Irritability Associated With Autism Spectrum Disorder
Conditions
Keywords
Randomized, Placebo-controlled
Brief summary
6-week, randomized, double-blind, fixed-dose, placebo-controlled, parallel group study in children and adolescents (aged 5 to17 years) with autism spectrum disorder (ASD) with irritability, agitation, or self-injurious behaviors to study the efficacy and safety of pimavanserin
Detailed description
This study will be conducted as a 6-week, randomized, double-blind, fixed-dose, placebo-controlled, parallel group study in children and adolescents (5 through 17 years of age) with ASD with irritability, agitation, or self-injurious behaviors.
Interventions
DRUGPimavanserin
Pimavanserin
DRUGPlacebo
Pimavanserin matching placebo
Sponsors
ACADIA Pharmaceuticals 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
* Male or female and 5 through 17 years of age * Informed consent prior to the conduct of any study procedures * Patients (to the best of his/her ability), parent/legally accepted representative, and designated caregiver (if applicable) are able to understand the nature of the study, follow protocol requirements, and be willing to comply with study drug administration requirements * Able to swallow a test placebo capsule without difficulty * Meets Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for a primary diagnosis of ASD (APA 2013) and diagnosis is confirmed by the Autism Diagnostic Interview-Revised (ADI-R) * Score ≥18 on the Irritability subscale of the Aberrant Behavior Checklist (ABC) * Score ≥4 (moderate or greater severity) on the Clinical Global Impression-Severity (CGI-S) of irritability score * No current comorbid psychiatric disorder other than attention-deficit hyperactivity disorder (ADHD) or anxiety disorder * Drug-naïve to antipsychotic treatment (or \<2 weeks antipsychotic treatment for any reason), or prior lack of tolerability to adequate dose of any duration of antipsychotic confirmed by caregiver and medical records review * If patient is undergoing concurrent behavioral therapy for autism related symptoms or behaviors, this non-pharmacological treatment regimen has been stable for at least 4 weeks, and will be consistent throughout the study * For female patients only: unable to become pregnant or agree to use a highly effective non-hormonal method of contraception. Females of childbearing potential must have a negative pregnancy test
Exclusion criteria
* Requires treatment with a medication prohibited by the protocol, including concomitant psychotropic drugs targeting irritability, including those used off-label (clonidine, guanfacine, and propranolol; lithium, valproate), medications that prolong the QT interval, and strong cytochrome P450 (CYP) 3A4 enzyme (CYP3A4) inhibitors and inducers * Changes in medications or medication doses (for medical and allowed comorbid psychiatric conditions) in the last 4 weeks * Any known history of angioedema, serotonin or neuroleptic malignant syndromes, dystonic reaction, or tardive dyskinesia, due to an antipsychotic or psychotropic medication * At a significant risk of suicide, or is a danger to self or others * At risk of significant violent behavior to the extent that participation would pose an undue risk to other patients, caregivers, or others * Positive urine drug test * Met DSM-5 criteria for substance use disorders within the last 6 months * Confirmed genetic disorder associated with ASD, a cognitive and/ or behavioral disturbance or profound intellectual disability (IQ ≤50) * History of seizures, unless seizure-free and off epileptic drugs for at least 6 months * Any condition that, in the opinion of the Investigator, would interfere with the ability to comply with study instructions, or that might confound the interpretation of the study results or put the subject at undue risk * Current evidence, or history within the last 12 weeks, of a serious and/or unstable psychiatric, neurologic, cardiovascular, respiratory, gastrointestinal, renal, hepatic, hematologic, or other medical disorder, including cancer or malignancies * Weight \<15 kg * History or presence on at least one ECG of protocol-defined cardiac conduction abnormalities * Known family or personal history or symptoms of long QT syndrome or history of cardiac arrhythmias or risk factors for torsade de pointes and/or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and presence of congenital prolongation of the QT interval * Any member of the household has suffered from COVID-19 or had a COVID-19 (PCR or immunoglobulin) positive test in the last 4 weeks * One or more clinical laboratory test value outside of protocol-defined limits * Breastfeeding or lactating, or has a positive pregnancy test result (for patients of childbearing potential) * Sensitivity to pimavanserin or any of the excipients * Participating in another clinical study of any investigational drug, device, or intervention * Participated in greater than 2 interventional pharmaceutical clinical research studies in the last 6 months * Additional inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Week 6 in Caregiver-rated Aberrant Behavior Checklist Irritability (ABC-I) Subscale Score | 6 weeks | The Aberrant Behavior Checklist (ABC) is a caregiver-rated scale comprised of 5 empirically-derived subscales encompassing 58 items that describe various behavior problems. It measures domains of irritability, lethargy/social withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech. ABC-I is one of the subscales and comprises of 15 items. Minimum score is 0, maximum is 45. A score for each item ranges from 0 indicating not at all a problem to 3 indicating the problem is severe in degree. Subscale scores are calculated by summing the items within that subscale. Higher scores indicate greater impairment. |
Countries
Australia, France, Hungary, Italy, Poland, Serbia, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Pimavanserin-matching placebo, given as 1 capsule once daily | 78 |
| Pimavanserin Low Dose Pimavanserin given as 1 capsule once daily. Patients aged 5-12 years: 10 mg/day; patients aged 13-17 years: 20 mg/day | 78 |
| Pimavanserin High Dose Pimavanserin given as 1 capsule once daily. Patients aged 5-12 years: 20 mg/day; patients aged 13-17 years: 34mg/day | 81 |
| Total | 237 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 | 2 |
| Overall Study | Noncompliance with study drug | 1 | 1 | 1 |
| Overall Study | Not further specified | 0 | 3 | 1 |
| Overall Study | Protocol Violation | 0 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 3 | 1 |
Baseline characteristics
| Characteristic | Pimavanserin Low Dose | Pimavanserin High Dose | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 9.8 years STANDARD_DEVIATION 3.54 | 9.8 years STANDARD_DEVIATION 3.11 | 9.8 years STANDARD_DEVIATION 2.88 | 9.8 years STANDARD_DEVIATION 3.18 |
| Age, Customized 13-17 years | 17 Participants | 17 Participants | 15 Participants | 49 Participants |
| Age, Customized 5-12 years | 61 Participants | 64 Participants | 63 Participants | 188 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 6 Participants | 1 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 11 Participants | 8 Participants | 31 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 6 Participants | 6 Participants | 16 Participants |
| Race (NIH/OMB) White | 56 Participants | 58 Participants | 61 Participants | 175 Participants |
| Region of Enrollment Australia | 1 participants | 2 participants | 4 participants | 7 participants |
| Region of Enrollment France | 1 participants | 4 participants | 6 participants | 11 participants |
| Region of Enrollment Hungary | 7 participants | 5 participants | 6 participants | 18 participants |
| Region of Enrollment Italy | 3 participants | 5 participants | 2 participants | 10 participants |
| Region of Enrollment Poland | 19 participants | 21 participants | 18 participants | 58 participants |
| Region of Enrollment Serbia | 5 participants | 3 participants | 3 participants | 11 participants |
| Region of Enrollment Spain | 4 participants | 1 participants | 0 participants | 5 participants |
| Region of Enrollment United States | 38 participants | 40 participants | 39 participants | 117 participants |
| Sex: Female, Male Female | 19 Participants | 13 Participants | 21 Participants | 53 Participants |
| Sex: Female, Male Male | 59 Participants | 68 Participants | 57 Participants | 184 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 78 | 0 / 77 | 0 / 81 |
| other Total, other adverse events | 11 / 78 | 17 / 77 | 16 / 81 |
| serious Total, serious adverse events | 1 / 78 | 0 / 77 | 0 / 81 |
Outcome results
Primary
Change From Baseline at Week 6 in Caregiver-rated Aberrant Behavior Checklist Irritability (ABC-I) Subscale Score
The Aberrant Behavior Checklist (ABC) is a caregiver-rated scale comprised of 5 empirically-derived subscales encompassing 58 items that describe various behavior problems. It measures domains of irritability, lethargy/social withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech. ABC-I is one of the subscales and comprises of 15 items. Minimum score is 0, maximum is 45. A score for each item ranges from 0 indicating not at all a problem to 3 indicating the problem is severe in degree. Subscale scores are calculated by summing the items within that subscale. Higher scores indicate greater impairment.
Time frame: 6 weeks
Population: Full Analysis Set: all randomized patients who received at least one dose of study drug and have a baseline value and at least one post-baseline value for the ABC-I subscale score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline at Week 6 in Caregiver-rated Aberrant Behavior Checklist Irritability (ABC-I) Subscale Score | -9.6 score on a scale | Standard Error 1.06 |
| Pimavanserin Low Dose | Change From Baseline at Week 6 in Caregiver-rated Aberrant Behavior Checklist Irritability (ABC-I) Subscale Score | -11.2 score on a scale | Standard Error 1.09 |
| Pimavanserin High Dose | Change From Baseline at Week 6 in Caregiver-rated Aberrant Behavior Checklist Irritability (ABC-I) Subscale Score | -11.2 score on a scale | Standard Error 1.05 |
p-value: 0.298695% CI: [-4.6, 1.4]Mixed Models Analysis
p-value: 0.285995% CI: [-4.5, 1.3]Mixed Models Analysis