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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Voxelotor (GBT440) in Pediatric Participants with Sickle Cell Disease (HOPE Kids 2)

    Summary
    EudraCT number
    		 2017-000903-26
    Trial protocol
    		 FR   GB   IT  
    Global end of trial date
    05 Nov 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Aug 2025
    First version publication date
    15 Aug 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    C5341021
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04218084
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Alias ID: GBT440-032
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    66 East Hudson boulevard, New York, United States, NY 10001
    Public contact
    Pfizer ClinicalTrials.gov Call Center, ClinicalTrials.gov_Inquiries@pfizer.com, 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002356-PIP02-20
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Jun 2025
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Nov 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the effect of voxelotor compared to placebo on the transcranial Doppler (TCD) time-averaged mean of the maximum velocity (TAMMV) arterial cerebral blood flow at 24 weeks in sickle cell disease (SCD) participants >= 2 to < 15 years of age with conditional (170 to < 200 cm/sec) TCD flow velocity.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Nov 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 19 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Egypt: 34
    Country: Number of subjects enrolled
    Ghana: 5
    Country: Number of subjects enrolled
    Kenya: 24
    Country: Number of subjects enrolled
    Nigeria: 166
    Country: Number of subjects enrolled
    Oman: 1
    Country: Number of subjects enrolled
    Saudi Arabia: 1
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    United States: 4
    Worldwide total number of subjects
    236
    EEA total number of subjects
    0
    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)
    207
    Adolescents (12-17 years)
    29
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 236 participants were assigned to the study treatment. Study was terminated - emerging clinical data evaluated by Pfizer and shared with regulatory authorities indicated risk profile of voxelotor in people with sickle cell disease (SCD) exceeded benefits observed in previously generated global research and required further assessment.

    Pre-assignment
    Screening details
    		 A total of 236 participants were assigned to the study treatment. Study was terminated - emerging clinical data evaluated by Pfizer and shared with regulatory authorities indicated risk profile of voxelotor in people with sickle cell disease (SCD) exceeded benefits observed in previously generated global research and required further assessment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    Blinded roles were subject, investigator, carer, assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Voxelotor
    Arm description
    		 Participants aged greater than or equal to 12 years of age received 1500 milligrams (mg) voxelotor tablet orally once daily for 96 weeks. Participants less than 12 years of age received voxelotor at a weight based (1500 mg-equivalent) dose. Participants were followed up to 4 weeks after last dose of study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Voxelotor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 1500 mg voxelotor tablet orally once daily for 96 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Participants received voxelotor matched placebo orally once daily for 96 weeks. Participants were followed up to 4 weeks after last dose of study drug.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received voxelotor matched placebo orally once daily for 96 weeks.

    Number of subjects in period 1
    		Voxelotor Placebo
    Started
    120
    116
    Completed
    37
    40
    Not completed
    83
    76
         Consent withdrawn by subject
    4
    5
         Physician decision
    1
    1
         Adverse event, non-fatal
    10
    2
         Abnormal transcranial doppler (TCD)
    21
    26
         Non-compliance with study drug
    2
    1
         Study terminated by sponsor
    24
    17
         Unspecified
    19
    22
         Lost to follow-up
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Voxelotor
    Reporting group description
    		 Participants aged greater than or equal to 12 years of age received 1500 milligrams (mg) voxelotor tablet orally once daily for 96 weeks. Participants less than 12 years of age received voxelotor at a weight based (1500 mg-equivalent) dose. Participants were followed up to 4 weeks after last dose of study drug.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received voxelotor matched placebo orally once daily for 96 weeks. Participants were followed up to 4 weeks after last dose of study drug.

    Reporting group values
    		 Voxelotor Placebo Total
    Number of subjects
    		 120 116
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 7.2 ( 3.11 ) 7.3 ( 3.22 ) -
    Gender categorical
    Units: Subjects
        Male
    		 57 57 114
        Female
    		 63 59 122
    Race
    Units: Subjects
        African
    		 69 80 149
        Arab
    		 12 11 23
        Black or African American
    		 8 2 10
        White
    		 2 0 2
        Multi-Racial
    		 29 23 52
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 0 1
        Not Hispanic or Latino
    		 114 113 227
        Not Reported
    		 5 3 8

    End points

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    End points reporting groups
    Reporting group title
    Voxelotor
    Reporting group description
    		 Participants aged greater than or equal to 12 years of age received 1500 milligrams (mg) voxelotor tablet orally once daily for 96 weeks. Participants less than 12 years of age received voxelotor at a weight based (1500 mg-equivalent) dose. Participants were followed up to 4 weeks after last dose of study drug.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received voxelotor matched placebo orally once daily for 96 weeks. Participants were followed up to 4 weeks after last dose of study drug.

    Primary: Change From Baseline in Time-Averaged Maximum of Mean Velocity (TAMMV) Arterial Cerebral Blood Flow at Week 24

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    End point title
    		 Change From Baseline in Time-Averaged Maximum of Mean Velocity (TAMMV) Arterial Cerebral Blood Flow at Week 24
    End point description
    TAMMV was defined the time averaged maximum of the mean velocity arterial cerebral blood flow and was measured using transcranial Doppler (TCD). Analysis was performed using mixed model for repeated measures (MMRM) including treatment, study visit, treatment by visit interaction, baseline hydroxyurea (HU) use (yes; no), age group (2 to <= 8 years; >8 to <15 years), and baseline TAMMV value (170 centimeter per second [cm/sec] to < 185 cm/sec; 185 cm/sec to < 200 cm/sec) as fixed effect terms and used a compound symmetry covariance matrix for within-participant variability. ITT analysis population included all randomized participants. Here, "Number of Participants Analyzed’’ signifies number of participants evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Voxelotor Placebo
    Number of subjects analysed
    114
    108
    Units: Centimeter per second (cm/sec)
        least squares mean (confidence interval 95%)
    -12.06 (-15.82 to -8.31)
    -4.29 (-8.17 to -0.40)
    Statistical analysis title
    		 Week 24
    Statistical analysis description
    Voxelotor versus Placebo
    Comparison groups
    Voxelotor v Placebo
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0048
    Method
    		 Mixed Model Repeated Measures analysis
    Parameter type
    		 Difference in LS mean
    Point estimate
    -7.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.18
         upper limit
    		 -2.37

    Secondary: Change From Baseline in Transcranial Doppler (TCD) Flow Velocity at Week 48

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    End point title
    		 Change From Baseline in Transcranial Doppler (TCD) Flow Velocity at Week 48
    End point description
    Change in TCD flow velocity from baseline to week 48 was analyzed using the MMRM model including treatment, study visit, treatment by visit interaction, baseline hydroxyurea use (yes; no), age group (2 to <= 8 years; >8 to <15 years), and baseline TAMMV value (170 cm/sec to < 185 cm/sec; 185 cm/sec to < 200 cm/sec) as fixed effect terms and used a compound symmetry covariance matrix for within-subject variability. ITT analysis population included all randomized participants. Here, 'Number Analyzed' signifies participants evaluable for specified rows.
    End point type
    Secondary
    End point timeframe
    Baseline (value at Screening), Weeks 48
    End point values
    		 Voxelotor Placebo
    Number of subjects analysed
    111
    107
    Units: Centimeter per second (cm/sec)
        least squares mean (confidence interval 95%)
    -10.33 (-14.14 to -6.52)
    -3.86 (-7.77 to 0.05)
    Statistical analysis title
    		 Week 48
    Statistical analysis description
    Voxelotor versus Placebo
    Comparison groups
    Voxelotor v Placebo
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0202
    Method
    		 Mixed Models for Repeated Measures
    Parameter type
    		 Difference in LS mean
    Point estimate
    -6.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.93
         upper limit
    		 -1.01

    Secondary: Time to Conversion to Abnormal TCD Flow

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    End point title
    		 Time to Conversion to Abnormal TCD Flow
    End point description
    Time to conversion was the number of weeks from the date of randomization to the date of TCD assessment when an abnormal TCD flow velocity (>= 200 cm/sec) is determined. ITT analysis population included all randomized participants. '99999' indicates due to limitations of the week 96 data as a result of the early termination of the study, the time to conversion to abnormal TCD flow secondary endpoints were considered exploratory and not subject to formal hypothesis testing.
    End point type
    Secondary
    End point timeframe
    Up to 96 weeks
    End point values
    		 Voxelotor Placebo
    Number of subjects analysed
    120
    116
    Units: Weeks
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Reversion to Normal TCD Flow

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    End point title
    		 Time to Reversion to Normal TCD Flow
    End point description
    Time to first normal TCD flow was the number of weeks from randomization to the date of first normal (<170 cm/sec) TCD flow. ITT analysis population included all randomized participants. The participants were grouped according to the treatment group to which they are randomized. Here, "Number of Participants Analyzed’’ signifies number of participants evaluable for this outcome measure. '99999' indicates due to limitations of the week 96 data as a result of the early termination of the study, the time to reversion to normal TCD flow secondary endpoints were considered exploratory and not subject to formal hypothesis testing.
    End point type
    Secondary
    End point timeframe
    Up to 96 weeks
    End point values
    		 Voxelotor Placebo
    Number of subjects analysed
    98
    90
    Units: Weeks
        median (full range (min-max))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With TCD Flow Velocity Reduction >=15 cm/sec at Weeks 24, 48 and 96

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    End point title
    		 Percentage of Participants With TCD Flow Velocity Reduction >=15 cm/sec at Weeks 24, 48 and 96
    End point description
    TCD flow velocity reduction from Baseline >=15 cm/sec at week 24, week 48 was analyzed using an exact Cochran-Mantel-Haenszel (CMH) general association test stratified for baseline HU use (yes; no), age group (2 to <= 8 years; >8 to <15 years), and baseline TAMMV value (170 cm/sec to < 185 cm/sec; 185 cm/sec to < 200 cm/sec). ITT analysis population included all randomized participants. Week 96 is not reported due to limitations of the week 96 data as a result of the early termination of the study and were considered exploratory and not subject to formal hypothesis testing.
    End point type
    Secondary
    End point timeframe
    Weeks 24, 48, 96
    End point values
    		 Voxelotor Placebo
    Number of subjects analysed
    120
    116
    Units: Percentage of participants
    number (not applicable)
        Week 24
    38.3
    25.9
        Week 48
    39.2
    27.6
    Statistical analysis title
    		 Difference in Adjusted Rate
    Statistical analysis description
    Difference in the adjusted response rates
    Comparison groups
    Voxelotor v Placebo
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0686
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Adjusted Rate
    Point estimate
    12.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 24.5

    Secondary: Change From Baseline in Hemoglobin (Hb) at Weeks 24, 48 and 96

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    End point title
    		 Change From Baseline in Hemoglobin (Hb) at Weeks 24, 48 and 96
    End point description
    Change from baseline in hemoglobin at weeks 24, 48, 96 was analyzed using the MMRM model including treatment, study visit, treatment by visit interaction, baseline hydroxyurea use (yes; no), age group (2 to <= 8 years; >8 to <15 years) and baseline TAMMV value (170 centimeter per second [cm/sec] to < 185 cm/sec; 185 cm/sec to < 200 cm/sec) as fixed effect terms and baseline value as a co-variate and used a compound symmetry covariance matrix for within-participant variability. ITT analysis population included all randomized participants. All participants reported under ‘Number of Participants Analyzed’ contributed data to the table but may not have evaluable data for every row. Here, ‘Number Analyzed’ signifies number of participants evaluable for each row. Week 96 is not reported due to limitations of the week 96 data as a result of the early termination of the study and were considered exploratory and not subject to formal hypothesis testing.
    End point type
    Secondary
    End point timeframe
    Baseline (value at Screening), Weeks 24, 48 and 96
    End point values
    		 Voxelotor Placebo
    Number of subjects analysed
    117
    115
    Units: Grams per deciliter (g/dL)
    least squares mean (confidence interval 95%)
        Week 24 (n=96,85)
    0.89 (0.65 to 1.14)
    0.18 (-0.08 to 0.44)
        Week 48 (n=94,86)
    0.79 (0.54 to 1.04)
    -0.19 (-0.45 to 0.07)
    Statistical analysis title
    		 Week 48
    Statistical analysis description
    Voxelotor versus Placebo
    Comparison groups
    Voxelotor v Placebo
    Number of subjects included in analysis
    232
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed Model Repeated Measures analysis
    Parameter type
    		 Difference in LS mean
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.35
    Statistical analysis title
    		 Week 24
    Statistical analysis description
    Voxelotor versus Placebo
    Comparison groups
    Voxelotor v Placebo
    Number of subjects included in analysis
    232
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0001
    Method
    		 Mixed Model Repeated Measures analysis
    Parameter type
    		 Difference in LS mean
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 1.07

    Secondary: Percent Change From Baseline in Unconjugated Bilirubin at Weeks 24, 48 and 96

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    End point title
    		 Percent Change From Baseline in Unconjugated Bilirubin at Weeks 24, 48 and 96
    End point description
    Percent change from baseline in unconjugated bilirubin at weeks 24 48, 96 was reported in this outcome measure. Analysis was performed using MMRM including treatment, study visit, treatment by visit interaction, baseline hydroxyurea use (yes; no), age group (2 to <= 8 years; >8 to <15 years), and baseline TAMMV value (170 centimeter per second [cm/sec] to < 185 cm/sec; 185 cm/sec to < 200 cm/sec) as fixed effect terms and baseline value as a co-variate and used a compound symmetry covariance matrix for within-subject variability. ITT analysis population included all randomized participants. All participants reported under ‘Number of Participants Analyzed’ contributed data to table but may not have evaluable data for every row. Here, ‘Number Analyzed’ = number of participants evaluable for each row. Week 96 is not reported due to limitations of the week 96 data as a result of early termination of study and were considered exploratory and not subject to formal hypothesis testing.
    End point type
    Secondary
    End point timeframe
    Baseline (value at Screening), Weeks 24, 48 and 96
    End point values
    		 Voxelotor Placebo
    Number of subjects analysed
    119
    116
    Units: Percent change
    least squares mean (confidence interval 95%)
        Change at Week 24 (n=109, 98)
    -21.83 (-30.65 to -13.01)
    11.78 (2.59 to 20.98)
        Change at Week 48 (n=97,92)
    -18.39 (-27.58 to -9.21)
    20.25 (10.84 to 29.65)
    Statistical analysis title
    		 Week 48
    Statistical analysis description
    Voxelotor versus Placebo
    Comparison groups
    Voxelotor v Placebo
    Number of subjects included in analysis
    235
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in LS mean
    Point estimate
    -38.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51.79
         upper limit
    		 -25.49
    Statistical analysis title
    		 Week 24
    Statistical analysis description
    Voxelotor versus Placebo
    Comparison groups
    Voxelotor v Placebo
    Number of subjects included in analysis
    235
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in LS mean
    Point estimate
    -33.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -46.36
         upper limit
    		 -20.86

    Secondary: Percent Change From Baseline in Reticulocyte at Weeks 24, 48 and 96

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    End point title
    		 Percent Change From Baseline in Reticulocyte at Weeks 24, 48 and 96
    End point description
    Percent change from baseline in reticulocyte at weeks 24, 48 and 96 was reported in this outcome measure. Analysis was performed using MMRM including treatment, study visit, treatment by visit interaction, baseline hydroxyurea use (yes; no), age group (2 to <= 8 years; >8 to <15 years), and baseline TAMMV value (170 centimeter per second [cm/sec] to < 185 cm/sec; 185 cm/sec to < 200 cm/sec) as fixed effect terms and baseline value as a co-variate and used a compound symmetry covariance matrix for within-participant variability. ITT analysis population included all randomized participants. All participants reported under ‘Number of Participants Analyzed’ contributed data to the table but may not have evaluable data for every row. Here, ‘Number Analyzed’ = number of participants evaluable for each row. Week 96 is not reported due to limitations of the week 96 data as a result of the early termination of study and were considered exploratory and not subject to formal hypothesis testing.
    End point type
    Secondary
    End point timeframe
    Baseline (value at Screening), Weeks 24, 48 and 96
    End point values
    		 Voxelotor Placebo
    Number of subjects analysed
    115
    115
    Units: Percent change
    least squares mean (confidence interval 95%)
        Week 24 (n=91,80)
    54.36 (-1.27 to 109.99)
    74.73 (18.24 to 131.22)
        Week 48 (n=89, 82)
    37.75 (-18.07 to 93.57)
    38.49 (-17.83 to 94.81)
    Statistical analysis title
    		 Week 48
    Statistical analysis description
    Voxelotor versus Placebo
    Comparison groups
    Voxelotor v Placebo
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9854
    Method
    		 Mixed Model Repeated Measures analysis
    Parameter type
    		 Difference in LS mean
    Point estimate
    -0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -80.1
         upper limit
    		 78.62
    Statistical analysis title
    		 Week 24
    Statistical analysis description
    Voxelotor versus Placebo
    Comparison groups
    Voxelotor v Placebo
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.614
    Method
    		 Mixed Models for Repeated Measures
    Parameter type
    		 Difference in LS mean
    Point estimate
    -20.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -99.72
         upper limit
    		 58.98

    Secondary: Percent Change From Baseline in Absolute Reticulocyte at Weeks 24, 48 and 96

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    End point title
    		 Percent Change From Baseline in Absolute Reticulocyte at Weeks 24, 48 and 96
    End point description
    Percent change from baseline in absolute reticulocyte at weeks 24 and 48 was reported in this outcome measure. Analysis was performed using MMRM including treatment, study visit, treatment by visit interaction, baseline hydroxyurea use (yes; no), age group (2 to <= 8 years; >8 to <15 years), and baseline TAMMV value (170 centimeter per second [cm/sec] to < 185 cm/sec; 185 cm/sec to < 200 cm/sec) as fixed effect terms and baseline value as a co-variate and used a compound symmetry covariance matrix for within-subject variability. ITT analysis population included all randomized participants. All participants reported under ‘Number of Participants Analyzed’ contributed data to the table but may not have evaluable data for every row. Here, ‘Number Analyzed’ = number of participants evaluable for each row. Week 96 is not reported due to limitations of week 96 data as a result of the early termination of study and were considered exploratory and not subject to formal hypothesis testing.
    End point type
    Secondary
    End point timeframe
    Baseline (value at Screening), Weeks 24, 48 and 96
    End point values
    		 Voxelotor Placebo
    Number of subjects analysed
    115
    114
    Units: Percent change
    least squares mean (confidence interval 95%)
        Week 24 (n=91,79)
    60.89 (7.22 to 114.56)
    67.93 (13.10 to 122.75)
        Week 48 (87, 81)
    43.52 (-10.51 to 97.54)
    37.74 (-16.91 to 92.40)
    Statistical analysis title
    		 Week 24
    Statistical analysis description
    Voxelotor versus Placebo
    Comparison groups
    Voxelotor v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8571
    Method
    		 Mixed Models for Repeated Measures
    Parameter type
    		 Difference in LS mean
    Point estimate
    -7.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -83.88
         upper limit
    		 69.8
    Statistical analysis title
    		 Week 48
    Statistical analysis description
    Voxelotor versus Placebo
    Comparison groups
    Voxelotor v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8828
    Method
    		 Mixed Models for Repeated Measures
    Parameter type
    		 Difference in LS mean
    Point estimate
    5.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -71.2
         upper limit
    		 82.75

    Secondary: Percent Change From Baseline in Lactate Dehydrogenase (LDH) at Weeks 24, 48 and 96

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    End point title
    		 Percent Change From Baseline in Lactate Dehydrogenase (LDH) at Weeks 24, 48 and 96
    End point description
    Percent change from baseline in LDH at weeks 24 and 48 was reported in this outcome measure. Analysis was performed using MMRM including treatment, study visit, treatment by visit interaction, baseline hydroxyurea use (yes; no), age group (2 to <= 8 years; >8 to <15 years), and baseline TAMMV value (170 centimeter per second [cm/sec] to < 185 cm/sec; 185 cm/sec to < 200 cm/sec) as fixed effect terms and baseline value as a co-variate and used a compound symmetry covariance matrix for within-subject variability. ITT analysis population included all randomized participants. All participants reported under ‘Number of Participants Analyzed’ contributed data to the table but may not have evaluable data for every row. Here, ‘Number Analyzed’ signifies number of participants evaluable for each row. Week 96 is not reported due to limitations of the week 96 data as a result of the early termination of the study and were considered exploratory and not subject to formal hypothesis testing.
    End point type
    Secondary
    End point timeframe
    Baseline (value at Screening), Weeks 24, 48 and 96
    End point values
    		 Voxelotor Placebo
    Number of subjects analysed
    119
    116
    Units: Percent change
    least squares mean (confidence interval 95%)
        Week 24 (n=109, 98)
    2.62 (-3.25 to 8.49)
    2.18 (-3.99 to 8.34)
        Week 48 (n=98, 92)
    -2.64 (-8.80 to 3.52)
    -0.03 (-6.38 to 6.32)
    Statistical analysis title
    		 Week 48
    Statistical analysis description
    Voxelotor versus Placebo
    Comparison groups
    Voxelotor v Placebo
    Number of subjects included in analysis
    235
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5635
    Method
    		 Mixed Models for Repeated Measures
    Parameter type
    		 Mixed Models for Repeated Measures
    Point estimate
    -2.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.46
         upper limit
    		 6.25
    Statistical analysis title
    		 Week 24
    Statistical analysis description
    Voxelotor versus Placebo
    Comparison groups
    Voxelotor v Placebo
    Number of subjects included in analysis
    235
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9181
    Method
    		 Mixed Models for Repeated Measures
    Parameter type
    		 Difference in LS mean
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.08
         upper limit
    		 8.97

    Secondary: Annualized Incidence Rate of Vaso-Occlusive Crises (VOCs)

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    End point title
    		 Annualized Incidence Rate of Vaso-Occlusive Crises (VOCs)
    End point description
    VOC was defined as a composite of acute painful crisis and/or acute chest syndrome (ACS). Annualized incidence rate was defined as total number of events per total person-years. Total person-years was the sum of participants treatment period in years, which included the time from randomisation to earliest of (last dose date, post-randomization HU initiation for subjects with no HU at baseline, and end of study). The 95% CI of rate displayed the exact Poisson confidence limits. ITT analysis population included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Time from randomisation to earliest of (last dose date, post-randomization HU initiation for subjects with no HU at baseline, and end of study) [maximum treatment exposure was 106 weeks]
    End point values
    		 Voxelotor Placebo
    Number of subjects analysed
    120
    116
    Units: Events per total person-years
        number (confidence interval 95%)
    1.098 (0.869 to 1.387)
    0.580 (0.439 to 0.765)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 up to 28 days after last dose of study drug (maximum treatment exposure was 106 weeks)
    Adverse event reporting additional description
    Same event may appear as both SAE and non-SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    v27.1
    Reporting groups
    Reporting group title
    Voxelotor
    Reporting group description
    		 Participants aged greater than or equal to 12 years of age received 1500 mg voxelotor tablet orally once daily for 96 weeks. Participants less than 12 years of age received voxelotor at a weight based (1500 mg-equivalent) dose. Participants were followed up to 4 weeks after last dose of study drug.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received voxelotor matched placebo orally once daily for 96 weeks.

    Serious adverse events
    		 Voxelotor Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    63 / 120 (52.50%)
    43 / 116 (37.07%)
         number of deaths (all causes)
    8
    2
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypertensive emergency
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         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
    Pyrexia
         subjects affected / exposed
    19 / 120 (15.83%)
    5 / 116 (4.31%)
         occurrences causally related to treatment / all
    0 / 25
    0 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute chest syndrome
         subjects affected / exposed
    8 / 120 (6.67%)
    8 / 116 (6.90%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Liver function test abnormal
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Eyelid ptosis congenital
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery thrombosis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 120 (0.00%)
    2 / 116 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Headache
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Sickle cell anaemia with crisis
         subjects affected / exposed
    44 / 120 (36.67%)
    18 / 116 (15.52%)
         occurrences causally related to treatment / all
    0 / 84
    0 / 26
         deaths causally related to treatment / all
    0 / 6
    0 / 0
    Anaemia
         subjects affected / exposed
    12 / 120 (10.00%)
    13 / 116 (11.21%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 13
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Haemolysis
         subjects affected / exposed
    1 / 120 (0.83%)
    3 / 116 (2.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytosis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersplenism
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Periorbital oedema
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 120 (5.00%)
    3 / 116 (2.59%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Glomerulonephritis acute
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    6 / 120 (5.00%)
    2 / 116 (1.72%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaria
         subjects affected / exposed
    20 / 120 (16.67%)
    16 / 116 (13.79%)
         occurrences causally related to treatment / all
    0 / 24
    0 / 17
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Sepsis
         subjects affected / exposed
    8 / 120 (6.67%)
    4 / 116 (3.45%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 120 (2.50%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis chronic
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diphtheria
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (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
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         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
    		 Voxelotor Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    81 / 120 (67.50%)
    83 / 116 (71.55%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Pallor
         subjects affected / exposed
    3 / 120 (2.50%)
    1 / 116 (0.86%)
         occurrences all number
    7
    2
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Gait disturbance
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 116 (0.86%)
         occurrences all number
    1
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 116 (0.86%)
         occurrences all number
    2
    1
    Chest pain
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 116 (0.00%)
         occurrences all number
    2
    0
    Pain
         subjects affected / exposed
    3 / 120 (2.50%)
    6 / 116 (5.17%)
         occurrences all number
    3
    10
    Pyrexia
         subjects affected / exposed
    20 / 120 (16.67%)
    12 / 116 (10.34%)
         occurrences all number
    24
    16
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 116 (0.86%)
         occurrences all number
    1
    1
    Productive cough
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Nasal congestion
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 116 (0.86%)
         occurrences all number
    1
    1
    Haemoptysis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Catarrh
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Acute chest syndrome
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Nasal turbinate hypertrophy
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    2
    0
    Epistaxis
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 116 (0.00%)
         occurrences all number
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 120 (2.50%)
    0 / 116 (0.00%)
         occurrences all number
    3
    0
    Tonsillar hypertrophy
         subjects affected / exposed
    4 / 120 (3.33%)
    4 / 116 (3.45%)
         occurrences all number
    6
    6
    Cough
         subjects affected / exposed
    12 / 120 (10.00%)
    3 / 116 (2.59%)
         occurrences all number
    14
    6
    Dyspnoea
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Urine albumin/creatinine ratio increased
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 120 (0.83%)
    3 / 116 (2.59%)
         occurrences all number
    1
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 120 (2.50%)
    2 / 116 (1.72%)
         occurrences all number
    3
    3
    Blood bilirubin increased
         subjects affected / exposed
    4 / 120 (3.33%)
    0 / 116 (0.00%)
         occurrences all number
    4
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 120 (3.33%)
    3 / 116 (2.59%)
         occurrences all number
    4
    3
    Cardiac murmur
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 116 (0.86%)
         occurrences all number
    1
    1
    Vitamin D decreased
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Platelet count increased
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Heart rate irregular
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Blood albumin decreased
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Upper limb fracture
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Overdose
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Nail injury
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Wound
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Soft tissue injury
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Bone fissure
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Right ventricular failure
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 120 (6.67%)
    4 / 116 (3.45%)
         occurrences all number
    9
    8
    Dizziness
         subjects affected / exposed
    1 / 120 (0.83%)
    2 / 116 (1.72%)
         occurrences all number
    1
    2
    Sciatica
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Seizure
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Sickle cell anaemia with crisis
         subjects affected / exposed
    45 / 120 (37.50%)
    33 / 116 (28.45%)
         occurrences all number
    98
    61
    Leukocytosis
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 116 (0.86%)
         occurrences all number
    1
    2
    Thrombocytosis
         subjects affected / exposed
    2 / 120 (1.67%)
    2 / 116 (1.72%)
         occurrences all number
    2
    2
    Lymphadenopathy
         subjects affected / exposed
    2 / 120 (1.67%)
    2 / 116 (1.72%)
         occurrences all number
    2
    2
    Anaemia
         subjects affected / exposed
    4 / 120 (3.33%)
    6 / 116 (5.17%)
         occurrences all number
    6
    8
    Splenomegaly
         subjects affected / exposed
    1 / 120 (0.83%)
    2 / 116 (1.72%)
         occurrences all number
    1
    2
    Haemolysis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Leukopenia
         subjects affected / exposed
    0 / 120 (0.00%)
    3 / 116 (2.59%)
         occurrences all number
    0
    3
    Neutrophilia
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Neutropenia
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 116 (0.86%)
         occurrences all number
    1
    1
    Ear and labyrinth disorders
    Motion sickness
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Night blindness
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Vernal keratoconjunctivitis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Ocular hyperaemia
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Abdominal tenderness
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 120 (0.83%)
    4 / 116 (3.45%)
         occurrences all number
    3
    4
    Vomiting
         subjects affected / exposed
    5 / 120 (4.17%)
    5 / 116 (4.31%)
         occurrences all number
    7
    5
    Diarrhoea
         subjects affected / exposed
    5 / 120 (4.17%)
    2 / 116 (1.72%)
         occurrences all number
    8
    2
    Abdominal pain
         subjects affected / exposed
    7 / 120 (5.83%)
    5 / 116 (4.31%)
         occurrences all number
    9
    5
    Gastritis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Mouth ulceration
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Ocular icterus
         subjects affected / exposed
    3 / 120 (2.50%)
    1 / 116 (0.86%)
         occurrences all number
    5
    4
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 120 (1.67%)
    1 / 116 (0.86%)
         occurrences all number
    2
    1
    Jaundice
         subjects affected / exposed
    2 / 120 (1.67%)
    4 / 116 (3.45%)
         occurrences all number
    2
    4
    Hepatosplenomegaly
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Hepatomegaly
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 116 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Macule
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 116 (0.86%)
         occurrences all number
    1
    1
    Keratosis pilaris
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Dermatitis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Rash macular
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 116 (0.00%)
         occurrences all number
    2
    0
    Miliaria
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Urticaria
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 116 (0.86%)
         occurrences all number
    1
    1
    Rash papular
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    3 / 120 (2.50%)
    4 / 116 (3.45%)
         occurrences all number
    3
    4
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Sickle cell nephropathy
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Dactylitis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Osteonecrosis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Bone pain
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Back pain
         subjects affected / exposed
    6 / 120 (5.00%)
    2 / 116 (1.72%)
         occurrences all number
    7
    3
    Arthralgia
         subjects affected / exposed
    6 / 120 (5.00%)
    2 / 116 (1.72%)
         occurrences all number
    8
    2
    Pain in extremity
         subjects affected / exposed
    6 / 120 (5.00%)
    2 / 116 (1.72%)
         occurrences all number
    10
    3
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    2
    0
    Malaria
         subjects affected / exposed
    18 / 120 (15.00%)
    16 / 116 (13.79%)
         occurrences all number
    25
    21
    Conjunctivitis
         subjects affected / exposed
    2 / 120 (1.67%)
    3 / 116 (2.59%)
         occurrences all number
    2
    3
    Pharyngotonsillitis
         subjects affected / exposed
    3 / 120 (2.50%)
    5 / 116 (4.31%)
         occurrences all number
    3
    5
    Pharyngitis
         subjects affected / exposed
    3 / 120 (2.50%)
    1 / 116 (0.86%)
         occurrences all number
    3
    1
    Bronchitis
         subjects affected / exposed
    3 / 120 (2.50%)
    2 / 116 (1.72%)
         occurrences all number
    3
    2
    Tonsillitis
         subjects affected / exposed
    5 / 120 (4.17%)
    6 / 116 (5.17%)
         occurrences all number
    6
    7
    Respiratory tract infection
         subjects affected / exposed
    6 / 120 (5.00%)
    6 / 116 (5.17%)
         occurrences all number
    9
    7
    Nasopharyngitis
         subjects affected / exposed
    7 / 120 (5.83%)
    5 / 116 (4.31%)
         occurrences all number
    9
    6
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 120 (10.00%)
    7 / 116 (6.03%)
         occurrences all number
    20
    8
    Urinary tract infection
         subjects affected / exposed
    1 / 120 (0.83%)
    2 / 116 (1.72%)
         occurrences all number
    2
    2
    Varicella
         subjects affected / exposed
    2 / 120 (1.67%)
    2 / 116 (1.72%)
         occurrences all number
    2
    2
    Acarodermatitis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Bacterial infection
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 116 (0.86%)
         occurrences all number
    1
    1
    Body tinea
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 116 (0.86%)
         occurrences all number
    1
    1
    COVID-19
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Metapneumovirus infection
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Mumps
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Osteomyelitis acute
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Otitis media
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Parotitis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 116 (0.86%)
         occurrences all number
    1
    2
    Rash pustular
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 120 (0.83%)
    1 / 116 (0.86%)
         occurrences all number
    1
    2
    Carbuncle
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Cellulitis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 120 (0.00%)
    4 / 116 (3.45%)
         occurrences all number
    0
    4
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    2 / 120 (1.67%)
    3 / 116 (2.59%)
         occurrences all number
    2
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Aug 2019
    Amendment 1.0: The open-label study in infants, Part B, was removed. Primary and key secondary objectives and endpoints were changed to focus on TCD flow velocity. Secondary objectives and endpoints regarding Hb and clinical measures of hemolysis were added. Exploratory objectives and endpoints were updated to evaluate SCD-related clinical complications and SCD-associated quality of life measures and biomarkers. Inclusion/exclusion criteria were updated, including but not limited to Updated age range to 2 to < 15 years of age (from 2 to <12 years of age). Added conditional TCD flow velocity (170 cm/sec to < 200 cm/sec) during screening (no prior criteria regarding TCD flow velocity). The treatment period was extended to 96 weeks (from 48 weeks).
    05 Dec 2019
    Amendment 2.0: Added TCD flow velocity secondary objectives for consistency with secondary endpoints. Revised inclusion criteria regarding stable Hb Levels and stable dose of HU and exclusion criteria including but not limited to cerebral vasculopathy and seizure disorder. Revised stratification factors to include screening TCD flow velocity and geographic regions (MENA, rest of world).
    13 Sep 2021
    Amendment 3.0: Added dispersible tablet(s) as an optional dosage form. Revised Exclusion Criterion 1 - to increase the weight threshold from < 5 kg to < 10 kg. Added new exclusion criterion for active symptomatic COVID-19 infection.
    24 Apr 2023
    Amendment 4.0: Added a secondary endpoint for annualized incidence of VOC. Added dose recommendations for participants < 12 years of age who receive DT dosage form. Added dose modification recommendations for DT dosage form.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 May 2024
    Study drug dosing was voluntarily paused on 01 May 2024 due to a potential concern related to an imbalance of participant deaths in those receiving voxelotor compared to those on placebo. The study was terminated effective 25 September 2024 when newly generated clinical data evaluated by Pfizer and shared with the regulatory authorities indicated that the risk profile of voxelotor in people living with SCD exceeded the benefits observed in previously generated global research. The benefit-risk assessment was based on preliminary data that required further analysis.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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