Dexmedetomidine in the Treatment of Agitation Associated With Schizophrenia and Bipolar Disorder (SERENITY III)

Study Overview
=================
Brief Summary
-----------------
In this study, an investigational medication named BXCL501 is being tested for the treatment of episodes of agitation associated with bipolar I and bipolar II disorder, schizophrenia, schizoaffective and schizophreniform disorder. This study compares the study drug to a placebo.

Detailed Description
-----------------
This is a randomized, double-blind, placebo-controlled, 2-Part, Phase III study to assess the efficacy, safety, and tolerability of a 60 mcg dose of BXCL501 in adult (18-75 years old) males and females with agitation episodes associated with a primary diagnosis of bipolar I disorder, bipolar II disorder, schizophrenia, schizoaffective disorder, or schizophreniform disorder. Part 1 of the study is a one-day, in-clinic treatment, and post-treatment observation period with patients experiencing an acute episode of agitation. Part 2 of the study is a 12-week study to determine the safety of BXCL501 when used as needed for episodes of agitation at home.

Official Title
-----------------
Efficacy And Safety of BXCL501 Evaluated For At-Home Use In A Multisite Double-Blind Placebo-Controlled Trial For Agitation Associated With Schizophrenia And Bipolar Disorder

Conditions
-----------------
Agitation,Psychomotor, Bipolar I Disorder, Bipolar II Disorder, Schizophrenia, Schizoaffective Disorder, Schizophreniform Disorders

Intervention / Treatment
-----------------
* Drug: BXCL501
* Drug: Matching Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
A patient may enroll in only one part of the study; either Part 1 or Part 2. Inclusion Criteria: Male and female patients between the ages of 18 to 75 years, inclusive Patients who can read, understand and provide written informed consent. Patients who have met Diagnostic and Statistical Manual5/5-Text Revision criteria for bipolar I or bipolar II disorder, schizophrenia, schizoaffective or schizophreniform disorder. Patients who, in the opinion of the Principal Investigator, are in good general health before study participation based on a detailed medical history, a physical examination, a 12-lead ECG, a blood chemistry profile, hematology, and urinalysis. Participants who agree to use a medically acceptable and effective birth control method Part 1 only Patients who are judged to be clinically agitated at Screening and Baseline with a total score of ≥ 14 on the 5 items (poor impulse control, tension, hostility, uncooperativeness, and excitement) comprising the PEC. Patients with a score of ≥4 on at least 1 of the 5 items on the PEC at Baseline. Part 2 only Patients have had at least three clinical presentations of agitation requiring an intervention in the past three months prior to Screening Patients who are receiving stable treatment for the last 3 months prior to Screening for the underlying primary diagnosis and who are expected to remain on stable treatment for the duration of the study Patients who manage agitation episodes with as needed (PRN) medication The patient has an Informant who can read, understand, and provide written informed consent and understand and follow the study procedures Exclusion Criteria: Patients with serious or unstable medical illnesses. A history of agitation episodes due to substance use. A diagnosis of antisocial personality disorder, borderline personality disorder, or narcissistic personality disorder that predated the diagnosis of schizophrenia or bipolar disorder Patients who are judged to be at significant risk of suicide Female patients who have a positive pregnancy test at Screening or Baseline, or are breastfeeding. Patients currently treated with alpha-1 noradrenergic blockers (terazosin, doxazosin, tamsulosin, alfuzosin, or prazosin), alpha-2 adrenergic agonists, or other prohibited medications. Patients with hydrocephalus, seizure disorder, or history of significant head trauma, stroke, transient ischemic attack, subarachnoid bleeding, brain tumor, encephalopathy, meningitis, Parkinson's disease, or focal neurological findings. History of syncope or other syncopal attacks, current evidence of hypovolemia, or orthostatic hypotension Patients with laboratory or ECG abnormalities considered clinically significant by the Investigator Patients who have received an investigational drug within 30 days before the study start Patients who have previously received BXCL501 via prescription (under the trade name IGALMI™) or received BXCL501 in an open-label clinical trial Patients considered by the Investigator to be unsuitable candidates for receiving dexmedetomidine or considered to be unsuitable for participating in the study for any reason. Part 1 only Patients with agitation caused by acute intoxication, including identification of alcohol by breathalyzer or drugs of abuse (except for THC) during urine screening. Use of benzodiazepines or other hypnotics or antipsychotic drugs in the 4 hours before study treatment. Patients who have previously received BXCL501 in a clinical trial

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Part 1: Patients randomized to receive 60 mcg of BXCL501 or a matching placebo. Part 2: Patients randomized to receive 80 mcg of BXCL501 or a matching placebo.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: 60 mcg of BXCL501<br>Sublingual film containing 60 Micrograms Dexmedetomidine | Drug: BXCL501<br>* Sublingual Film<br>* Other names: Dexmedetomidine;|
| Placebo Comparator: Part 1: Matching Placebo<br>Sublingual Placebo film | Drug: Matching Placebo<br>* Sublingual Placebo Film<br>* Other names: Placebo;|
| Experimental: Part 2: 80 mcg of BXCL501<br>Sublingual film containing 80 Micrograms Dexmedetomidine | Drug: BXCL501<br>* Sublingual Film<br>* Other names: Dexmedetomidine;|
| Placebo Comparator: Part 2: Matching Placebo<br>Sublingual Placebo film | Drug: Matching Placebo<br>* Sublingual Placebo Film<br>* Other names: Placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Change from baseline in Positive and Negative Syndrome Scale - Excited (PEC) total score | The Positive and Negative Syndrome Scale - Excited Component (PEC) comprises 5 items associated with agitation: poor impulse control, tension, hostility, uncooperativeness, and excitement; each scored 1 (minimum) to 7 (maximum). The PEC, the sum of these 5 subscales, thus ranges from 5 (absence of agitation) to 35 (extremely severe) | 2 hours | 
| Part 2: Incidence of treatment-emergent adverse events (TEAEs) | To assess the safety of BXCL501 when used in an at-home environment based on treatment-emergent adverse events (TEAEs) | Through study completion, an average of 12 weeks | 
| Part 2: Incidence of serious adverse events (SAEs) | To assess the safety of BXCL501 when used in an at-home environment based on serious adverse events (SAEs) | Through study completion, an average of 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Clinical Global Impression - Improvement (CGI-I) | The Clinical Global Impression - Improvement (CGI-I) for agitation in response to treatment measures the current level of agitation relative to the level of agitation prior to administration of study intervention. The CGI-I scores range from 1 to 7 with a score of 1 indicating very much improved, and a score of 7 indicating very much worse. | 2 hours | 
| Part 1: Change in Modified Clinical Global Impression - Severity (mCGI-S) scores from Baseline | The Modified Clinical Global Impression - Severity (mCGI-S) measures the current level of agitation. For this study, the mCGI-S is a 4-point scale where a score of 0 represents no agitation, and scores of 1-3 describe increasing severities of agitation (mild, moderate, severe). | 2 hours | 
| Part 1:The number of responders based on the Modified Clinical Global Impression - Severity (mCGI-S) score | The Modified Clinical Global Impression - Severity (mCGI-S) measures the current level of agitation. A responder is characterized as a participant with a score of 0 (represents no agitation) or 1 (mild agitation) | 2 hours | 
| Part 1:Change from baseline in Agitation-Calmness Evaluation Scale (ACES) | The Agitation-Calmness Evaluation Scale (ACES) is a single item scale that measures overall agitation and sedation, where a score of 1 indicates marked agitation; 2 - moderate agitation; 3 - mild agitation; 4 - normal behavior; 5 - mild calmness; 6 - moderate calmness; 7 - marked calmness; 8 - deep sleep; and 9 - unarousable. | 2 hours | 
| Part 1: Incidence of treatment-emergent adverse events (TEAEs) | To assess the safety of BXCL501 based on treatment-emergent adverse events (TEAEs) | Through study completion, an average of 8 hours | 
| Part 1: Change from baseline in heart rate (HR) at rest | The effect of BXCL501 on heart rate at rest | Baseline, and 2, 4, 6, and 8 hours postdose | 
| Part 1: Change from baseline in heart rate (HR) under orthostatic stress | The effect of BXCL501 on heart rate under orthostatic stress | Baseline, and 2, 4, 6, and 8 hours postdose | 
| Part 1: Change from baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at rest | The effect of BXCL501 on systolic and diastolic blood pressure at rest | Baseline, and 2, 4, 6, and 8 hours postdose | 
| Part 1: Change from baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) under orthostatic stress | The effect of BXCL501 on systolic and diastolic blood pressure under orthostatic stress | Baseline, and 2, 4, 6, and 8 hours postdose | 
| Part 1: Incidence of abnormal electrocardiograms (ECG) reported as an adverse event (AE) | Any abnormal ECG value that is reported as an adverse event (AE) | Through study completion, an average of 8 hours | 
| Part 1: Incidence of abnormal clinical laboratory values reported as an adverse event (AE) | Any abnormal clinical laboratory value that is reported as an adverse event (AE) | Through study completion, an average of 8 hours | 
| Part 2: Incidence of interactions with emergency services related to agitation | Evaluate the impact of BXCL501 on the use of healthcare and emergency service resources because of agitation episodes | Through study completion, an average of 12 weeks | 
| Part 2: Incidence of overall adverse events and AEs leading to discontinuation | To evaluate the safety and tolerability profile of BXCL501 | Through study completion, an average of 12 weeks | 
| Part 2: Proportion of patients who report somnolence (ACES score ≥8 reported by Informant) pre-dose to post-dose | To evaluate the safety and tolerability profile of BXCL501 | 2 hours after each treatment for an episode of agitation | 
| Part 2: Proportion of patients who report somnolence (KSS score ≥8 reported by patient) pre-dose to post-dose | To evaluate the safety and tolerability profile of BXCL501 | 2 hours after each treatment for an episode of agitation | 
| Part 2: Evaluate the effect of BXCL501 on the signs and symptoms of agitation following study drug administration in patients with schizophrenia and bipolar disorder | Proportion of patients with an improvement in agitation (Yes/No) post-dose for the first treated episode compared with placebo | 2 hours after treatment for the first episode of agitation | 
| Part 2: Evaluate the effect of BXCL501 on the signs and symptoms of agitation following study drug administration in patients with schizophrenia and bipolar disorder | Proportion of mCGI-S responders (patients who achieve a mCGI-S score of 0 or 1) following drug administration for the first treated episode | 2 hours after treatment for the first episode of agitation | 
| Part 2: Evaluate the effect of BXCL501 on the signs and symptoms of agitation following study drug administration in patients with schizophrenia and bipolar disorder | Proportion of patients with a 1-point improvement in mCGI-S score following drug administration for the first treated episode | 2 hours after treatment for the first episode of agitation | 
| Part 2: Evaluate the effect of BXCL501 on the signs and symptoms of agitation following study drug administration in patients with schizophrenia and bipolar disorder | Proportion of CGI-C responders (patients who achieve a CGI-C score of 1 or 2) following drug administration for the first treated episode | 2 hours after treatment for the first episode of agitation | 
| Part 2: Evaluate the effect of BXCL501 on the signs and symptoms of agitation following study drug administration in patients with schizophrenia and bipolar disorder | Change in mCGI-S scores from pre-dose to post dose for the first treated episode | 2 hours after treatment for the first episode of agitation | 
| Part 2: Evaluate the effect of BXCL501 on the signs and symptoms of agitation following study drug administration in patients with schizophrenia and bipolar disorder | CGI-C scores following drug administration for the first treated episode | 2 hours after treatment for the first episode of agitation | 
| Part 2: Evaluate the effect of BXCL501 on the signs and symptoms of agitation following study drug administration in patients with schizophrenia and bipolar disorder | Time to end of an agitation episode from dosing for the first treated episode | Up to 24 hours after treatment for the first episode of agitation | 
| Part 2: Assess the continued efficacy of BXCL501 in the treatment of episodes of agitation | Proportion of patients with an improvement in agitation (Yes/No) post-dose for all treated episodes compared with placebo | 2 hours after treatment for all episodes of agitation, up to 12 weeks | 
| Part 2: Assess the continued efficacy of BXCL501 in the treatment of episodes of agitation | Proportion of mCGI-S responders following drug administration for the last treated episode and all treated episodes | 2 hours after treatment for all episodes of agitation, up to 12 weeks | 
| Part 2: Assess the continued efficacy of BXCL501 in the treatment of episodes of agitation | Proportion of patients with a 1-point improvement in mCGI-S score following drug administration for the last treated episode and all treated episodes | 2 hours after treatment for all episodes of agitation, up to 12 weeks | 
| Part 2: Assess the continued efficacy of BXCL501 in the treatment of episodes of agitation | Proportion of CGI-C responders following drug administration for the last treated episode and all treated episodes | 2 hours after treatment for all episodes of agitation, up to 12 weeks | 
| Part 2: Assess the continued efficacy of BXCL501 in the treatment of episodes of agitation | Change in mCGI-S scores from pre dose to post dose following drug administration for the last treated episode and all treated episodes | 2 hours after treatment for all episodes of agitation, up to 12 weeks | 
| Part 2: Assess the continued efficacy of BXCL501 in the treatment of episodes of agitation | CGI-C scores following drug administration for the last treated episode and all treated episodes | 2 hours after treatment for all episodes of agitation, up to 12 weeks | 
| Part 2: Assess the continued efficacy of BXCL501 in the treatment of episodes of agitation | The frequency of treated agitation episodes compared with placebo | Through study completion, an average of 12 weeks | 
| Part 2: Assess the continued efficacy of BXCL501 in the treatment of episodes of agitation | Time to end of an agitation episode from dosing for the last treated episode and across all treated episodes | Up to 24 hours after treatment for all episodes of agitation, up to 12 weeks | 
| Part 2: Assess the continued efficacy of BXCL501 in the treatment of episodes of agitation | Change in agitation behaviors scale following drug administration | 2 hours after treatment for all episodes of agitation, up to 12 weeks | 
| Part 2: Determine the overall clinical improvement after drug administration as measured by the use of rescue medications | Proportion of patients who receive rescue medication compared with placebo | Through study completion, an average of 12 weeks | 
| Part 2: Determine the overall clinical improvement after drug administration as measured by the use of rescue medications | Time to use of rescue medication for patients receiving BXCL501 compared with placebo | Through study completion, an average of 12 weeks |