Irritability Associated With Autism Spectrum Disorder (ASD)
Conditions
Keywords
Autism, Irritability, Autism Spectrum Disorder, ASD
Brief summary
The purpose of this study is to find out about the potential benefits and safety of brexpiprazole in children and adolescent participants, aged 5 to 17, with irritability associated with autism spectrum disorder.
Interventions
DRUGBrexpiprazole
Oral tablet; take once daily
DRUGPlacebo
Administered orally daily for up to Week 8.
Sponsors
H. Lundbeck A/S
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
5 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Primary Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of ASD * Aberrant Behavior checklist - Irritability (ABC-I) subscale score of ≥ 18 * Clinical Global Impressions - Severity (CGI-S) scale score pertaining to irritability ≥ 4 * Mental age of ≥ 2 years as determined by Investigator based upon school participation, social history or medical records * Ability for parent/caregiver to follow all protocol procedures * Able to swallow tablets * Able to discontinue all prohibited concomitant medications to meet protocol required washouts prior to and during the trial period Key
Exclusion criteria
* Primary diagnosis of bipolar I disorder, including any DSM-5 current diagnosis of bipolar II disorder, schizophrenia, schizoaffective disorder, major depressive episode, and post-traumatic stress disorder (PTSD). Attention-deficit/hyperactivity disorder (ADHD) maybe exclusionary if it is the primary disorder, or is not stable or adequately treated. * current or historical diagnosis of Fragile-X Syndrome or Rett's Disorder * history of neuroleptic malignant syndrome * a significant risk of committing violent acts, serious self-harm, or suicide * epilepsy, a history of seizures, or a history of severe head trauma or stroke, or have a history or current evidence of other unstable medical conditions * current hypothyroidism or hyperthyroidism * uncontrolled Type I or Type II diabetes * uncontrolled hypertension or symptomatic hypotension, or orthostatic hypotension * Weight \< 15 kg * Previous exposure to brexpiprazole * Sexually active males or females, who could become pregnant, not agreeing to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days at the end of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline to Week 8 in Aberrant Behavior Checklist - Irritability (ABC-I) Subscale Score | Baseline to Week 8 | The ABC is a parent-reported rating scale designed to assess treatment effects on problem behavior in participants with intellectual disabilities. The ABC scale has 58 items, which divide into 5 subscales as follows: (1) Irritability, Agitation; (2) Lethargy, Social Withdrawal; (3) Stereotypic Behavior; (4) Hyperactivity, Noncompliance; and (5) Inappropriate Speech. Each of the 58 ABC items is rated on a 4-point scale (0=not at all a problem; 1=the behavior is a problem, but slight in degree;2=the problem is moderately serious; 3=the problem is severe in degree). ABC-I measures emotional and behavioral symptoms of ASD, including aggression toward others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. ABC-I total score is the sum of the ratings over 15 ABC items. Individual scores were summed, thus the ABC-I total score ranges from 0 to 45. Higher scores represent the worst condition. A negative change from baseline indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline to Week 8 in Clinical Global Impression - Severity (CGI-S) Score | Baseline to Week 8 | The CGI-S scale is a clinician-rated assessment that evaluates the severity of a participant's condition with a focus on symptoms of irritability on a 7-point scale. The investigator (or rater) answered the following question: Considering your total clinical experience with this particular population, how ill was the participant at this time with regard to symptoms of irritability? Response choices were 0 = not assessed; 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients. Higher scores indicate more severe illness. A negative change from baseline indicates improvement. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 40 sites in the United States from 30 October 2019 to 9 September 2022.
Pre-assignment details
A total of 260 participants were screened, of which 119 participants were randomized to receive brexpiprazole or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Brexpiprazole Participants received flexible doses of brexpiprazole 0.25 to 3 mg/day, orally, QD up to Week 8. For participants 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 participants 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. | 60 |
| Placebo Participants received brexpiprazole matching placebo orally, QD, in the same way as brexpiprazole up to Week 8. | 59 |
| Total | 119 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Disease Relapse | 1 | 0 |
| Overall Study | Lack of Efficacy | 0 | 2 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Protocol Deviation | 1 | 0 |
| Overall Study | Reason Not Specified | 0 | 1 |
| Overall Study | Subject Was Withdrawn From Participation By Parent/Guardian | 2 | 1 |
| Overall Study | Subject Withdrew Consent To Participate | 1 | 0 |
Baseline characteristics
| Characteristic | Brexpiprazole | Placebo | Total |
|---|---|---|---|
| Aberrant Behavior Checklist - Irritability (ABC-I) Subscale Score | 29.7 score on a scale STANDARD_DEVIATION 8 | 28.6 score on a scale STANDARD_DEVIATION 7.6 | 29.1 score on a scale STANDARD_DEVIATION 7.8 |
| Age, Continuous | 9.8 years STANDARD_DEVIATION 2.9 | 10.0 years STANDARD_DEVIATION 3.2 | 9.9 years STANDARD_DEVIATION 3 |
| Clinical Global Impression - Severity (CGI-S) Score | 4.9 score on a scale STANDARD_DEVIATION 0.7 | 4.7 score on a scale STANDARD_DEVIATION 0.5 | 4.8 score on a scale STANDARD_DEVIATION 0.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 7 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 52 Participants | 52 Participants | 104 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 2 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Race Black or African American | 3 Participants | 10 Participants | 13 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 5 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized Race White | 49 Participants | 45 Participants | 94 Participants |
| Region of Enrollment United States | 60 participants | 59 participants | 119 participants |
| Sex: Female, Male Female | 6 Participants | 9 Participants | 15 Participants |
| Sex: Female, Male Male | 54 Participants | 50 Participants | 104 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 58 | 0 / 57 |
| other Total, other adverse events | 13 / 58 | 5 / 57 |
| serious Total, serious adverse events | 0 / 58 | 0 / 57 |
Outcome results
Primary
Mean Change From Baseline to Week 8 in Aberrant Behavior Checklist - Irritability (ABC-I) Subscale Score
The ABC is a parent-reported rating scale designed to assess treatment effects on problem behavior in participants with intellectual disabilities. The ABC scale has 58 items, which divide into 5 subscales as follows: (1) Irritability, Agitation; (2) Lethargy, Social Withdrawal; (3) Stereotypic Behavior; (4) Hyperactivity, Noncompliance; and (5) Inappropriate Speech. Each of the 58 ABC items is rated on a 4-point scale (0=not at all a problem; 1=the behavior is a problem, but slight in degree;2=the problem is moderately serious; 3=the problem is severe in degree). ABC-I measures emotional and behavioral symptoms of ASD, including aggression toward others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. ABC-I total score is the sum of the ratings over 15 ABC items. Individual scores were summed, thus the ABC-I total score ranges from 0 to 45. Higher scores represent the worst condition. A negative change from baseline indicates improvement.
Time frame: Baseline to Week 8
Population: Efficacy sample included all randomized participants 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. 'Overall number of participants analyzed' indicates the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline to Week 8 in Aberrant Behavior Checklist - Irritability (ABC-I) Subscale Score | -10.1 score on a scale | Standard Error 1.28 |
| Placebo | Mean Change From Baseline to Week 8 in Aberrant Behavior Checklist - Irritability (ABC-I) Subscale Score | -8.87 score on a scale | Standard Error 1.25 |
p-value: 0.459795% CI: [-4.49, 2.05]Mixed model repeated measures(MMRM)
Secondary
Mean Change From Baseline to Week 8 in Clinical Global Impression - Severity (CGI-S) Score
The CGI-S scale is a clinician-rated assessment that evaluates the severity of a participant's condition with a focus on symptoms of irritability on a 7-point scale. The investigator (or rater) answered the following question: Considering your total clinical experience with this particular population, how ill was the participant at this time with regard to symptoms of irritability? Response choices were 0 = not assessed; 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients. Higher scores indicate more severe illness. A negative change from baseline indicates improvement.
Time frame: Baseline to Week 8
Population: Efficacy sample included all randomized participants 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. 'Overall number of participants analyzed' indicates the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Brexpiprazole | Mean Change From Baseline to Week 8 in Clinical Global Impression - Severity (CGI-S) Score | -1.16 score on a scale | Standard Error 0.15 |
| Placebo | Mean Change From Baseline to Week 8 in Clinical Global Impression - Severity (CGI-S) Score | -1.09 score on a scale | Standard Error 0.15 |
p-value: 0.731595% CI: [-0.46, 0.32]MMRM