INP105 Proof-of-concept Study for the Acute Treatment of Agitation in Adolescents and Young Adults With ASD

Study Overview
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Brief Summary
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This is a Phase 2a, proof-of concept, 2-way, 2-period crossover, double-blind study to evaluate the safety and efficacy of INP105 as an acute treatment versus placebo in adolescents and young adults with autism spectrum disorder (ASD) experiencing agitation. Approximately 32 ASD patients who are currently being treated for agitation/aggression at several inpatient units specializing in behavioral treatment will be enrolled. INP105 is a novel combination product that sprays a powder formulation of olanzapine to the upper nasal space. An earlier formulation showed a similar extent, but faster rate of absorption compared to the approved intramuscular product. In this study, 5 mg of olanzapine or placebo will be delivered nasally by this combination product to moderately or severely agitated participants. Participants will undergo several screening assessments, including observation session(s) of episode(s) of agitation resulting from a frustration task (eg, a non-preferred activity). At least one observation session must result in a documented moderate to severe agitation episode prior to the participant being eligible to enroll in the study and be randomized to treatment. The study will be conducted in 2 phases. A pilot phase will initially enroll at least 6 participants, who will receive both 5 mg INP105 (5 mg olanzapine) and placebo in random order, in the same crossover design as later participants. Participants will be dosed during a documented moderate to severe episode of agitation. Once 6 participants have completed both dosing periods and have at least 48 hours of post-dose safety data collected, a safety and preliminary efficacy analysis will be performed by an independent unblinded statistical group, and a summary report forwarded to a sponsor-led Data and Safety Review Committee (DSRC), who will remain blinded. Enrollment will be paused during the DSRC pilot phase safety and preliminary efficacy results review. Absent any concerning safety signals, the second phase will enroll all remaining participants. The DSRC may suggest revisions to the protocol, and the protocol amended and approved as necessary, prior to further participants being enrolled.

Official Title
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A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Single Dose, 2-Way, 2-Period Crossover Safety and Exploratory Efficacy Study of INP105 (POD-OLZ) for the Acute Treatment of Agitation in Adolescents and Young Adults With Autism Spectrum Disorder

Conditions
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Agitation in Adolescents and Young Adults With ASD

Intervention / Treatment
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* Combination Product: INP105
* Combination Product: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed autism spectrum disorder diagnosis Admitted as an inpatient to a behavioral unit prior to informed consent Displays episodes of moderate to severe agitation Exclusion Criteria: Hypersensitivity to olanzapine History of severe head trauma, stroke, endocrine disorder, or cardiovascular disease History of hypotension Currently on a chronic dose of olanzapine Currently taking ciprofloxacin, enoxacin, fluvoxamine, or carbamazepine

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 21 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: INP105<br>POD-olanzapine (INP105), 5 mg, single dose, to be delivered to each participant | Combination Product: INP105<br>* A single 5 mg dose of POD-OLZ (Precision Olfactory Delivery [POD®]-olanzapine)<br>* Other names: POD-OLZ;|
| Placebo Comparator: Placebo<br>POD-placebo, single dose, to be delivered to each participant | Combination Product: Placebo<br>* A single dose of POD-placebo (Precision Olfactory Delivery [POD®]-placebo)<br>* Other names: POD-PBO;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events and serious adverse events in the INP105 and placebo groups up to 48 hours post-dose | All adverse events, serious or not, will be recorded from time of dosing with either INP105 or placebo up until 48 hours post-dose, or until the next treatment is given, which ever is sooner. | From dosing to 48 hours post dosing | 
| Overall incidence of adverse events and serious adverse events in the INP105 and placebo groups | All adverse events will be recorded as treatment emergent from after dosing until the next treatment, or until last study visit, as applicable. | From dosing to end of follow-up (7 days), or to the start of next blinded treatment (48 hours), as applicable | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Agitation-Calmness Evaluation Scale (ACES) score at 30 minutes post-dose | The ACES is a 9 point scale that measures the degree of agitation versus sedation, ranging from a score of 1 marked agitation to 4 normal to 9 unable to be aroused. | Pre-dose to 30 minutes post-dose | 
| Change in Behavioral Activity Rating Scale (BARS) score at 30 minutes post-dose | The BARS is a 7 point scale measuring the degree of agitated behavior, ranging from 1 difficult or unable to rouse to 4 quiet and awake (normal level of activity) to 7 violent, requires restraint. | Pre-dose to 30 minutes post-dose | 
| Change in Overt Aggression Scale (OAS) score at 30 minutes post-dose | The OAS measures the degree of aggression, using 4 categories of aggression, defined as verbal aggression, aggression against objects, aggression against self, and aggression against other people. The higher a category is rated, the more severe the degree of aggression. The total score is the sum of the scores from the 4 categories. | Pre-dose to 30 minutes post-dose | 
| Change in Positive and Negative Syndrome Scale - Excited Component (PEC) score at 30 minutes post-dose | The PEC describes 5 behaviors related to negative aspects of excitability; excitement, tension, hostility, uncooperativeness, poor impulse control. The rater scores each of these aspects from 1 (not present) to 7 (extreme), for a total score that can range from 5 to 35. | Pre-dose to 30 minutes post-dose | 
| Change in irritability behavior frequency counts at 30 minutes post-dose | Persons with autism can often display repetitive behaviors. These repetitive behaviors, such as rocking, hitting, kicking, will be counted pre-dose and during intervals post-dose. | Pre-dose to 30 minutes post-dose | 
| Clinical Global Impressions - Improvement (CGI-I) score at 30 minutes post-dose | The CGI-I is a 7 point scale that will be used to assess global improvement in the patient's condition on a scale that ranges from 0 not assessed, 1 very much improved to 7 very much worse. | Pre-dose to 30 minutes post-dose | 
| Clinical Global Impressions - Efficacy (CGI-E) score at 30 minutes post-dose | The CGI-E is a scale that measures the efficacy of an intervention balanced by any negative side effects. Scores can range from 1 (vast improvement and no side effects) to 16 (unchanged or worse and side effects that outweigh therapeutic effect). | Pre-dose to 30 minutes post-dose | 
| Change in modified Aberrant Behavior Checklist - Irritability Subscale (ABC-I) score at 60 minutes post-dose | The ABC-I lists15 behaviors, including aggression, tantrums, crying, seen with irritability and these are scored from 0 absent to 3 severe. Score can therefore range from 0 to 45 (worst irritability). | Pre-dose and at 60 minutes post-dose | 
| Time to reach an ACES score of 4 (normal) post-dosing | The length of time it will take the participant to move from a score of 2 or 1 on the ACES scale to a score of 4 will be determined. | Dosing until 120 minutes post-dose | 
| Frequency of administering pharmaceutical rescue intervention within 120 minutes after dosing | The frequency of administering any pharmaceutical intervention other than the study intervention from dosing until 120 minutes after dosing will be recorded and compared for INP105 versus placebo. | Dosing until 120 minutes post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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agitation, olanzapine, autism