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    Clinical Trial Results:
    A Phase 2, Randomized, Open Label Study of Bitopertin to Evaluate the Safety, Tolerability, Efficacy, and Protoporphyrin IX (PPIX) Concentrations in Participants with Erythropoietic Protoporphyria (EPP)

    Summary
    EudraCT number
    		 2025-000481-28
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    02 May 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jun 2026
    First version publication date
    11 Jun 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DISC-1459-202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Disc Medicine, Inc.
    Sponsor organisation address
    321 Arsenal Street, Suite 101, Watertown, MA, United States, 02472
    Public contact
    Disc Medicine Clinical Trials, Disc Medicine, Inc., +1 617-674-9274, info@discmedicine.com
    Scientific contact
    Disc Medicine Clinical Trials, Disc Medicine, Inc., +1 617-674-9274, medinfo@discmedicine.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMA/PE/0004390323
    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
    16 Dec 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 May 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To assess changes in protoporphyrin IX (PPIX) concentration in response to bitopertin treatment
    Protection of trial subjects
    This study was designed and monitored in accordance with sponsor procedures, which comply with the ethical principles of Good Clinical Practice (GCP) as required by the major regulatory authorities, and in accordance with the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 26
    Worldwide total number of subjects
    26
    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)
    0
    Adolescents (12-17 years)
    4
    Adults (18-64 years)
    20
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 2 sites in Australia. Up to 22 participants, aged 12 years and older, were initially planned to be enrolled. Up to 55 participants ≥12 years of age could have been enrolled if additional cohorts were added.

    Pre-assignment
    Screening details
    		 Potential participants were screened for eligibility within 28 days of randomization. During screening, all potential participants underwent a light tolerance assessment that included a diary assessment of historical light tolerance and maximal direct sunlight tolerance time until phototoxic prodrome during 1 day/week over 2-week run-in period.

    Period 1
    Period 1 title
    Treatment phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bitopertin 20 mg
    Arm description
    		 Adult subjects (N=11) enrolled in Bitopertin 20 mg received two 10-mg tablets of Bitopertin from Day 1. Adolescent subjects (N=3) enrolled in the same treatment arm were started on 50% of the randomized dose (i.e., bitopertin 10 mg), and on Day 15 (±2 days), were dose-escalated to receive the randomized dose of 20 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    DISC-1459
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received oral bitopertin (20 mg) once daily (QD) for 24 weeks (168 days).

    Arm title
    		 Bitopertin 60 mg
    Arm description
    		 Adult subjects (N=11) enrolled in Bitopertin 60 mg received two 30-mg tablets of Bitopertin from Day 1. Adolescent subjects (N=1) in the same treatment arm were started on 50% of the randomized dose (i.e., bitopertin 30 mg), and on Day 15 (±2 days), were dose-escalated to receive the randomized dose of 60 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    DISC-1459
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received oral bitopertin (60 mg) once daily (QD) for 24 weeks (168 days).

    Number of subjects in period 1
    		Bitopertin 20 mg Bitopertin 60 mg
    Started
    14
    12
    Completed
    13
    12
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -
    Period 2
    Period 2 title
    Extension phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bitopertin 20 mg
    Arm description
    		 Subjects enrolled in Bitopertin 20 mg received two 10-mg tablets of Bitopertin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    DISC-1459
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received oral bitopertin (20 mg) once daily (QD) for additional 24 weeks, or up to 1 year of total treatment from Day 1.

    Arm title
    		 Bitopertin 60 mg
    Arm description
    		 Subjects enrolled in Bitopertin 60 mg received two 30-mg tablets of Bitopertin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    DISC-1459
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received oral bitopertin (60 mg) once daily (QD) for additional 24 weeks, or up to 1 year of total treatment from Day 1.

    Number of subjects in period 2 [1]
    		Bitopertin 20 mg Bitopertin 60 mg
    Started
    7
    7
    Completed
    0
    1
    Not completed
    7
    6
         Consent withdrawn by subject
    2
    1
         Rolled over to DISC-1459-501 study
    5
    4
         Lost to follow-up
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: As per the protocol, after completing the treatment period, the participant could enter the extension period. Based on this, in the extension phase of the study, oral bitopertin was evaluated in 7 adult participants in each of the 20 mg and 60 mg arms.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bitopertin 20 mg
    Reporting group description
    		 Adult subjects (N=11) enrolled in Bitopertin 20 mg received two 10-mg tablets of Bitopertin from Day 1. Adolescent subjects (N=3) enrolled in the same treatment arm were started on 50% of the randomized dose (i.e., bitopertin 10 mg), and on Day 15 (±2 days), were dose-escalated to receive the randomized dose of 20 mg.

    Reporting group title
    Bitopertin 60 mg
    Reporting group description
    		 Adult subjects (N=11) enrolled in Bitopertin 60 mg received two 30-mg tablets of Bitopertin from Day 1. Adolescent subjects (N=1) in the same treatment arm were started on 50% of the randomized dose (i.e., bitopertin 30 mg), and on Day 15 (±2 days), were dose-escalated to receive the randomized dose of 60 mg.

    Reporting group values
    		 Bitopertin 20 mg Bitopertin 60 mg Total
    Number of subjects
    		 14 12 26
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 3 1 4
        Adults (18-64 years)
    		 10 10 20
        From 65-84 years
    		 1 1 2
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.0 ( 19.53 ) 42.0 ( 16.25 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 8 16
        Male
    		 6 4 10
    Race
    Units: Subjects
        White
    		 14 11 25
        Asian
    		 0 1 1
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 14 12 26
    Time to prodrome
    Units: Subjects
        <30 minutes
    		 7 6 13
        ≥30 minutes
    		 7 6 13
    Erythropoietic protoporphyria/X-linked protoporphyria Subgroup
    Units: Subjects
        Erythropoietic protoporphyria
    		 14 11 25
        X-linked protoporphyria
    		 0 1 1
    Weight
    Units: Kg
        arithmetic mean (standard deviation)
    		 78.09 ( 12.745 ) 79.50 ( 21.017 ) -
    BMI
    Units: Kg/m^2
        arithmetic mean (standard deviation)
    		 27.45 ( 4.753 ) 27.78 ( 8.414 ) -
    Whole Blood Metal-Free PPIX
    Units: ng/mL
        arithmetic mean (standard deviation)
    		 10337.9 ( 7303.43 ) 8143.8 ( 6505.42 ) -
    Whole Blood Total PPIX
    Units: ng/mL
        arithmetic mean (standard deviation)
    		 10947.54 ( 7336.749 ) 9116.00 ( 6653.471 ) -
    Plasma PPIX
    Baseline plasma PPIX levels were available for all 14 subjects in the bitopertin 20-mg arm and 11 of 12 subjects in the bitopertin 60-mg arm.
    Units: ng/mL
        arithmetic mean (standard deviation)
    		 994.89 ( 634.764 ) 671.68 ( 454.607 ) -

    End points

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    End points reporting groups
    Reporting group title
    Bitopertin 20 mg
    Reporting group description
    		 Adult subjects (N=11) enrolled in Bitopertin 20 mg received two 10-mg tablets of Bitopertin from Day 1. Adolescent subjects (N=3) enrolled in the same treatment arm were started on 50% of the randomized dose (i.e., bitopertin 10 mg), and on Day 15 (±2 days), were dose-escalated to receive the randomized dose of 20 mg.

    Reporting group title
    Bitopertin 60 mg
    Reporting group description
    		 Adult subjects (N=11) enrolled in Bitopertin 60 mg received two 30-mg tablets of Bitopertin from Day 1. Adolescent subjects (N=1) in the same treatment arm were started on 50% of the randomized dose (i.e., bitopertin 30 mg), and on Day 15 (±2 days), were dose-escalated to receive the randomized dose of 60 mg.
    Reporting group title
    Bitopertin 20 mg
    Reporting group description
    		 Subjects enrolled in Bitopertin 20 mg received two 10-mg tablets of Bitopertin

    Reporting group title
    Bitopertin 60 mg
    Reporting group description
    		 Subjects enrolled in Bitopertin 60 mg received two 30-mg tablets of Bitopertin

    Primary: Percent change from baseline in whole blood metal-free PPIX levels

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    End point title
    		 Percent change from baseline in whole blood metal-free PPIX levels
    End point description
    End point type
    Primary
    End point timeframe
    At Day 169
    End point values
    		 Bitopertin 20 mg Bitopertin 60 mg
    Number of subjects analysed
    12
    11
    Units: Percentage
        least squares mean (standard error)
    -31.7 ( 6.98 )
    -57.7 ( 7.40 )
    Statistical analysis title
    		 Mixed Model Repeated Measures (MMRM) Model
    Statistical analysis description
    For the MMRM model, the dependent variable was the percentage change from baseline whole blood metal-free PPIX level for all post-baseline assessments for each participant. The model included fixed effects for treatment, randomization stratification factor, baseline whole blood metal-free PPIX level, visit, and visit-by treatment interaction and a random effect for the participant. The model was fit using restricted maximum likelihood estimation with the Kenward-Roger method.
    Comparison groups
    Bitopertin 20 mg v Bitopertin 60 mg
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.018
    Method
    		 t-test, 2-sided
    Parameter type
    		 LS Mean Difference
    Point estimate
    -26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -47.16
         upper limit
    		 -4.902
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.21

    Secondary: Total hours of direct sunlight exposure to skin on days with no pain from 1000 to 1800 hours (10:00 AM to 6:00 PM)

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    End point title
    		 Total hours of direct sunlight exposure to skin on days with no pain from 1000 to 1800 hours (10:00 AM to 6:00 PM)
    End point description
    End point type
    Secondary
    End point timeframe
    At Day 169
    End point values
    		 Bitopertin 20 mg Bitopertin 60 mg
    Number of subjects analysed
    14
    12
    Units: Hours
        least squares mean (standard error)
    186.01 ( 33.51 )
    209.85 ( 36.20 )
    Statistical analysis title
    		 Analysis of variance (ANOVA) Model
    Statistical analysis description
    An ANOVA model was used for the ITT Analysis Set with effects for randomized dose group and the sunlight exposure time to prodromal symptom randomization stratification factor. The model was used to estimate the mean total hours of sunlight exposure on days with no pain from 1000 to 1800 hours (10:00 AM to 6:00 PM) summed over the entire treatment period from randomization to Day 169 for the dose groups.
    Comparison groups
    Bitopertin 20 mg v Bitopertin 60 mg
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.633
    Method
    		 t-test, 2-sided
    Parameter type
    		 LS Mean Difference
    Point estimate
    23.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -78.2
         upper limit
    		 125.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    49.33

    Secondary: Maximum and average total daily pain intensity scores of phototoxic reactions

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    End point title
    		 Maximum and average total daily pain intensity scores of phototoxic reactions
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 169
    End point values
    		 Bitopertin 20 mg Bitopertin 60 mg
    Number of subjects analysed
    6
    6
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Maximum pain
    4.7 ( 3.08 )
    4.2 ( 1.33 )
        Average daily pain
    11.3 ( 11.96 )
    5.0 ( 1.10 )
    No statistical analyses for this end point

    Secondary: Change in 2-week average daily exposure time to first prodromal symptom (collected during weekly sunlight exposure challenges)

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    End point title
    		 Change in 2-week average daily exposure time to first prodromal symptom (collected during weekly sunlight exposure challenges)
    End point description
    Two (2)-week averages of daily sunlight exposure time prior to first prodromal symptom (e.g., burning, tingling, itching, or stinging) associated with sunlight exposure between 1 hour post-sunrise and 1 hour pre-sunset were calculated for the two weeks immediately prior to randomization and for the treatment period from randomization to Day 169 visit, for each participant.
    End point type
    Secondary
    End point timeframe
    Day 155 to Day 168
    End point values
    		 Bitopertin 20 mg Bitopertin 60 mg
    Number of subjects analysed
    10
    8
    Units: Hours
        least squares mean (standard error)
    75.78 ( 28.35 )
    148.23 ( 31.52 )
    Statistical analysis title
    		 Mixed-Model Repeated Measures (MMRM) Model
    Statistical analysis description
    The main analysis for this endpoint was based on the mean change from baseline in 2-week average daily exposure time to first prodromal symptom over time, analyzed using a MMRM approach, with 2-week time points being used.
    Comparison groups
    Bitopertin 20 mg v Bitopertin 60 mg
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.095
    Method
    		 t-test, 2-sided
    Parameter type
    		 LS Mean Difference
    Point estimate
    72.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.18
         upper limit
    		 158.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    42.65

    Secondary: Percent change from baseline for erythrocyte metal-free PPIX concentrations

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    End point title
    		 Percent change from baseline for erythrocyte metal-free PPIX concentrations
    End point description
    End point type
    Secondary
    End point timeframe
    At Day 169
    End point values
    		 Bitopertin 20 mg Bitopertin 60 mg
    Number of subjects analysed
    9
    6
    Units: Percentage
        least squares mean (standard error)
    -31.1 ( 6.95 )
    -61.6 ( 7.90 )
    Statistical analysis title
    		 Mixed-Model Repeated Measures (MMRM) Model
    Statistical analysis description
    The PPIX concentrations were converted into percent change from baseline for analysis.
    Comparison groups
    Bitopertin 20 mg v Bitopertin 60 mg
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.008
    Method
    		 t-test, 2-sided
    Parameter type
    		 LS Mean Difference
    Point estimate
    -30.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -52.34
         upper limit
    		 -8.688
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.74

    Secondary: Percent change from baseline for total whole blood PPIX concentrations

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    End point title
    		 Percent change from baseline for total whole blood PPIX concentrations
    End point description
    End point type
    Secondary
    End point timeframe
    At Day 169
    End point values
    		 Bitopertin 20 mg Bitopertin 60 mg
    Number of subjects analysed
    9
    7
    Units: Percentage
        least squares mean (standard error)
    -27.2 ( 5.64 )
    -56.5 ( 6.05 )
    Statistical analysis title
    		 Mixed-Model Repeated Measures (MMRM) Model
    Statistical analysis description
    The PPIX concentrations were converted into percent change from baseline for analysis.
    Comparison groups
    Bitopertin 20 mg v Bitopertin 60 mg
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.002
    Method
    		 t-test, 2-sided
    Parameter type
    		 LS Mean Difference
    Point estimate
    -29.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -46.53
         upper limit
    		 -12.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.3

    Secondary: Percent change from baseline for total plasma PPIX concentrations

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    End point title
    		 Percent change from baseline for total plasma PPIX concentrations
    End point description
    End point type
    Secondary
    End point timeframe
    At Day 169
    End point values
    		 Bitopertin 20 mg Bitopertin 60 mg
    Number of subjects analysed
    9
    6
    Units: Percentage
        least squares mean (standard error)
    -37.4 ( 10.65 )
    -47.2 ( 11.82 )
    Statistical analysis title
    		 Mixed-Model Repeated Measures (MMRM) Model
    Statistical analysis description
    The PPIX concentrations were converted into percent change from baseline for analysis.
    Comparison groups
    Bitopertin 60 mg v Bitopertin 20 mg
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.547
    Method
    		 t-test, 2-sided
    Parameter type
    		 LS Mean Difference
    Point estimate
    -9.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -43.42
         upper limit
    		 23.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    16

    Secondary: Maximum plasma concentration (Cmax) following single oral administrations of bitopertin in adolescents

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    End point title
    		 Maximum plasma concentration (Cmax) following single oral administrations of bitopertin in adolescents
    End point description
    Pharmacokinetic (PK) parameters were evaluated on Day 1 when the adolescents were on half the randomized dose (i.e., 10 mg and 30 mg). From Day 15 (±2 days), adolescent participants were dose-escalated to receive the randomized doses of 20 mg and 60 mg. Hence, PK data evaluated for adolescents is after administration of bitopertin at the doses of 10 and 30 mg. Note: Considering only one subject was evaluable in the bitopertin 60-mg arm, range (min-max) is selected as the precision/dispersion type.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Bitopertin 20 mg Bitopertin 60 mg
    Number of subjects analysed
    3
    1
    Units: ng/mL
        arithmetic mean (full range (min-max))
    65.2 (52.2 to 81.3)
    145 (145 to 145)
    No statistical analyses for this end point

    Secondary: Observed time of the maximum drug concentration (Tmax) following single oral administrations of bitopertin in adolescents

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    End point title
    		 Observed time of the maximum drug concentration (Tmax) following single oral administrations of bitopertin in adolescents
    End point description
    Pharmacokinetic (PK) parameters were evaluated on Day 1 when the adolescents were on half the randomized dose (i.e., 10 mg and 30 mg). From Day 15 (±2 days), adolescent participants were dose-escalated to receive the randomized doses of 20 mg and 60 mg. Hence, PK data evaluated for adolescents is after administration of bitopertin at the doses of 10 and 30 mg. Note: Considering only one subject was evaluable in the bitopertin 60-mg arm, range (min-max) is selected as the precision/dispersion type.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Bitopertin 20 mg Bitopertin 60 mg
    Number of subjects analysed
    3
    1
    Units: Hours
        arithmetic mean (full range (min-max))
    1.87 (1.75 to 1.97)
    4.08 (4.08 to 4.08)
    No statistical analyses for this end point

    Secondary: AUC from time 0 to 24 hours post-dose on Day 1 (AUC0-24) in adolescents

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    End point title
    		 AUC from time 0 to 24 hours post-dose on Day 1 (AUC0-24) in adolescents
    End point description
    Pharmacokinetic (PK) parameters were evaluated on Day 1 when the adolescents were on half the randomized dose (i.e., 10 mg and 30 mg). From Day 15 (±2 days), adolescent participants were dose-escalated to receive the randomized doses of 20 mg and 60 mg. Hence, PK data evaluated for adolescents is after administration of bitopertin at the doses of 10 and 30 mg. Note: Considering only one subject was evaluable in the bitopertin 60-mg arm, range (min-max) is selected as the precision/dispersion type.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Bitopertin 20 mg Bitopertin 60 mg
    Number of subjects analysed
    3
    1
    Units: ng*h/mL
        arithmetic mean (full range (min-max))
    693 (530 to 970)
    2570 (2570 to 2570)
    No statistical analyses for this end point

    Secondary: Plasma bitopertin concentrations in adolescents at Day 1

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    End point title
    		 Plasma bitopertin concentrations in adolescents at Day 1
    End point description
    Plasma bitopertin concentration was evaluated on Day 1 when the adolescents were on half the randomized dose (i.e., 10 mg and 30 mg). From Day 15 (±2 days), adolescent participants were dose-escalated to receive the randomized doses of 20 mg and 60 mg. Hence, plasma bitopertin concentration on Day 1, for adolescents, is after administration of bitopertin at the doses of 10 and 30 mg. Note: Considering only one subject was evaluable in the bitopertin 60-mg arm, range (min-max) is selected as the precision/dispersion type.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Bitopertin 20 mg Bitopertin 60 mg
    Number of subjects analysed
    3
    1
    Units: ng/mL
    arithmetic mean (full range (min-max))
        0 h
    0.00 (0.00 to 0.00)
    0.00 (0.00 to 0.00)
        2 h
    65.2 (52.2 to 81.3)
    135 (135 to 135)
        4 h
    41.2 (29.4 to 60.1)
    145 (145 to 145)
        6 h
    31.9 (23.2 to 47.0)
    121 (121 to 121)
        24 h
    16.4 (11.6 to 22.2)
    77.9 (77.9 to 77.9)
    No statistical analyses for this end point

    Secondary: Plasma bitopertin concentrations in adolescents at Day 29

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    End point title
    		 Plasma bitopertin concentrations in adolescents at Day 29
    End point description
    Note: Considering only one subject was evaluable in the bitopertin 60-mg arm, range (min-max) is selected as the precision/dispersion type.
    End point type
    Secondary
    End point timeframe
    Day 29
    End point values
    		 Bitopertin 20 mg Bitopertin 60 mg
    Number of subjects analysed
    3 [1]
    1
    Units: ng/mL
    arithmetic mean (full range (min-max))
        0 h
    112 (82.2 to 142)
    461 (461 to 461)
        4 h
    191 (121 to 228)
    640 (640 to 640)
    Notes
    [1] - There were 2 subjects evaluated at the 0 h timepoint and 3 subjects evaluated at 4 h timepoint.
    No statistical analyses for this end point

    Secondary: Maximum plasma concentration (Cmax) following single oral administrations of bitopertin in adults

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    End point title
    		 Maximum plasma concentration (Cmax) following single oral administrations of bitopertin in adults
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Bitopertin 20 mg Bitopertin 60 mg
    Number of subjects analysed
    11
    11
    Units: ng/mL
        arithmetic mean (standard deviation)
    126 ( 25.6 )
    286 ( 88.3 )
    No statistical analyses for this end point

    Secondary: Observed time of the maximum drug concentration (Tmax) following single oral administrations of bitopertin in adults

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    End point title
    		 Observed time of the maximum drug concentration (Tmax) following single oral administrations of bitopertin in adults
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Bitopertin 20 mg Bitopertin 60 mg
    Number of subjects analysed
    11
    11
    Units: Hours
        arithmetic mean (standard deviation)
    4.15 ( 6.56 )
    2.49 ( 1.28 )
    No statistical analyses for this end point

    Secondary: AUC from time 0 to 24 hours post-dose on Day 1 (AUC0-24) in adults

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    End point title
    		 AUC from time 0 to 24 hours post-dose on Day 1 (AUC0-24) in adults
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Bitopertin 20 mg Bitopertin 60 mg
    Number of subjects analysed
    11
    11
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    1570 ( 406 )
    3900 ( 1330 )
    No statistical analyses for this end point

    Secondary: Plasma bitopertin concentrations in adults at Day 1

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    End point title
    		 Plasma bitopertin concentrations in adults at Day 1
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Bitopertin 20 mg Bitopertin 60 mg
    Number of subjects analysed
    11
    11
    Units: ng/mL
    arithmetic mean (standard deviation)
        0 h
    0.00 ( 0.00 )
    0.00 ( 0.00 )
        2 h
    123 ( 22.9 )
    279 ( 90.8 )
        4 h
    90.1 ( 23.2 )
    218 ( 72.0 )
        6 h
    71.5 ( 22.3 )
    195 ( 73.3 )
        24 h
    47.3 ( 38.8 )
    107 ( 33.6 )
    No statistical analyses for this end point

    Secondary: Plasma bitopertin concentrations in adults at Day 29

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    End point title
    		 Plasma bitopertin concentrations in adults at Day 29
    End point description
    End point type
    Secondary
    End point timeframe
    Day 29
    End point values
    		 Bitopertin 20 mg Bitopertin 60 mg
    Number of subjects analysed
    11 [2]
    11 [3]
    Units: ng/mL
    arithmetic mean (standard deviation)
        0 h
    152 ( 63.8 )
    531 ( 335 )
        4 h
    249 ( 72.0 )
    770 ( 309 )
    Notes
    [2] - There were 11 subjects evaluated at the 0 h timepoint and 10 subjects evaluated at 4 h timepoint.
    [3] - There were 11 subjects evaluated at the 0 h timepoint and 8 subjects evaluated at 4 h timepoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment phase (Up to and including Day 169)
    Adverse event reporting additional description
    All safety analyses were based on the Safety Analysis Set (SAS), defined as all randomized participants who received at least one dose of study drug. Treatment-emergent AEs that began after the first administration of study drug, or existing AEs that worsened after the first dose of study drug were considered TEAEs and were analyzed.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Bitopertin 20 mg
    Reporting group description
    		 Subjects enrolled in Bitopertin 20 mg received two 10-mg tablets of Bitopertin

    Reporting group title
    Bitopertin 60 mg
    Reporting group description
    		 Subjects enrolled in Bitopertin 60 mg will receive two 30-mg tablets of Bitopertin

    Serious adverse events
    		 Bitopertin 20 mg Bitopertin 60 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bitopertin 20 mg Bitopertin 60 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 14 (85.71%)
    12 / 12 (100.00%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Peripheral Swelling
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Menstruation Irregular
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Ovarian Cyst Ruptured
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Suicidal Ideation
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 14 (64.29%)
    8 / 12 (66.67%)
         occurrences all number
    11
    8
    Headache
         subjects affected / exposed
    3 / 14 (21.43%)
    1 / 12 (8.33%)
         occurrences all number
    3
    1
    Cluster Headache
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Disturbance In Attention
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Dizziness Exertional
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Migraine
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Presyncope
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Sinus Headache
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Photophobia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 12 (16.67%)
         occurrences all number
    1
    2
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Lip Dry
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Toothache
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Decubitus Ulcer
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Myofascial Pain Syndrome
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Diverticulitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Tooth Infection
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Iron Deficiency
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Apr 2023
    Primary endpoint updated to include whole blood metal free-PPIX levels. Secondary endpoints were updated to Erythrocyte metal-free PPIX concentrations, plasma and whole blood total PPIX concentrations and porphyrins (metal-free whole blood PPIX, metal-free erythrocyte PPIX, whole blood total PPIX, plasma total PPIX). Changes were made regarding porphyrin assessment schedule in alignment with the schedule of assessments (SoA). Information clarified for prohibited iron medications to state that the initiation of iron supplementation (oral or intravenous) during screening or the study was disallowed. Text updated to indicate that RDW, reticulocyte %, and reticulocyte hemoglobin concentration were optional. Remote visits in text and SoA clarified. Additional language added to further describe study rationale and dose-selection rationale in adolescents. Age of adolescents revised to 12 for inclusion in the study. Inclusion criteria revised for the inclusion of adolescent participants and adjusted weight restrictions. Exclusion criteria were revised that new treatment for anemia, including initiation of iron supplementation within the 2 months prior to screening was exclusionary and to exclude any type of active hepatitis and clarify HIV status. Information on dosing schedule for adolescents added. Patient Global Impression of Severity (PGIS) added as one of the exploratory endpoints and protocol updated to include the description of PGIS assessment to the patient reported outcome section. Information updated to include “optional” for blood samples for 3 hematology assessments. Text updated to clarify that clinical laboratory samples were to be analyzed at a local laboratory, and that fasting was only required for blood sample for iron studies. Protocol was updated to include percentage of adolescents and adults to all analysis sets. Additional collection timepoints added for bodyweight/height. Information updated to clarify the dispense of the drug diary.

    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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