=3, Day 14: n=2, Day 28: n=2
    No statistical analyses for this end point

    Secondary: Body weight - Change from baseline

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    End point title
    		 Body weight - Change from baseline
    End point description
    A negative change in body weight denotes a weight decrease, a positive change in body weight denotes a weight increase.
    End point type
    Secondary
    End point timeframe
    Measured prior to, during and after the end of dosing in the double-blind treatment period, ie, at baseline, Day 1, Day 4, Day 7, Day 14, Day 21, Day 28.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    11 [13]
    3 [14]
    Units: kg
    arithmetic mean (standard deviation)
        Day 1
    -0.2 ( 0.7 )
    -0.6 ( 0.4 )
        Day 4
    -0.3 ( 1.6 )
    -0.4 ( 0.8 )
        Day 7
    -0.5 ( 1.6 )
    -0.7 ( 1.3 )
        Day 14
    1.1 ( 0.8 )
    0.8 ( 0.7 )
        Day 21
    0.1 ( 1.4 )
    0.5 ( 0.1 )
        Day 28
    0.6 ( 0.9 )
    0.4 ( 0.4 )
    Notes
    [13] - Day 1: n=11, Day 4: n=10, Day 7: n=10, Day 14: n=8, Day 21: n=6, Day 28: n=10
    [14] - Day 1: n=3, Day 4: n=3, Day 7: n=3, Day 14: n=2, Day 21: n=2, Day 28: n=2
    No statistical analyses for this end point

    Secondary: Exercise Tolerance: 6-Minute Walk Distance during the double-blind treatment period - Change from baseline

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    End point title
    		 Exercise Tolerance: 6-Minute Walk Distance during the double-blind treatment period - Change from baseline
    End point description
    Functional exercise capacity was evaluated by using the 6-minute walk test (6MWT) which measures the distance that a subject can quickly walk on a flat, hard surface in a period of 6 minutes. Guidelines developed by the American Thoracic Society were used for conducting the test and interpreting the results.
    End point type
    Secondary
    End point timeframe
    Measured prior to, during and after the end of dosing in the double-blind treatment period, ie, at baseline (= most recent value obtained prior to the start of dosing on Day 1), Day 4, Day 7, Day 14, and Day 28.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    11 [15]
    3 [16]
    Units: meter
    arithmetic mean (standard deviation)
        Day 4
    -8.5 ( 38.2 )
    20.6 ( 8 )
        Day 7
    36.9 ( 44.6 )
    28.3 ( 24.3 )
        Day 14
    -0.1 ( 31.5 )
    4.1 ( 6.1 )
        Day 28
    -14.9 ( 41.2 )
    -8.2 ( 8.2 )
    Notes
    [15] - Day 4: n=9, Day 7: n=9, Day 14: n=8, Day 28: n=8
    [16] - Day 4: n=3, Day 7: n=3, Day 14: n=2, Day 28: n=2
    No statistical analyses for this end point

    Secondary: Exercise Tolerance: 6-Minute Walk Distance on Day 49 of the post-treatment observation period - Change from baseline

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    End point title
    		 Exercise Tolerance: 6-Minute Walk Distance on Day 49 of the post-treatment observation period - Change from baseline
    End point description
    Functional exercise capacity was evaluated by using the 6-minute walk test (6MWT) which measures the distance that a subject can quickly walk on a flat, hard surface in a period of 6 minutes. Guidelines developed by the American Thoracic Society were used for conducting the test and interpreting the results.
    End point type
    Secondary
    End point timeframe
    Measured prior to dosing at baseline (= most recent value obtained prior to the start of dosing on Day 1) and on Day 49 of the post-treatment observation period.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    8
    2
    Units: meter
        arithmetic mean (standard deviation)
    -20.6 ( 41.3 )
    -1.1 ( 3.5 )
    No statistical analyses for this end point

    Secondary: Exercise Tolerance: 6-Minute Walk Distance on Day 49 of the post-treatment observation period - Change from last day of double-blind treatment period (Day 28)

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    End point title
    		 Exercise Tolerance: 6-Minute Walk Distance on Day 49 of the post-treatment observation period - Change from last day of double-blind treatment period (Day 28)
    End point description
    Functional exercise capacity was evaluated by using the 6-minute walk test (6MWT) which measures the distance that a subject can quickly walk on a flat, hard surface in a period of 6 minutes. Guidelines developed by the American Thoracic Society were used for conducting the test and interpreting the results.
    End point type
    Secondary
    End point timeframe
    Measured on last day of double-blind treatment period (Day 28) and on Day 49 of the post-treatment observation period.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    8
    2
    Units: meter
        arithmetic mean (standard deviation)
    -5.6 ( 63.6 )
    7.2 ( 4.7 )
    No statistical analyses for this end point

    Secondary: Numerical Pain Rating Scale (NPRS): Worst pain (weekly average) in the double-blind treatment period - Change from baseline

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    End point title
    		 Numerical Pain Rating Scale (NPRS): Worst pain (weekly average) in the double-blind treatment period - Change from baseline
    End point description
    Subjects assessed their pain levels by using the 0-10 Numeric Rating Scale: 0 = No pain 1-3 = Mild pain (nagging, annoying, interfering little with activities of daily living [ADLs]) 4-6 = Moderate pain (interferes significantly with ADLs) 7-10 = Severe pain (disabling; unable to perform ADLs A negative mean change denotes a pain decrease. A positive mean change denotes an increase in pain. Baseline was defined as the average of all measures taken from screening through the period prior to start of dosing on Day 1. Area under the curve (AUC) was computed using change from baseline in weekly average values at Day 7, Day 14, Day 21. and Day 28.
    End point type
    Secondary
    End point timeframe
    Subjects assessed and recorded their pain level daily. Weekly averages were calculated for the Day 7, Day 14, Day 21, and Day 28 assessments.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    11 [17]
    3 [18]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Day 7
    1.682 ( 3.482 )
    4.533 ( 4.536 )
        Day 14
    -0.85 ( 1.255 )
    -0.65 ( 0.071 )
        Day 21
    -0.825 ( 1.302 )
    -0.65 ( 0.071 )
        Day 28
    -0.689 ( 1.279 )
    -0.65 ( 0.071 )
        Area under the curve (AUC)
    -2.352 ( 2.674 )
    -3.229 ( 2.847 )
    Notes
    [17] - Day 7: n=11, Day 14: n=10, Day 21: n=8, Day 28: n=9, AUC: n=11
    [18] - Day 7: n=3, Day 14: n=2, Day 21: n=2, Day 28: n=2, AUC: n=3
    No statistical analyses for this end point

    Secondary: Numerical Pain Rating Scale (NPRS): Worst pain (weekly average) in the post-treatment observation period - Change from baseline

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    End point title
    		 Numerical Pain Rating Scale (NPRS): Worst pain (weekly average) in the post-treatment observation period - Change from baseline
    End point description
    Subjects assessed their pain levels by using the 0-10 Numeric Rating Scale: 0 = No pain 1-3 = Mild pain (nagging, annoying, interfering little with activities of daily living [ADLs]) 4-6 = Moderate pain (interferes significantly with ADLs) 7-10 = Severe pain (disabling; unable to perform ADLs A negative mean change denotes a pain decrease. A positive mean change denotes an increase in pain. Baseline was defined as the average of all measures taken from screening through the period prior to start of dosing on Day 1. Area under the curve (AUC) was computed using change from baseline in weekly average values at Day 7, Day 14, Day 21, Day 28, Day 35, Day 42 and Day 49.
    End point type
    Secondary
    End point timeframe
    Subjects assessed and recorded their pain level daily. Weekly averages were calculated for the Day 35, Day 42 and Day 49 assessments.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    10 [19]
    2 [20]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Day 35
    -4.675 ( 3.729 )
    -7.75 ( 1.202 )
        Day 42
    -2.83 ( 5.494 )
    -7.75 ( 1.202 )
        Day 49
    -3.089 ( 6.049 )
    -8.15 ( 0.212 )
        Area under the curve (AUC)
    -2.836 ( 3.637 )
    -6.118 ( 0.874 )
    Notes
    [19] - Day 35: n=8, Day 42: n=10, Day 49: n=9, AUC: n=10
    [20] - Day 35: n=2, Day 42: n=2, Day 49: n=2, AUC: n=2
    No statistical analyses for this end point

    Secondary: Numerical Pain Rating Scale (NPRS): Worst pain (weekly average) in the post-treatment observation period - Change from last day of double-blind treatment period (Day 28)

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    End point title
    		 Numerical Pain Rating Scale (NPRS): Worst pain (weekly average) in the post-treatment observation period - Change from last day of double-blind treatment period (Day 28)
    End point description
    Subjects assessed their pain levels by using the 0-10 Numeric Rating Scale: 0 = No pain 1-3 = Mild pain (nagging, annoying, interfering little with activities of daily living [ADLs]) 4-6 = Moderate pain (interferes significantly with ADLs) 7-10 = Severe pain (disabling; unable to perform ADLs A negative mean change denotes a pain decrease. A positive mean change denotes an increase in pain. Baseline was defined as the most recent value obtained on the last day of the double-blind dosing period (Day 28). Area under the curve (AUC) was computed using change from baseline (Day 28) in weekly average values at Day 35, Day 42 and Day 49.
    End point type
    Secondary
    End point timeframe
    Subjects assessed and recorded their pain level daily. Weekly averages were calculated for the Day 35, Day 42 and Day 49 assessments.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    10 [21]
    2 [22]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Day 35
    -3.425 ( 3.302 )
    -7.75 ( 1.202 )
        Day 42
    -1.83 ( 4.905 )
    -7.75 ( 1.202 )
        Day 49
    -1.978 ( 5.479 )
    -8.15 ( 0.212 )
        AUC
    -2.836 ( 3.637 )
    -6.118 ( 0.874 )
    Notes
    [21] - Day 35: n=8, Day 42: n=10, Day 49: n=9, AUC: n=10
    [22] - Day 35: n=2, Day 42: n=2, Day 49: n=2, AUC: n=2
    No statistical analyses for this end point

    Secondary: Brief Pain Inventory (BPI): Average pain level in last 24 hours (double-blind treatment period) - Change from baseline

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    End point title
    		 Brief Pain Inventory (BPI): Average pain level in last 24 hours (double-blind treatment period) - Change from baseline
    End point description
    Subjects rated the severity of their pain by using the BPI short form. Pain was rated on a scale from 0 (no pain) to 10 (pain as bad as you can imagine). A negative mean change denotes a pain decrease. A positive mean change denotes an increase in pain.
    End point type
    Secondary
    End point timeframe
    At baseline (= the most recent value obtained prior to the start of the dosing on Day 1 of the double-blind dosing period) and on Days 7 and 28 of the double-blind treatment period.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    10 [23]
    3 [24]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Day 7
    -0.4 ( 2.3 )
    -3 ( 3.3 )
        Day 28
    -0.6 ( 1.2 )
    -1.3 ( 3.2 )
    Notes
    [23] - Day 7: n=10, Day 28: n=8
    [24] - Day 7: n=3, Day 28: n=2
    No statistical analyses for this end point

    Secondary: Brief Pain Inventory (BPI): Worst pain level in last 24 hours (double-blind treatment period) - Change from baseline

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    End point title
    		 Brief Pain Inventory (BPI): Worst pain level in last 24 hours (double-blind treatment period) - Change from baseline
    End point description
    Subjects rated the severity of their pain by using the BPI short form. Pain was rated on a scale from 0 (no pain) to 10 (pain as bad as you can imagine). A negative mean change denotes a pain decrease. A positive mean change denotes an increase in pain.
    End point type
    Secondary
    End point timeframe
    At baseline (= the most recent value obtained prior to the start of the dosing on Day 1 of the double-blind dosing period) and on Days 7 and 28 of the double-blind treatment period.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    10 [25]
    3 [26]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Day 7
    -1 ( 3 )
    0 ( 0 )
        Day 28
    -1 ( 3 )
    1 ( 1 )
    Notes
    [25] - Day 7: n=10, Day 28: n=8
    [26] - Day 7: n=3, Day 28: n=2
    No statistical analyses for this end point

    Secondary: Brief Pain Inventory (BPI): Worst pain level in last 24 hours (post-treatment observation period) - Change from baseline

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    End point title
    		 Brief Pain Inventory (BPI): Worst pain level in last 24 hours (post-treatment observation period) - Change from baseline
    End point description
    Subjects rated the severity of their pain by using the BPI short form. Pain was rated on a scale from 0 (no pain) to 10 (pain as bad as you can imagine). A negative mean change denotes a pain decrease. A positive mean change denotes an increase in pain.
    End point type
    Secondary
    End point timeframe
    At baseline (= the most recent value obtained prior to the start of the dosing on Day 1 of the double-blind dosing period) and Day 49 of the post-treatment observation period.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    8
    2
    Units: score on a scale
        arithmetic mean (standard deviation)
    -1 ( 5 )
    0 ( 0 )
    No statistical analyses for this end point

    Secondary: Brief Pain Inventory (BPI): Interference of pain with aspects of life (general activity) during double-blind treatment period - Change from baseline

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    End point title
    		 Brief Pain Inventory (BPI): Interference of pain with aspects of life (general activity) during double-blind treatment period - Change from baseline
    End point description
    Subjects rated the degree to which their pain interfered with various daily functions by using the BPI short form. Interference with general activity was rated on a scale from 0 (does not interfere) to 10 (completely interferes).
    End point type
    Secondary
    End point timeframe
    At baseline (= the most recent value obtained prior to the start of the dosing on Day 1 of the double-blind dosing period) and on Days 7 and 28 of the double-blind treatment period.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    10 [27]
    3 [28]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Day 7
    0 ( 2 )
    0 ( 0 )
        Day 28
    1 ( 2 )
    0 ( 0 )
    Notes
    [27] - Day 7: n=10, Day 28: n=8
    [28] - Day 7: n=3, Day 28: n=2
    No statistical analyses for this end point

    Secondary: Brief Pain Inventory (BPI): Interference of pain with aspects of life (general activity) during post-treatment observation period - Change from baseline

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    End point title
    		 Brief Pain Inventory (BPI): Interference of pain with aspects of life (general activity) during post-treatment observation period - Change from baseline
    End point description
    Subjects rated the degree to which their pain interfered with various daily functions by using the BPI short form. Interference with general activity was rated on a scale from 0 (does not interfere) to 10 (completely interferes).
    End point type
    Secondary
    End point timeframe
    At baseline (= the most recent value obtained prior to the start of the dosing on Day 1 of the double-blind dosing period) and on Day 49 of the post-treatment observation period.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    8
    2
    Units: score on a scale
        arithmetic mean (standard deviation)
    0 ( 1 )
    0 ( 0 )
    No statistical analyses for this end point

    Secondary: Patients´ Global Impression of Change (PGIC) during the double-blind treatment period - Change from baseline

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    End point title
    		 Patients´ Global Impression of Change (PGIC) during the double-blind treatment period - Change from baseline
    End point description
    Subjects assessed the change in activity limitations, symptoms, emotions, and overall quality of life by using the 1- to 7-point PGIC scale. The question and scale was as follows: Since beginning treatment at this clinic, how would you describe the change in your sickle cell condition? Please circle the number that matches your overall judgment. -3 - much worse -2 - moderately worse -1 - minimally worse 0 - no change +1 - minimally improved +2 - moderately improved +3 - much improved
    End point type
    Secondary
    End point timeframe
    PGIC was measured at baseline and once weekly on Days 7, 14,21, and 28. Baseline was defined as the most recent value obtained prior to the start of dosing on Day 1 of the double-blind treatment period. No values available for placebo group for Day 28.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    10 [29]
    3 [30]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Day 7
    0 ( 1 )
    0 ( 0 )
        Day 14
    0 ( 0 )
    0 ( 0 )
        Day 21
    0 ( 1 )
    0 ( 0 )
    Notes
    [29] - Day 7: n=10, Day 14: n=9, Day 21: n=8, Day 28: n=9
    [30] - Day 7: n=3, Day 14: n=2, Day 21: n=2, Day 28: n=1
    No statistical analyses for this end point

    Secondary: Patients´ Global Impression of Change (PGIC) during the post-treatment observation period - Change from baseline

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    End point title
    		 Patients´ Global Impression of Change (PGIC) during the post-treatment observation period - Change from baseline
    End point description
    Subjects assessed the change in activity limitations, symptoms, emotions, and overall quality of life by using the 1- to 7-point PGIC scale. The question and scale was as follows: Since beginning treatment at this clinic, how would you describe the change in your sickle cell condition? Please circle the number that matches your overall judgment. -3 - much worse -2 - moderately worse -1 - minimally worse 0 - no change +1 - minimally improved +2 - moderately improved +3 - much improved
    End point type
    Secondary
    End point timeframe
    PGIC was measured at baseline and once weekly in the post-treatment observation period on Days 35, 42, and 49. Baseline was defined as the most recent value obtained prior to the start of dosing on Day 1 of the double-blind treatment period.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    10 [31]
    2 [32]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Day 35
    0 ( 1 )
    0 ( 0 )
        Day 42
    0 ( 1 )
    0 ( 0 )
        Day 49
    0 ( 1 )
    0 ( 0 )
    Notes
    [31] - Day 35: n=8, Day 42: n=10, Day 49: n=8
    [32] - Day 35: n=2, Day 42: n=2, Day 49: n=2
    No statistical analyses for this end point

    Secondary: Patients´ Global Impression of Change (PGIC) during the post-treatment observation period - Change from last day of double-blind treatment period

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    End point title
    		 Patients´ Global Impression of Change (PGIC) during the post-treatment observation period - Change from last day of double-blind treatment period
    End point description
    Subjects assessed the change in activity limitations, symptoms, emotions, and overall quality of life by using the 1- to 7-point PGIC scale. The question and scale was as follows: Since beginning treatment at this clinic, how would you describe the change in your sickle cell condition? Please circle the number that matches your overall judgment. -3 - much worse -2 - moderately worse -1 - minimally worse 0 - no change +1 - minimally improved +2 - moderately improved +3 - much improved
    End point type
    Secondary
    End point timeframe
    PGIC was measured at baseline, once weekly during double-blind treatment and on Days 35, 42, and 49 of the post-treatment observation period. Baseline was defined as the most recent value obtained on the last day of the double-blind treatment period.
    End point values
    		 Study Drug Placebo
    Number of subjects analysed
    10 [33]
    2 [34]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Day 35
    0 ( 0 )
    0 ( 0 )
        Day 42
    0 ( 0 )
    0 ( 0 )
        Day 49
    0 ( 0 )
    0 ( 0 )
    Notes
    [33] - Day 35: n=8, Day 42: n=10, Day 49: n=8
    [34] - Day 35: n=2, Day 42: n=2, Day 49: n=2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately 9 weeks
    Adverse event reporting additional description
    Adverse events, including sickle-cell specific symptoms, were to be monitored throughout the study, beginning from the time the subject is administered the first dose at the start of the outpatient placebo lead-in period through the final clinical visit, for a total of approximately 9 weeks.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    N/A
    Reporting groups
    Reporting group title
    Placebo lead-in period (Day -14 to Day -1)
    Reporting group description
    		 Subjects who received at least 1 dose of placebo in the lead-in period, ie, prior to the double-blind treatment period; n=23, time frame: 2 weeks

    Reporting group title
    Double-blind treatment period (Day 1 to Day 28)
    Reporting group description
    		 Subjects treated in the double-blind treatment period, (ie, randomized to study drug or placebo); n=14, time frame: 4 weeks

    Reporting group title
    Post-treatment observation period (Day 29 to Day 49)
    Reporting group description
    		 Subjects who completed the double-blind treatment period and entered the post-treatment observation period; n=12, time frame: 3 weeks

    Serious adverse events
    		 Placebo lead-in period (Day -14 to Day -1) Double-blind treatment period (Day 1 to Day 28) Post-treatment observation period (Day 29 to Day 49)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    1 / 12 (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
    Sickle cell anaemia with crisis
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sickle cell anaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         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: 0%
    Non-serious adverse events
    		 Placebo lead-in period (Day -14 to Day -1) Double-blind treatment period (Day 1 to Day 28) Post-treatment observation period (Day 29 to Day 49)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 23 (91.30%)
    12 / 14 (85.71%)
    4 / 12 (33.33%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 14 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Pain
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 14 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Investigations
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Liver function test abnormal
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Transaminases increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Congenital, familial and genetic disorders
    Sickle cell anaemia
         subjects affected / exposed
    5 / 23 (21.74%)
    5 / 14 (35.71%)
    2 / 12 (16.67%)
         occurrences all number
    5
    6
    2
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    13 / 23 (56.52%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    13
    1
    0
    Headache
         subjects affected / exposed
    5 / 23 (21.74%)
    6 / 14 (42.86%)
    1 / 12 (8.33%)
         occurrences all number
    6
    6
    1
    Migraine
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    2
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal distension
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Dyspepsia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Faeces discoloured
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Flatulence
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    3 / 23 (13.04%)
    4 / 14 (28.57%)
    0 / 12 (0.00%)
         occurrences all number
    3
    4
    0
    Toothache
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 14 (7.14%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    1
    Vomiting
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 14 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    The study was put on hold (before completion of Cohort A) due to problems with the PK assay which rendered all PK data invalid, before being closed by the sponsor due to unblinding of the subject, site and sponsor to study drug and placebo treatment.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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