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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Subjects With Pyruvate Kinase Deficiency

    Summary
    EudraCT number
    		 2017-003823-31
    Trial protocol
    		 DE   GB   FR   PT   ES   DK   NL   CZ   IT  
    Global end of trial date
    09 Oct 2020

    Results information
    Results version number
    		 v1
    This version publication date
    24 Oct 2021
    First version publication date
    24 Oct 2021
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    AG348-C-006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03548220
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Agios Pharmaceuticals, Inc.
    Sponsor organisation address
    88 Sidney Street, Cambridge, , United States, MA 02139-4169,
    Public contact
    Director, Scientific Communications, Agios Pharmaceuticals, Inc., +1 844633 2332, medinfo@agios.com
    Scientific contact
    Director, Scientific Communications, Agios Pharmaceuticals, Inc., +1 844633 2332, medinfo@agios.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
    09 Oct 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of treatment with AG-348 compared with placebo in increasing haemoglobin (Hb) concentrations.
    Protection of trial subjects
    All study subjects were required to read and sign an informed consent form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Aug 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 2
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Japan: 6
    Country: Number of subjects enrolled
    United States: 28
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Brazil: 1
    Country: Number of subjects enrolled
    Turkey: 1
    Worldwide total number of subjects
    80
    EEA total number of subjects
    34
    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)
    76
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 80 subjects were randomised in the study which was conducted across multiple sites in 14 countries: Brazil, Canada, Denmark, France, Germany, Italy, Japan, Republic of Korea, Netherlands, Spain, Switzerland, Turkey, United Kingdom and United States. The study was conducted from 9 August 2018 to 9 October 2020.

    Pre-assignment
    Screening details
    		 Screening was done for a period of 42 days after the subject provided the informed consent. Investigators determined if the subjects met all the inclusion criteria and none of the exclusion criteria to enroll in Part 1: Dose Optimisation Period to receive AG-348 or placebo to determine the optimised dose followed by Part 2: Fixed Dose Period.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received matching placebo to AG-348 tablets, administered orally, at a starting dose of 5 milligrams (mg) twice daily (BID) followed by two sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively, for a period of 12 weeks in Part 1. This was followed by the optimised dose BID, as determined by the investigator in Part 1, for a period of 12 weeks in Part 2.
    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
    AG-348 matching-placebo tablets BID administered orally in Part 1 and Part 2.

    Arm title
    		 AG-348
    Arm description
    		 Subjects received AG-348 tablets, administered orally, at a starting dose of 5 mg BID followed by two sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively, for a period of 12 weeks in Part 1. This was followed by the optimised dose BID, as determined by investigator in Part 1, for a period of 12 weeks in Part 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AG-348
    Investigational medicinal product code
    Other name
    Mitapivat
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    AG-348 5mg, 20mg. and 50mg tablets BID administered orally in Part 1 and Part 2.

    Number of subjects in period 1
    		Placebo AG-348
    Started
    40
    40
    Completed
    39
    40
    Not completed
    1
    0
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo to AG-348 tablets, administered orally, at a starting dose of 5 milligrams (mg) twice daily (BID) followed by two sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively, for a period of 12 weeks in Part 1. This was followed by the optimised dose BID, as determined by the investigator in Part 1, for a period of 12 weeks in Part 2.

    Reporting group title
    AG-348
    Reporting group description
    		 Subjects received AG-348 tablets, administered orally, at a starting dose of 5 mg BID followed by two sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively, for a period of 12 weeks in Part 1. This was followed by the optimised dose BID, as determined by investigator in Part 1, for a period of 12 weeks in Part 2.

    Reporting group values
    		 Placebo AG-348 Total
    Number of subjects
    		 40 40 80
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.2 ( 15.92 ) 36.0 ( 15.18 ) -
    Gender categorical
    Units: Subjects
        Female
    		 24 24 48
        Male
    		 16 16 32
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 3 5 8
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 0 0 0
        White
    		 32 28 60
        More than one race
    		 1 0 1
        Unknown or Not Reported
    		 4 6 10
    Ethinicity
    Units: Subjects
        Hispanic or Latino
    		 1 2 3
        Not Hispanic or Latino
    		 34 28 62
        Unknown or Not Reported
    		 5 10 15

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo to AG-348 tablets, administered orally, at a starting dose of 5 milligrams (mg) twice daily (BID) followed by two sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively, for a period of 12 weeks in Part 1. This was followed by the optimised dose BID, as determined by the investigator in Part 1, for a period of 12 weeks in Part 2.

    Reporting group title
    AG-348
    Reporting group description
    		 Subjects received AG-348 tablets, administered orally, at a starting dose of 5 mg BID followed by two sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively, for a period of 12 weeks in Part 1. This was followed by the optimised dose BID, as determined by investigator in Part 1, for a period of 12 weeks in Part 2.

    Subject analysis set title
    AG-348 5mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received 5mg AG-348 tablets BID at Week 12.

    Subject analysis set title
    AG-348 20mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received 20mg AG-348 tablets BID at Week 12.

    Subject analysis set title
    AG-348 50mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received 50mg AG-348 tablets BID at Week 12.

    Primary: Percentage of Subjects Achieving a Haemoglobin (Hb) Response (HR) in Part 2

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    End point title
    		 Percentage of Subjects Achieving a Haemoglobin (Hb) Response (HR) in Part 2
    End point description
    Haemoglobin response (HR) is defined as a ≥1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 16, 20, and 24 during the Fixed Dose Period. The baseline Hb concentration is the average of all available Hb concentrations for a subject during the Screening Period up to the first dose of study treatment. Full analysis set included all subjects who were randomised.
    End point type
    Primary
    End point timeframe
    Baseline, Part 2: Weeks 16, 20, 24
    End point values
    		 Placebo AG-348
    Number of subjects analysed
    40
    40
    Units: percentage of subjects
        number (not applicable)
    0
    40.0
    Statistical analysis title
    		 Hemoglobin response Response (HR) in Part 2
    Comparison groups
    Placebo v AG-348
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Exact Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - 2-sided p-value

    Secondary: Average Change From Baseline in Hb Concentration at Weeks 16, 20 and 24 in Part 2

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    End point title
    		 Average Change From Baseline in Hb Concentration at Weeks 16, 20 and 24 in Part 2
    End point description
    This is the change in Hb concentration at Weeks 16, 20 and 24 compared to that of baseline. Data presented represents the average change from baseline at Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomisation for subjects randomised and not dosed or before start of study treatment for subjects randomised and dosed. Full analysis set included all subjects who were randomised.
    End point type
    Secondary
    End point timeframe
    Baseline, Part 2: Weeks 16, 20, 24
    End point values
    		 Placebo AG-348
    Number of subjects analysed
    40
    40
    Units: g/L
        least squares mean (standard error)
    -1.48 ( 2.082 )
    16.73 ( 2.075 )
    Statistical analysis title
    		 Average Change in Hemoglobin Concentration
    Comparison groups
    AG-348 v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed-effect Model Repeated Measure
    Parameter type
    		 LS Mean Difference
    Point estimate
    18.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12.41
         upper limit
    		 24.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.913

    Secondary: Maximum Change From Baseline in Hb Concentration

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    End point title
    		 Maximum Change From Baseline in Hb Concentration
    End point description
    This is the maximum change from baseline in Hb concentration in Part 2. Full analysis set included all subjects who were randomised.
    End point type
    Secondary
    End point timeframe
    Baseline, Part 2, up to Week 24
    End point values
    		 Placebo AG-348
    Number of subjects analysed
    39 [2]
    39 [3]
    Units: g/L
        arithmetic mean (standard deviation)
    4.76 ( 4.217 )
    23.94 ( 21.367 )
    Notes
    [2] - Number analysed is the number of subjects evaluated for the endpoint.
    [3] - Number analysed is the number of subjects evaluated for the endpoint.
    No statistical analyses for this end point

    Secondary: Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More

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    End point title
    		 Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More
    End point description
    This is the time taken to first achieve an increase of haemoglobin concentration of 1.5 g/dL or more from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Part 2, up to Week 24
    End point values
    		 Placebo AG-348
    Number of subjects analysed
    0 [4]
    17 [5]
    Units: weeks
        arithmetic mean (standard deviation)
    ( )
    7.66 ( 4.050 )
    Notes
    [4] - No subjects were analysed for this endpoint in this arm.
    [5] - Number analysed is the number of subjects evaluated for the endpoint.
    No statistical analyses for this end point

    Secondary: Average Change From Baseline in Bilirubin at Weeks 16, 20 and 24 in Part 2

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    End point title
    		 Average Change From Baseline in Bilirubin at Weeks 16, 20 and 24 in Part 2
    End point description
    The change from baseline in bilirubin levels was summarised. Bilirubin is a marker for haemolysis. Data presented represents the average change from baseline at Week 16, 20 and Week 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomisation for subjects randomised and not dosed or before start of study treatment for subjects randomised and dosed. Full analysis set included all subjects who were randomised.
    End point type
    Secondary
    End point timeframe
    Baseline, Part 2: Weeks 16, 20, 24
    End point values
    		 Placebo AG-348
    Number of subjects analysed
    39 [6]
    37 [7]
    Units: micromoles per litre (μmol/L)
        least squares mean (standard error)
    5.10 ( 4.061 )
    -21.16 ( 4.228 )
    Notes
    [6] - Number analysed is the number of subjects evaluated for the endpoint.
    [7] - Number analysed is the number of subjects evaluated for the endpoint.
    Statistical analysis title
    		 Average Change From Baseline in Bilirubin
    Comparison groups
    Placebo v AG-348
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed-effect Model Repeated Measure
    Parameter type
    		 LS Mean Difference
    Point estimate
    -26.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.82
         upper limit
    		 -14.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.788

    Secondary: Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24 in Part 2

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    End point title
    		 Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24 in Part 2
    End point description
    The change from baseline in LDH levels was summarised. LDH is a marker for haemolysis. Data presented represents the average change from baseline at Weeks 16, 20 and Week 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomisation for subjects randomised and not dosed or before start of study treatment for subjects randomised and dosed. Full analysis set included all subjects who were randomised.
    End point type
    Secondary
    End point timeframe
    Baseline, Part 2: Weeks 16, 20, 24
    End point values
    		 Placebo AG-348
    Number of subjects analysed
    40
    39 [8]
    Units: units per litre (U/L)
        least squares mean (standard error)
    -21.18 ( 16.040 )
    -91.99 ( 16.222 )
    Notes
    [8] - Number analysed is the number of subjects evaluated for the endpoint.
    Statistical analysis title
    		 Average Change From Baseline in Lactic Acid Dehydr
    Comparison groups
    Placebo v AG-348
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0027
    Method
    		 Mixed-effect Model Repeated Measure
    Parameter type
    		 LS Mean Difference
    Point estimate
    -70.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -115.88
         upper limit
    		 -25.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    22.488

    Secondary: Average Change From Baseline in Haptoglobin at Weeks 16, 20 and 24 in Part 2

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    End point title
    		 Average Change From Baseline in Haptoglobin at Weeks 16, 20 and 24 in Part 2
    End point description
    The change from baseline in haptoglobin levels were summarised. Haptoglobin levels are markers for haemolysis. Data presented represents the average change from baseline at Weeks 16, 20 and Week 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomisation for subjects randomised and not dosed or before start of study treatment for subjects randomised and dosed. Full analysis set included all subjects who were randomised.
    End point type
    Secondary
    End point timeframe
    Baseline, Part 2: Weeks 16, 20, 24
    End point values
    		 Placebo AG-348
    Number of subjects analysed
    40
    40
    Units: g/L
        least squares mean (standard error)
    0.012 ( 0.0412 )
    0.169 ( 0.0408 )
    Statistical analysis title
    		 Average Change From Baseline in Haptoglobin
    Comparison groups
    Placebo v AG-348
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0079
    Method
    		 Mixed-effect Model Repeated Measure
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.158
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.043
         upper limit
    		 0.273
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0578

    Secondary: Average Change From Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24 in Part 2

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    End point title
    		 Average Change From Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24 in Part 2
    End point description
    The change from baseline in reticulocyte percentage was summarised. Reticulocyte levels are markers for haematopoietic activity. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomisation for subjects randomised and not dosed or before start of study treatment for subjects randomised and dosed. Full analysis set included all subjects who were randomised.
    End point type
    Secondary
    End point timeframe
    Baseline, Part 2: Weeks 16, 20, 24
    End point values
    		 Placebo AG-348
    Number of subjects analysed
    40
    40
    Units: fraction of 1
        least squares mean (standard error)
    0.0038 ( 0.01390 )
    -0.0973 ( 0.01401 )
    Statistical analysis title
    		 Change From Baseline in Reticulocyte Percentage
    Comparison groups
    Placebo v AG-348
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed-effect Model Repeated Measure
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.1011
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1391
         upper limit
    		 -0.0632
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.01904

    Secondary: Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score at Week 24

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    End point title
    		 Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score at Week 24
    End point description
    The PKDD is a 7-item patient reported outcome (PRO) measure of the core signs and symptoms associated with PK deficiency in adults. Subjects rate their experience with symptoms of PK deficiency on the present day. The symptoms include those associated with tiredness, jaundice, bone pain, shortness of breath, and energy level. The score ranges from 25 to 76, with higher scores indicating a higher disease burden. The change from baseline in PKDD weekly scores was evaluated. A negative change from baseline indicates a lower disease burden. Full analysis set included all subjects who were randomised.
    End point type
    Secondary
    End point timeframe
    Baseline, to Week 24
    End point values
    		 Placebo AG-348
    Number of subjects analysed
    36 [9]
    37 [10]
    Units: score on a scale
        least squares mean (standard error)
    -2.05 ( 0.976 )
    -5.16 ( 0.955 )
    Notes
    [9] - Number analysed is the number of subjects evaluated for the endpoint.
    [10] - Number analysed is the number of subjects evaluated for the endpoint.
    Statistical analysis title
    		 Change From Baseline in PKDD Score
    Comparison groups
    Placebo v AG-348
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0247
    Method
    		 Mixed-effect Model Repeated Measure
    Parameter type
    		 LS Mean Difference
    Point estimate
    -3.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.8
         upper limit
    		 -0.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.352

    Secondary: Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score at Week 24

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    End point title
    		 Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score at Week 24
    End point description
    The PKDIA is a 12-item patient reported outcome (PRO) measure of the common impacts of PK deficiency on activities of daily living. Subjects rate how PK deficiency has impacted aspects of daily living in the past 7 days, including impacts on relationships; perceived appearance; work performance; and leisure, social, mental, and physical activities. The score range is 30 to 76, with higher scores indicating a higher disease burden. The change from baseline in PKDIA scores was evaluated. A negative change from baseline indicates a lower disease burden. Full analysis set included all subjects who were randomised.
    End point type
    Secondary
    End point timeframe
    Baseline, to Week 24
    End point values
    		 Placebo AG-348
    Number of subjects analysed
    39 [11]
    39 [12]
    Units: score on a scale
        least squares mean (standard error)
    -1.39 ( 1.157 )
    -4.65 ( 1.123 )
    Notes
    [11] - Number analysed is the number of subjects evaluated for the endpoint.
    [12] - Number analysed is the number of subjects evaluated for the endpoint.
    Statistical analysis title
    		 Change From Baseline in PKDIA Score
    Comparison groups
    Placebo v AG-348
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0421
    Method
    		 Mixed-effect Model Repeated Measure
    Parameter type
    		 LS Mean Difference
    Point estimate
    -3.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.39
         upper limit
    		 -0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.574

    Secondary: Percentage of Subjects With Adverse Events

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    End point title
    		 Percentage of Subjects With Adverse Events
    End point description
    An AE is any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Safety analysis set included all subjects who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197)
    End point values
    		 Placebo AG-348
    Number of subjects analysed
    39
    40
    Units: percentage of subjects
        number (not applicable)
    89.7
    87.5
    No statistical analyses for this end point

    Secondary: Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12

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    End point title
    		 Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12
    End point description
    Pharmacokinetic analysis population consisted of all subjects who were enrolled and received a dose of study medication (mitapivat) with at least 1 non-zero pharmacokinetic plasma concentration of mitapivat at the Week 12 visit. 99999 indicates the standard deviation for AG-348 arm due to low number of subjects evaluated.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose Day 85 (Week 12)
    End point values
    		 AG-348 5mg AG-348 20mg AG-348 50mg
    Number of subjects analysed
    2
    3
    24 [13]
    Units: h*ng/mL
        geometric mean (geometric coefficient of variation)
    565.9 ( 99999 )
    1481.2 ( 26.9 )
    2973.3 ( 35.6 )
    Notes
    [13] - Number analysed is the number of subjects evaluated for the endpoint.
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (Cmax) for AG-348

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    End point title
    		 Maximum Plasma Concentration (Cmax) for AG-348
    End point description
    Pharmacokinetic analysis population consisted of all subjects who were enrolled and received a dose of study medication (mitapivat) with at least 1 non-zero pharmacokinetic plasma concentration of mitapivat at the Week 12 visit. 99999 indicates the standard deviation for AG-348 arm due to low number of subjects evaluated.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose Day 85 (Week 12)
    End point values
    		 AG-348 5mg AG-348 20mg AG-348 50mg
    Number of subjects analysed
    2
    3
    26 [14]
    Units: nanogram/millilitre (ng/mL)
        geometric mean (geometric coefficient of variation)
    156.9 ( 99999 )
    373.1 ( 13.6 )
    1033 ( 31.2 )
    Notes
    [14] - Number analysed is the number of subjects evaluated for the endpoint.
    No statistical analyses for this end point

    Secondary: Time to Cmax (Tmax) for AG-348

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    End point title
    		 Time to Cmax (Tmax) for AG-348
    End point description
    Pharmacokinetic analysis population consisted of all subjects who were enrolled and received a dose of study medication (mitapivat) with at least 1 non-zero pharmacokinetic plasma concentration of mitapivat at the Week 12 visit. 99999 indicates the standard deviation for AG-348 arm due to low number of subject evaluated.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose Day 85 (Week 12)
    End point values
    		 AG-348 5mg AG-348 20mg AG-348 50mg
    Number of subjects analysed
    2
    3
    26 [15]
    Units: hours (h)
        median (full range (min-max))
    0.75 (0.50 to 1.00)
    1.02 (0.92 to 2.17)
    0.50 (0.42 to 1.92)
    Notes
    [15] - Number analysed is the number of subjects evaluated for the endpoint.
    No statistical analyses for this end point

    Secondary: Time to Last Measurable Concentration (Tlast) for AG-348

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    End point title
    		 Time to Last Measurable Concentration (Tlast) for AG-348
    End point description
    Pharmacokinetic analysis population consisted of all subjects who were enrolled and received a dose of study medication (mitapivat) with at least 1 non-zero pharmacokinetic plasma concentration of mitapivat at the Week 12 visit. 99999 indicates the standard deviation for AG-348 arm due to low number of subjects evaluated.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose Day 85 (Week 12)
    End point values
    		 AG-348 5mg AG-348 20mg AG-348 50mg
    Number of subjects analysed
    2
    3
    24 [16]
    Units: hours (h)
        geometric mean (geometric coefficient of variation)
    7.787 ( 99999 )
    7.809 ( 4.2 )
    7.162 ( 28.0 )
    Notes
    [16] - Number analysed is the number of subjects evaluated for the endpoint.
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment Emergent Adverse Events (TEAEs) Based on Exposure -Safety Response Relationship

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    End point title
    		 Number of Subjects with Treatment Emergent Adverse Events (TEAEs) Based on Exposure -Safety Response Relationship
    End point description
    This is the relationship between the TEAEs and study drug exposure. Safety analysis set included all subjects who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197)
    End point values
    		 Placebo AG-348
    Number of subjects analysed
    39
    40
    Units: subjects
        Insomnia
    7
    7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    F rom signing of informed consent form to end of Part 2, including follow-up (up to Day 197)
    Adverse event reporting additional description
    The safety analysis set included all subjects who received at least 1 dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo to AG-348 tablets, administered orally, at a starting dose of 5 milligrams (mg) twice daily (BID) followed by two sequential dose level increases to 20mg and 50mg BID at Weeks 4 and 8 respectively, for a period of 12 weeks in Part 1. This was followed by the optimised dose BID, as determined by the investigator in Part 1, for a period of 12 weeks in Part 2.

    Reporting group title
    AG-348
    Reporting group description
    		 Participants received AG-348 tablets, administered orally, at a starting dose of 5 mg BID followed by two sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively, for a period of 12 weeks in Part 1. This was followed by the optimized dose BID, as determined by investigator in Part 1, for a period of 12 weeks in Part 2.

    Serious adverse events
    		 Placebo AG-348
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 39 (5.13%)
    4 / 40 (10.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Rib fracture
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Obstructive pancreatitis
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 40 (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
    Musculoskeletal pain
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo AG-348
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 39 (89.74%)
    35 / 40 (87.50%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 39 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    Hypertension
         subjects affected / exposed
    0 / 39 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 39 (10.26%)
    5 / 40 (12.50%)
         occurrences all number
    6
    5
    Influenza like illness
         subjects affected / exposed
    0 / 39 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Pyrexia
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Reproductive system and breast disorders
    Breast discomfort
         subjects affected / exposed
    0 / 39 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    4
    Dysmenorrhoea
         subjects affected / exposed
    3 / 39 (7.69%)
    1 / 40 (2.50%)
         occurrences all number
    6
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    4 / 39 (10.26%)
    3 / 40 (7.50%)
         occurrences all number
    4
    3
    Cough
         subjects affected / exposed
    2 / 39 (5.13%)
    3 / 40 (7.50%)
         occurrences all number
    2
    3
    Oropharyngeal pain
         subjects affected / exposed
    2 / 39 (5.13%)
    3 / 40 (7.50%)
         occurrences all number
    3
    4
    Nasal congestion
         subjects affected / exposed
    3 / 39 (7.69%)
    2 / 40 (5.00%)
         occurrences all number
    5
    3
    Rhinitis allergic
         subjects affected / exposed
    3 / 39 (7.69%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Epistaxis
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Psychiatric disorders
    Middle insomnia
         subjects affected / exposed
    3 / 39 (7.69%)
    3 / 40 (7.50%)
         occurrences all number
    18
    3
    Insomnia
         subjects affected / exposed
    0 / 39 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Initial insomnia
         subjects affected / exposed
    4 / 39 (10.26%)
    1 / 40 (2.50%)
         occurrences all number
    4
    1
    Stress
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 39 (15.38%)
    1 / 40 (2.50%)
         occurrences all number
    7
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 39 (7.69%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 39 (2.56%)
    2 / 40 (5.00%)
         occurrences all number
    1
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 39 (33.33%)
    6 / 40 (15.00%)
         occurrences all number
    19
    12
    Dizziness
         subjects affected / exposed
    3 / 39 (7.69%)
    4 / 40 (10.00%)
         occurrences all number
    4
    5
    Presyncope
         subjects affected / exposed
    1 / 39 (2.56%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    Paraesthesia
         subjects affected / exposed
    0 / 39 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    9 / 39 (23.08%)
    7 / 40 (17.50%)
         occurrences all number
    9
    11
    Diarrhoea
         subjects affected / exposed
    7 / 39 (17.95%)
    4 / 40 (10.00%)
         occurrences all number
    8
    4
    Abdominal pain
         subjects affected / exposed
    2 / 39 (5.13%)
    4 / 40 (10.00%)
         occurrences all number
    3
    4
    Abdominal distension
         subjects affected / exposed
    0 / 39 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    3
    Constipation
         subjects affected / exposed
    0 / 39 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Dyspepsia
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Abdominal pain upper
         subjects affected / exposed
    3 / 39 (7.69%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 39 (7.69%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Dermatitis acneiform
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Dry skin
         subjects affected / exposed
    1 / 39 (2.56%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 39 (7.69%)
    5 / 40 (12.50%)
         occurrences all number
    5
    5
    Arthralgia
         subjects affected / exposed
    2 / 39 (5.13%)
    4 / 40 (10.00%)
         occurrences all number
    5
    5
    Pain in extremity
         subjects affected / exposed
    3 / 39 (7.69%)
    2 / 40 (5.00%)
         occurrences all number
    4
    2
    Neck pain
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 39 (15.38%)
    5 / 40 (12.50%)
         occurrences all number
    9
    6
    Gastroenteritis
         subjects affected / exposed
    0 / 39 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    Urinary tract infection
         subjects affected / exposed
    3 / 39 (7.69%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 39 (10.26%)
    0 / 40 (0.00%)
         occurrences all number
    4
    0
    Oral herpes
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 39 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Feb 2018
    Removed dose escalation restrictions after the Week 8 Visit. • Added detailed guidance on re-introducing or escalating study treatment after resolution of a Grade 3 AE that caused study treatment to be stopped or reduced. • Removed the requirement that subjects must be receiving study treatment at Week 24 to be potentially eligible for an extension study. • Added an exclusion criterion to exclude subjects who have not stopped using haematopoietic stimulating agents at least 28 days before the first dose of study treatment. • Added clarity to the dose modification guidance for Grade 3 and Grade 4 AEs that are deemed by the Investigator to be related to study treatment. • Added new laboratory assessments for biomarkers (iron-related markers, known markers of erythropoietic activity, circulating haeme, and to be identified markers of iron metabolism or erythropoiesis).
    15 Aug 2018
    Consolidated iron-related secondary and exploratory endpoints into 1 exploratory endpoint for markers of iron metabolism. • Revised the instructions for dose optimisation. • Clarified that unblinding before database lock will occur only in the subjects who enter the planned mitapivat extension study and that subjects undergoing a dose taper should remain blinded through the taper. • Amended the inclusion criterion for renal function. • Amended the absolute neutrophil count (ANC) and platelet count inclusion criteria to be assessed via 2 measurements. • Amended the inclusion criterion for contraception requirements and added monthly pregnancy tests for applicable subjects. • Added an exception for subjects who have concurrent disorders that in isolation are predicted to be insufficient to explain the observed clinical phenotype to the exclusion criterion for congenital or genetic disorders. • Corrected the exclusion criterion for splenectomy to require subjects to wait at least 12 months after splenectomy before starting screening. • Added a subsection under Section 9.3, Blinding, to provide details on handling of restricted data and to add the role of an Independent Medical Monitor to handle restricted data. • Amended the unblinding language such that the unblinding of a subject for a medical emergency or pregnancy does not require confirmation by the Sponsor’s Medical Monitor. • Redefined the definition of Hb overshoot, and subsequent study treatment dose decrease, to higher than 20 g/L (2 g/dL) below the upper limit of normal (ULN). • Added historical data for iron chelation therapy, iron serum, transferrin saturation, and liver iron concentration (LIC) and removed some iron-related laboratory assessments. • Added further details for assessments after a transaminase increase
    14 Aug 2019
    Revised the dose optimisation language to allow dosing decisions to be based on results from local laboratories at the Week 4 and Week 8 Visit • Revised the inclusion criterion for platelet count • Increased the length of the contraception period for males exposed to study treatment to cover 1 complete spermatogenesis cycle • Revised the handling of restricted data such that the subject’s dose levels were no longer maintained as part of the restricted data and hormone data were considered restricted data for Investigators • Removed the option for a rapid dose taper and simplified the recommended gradual dose taper • Added language to provide previously ineligible subjects the opportunity to rescreen for enrollment into the study should they become eligible based on an amended protocol • Revised the requirements for clinical laboratory results, allowing Investigators the flexibility to use local laboratory results when results from central laboratories are not available • Added further details for assessments after a transaminase increase that meet the criteria for an AESI • Added ability to extend the Screening Period duration beyond 42 days

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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