| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of irritability associated with autistic disorder in children and adolescents with ASD |
|
| E.1.1.1 | Medical condition in easily understood language |
| Treatment of irritability associated with autistic disorder in children and adolescents with ASD |
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063844 |
| E.1.2 | Term | Autism spectrum disorder |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary efficacy objective
• To evaluate the efficacy of pimavanserin compared with placebo in the treatment of irritability associated with ASD in children and adolescents
Safety objective
• To evaluate the safety and tolerability of pimavanserin compared with placebo in the treatment of irritability associated with ASD in children and adolescents
Pharmacokinetic objective
• To characterize the pharmacokinetics (PK) of pimavanserin in children and adolescents with ASD
Pharmacokinetic/pharmacodynamic objective
• To characterize the pharmacokinetic/ pharmacodynamic (PK/PD) relationship of pimavanserin for the treatment of irritability associated with ASD in children and adolescents
|
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives
• To evaluate the efficacy of pimavanserin compared with placebo, in both the treatment of non irritability symptoms, magnitude of improvement in irritability and the response rate in children and adolescents with ASD. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Study Population
1. Is a male or female 5 through 17 years of age at Screening and Baseline visits
2. Is within the 5th to 95th percentile for gender specific weight for-age and height-for-age growth charts from the National Center for Health Statistics
3. Informed consent prior to the conduct of any study procedures is required as follows:
a. The subject should provide written or oral assent if deemed able by the Investigator. The process of obtaining informed consent will be conducted in accordance with institutional review board or ethics committee policy and applicable local law.
b. The subject’s parent/legally acceptable representative must provide written consent. The subject’s parent/LAR must be considered reliable by the Investigator, able to complete assessments regarding the subject’s development and behavior throughout the study, and able to help ensure compliance with study treatment, study visits, and protocol procedures
c.If a person other than the parent/LAR has been designated as a caregiver for the purpose of providing input for caregiver-reported scales, that person must also provide written consent. Such a designee should be a family member, adult and responsible, living with or in very frequent contact with the subject participating in the study, who is committed to providing responses for the caregiver-reported scales for the duration of the study. The process of obtaining informed consent will be conducted in accordance with institutional review board or ethics committee policy and applicable local law
4. In the Investigator’s opinion, the subject to the best of his/her ability and parent/LAR are able to understand the nature of the study, follow protocol requirements, and be willing to comply with study drug administration requirements
5. Is able to swallow the test placebo capsule without difficulty during the Screening or Baseline visits
6. Has a mental age of ≥2 years as determined by Investigator based upon school evaluation social history or medical records documented at any time before or at Screening
Psychiatric Diagnosis and Concomitant Medications
7. Meets Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for a primary diagnosis of ASD (APA 2013) and the diagnosis is confirmed by the Autism Diagnostic Interview–Revised (ADI-R)
Has a score ≥18 on the Irritability subscale of the Aberrant Behavior Checklist at Screening and Baseline. If the ABC-Irritability score at Baseline exceeds ≥20% improvement from Screening, the patient will not be randomized and will be screen failed
9. Has a score ≥4 (moderate or greater severity) on the Clinical Global Impression–Severity (CGI-S) of irritability score at Screening and Baseline
10. Has no current comorbid psychiatric disorder other than attention-deficit hyperactivity disorder, or anxiety disorder
11. Is drug-naïve to antipsychotic treatment (including prior antipsychotic treatment, approved or off-label, of less than 2 weeks for any reason), or had prior lack of tolerability to adequate dose of any duration of antipsychotic confirmed by caregiver and medical records review when available
12. Has been discontinued from previous treatments for irritability associated with ASD and washed out for at least 5 drug half-lives or 2
weeks (whichever is longer) prior to Baseline
13. Is able to discontinue all prohibited concomitant medications to meet protocol requirements prior to and during the study period. Investigators should not withdraw a subject’s medication solely for the purpose of enrolling them into the study unless discontinuation of the medication is deemed to be clinically appropriate (e.g., symptoms are not well controlled or the subject cannot tolerate the current medication)
14. If subject is undergoing concurrent behavioral therapy for autism related symptoms or behaviors, this non pharmacological treatment regimen has been stable for at least 4 weeks prior to Screening, and will be consistent throughout the study
15. Is judged by the Investigator to be clinically stable (i.e., no psychiatric hospitalization, unless it took place exclusively for social reasons, within 12 weeks prior to Screening) and not at imminent risk of suicide or injury to self, others, or property
16. Female subjects who participate in this study must either be unable to become pregnant (e.g., premenarchal, surgically sterile, etc.) - OR- agree to use a highly effective non-hormonal method of contraception (e.g., intrauterine device, condom or diaphragm with spermicides, or contraceptive sponge) from 28 days before Baseline to 45 days after last dose (if subject does not roll over into the open-label extension study). Females of childbearing potential must have a negative serum human chorionic gonadotropin pregnancy test at Screening and a negative urine hCG pregnancy test at Baseline. Females of childbearing potential are defined as females who have begun menstruating |
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| E.4 | Principal exclusion criteria |
Central Nervous System, Psychiatric, and Illicit Drug Use Criteria
1. 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
2. Subjects who have had changes in medications or medication doses (for medical and allowed comorbid psychiatric conditions) within 4 weeks of Baseline
3. Any history as reported by the caregiver or documented by medical records, when available, of angioedema, serotonin or neuroleptic malignant syndromes, dystonic reaction, or tardive dyskinesia, due to an antipsychotic or psychotropic medication.
4. Is at a significant risk of suicide, or is a danger to self or others, in the opinion of the Investigator based upon all available sources of information including C-SSRS (positive answer to suicidal ideation questions 4 or 5 [current or over last 6 months]) at Screening or Baseline and including more than one life-threatening suicide attempt (positive answer to suicidal behavior questions [over last 6 months])
5. Is at risk of significant violent behavior to the extent that participation would pose an undue risk to other patients, caregivers, or others in the opinion of the Investigator
6. Has a positive urine drug test at Screening or Baseline or positive urine drug dipstick test result at Baseline (Day 1). For study eligibility, the urine toxicology (drug) screen (UDS) must be negative for any substance of which the subject does not have a valid prescription.
7. Has met DSM-5 criteria for substance use disorders within the last 6 months prior to Baseline
8. Has been treated once or several times for ≥2 weeks for irritability with an adequate dose of any antipsychotic treatment including off-label medication and has discontinued due to lack of efficacy as confirmed by caregiver reports and medical records when available. Discontinuation due to lack of tolerability for antipsychotic treatments of any duration is not exclusionary.
9. Has a current comorbid diagnosis of bipolar disorder, schizophrenia, major depressive disorder, substance use disorder, Rett syndrome, or fragile-X syndrome, as confirmed by the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) at Screening. ADHD and anxiety disorders are exclusionary if they are the primary disorder, or are not stable or adequately treated.
Medical Criteria
10. Has any of the following: a) a confirmed genetic disorder associated with ASD; b) a cognitive and/or behavioral disturbance or profound intellectual disability (IQ≤50) documented at any time before or at Screening (measured and documented standardized, individualized, test of intelligence)
11. Has a history of seizures, unless seizure-free and off epileptic drugs for at least 6 months prior to Screening
12. Has 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
13. Has current evidence, or history within the previous 12 weeks prior to Screening, of a serious and/or unstable psychiatric, neurologic, cardiovascular, respiratory, gastrointestinal, renal, hepatic, hematologic, or other medical disorder, including cancer or malignancies that in the judgment of the Investigator would jeopardize the safe participation of the subject in the study
14. Clinically significant finding(s) on physical examination determined by the Investigator to pose a health concern to the subject while on study
15. Weight <15 kg
16. For age <13 years, a resting position (sitting or supine) systolic (SBP) and/or diastolic blood pressure (DBP) level ≥90th percentile for gender-specific age and height charts from the National Heart and Lung Institute (NHLI), at Screening or Baseline. For age ≥13 years a resting position (sitting or supine) SBP ≥120 mmHg and/or a DBP ≥80 mmHg, at Screening or Baseline.
17.Has a clinically significant abnormal ECG at Screening or at Baseline
18.Has a history or presence on at least one ECG at Screening or at Baseline, of any of the following cardiac conduction abnormalities:
a.QTcF ≥450 ms
b.PR interval >220 ms
c.Evidence of second- or third-degree atrioventricular block
d.Evidence of complete left bundle branch block e.Intraventricular conduction delay with QRS >110 ms f.QRS or T wave morphology that could, in the Investigator’s opinion, render QT interval assessment unreliable
g.Sick sinus syndrome
h.Non-sinus rhythm
i.Resting heart rate <50 beats per minute
(continues in the protocol)
|
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Change from Baseline at Week 6 in the caregiver-rated Aberrant Behavior Checklist (ABC) Irritability subscale score |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints
• Change from Baseline at Week 6 in the caregiver-rated ABC subscale scores
o Stereotypic behavior
o Lethargy
o Hyperactivity
o Inappropriate speech
• Change from Baseline at Week 6 in the Clinical Global Impression–Severity (CGI-S) of irritability score
• Clinical Global Impression–Improvement (CGI-I) of irritability score at Week 6
• Change from Baseline at Week 6 in the Repetitive Behavior Scale–Revised (RBS-R) scores
• Change from Baseline at Week 6 in the Vineland Adaptive Behavior Scales (VABS)–Socialization subscale score
• Change from Baseline at Week 6 in the Caregiver Strain Questionnaire (CGSQ) scores
• Proportion of subjects who have at least 25% reduction from Baseline in the ABC–Irritability subscale score at Week 6
• Proportion of subjects who have CGI-I of irritability score of 1 (very much improved) or 2 (much improved) at Week 6
• Proportion of subjects who have at least 25% reduction from Baseline in the ABC–Irritability subscale score AND a CGI-I of irritability score of 1 (very much improved) or 2 (much improved) at Week 6
Safety endpoints
Safety will be evaluated by analyses of the following:
• Treatment-emergent adverse events
• Vital signs
• Weight and body mass index (BMI)
• 12-lead electrocardiograms (ECGs)
• Physical examination results
• Clinical laboratory tests (including urinalysis) and hormonal assessments
• Columbia–Suicide Severity Rating Scale (C-SSRS)
• Extrapyramidal Symptom Rating Scale–Abbreviated (ESRS-A)
Pharmacokinetic endpoints
• Plasma concentrations of pimavanserin, and AC-279
• Pimavanserin PK parameters such as, but not limited to, Cmax and AUC, using a population PK approach
Pharmacokinetic/pharmacodynamic endpoint
• PK/PD using appropriate PK/PD analysis
methods (e.g., evaluate the relationship
between exposure and efficacy/safety
endpoints) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 36 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| United States |
| France |
| Hungary |
| Italy |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 9 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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