Pimavanserin for the Treatment of Irritability Associated With Autism Spectrum Disorder

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Pimavanserin for the Treatment of Irritability Associated With Autism Spectrum Disorder

Conditions
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Irritability Associated With Autism Spectrum Disorder

Intervention / Treatment
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* Drug: Pimavanserin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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/exclusion criteria apply. Subjects will be evaluated at screening to ensure that all criteria for study participation are met.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo given once daily, as one capsule matching in size and color the respective pimavanserin treatment | Drug: Placebo<br>* Pimavanserin matching placebo<br>|
| Experimental: Pimavanserin low dose<br>Patients aged 5 to 12 years: 10 mg/day pimavanserin Patients aged 13 to 17 years: 20 mg/day pimavanserin Pimavanserin given once daily, as capsule of 10 or 20 mg dose strength, respectively, according to the patient's age | Drug: Pimavanserin<br>* Pimavanserin<br>* Other names: Nuplazid;|
| Experimental: Pimavanserin high dose<br>Patients aged 5 to 12 years: 20 mg/day pimavanserin Patients aged 13 to 17 years: 34 mg/day pimavanserin Pimavanserin given once daily, as capsule of 20 or 34 mg dose strength, respectively, according to the patient's age | Drug: Pimavanserin<br>* Pimavanserin<br>* Other names: Nuplazid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline at Week 6 in caregiver-rated Aberrant Behavior Checklist (ABC) Irritability subscale score | The Aberrant Behavior Checklist (ABC) is a caregiver-rated scale comprised of five 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-Irritability is one of the subscales and comprises of 15 items. Minimum score is 0, maximum is 45. The ABC will be administered at Screening and Baseline, and at all post-Baseline visits from Week 1 through Week 6. 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. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline at Week 6 in caregiver-rated ABC subscale scores: Stereotypic Behavior; Lethargy; Hyperactivity; Inappropriate speech |  | 6 weeks | 
| Change from Baseline at Week 6 in Clinical Global Impression-Severity (CGI-S) of Irritability score |  | 6 weeks | 
| Clinical Global Impression-Improvement (CGI-I) of irritability score at Week 6 |  | 6 weeks | 
| Change from Baseline at Week 6 in Repetitive Behavior Scale-Revised (RBS-R) scores |  | 6 weeks | 
| Change from Baseline at Week 6 in Vineland Adaptive Behavior Scales (VABS)-Socialization subscale score |  | 6 weeks | 
| Change from Baseline at Week 6 in Caregiver Strain Questionnaire (CGSQ) scores |  | 6 weeks | 
| Proportion of patients with at least 25% reduction from Baseline in ABC-Irritability subscale score at Week 6 |  | 6 weeks | 
| Proportion of patients with CGI-I of irritability score of 1 (very much improved) or 2 (much improved) at Week 6 |  | 6 weeks | 
| Proportion of patients with at least 25% reduction from Baseline in ABC-Irritability subscale score and CGI-I of irritability score of 1 or 2 at Week 6 |  | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomized, Placebo-controlled