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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Brexpiprazole in Treatment of Children and Adolescents With Irritability Associated With Autism Spectrum Disorder

    Summary
    EudraCT number
    		 2019-000723-40
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    09 Sep 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Oct 2024
    First version publication date
    24 Oct 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    331-201-00148
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04174365
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    Sponsor organisation address
    2440 Research Boulevard, Rockville, United States, 20850
    Public contact
    Krista Martinko, Otsuka Pharmaceutical Development & Commercialization, Inc., 1 8446878522, clinicaltransparency@otsuka-us.com
    Scientific contact
    Krista Martinko, Otsuka Pharmaceutical Development & Commercialization, Inc., 1 8446878522, clinicaltransparency@otsuka-us.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 Sep 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to find out about the potential benefits and safety of brexpiprazole in children and adolescent subjects, aged 5 to 17, with irritability associated with autism spectrum disorder.
    Protection of trial subjects
    Written informed consent, assent, or both were obtained from a legally acceptable representative (eg, guardian) or from the subject.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Oct 2019
    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
    United States: 119
    Worldwide total number of subjects
    119
    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)
    86
    Adolescents (12-17 years)
    33
    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
    		 Subjects took part in the study at 40 sites in the United States from 30 October 2019 to 9 September 2022.

    Pre-assignment
    Screening details
    		 A total of 260 subjects were screened, of which 119 subjects were randomised to receive brexpiprazole or placebo.

    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
    		 Brexpiprazole
    Arm description
    		 Subjects received flexible doses of brexpiprazole 0.25 to 3 milligram per day (mg/day), orally, once daily (QD) up to Week 8. For subjects with body weight < 50 kilograms (kg) the dose was titrated up from 0.25 mg/day on Days 1 to 3, followed by 0.5 mg on Days 4 to 7, and to 1 mg on Days 8 to 14. Based on the investigator’s judgment the dose was increased to 1.5 mg/day after Day 15. The dose was fixed after Week 6 and administration continued for another 2 weeks until Week 8. For subjects with body weight ≥ 50 kg the dose was titrated up from 0.5 mg/day on Days 1 to 3, followed by 1.5 mg on Days 4 to 7, and to 2 mg on Days 8 to 14. Based on the investigator’s judgment the dose was increased to 3 mg/day after Day 15. The dose was fixed after Week 6 and administration continued for another 2 weeks until Week 8.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    OPC-34712
    Other name
    LuAF41156
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Brexpiprazole tablets, flexible dosing from 0.25 to 3 mg/day administered orally up to Week 8.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received brexpiprazole matching placebo orally, QD, in the same way as brexpiprazole up to Week 8.
    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
    Brexpiprazole matching placebo tablets were administered orally up to Week 8.

    Number of subjects in period 1
    		Brexpiprazole Placebo
    Started
    60
    59
    Randomised Sample
    60
    59
    Safety Sample
    58
    57
    Efficacy Sample
    58
    56
    Completed
    52
    52
    Not completed
    8
    7
         Disease Relapse
    1
    -
         Adverse Event
    2
    1
         Reason Not Specified
    -
    1
         Lost to follow-up
    1
    2
         Subject Withdrew Consent To Participate
    1
    -
         Subject Was Withdrawn From Participation By Parent
    2
    1
         Protocol deviation
    1
    -
         Lack of efficacy
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brexpiprazole
    Reporting group description
    		 Subjects received flexible doses of brexpiprazole 0.25 to 3 milligram per day (mg/day), orally, once daily (QD) up to Week 8. For subjects with body weight < 50 kilograms (kg) the dose was titrated up from 0.25 mg/day on Days 1 to 3, followed by 0.5 mg on Days 4 to 7, and to 1 mg on Days 8 to 14. Based on the investigator’s judgment the dose was increased to 1.5 mg/day after Day 15. The dose was fixed after Week 6 and administration continued for another 2 weeks until Week 8. For subjects with body weight ≥ 50 kg the dose was titrated up from 0.5 mg/day on Days 1 to 3, followed by 1.5 mg on Days 4 to 7, and to 2 mg on Days 8 to 14. Based on the investigator’s judgment the dose was increased to 3 mg/day after Day 15. The dose was fixed after Week 6 and administration continued for another 2 weeks until Week 8.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received brexpiprazole matching placebo orally, QD, in the same way as brexpiprazole up to Week 8.

    Reporting group values
    		 Brexpiprazole Placebo Total
    Number of subjects
    		 60 59 119
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.8 ( 2.9 ) 10.0 ( 3.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 9 15
        Male
    		 54 50 104
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 8 7 15
        Not Hispanic or Latino
    		 52 52 104
        Unknown or Not Reported
    		 0 0 0
    Race
    Units: Subjects
        White
    		 49 45 94
        Black or African American
    		 3 10 13
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 2 3 5
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Other
    		 5 1 6

    End points

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    End points reporting groups
    Reporting group title
    Brexpiprazole
    Reporting group description
    		 Subjects received flexible doses of brexpiprazole 0.25 to 3 milligram per day (mg/day), orally, once daily (QD) up to Week 8. For subjects with body weight < 50 kilograms (kg) the dose was titrated up from 0.25 mg/day on Days 1 to 3, followed by 0.5 mg on Days 4 to 7, and to 1 mg on Days 8 to 14. Based on the investigator’s judgment the dose was increased to 1.5 mg/day after Day 15. The dose was fixed after Week 6 and administration continued for another 2 weeks until Week 8. For subjects with body weight ≥ 50 kg the dose was titrated up from 0.5 mg/day on Days 1 to 3, followed by 1.5 mg on Days 4 to 7, and to 2 mg on Days 8 to 14. Based on the investigator’s judgment the dose was increased to 3 mg/day after Day 15. The dose was fixed after Week 6 and administration continued for another 2 weeks until Week 8.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received brexpiprazole matching placebo orally, QD, in the same way as brexpiprazole up to Week 8.

    Primary: Mean Change From Baseline to Week 8 in Aberrant Behavior Checklist - Irritability (ABC-I) Subscale Score

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    End point title
    		 Mean Change From Baseline to Week 8 in Aberrant Behavior Checklist - Irritability (ABC-I) Subscale Score
    End point description
    ABC, a parent-reported scale evaluates treatment effects on problem behavior in subjects with intellectual disabilities. ABC scale has 58 items, divided in 5 subscales Irritability, Agitation; Lethargy, Social Withdrawal; Stereotypic Behavior; Hyperactivity, Noncompliance; & Inappropriate Speech. Each of 58 ABC items is rated on 4-point scale from 0=not at all a problem to 3=problem is severe in degree. ABC-I measures emotional & behavioral symptoms of ASD. ABC-I total score is sum of ratings over 15 ABC items. Individual scores were summed, thus ABC-I total score ranges from 0 to 45. Higher scores=worst condition.Negative change from baseline indicates improvement. Efficacy sample:all randomised subjects who took at least 1 dose of brexpiprazole or placebo & had baseline & at least 1 post-baseline assessment of primary efficacy variable ABC-I subscale score during double-blind treatment phase. Number of subjects analysed indicates number of subjects with data available for analysis.
    End point type
    Primary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Brexpiprazole Placebo
    Number of subjects analysed
    48
    46
    Units: score on a scale
        least squares mean (standard error)
    -10.1 ( 1.28 )
    -8.87 ( 1.25 )
    Statistical analysis title
    		 Brexpiprazole, Placebo
    Comparison groups
    Brexpiprazole v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4597 [1]
    Method
    		 Mixed model repeated measures (MMRM)
    Parameter type
    		 Least squares (LS) mean Difference
    Point estimate
    -1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.49
         upper limit
    		 2.05
    Notes
    [1] - MMRM method with model terms: treatment, trial site, baseline body weight stratum, visit, treatment-by-visit and baseline-by-visit interaction.

    Secondary: Mean Change From Baseline to Week 8 in Clinical Global Impression - Severity (CGI-S) Score

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    End point title
    		 Mean Change From Baseline to Week 8 in Clinical Global Impression - Severity (CGI-S) Score
    End point description
    The CGI-S is a 7-point clinician rated scale to assess severity of subject's current illness state with a focus on symptoms of irritability. The investigator (or rater) answered the following question: "Considering your total clinical experience with this particular population, how ill was the subject at this time with regard to symptoms of irritability? Response choices were from 1 (normal - not ill at all) to 7 (among the most extremely ill patients). Higher score = more severe illness. A negative change from baseline indicates improvement. Efficacy sample included all randomised subjects who took at least 1 dose of brexpiprazole or placebo and had baseline and at least 1 post-baseline assessment of the primary efficacy variable ABC-I subscale score during the double-blind treatment phase. Number of subjects analysed indicates the number of subjects with data available for analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Brexpiprazole Placebo
    Number of subjects analysed
    50
    46
    Units: score on a scale
        least squares mean (standard error)
    -1.16 ( 0.15 )
    -1.09 ( 0.15 )
    Statistical analysis title
    		 Brexpiprazole, Placebo
    Comparison groups
    Brexpiprazole v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7315 [2]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 0.32
    Notes
    [2] - MMRM method with model terms: treatment, trial site, baseline body weight stratum, visit, treatment-by-visit and baseline-by-visit interaction.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose through 21 (±2) days after last dose of study drug (up to approximately Week 11)
    Adverse event reporting additional description
    Safety sample included all enrolled subjects who received at least 1 dose of brexpiprazole or placebo.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Brexpiprazole
    Reporting group description
    		 Subjects received flexible doses of brexpiprazole 0.25 to 3 mg/day, orally, QD up to Week 8. For subjects with body weight < 50 kg the dose was titrated up from 0.25 mg/day on Days 1 to 3, followed by 0.5 mg on Days 4 to 7, and to 1 mg on Days 8 to 14. Based on the investigator’s judgment the dose was increased to 1.5 mg/day after Day 15. The dose was fixed after Week 6 and administration continued for another 2 weeks until Week 8. For subjects with body weight ≥ 50 kg the dose was titrated up from 0.5 mg/day on Days 1 to 3, followed by 1.5 mg on Days 4 to 7, and to 2 mg on Days 8 to 14. Based on the investigator’s judgment the dose was increased to 3 mg/day after Day 15. The dose was fixed after Week 6 and administration continued for another 2 weeks until Week 8.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received brexpiprazole matching placebo orally, QD, in the same way as brexpiprazole up to Week 8.

    Serious adverse events
    		 Brexpiprazole Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (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
    		 Brexpiprazole Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 58 (22.41%)
    5 / 57 (8.77%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 58 (10.34%)
    1 / 57 (1.75%)
         occurrences all number
    7
    2
    Somnolence
         subjects affected / exposed
    7 / 58 (12.07%)
    3 / 57 (5.26%)
         occurrences all number
    8
    3
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 57 (1.75%)
         occurrences all number
    4
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Aug 2019
    -Revised Week 2 visit to occur in-clinic. -Clarified caregiver and subject interacting for virtual visit. -Clarifications provided for details around urogenital assessment, procedures on clinical laboratory tests at screening and use of propanolol. -Visits were adjusted for prolactin, clinical laboratory tests, electrocardiogram (ECG), extrapyramidal symptoms (EPS) scales, thyroid stimulating hormone (TSH), and coagulation assessments. -Clarification provided that ECGs done at screening do not need to be repeated if within normal ranges. -The pharmacogenomic and future biospecimen research (FBR) sampling should be taken with pharmacokinetic (PK) draws. -Added additional tests under hematology assessments. -Washout days updated for washout medications. -Revised the appendices and corresponding protocol sections containing normal ranges for glucose levels, TSH, free thyroxine (T4), prothrombin time, activated partial thromboplastin time, and international normalized ratio.
    22 Nov 2019
    - Added bicarbonate to the laboratory tests at screening, baseline, and Week 8. Parameters and criteria also added to Appendix 2.
    12 Feb 2020
    - Revised lower limit of adolescent systolic blood pressure. - Revised glycosylated hemoglobin laboratory value of potential relevance. - Added assessments and laboratory value of potential relevance for adrenocorticotropic hormone and cortisol.
    06 Jul 2020
    - A COVID-19 Addendum was introduced for any protocol specified activities that are not able to be performed or cannot be performed due to COVID-19 considerations. - Corrected PK parameter values in the Introduction. - Excluded the simultaneous participation of siblings or unrelated members of the same residence. - Stated that the Kiddie-Schedule for Affective Disorders and Schizophrenia - Present and Lifetime version (K-SADS-PL) does not need to be repeated at the screening visit for subjects that are rescreened. - Allowed for the extension of the screening period to accommodate repeating clinical laboratory tests or ECGs.
    07 Jul 2022
    - Revised the treatment effect assumption from 5.5 to 6.0, resulting in a new sample size of 102 randomised subjects. - Allowed in clinic visits in lieu of virtual visits if investigators and caregivers feel that an in person visit may be more appropriate. This change reflects feedback/requests from the trial site staff and principal investigators. - Introduced an estimand. - Clarified that the ± 2 day visit window is applicable to the dose titration schedule. - Added clarifications to prohibited and permitted medications. - Updated information based on the latest Investigator Brochure. Clarified/added abbreviations.

    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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