Safety, Tolerability and Activity of SRX246 in Adults With Intermittent Explosive Disorder

Study Overview
=================
Brief Summary
-----------------
This study is designed to explore the safety and tolerability, and to compare the activity of SRX246 against placebo, in adults with Intermittent Explosive Disorder (IED). Adult Male and Female subjects with a current diagnosis of IED will be enrolled. After a two-week baseline lead-in phase, study subjects who continue to meet enrollment criteria will be randomized to either SRX246 or Placebo treatment groups. Study subjects will be examined and asked to answer questionnaires at weekly scheduled visits throughout the trial. The study results will be determined based on any changes observed over the study period.

Detailed Description
-----------------
This exploratory Phase II study has been designed to examine the safety and tolerability profile, and to compare the activity of the novel V1a vasopressin antagonist (SRX246) against placebo, in adults with DSM-5 Intermittent Explosive Disorder (IED). Adult Male and Female subjects with a current DSM-5 diagnosis of IED will be enrolled. All subjects will undergo systematic diagnostic assessment for DSM-5 Axis I and II disorders. Subjects with DSM-5 IED (without current, co-morbid, DSM-5 Major Depression) whose: (a) Life History of Aggression (LHA) score is > 12, (b) Overt Aggression Scale Modified (OAS-M) Irritability score is > 6 and, (c) screening OAS-M Aggression score is > 15, will be entered into a two-week baseline lead-in phase. After the lead-in phase, study subjects who continue to meet OAS-M criteria will be randomized to one of the two (2) treatment conditions and stratified by gender so that equal numbers of males and females are assigned to SRX246 and Placebo Groups. Those who do not meet the criteria will exit the protocol at that time. Treatment Conditions: (a) 8-week course of SRX246 (4 weeks at 120 mg bid, and 4 weeks at 160 mg bid) or (b) 8-week course of Placebo, followed by a one-week taper to withdraw subjects from study medication. IED subjects in all conditions will have structured diagnostic interview sessions and questionnaires administered throughout the trial. Blinding to treatment condition will be maintained by using different personnel for these activities. Analysis of a change from baseline in the diagnostic measures will be performed.

Official Title
-----------------
An Exploratory Phase II Study to Determine the Safety, Tolerability and Activity of a Novel Vasopressin 1a Receptor Antagonist (SRX246) in Adults With Diagnostic and Statistical Manual Version 5 (DSM-5) Intermittent Explosive Disorder (IED)

Conditions
-----------------
Intermittent Explosive Disorder

Intervention / Treatment
-----------------
* Drug: SRX246
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or Female (Women of child bearing potential must be non-pregnant, non-lactating and agree to be on an acceptable method of contraception.) Age 21 to 55 years, inclusive. In good general physical health as determined by medical history, a baseline physical examination, vital signs, clinical laboratory tests and electrocardiogram (EKG) measurement. Current IED by DSM-5 LHA-Aggression ≥ 12. OAS-M Irritability score ≥ 6, and OAS-M Total Aggression score ≥ 15, respectively at Visit 1 Mean Irritability and Total Aggression scores for Visit 2 and Visit 3, ≥ 6 and ≥ 15, respectively. Subject is willing and able to sign written informed consent prior to receipt of any study medication or beginning study procedures. Subject is willing and able to follow instructions, comply with the protocol requirements and make all required study visits. Exclusion Criteria: Subject with a positive test for alcohol and/or drugs of abuse at screening or at any time during the study. Presence of any of the following serious and active medical conditions: Seizure Disorder (n.b.: history of < 2 febrile seizures prior to one year of age is acceptable); Demyelinating or Progressive Degenerative Disorders; central nervous system (CNS) Infection; Progressive Degenerative Neurological Disorder; Ischemic Heart Disease, Respiratory Disease, Renal Disease; Liver Disease; Type I Diabetes; Malignant Neoplasm; Hyper- or Hypo-Coagulopathy; Acquired Immuno-Deficiency Syndrome (AIDS). Routine or as needed consumption of medications or herbal supplements that the subject is unable or unwilling to discontinue during the study. Other ongoing psychotherapeutic treatment for the treatment of IED or anger begun less than three months before entry into this study. Not Current DSM-5 IED. LHA score < 12 at Visit 1 (screen). OAS-M Irritability score < 6 or OAS-M Total Aggression score < 15 at Visit 1 (screen). Current major depressive episode or life history of bipolar disorder, schizophrenia, organic mental syndrome, or mental retardation. Current DSM-5 Substance Use Disorder of moderate or greater severity (i.e., ≥ 4 Substance Use Disorder (SUD) symptoms). Active suicidal ideation as determined by clinical assessment and Columbia-Suicide Severity Rating Scale (C-SSRS). Evidence of any out-of range laboratory value at screening that has not been reviewed, approved and documented as not clinically significant by the Study Investigator. A history of significant drug allergy or systemic allergic disease (e.g., urticaria, atopic dermatitis), or any known/suspected hypersensitivity to SRX246. A general medical or psychological condition or behavior, including current substance dependence or abuse that, in the opinion of the investigator, might not permit the subject to complete the study or sign the informed consent. Unwilling/unable to sign informed consent document. Any clinically significant abnormality on screening resting 12-lead EKG (e.g., heart block, conduction disorders, ventricular and/or atrial arrhythmias). Any other condition or clinically significant abnormal findings on the physical examination, medical history, or clinical laboratory results during screening that, in the opinion of the Study Investigator, would make the subject unsuitable for the study or put them at additional risk. Inability to understand or follow study instructions. Treatment with an investigational drug within 30 days preceding the first dose of study medication. Women who are currently breastfeeding and/or lactating.

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 55 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SRX246<br>SRX246 capsules, 120mg bid for 4 weeks followed by 160mg bid for 4 weeks | Drug: SRX246<br>* capsules<br>|
| Placebo Comparator: Placebo<br>Placebo capsules to match the amount of SRX246 capsules for 8 weeks | Drug: Placebo<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability | measured as the number of participants with adverse events | from initial dose of intervention until completion of the study up to 8 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
IED, Aggression, Intermittent Explosive Disorder, SRX246, Vasopressin 1a Receptor Antagonist, V1a