Sub-Lingual Dexmedetomidine in Agitation Associated With Schizophrenia

Study Overview
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Brief Summary
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This is a two-stage adaptive Phase Ib trial design, that will identify two doses (lowest dose with clinical benefit and highest safe dose) in a first stage and better evaluate safety, tolerability and variability of effect in the second stage.

Detailed Description
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This is a two-stage adaptive Phase Ib trial design. It is a randomized, double-blind, placebo-controlled, multiple ascending dose study assessing efficacy, pharmacokinetics, safety and tolerability of BXCL501 dosing in adult (18-65 years old) males and females with acute agitation associated with schizophrenia, schizoaffective disorder, or schizophreniform disorder. The first stage will characterize a safe and tolerable dose range that results in a calming effect as measured using the PEC total score. The lowest dose with clear clinical benefit, and the highest safe and well-tolerated dose that demonstrates efficacy in a large proportion of subjects will be selected over the course of testing multiple escalating dose cohorts. The second stage will comprise a total of 40 subjects per dose group in a three-arm placebo-controlled design in order to better characterize the broader range of safety and tolerability as well as better estimate variability (effect size) which may be observed in later phase placebo-controlled trials.

Official Title
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A Phase Ib Multicenter, Randomized, Double-blind, Placebo-controlled, Multiple Ascending Dose Study to Determine Efficacy, Pharmacokinetics and Safety of BXCL501 in Agitation Associated With Schizophrenia

Conditions
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Agitation, Schizophrenia

Intervention / Treatment
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* Drug: Sublingual film containing BXCL501 (Dexmedetomidine)
* Drug: Placebo film


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients between the ages of 18 to 65 years, inclusive. Patients who have met Diagnostic and Statistical Manual (DSM) -5 criteria for schizophrenia, schizoaffective, or schizophreniform disorder. Patients who are judged to be clinically agitated at Baseline with a total score of ≥ 14 on the 5 items (poor impulse control, tension, hostility, uncooperativeness, and excitement) comprising the PANSS Excited Component (PEC). Patients who have a score of ≥ 4 on at least 1 of the 5 items on the PEC. Patients who read, understand and provide written informed consent. Patients who are in good general health prior to study participation as determined by a detailed medical history, physical examination, 12-lead ECG, blood chemistry profile, hematology, urinalysis and in the opinion of the Principal Investigator. Female participants, if of child-bearing potential and sexually active, and male participants, if sexually active with a partner of child-bearing potential, who agree to use a medically acceptable and effective birth control method throughout the study and for one week following the end of the study. Medically acceptable methods of contraception that may be used by the participant and/or his/her partner include abstinence, birth control pills or patches, diaphragm with spermicide, intrauterine device (IUD), condom with foam or spermicide, vaginal spermicidal suppository, surgical sterilization and progestin implant or injection. Prohibited methods include: the rhythm method, withdrawal, condoms alone, or diaphragm alone. Exclusion Criteria: Patients with agitation caused by acute intoxication, including positive identification of alcohol by breathalyzer or non-prescription drugs (with the exception of THC) during urine screening. Patients treated within 4 hours prior to study drug administration with benzodiazepines, other hypnotics or oral or short-acting intramuscular antipsychotics. Treatment with alpha-1 noradrenergic blockers (terazosin, doxazosin, tamsulosin, and alfuzosin, and prazosin) or other prohibited medications. Patients with significant risk of suicide or homicide per the investigator's assessment, or any suicidal behavior in last 6 months prior to screening. Female patients who have a positive pregnancy test at screening or are breastfeeding. Patients who have 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, orthostatic hypotension, a screening heart rate of < 55 beats per minutes or systolic blood pressure <110 mmHg or diastolic BP <70 mmHg. Patients with laboratory or ECG abnormalities considered clinically significant by the investigator or qualified designee [Advanced heart block (second-degree or above atrioventricular block without pacemaker), diagnosis of Sick sinus syndrome] that would have clinical implications for the patient's participation in the study. Patients with serious or unstable medical illnesses. These include current hepatic (moderate-severe hepatic impairment), renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease, congestive heart failure), endocrinologic, or hematologic disease. Patients who have received an investigational drug within 30 days prior to the current agitation episode. Patients who are unable to use the sublingual film or considered by the investigator, for any reason, to be an unsuitable candidate for receiving dexmedetomidine; e.g. patients with a history of allergic reactions to dexmedetomidine.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Interventional Model Description: This is a two-stage adaptive Phase Ib trial design. It is a randomized, double-blind, placebo-controlled, multiple ascending dose study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Sublingual Film with no active drug; single administration with the possibility of repeating dose after 1 hour in case of lack of significant efficacy | Drug: Placebo film<br>* Placebo film for BXCL501<br>* Other names: Placebo;|
| Experimental: 20 micrograms<br>Sublingual Film containing 20 micrograms BXCL501; single administration with the possibility of repeating dose after 1 hour in case of lack of significant efficacy | Drug: Sublingual film containing BXCL501 (Dexmedetomidine)<br>* Sublingual film containing BXCL501 (Dexmedetomidine) for the treatment of agitation associated with Schizophrenia<br>* Other names: Dexmedetomidine;|
| Experimental: 60 micrograms<br>Sublingual Film containing 60 micrograms BXCL501; single administration with the possibility of repeating dose after 1 hour in case of lack of significant efficacy | Drug: Sublingual film containing BXCL501 (Dexmedetomidine)<br>* Sublingual film containing BXCL501 (Dexmedetomidine) for the treatment of agitation associated with Schizophrenia<br>* Other names: Dexmedetomidine;|
| Experimental: 120 micrograms<br>2 Sublingual Films, each containing 60 micrograms BXCL501; single administration of 2 films with the possibility of repeating dose after 1 hour in case of lack of significant efficacy | Drug: Sublingual film containing BXCL501 (Dexmedetomidine)<br>* Sublingual film containing BXCL501 (Dexmedetomidine) for the treatment of agitation associated with Schizophrenia<br>* Other names: Dexmedetomidine;|
| Experimental: 180 micrograms<br>2 Sublingual Films, each containing 60 micrograms BXCL501. | Drug: Sublingual film containing BXCL501 (Dexmedetomidine)<br>* Sublingual film containing BXCL501 (Dexmedetomidine) for the treatment of agitation associated with Schizophrenia<br>* Other names: Dexmedetomidine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PANSS-EC Change From Baseline | Positive and Negative Syndrome Scale - Excited Component (PEC). The 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 to 35. | 120 minutes |