Assessing SLS-002 (Intranasal Racemic Ketamine) in Adults With Major Depressive Disorder at Imminent Risk of Suicide

Depression Clinical Trial

Official title:

A 2-Part Phase 2 Study to Assess the Efficacy, Safety, and Tolerability of SLS-002 (Intranasal Racemic Ketamine) Administered to Adults With Major Depressive Disorder at Imminent Risk of Suicide

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05417074
• Other study ID #: IRB00331675
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: August 15, 2022
• Est. completion date: August 15, 2023

Study information

• Verified date: June 2022
• Source: Johns Hopkins University
• Contact: Paul Kim, MD, PhD
• Phone: 4105020622
• Email: pmkim[@]jhmi.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to evaluate the efficacy, safety, and tolerability of SLS-002 (intranasal racemic ketamine) in addition to standard of care on symptoms of depression and suicidality in adults with Major Depressive Disorder who are at imminent risk for suicide.

Description:

This Phase 2, multicenter, 2-part study in adult subjects diagnosed with MDD at imminent risk of suicide will evaluate the efficacy, safety, and tolerability of intranasally (IN) administered SLS-002 (IN spray) plus SOC. In Part 1, 16 subjects will receive open-label SLS-002 (90 mg). Part 2 of the study is double-blind and 220 subjects will be randomized 1:1 to receive either SLS-002 (90 mg) or matching placebo. The Johns Hopkins Hospital Department of Psychiatry and Behavioral Sciences will be working with Seelos Therapeutics on Part 2 of the study with an estimated enrollment of 10 participants.

After admission to the emergency room or hospital, each subject will participate in a 1- to 2-day screening phase, a 16-day treatment phase including standard of care during which study drug will be administered 2 times per week for a total of 5 doses, and a 2-week safety follow-up phase for a total of up to 5 weeks of study participation. Subjects will be treated as inpatients for approximately 7 days (including screening), and assuming the subject meets readiness for discharge criteria, will be discharged on Day 6 to continue the trial as outpatients, provided it is clinically appropriate to do so.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 10
• Est. completion date: August 15, 2023
• Est. primary completion date: March 15, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• The subject is able to speak, read, and understand English and/or the language of the investigative staff to sufficiently understand the nature of the study, to provide written informed consent, and to allow the completion of all study assessments.

• Subject is 18 to 65 years of age at the time of informed consent.

• Male subjects who are sexually active must agree to abstain from sexual activity or be willing to use medically acceptable contraception if they become sexually active from time of consent and for 3 months after the last dose of study drug.

• Female subjects must have a negative serum pregnancy test at screening, and must not be breastfeeding or lactating. Females must be willing to abstain from sexual activity or use medically accepted contraception if they are sexually active from time of consent and for 1 month after the last dose of study drug.

• The subject meets Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for a diagnosis of current MDD (unipolar without psychotic features), with symptoms present for at least 4 weeks, based on psychiatric intake and confirmed by the Mini International Psychiatric Interview Version 7.02 for Suicidality Disorders (MINI).

• The subject has a Montgomery Åsberg Depression Rating Scale (MADRS) total score of =28 predose on Day 1.

• The subject has a score of 5 or 6 on item 10 of the MADRS predose on Day 1.

• The subject has a Clinical Global Impression (CGI) of Severity for Suicidal Ideation and Behavior (SI/B) (CGIS-SI/B) score of =4 predose on Day 1.

• In the investigator's opinion, the subject requires psychiatric hospitalization due to significant risk of suicide, has =15 on the S-STS CMCM total score, and a score of 6-9 (inclusive) on the S-STS CMCM Clinician judgment of subject's risk of a suicide attempt or death by suicide at this time (p12 top) predose on Day 1.

• In the investigator's opinion, the subject has current suicidal ideation with intent, which is confirmed by the MINI Suicidality Module at screening and baseline, specifically a positive response related to present symptoms on Question B3, as well as a positive response related to symptoms within the past 24 hours on Question B10 or B11. NOTE: Although the full MINI assessment is not conducted at baseline, the investigator must confirm that the subject continues to meet this criterion prior to enrollment (i.e., Questions B3, B10, and B11 should be revisited with the subject predose at baseline).

• In the investigator's opinion, if the imminent suicidality is based upon a precipitating event (i.e., a clearly identifiable situational stressor that contributes to initiation or exacerbation of the subject's current suicidality), the active suicidality must be present for >72 hours.

• The subject has a history of previous suicide attempt(s), as confirmed on the Columbia Suicide Severity Rating Scale (C-SSRS) with a history of at least one actual attempt, or if the attempt was interrupted or aborted, is judged to have been serious in intent in the investigator's opinion.

• As part of SOC treatment, the subject agrees to be hospitalized voluntarily for a recommended period of approximately 7 days (screening to Day 6), and fully understands that the duration of hospitalization may be longer if clinically indicated (i.e., he/she is not safe to be discharged on Day 6).

• The subject is willing and able to take prescribed non- investigational antidepressant therapy(ies) at investigator's discretion for at least the duration of the study.

• The subject is willing and able to maintain other existing treatments and to avoid the use of alcohol, cannabidiol (CBD) oil, and recreational drugs, from screening through the last study visit (Day 29/30). Note: Subjects with acute alcohol intoxication should not be screened (but can be screened once sober); subjects suspected of intoxication can be confirmed by blood alcohol concentration (BAC) or breathalyzer.

• The subject is able to complete IN administration of study drug.

Exclusion Criteria:

• Subjects who have ongoing sequelae from prior Coronavirus disease of 2019 (COVID) illness, or subjects who have either documented COVID infection or symptoms suggestive of recent COVID infection within 1 month of screening.

• The subject has a lifetime diagnosis of bipolar disorder, any mood disorder with psychotic features, schizophrenia or other psychotic disorder, obsessive-compulsive disorder, or antisocial personality disorder, as confirmed by the MINI. (Note subjects who have post-traumatic stress disorder and generalized anxiety disorder (GAD)/panic disorder are not necessarily excluded as long as MDD is the most prominent diagnosis.) Subject has impulse attack suicidality disorder, homicidal suicidality disorder, or any suicidality disorder associated with the above diagnoses.

• In the investigator's opinion, the subject has chronic, refractory treatment-resistant depression (TRD) from >4 adequate therapeutic trials of antidepressants (with or without adjuvants and/or electroconvulsive therapy [ECT]) as confirmed by Antidepressant Treatment Response Questionnaire (ATRQ).

• In the investigator's opinion, the subject has a current diagnosis of borderline personality disorder or, if the subject has not met full diagnostic criteria for borderline personality disorder within the last 5 years, the subject has a history of recurrent non-suicidal self-injury, or self-mutilating behavior.

• The subject has a score of 10 on the S-STS CMCM Clinician judgment of subject's risk of a suicide attempt or death by suicide at this time (top of S-STS CMCM p12).

• The subject is diagnosed with intellectual disability, a neurocognitive disorder including dementia, or has a history of moderate or severe traumatic brain injury. Mild traumatic brain injuries are not necessarily exclusionary provided the investigator believes current symptoms would not interfere with conduct or interpretation of safety and/or efficacy assessments.

• The subject has a history or current finding of any clinically significant, hematological, hepatic, respiratory, renal, neurological, known positive human immunodeficiency virus (HIV) infection, gastrointestinal disorder, or other disease that might confound the results of safety assessments conducted in the study.

• The subject has a history of seizures (other than childhood febrile seizures).

• The subject has a body mass index (BMI) >40 or <18 at screening.

• The subject has known, uncontrolled hypertension or blood pressure (BP) that, in the investigator's judgment, should exclude the subject at screening or baseline (BP may be repeated as per the site's standard operating procedures [SOPs]).

• The subject has a known history or current finding of cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, congenital heart disease, ischemic heart disease, cardiac insufficiency, supraventricular and ventricular heart rhythm disorder, prolonged QT syndrome (i.e., the QT interval corrected for heart rate using Fridericia's formula [QTcF] >450 msec) and associated risk factors (i.e., hypokalemia, family history of long QT syndrome), syncope, cardiac conduction problems (e.g., clinically significant heart block), exercise-related cardiac events including syncope and pre-syncope, clinically significant bradycardia, or other serious cardiac problems.

• The subject has a known family history of sudden cardiac death or ventricular arrhythmia.

• The subject has any clinically significant abnormality on 12-lead ECG performed at screening or baseline such as serious arrhythmia, cardiac conduction problems, or other abnormalities deemed to be a potential safety issue.

• The subject has a concurrent chronic or acute illness, disability, or other condition (e.g., narcolepsy) that might confound the results of safety assessments conducted in the study.

• The subject has any medical condition that could interfere with the absorption of IN ketamine (e.g., nasal polyps, clinically significant deviated septum [corrected or persistent], or other physical abnormalities of the nose).

• The subject has symptomatic or uncontrolled hyper- or hypothyroidism or has had changes to their treatment for hyper- or hypothyroidism within 90 days prior to Day 1.

• The subject meets the DSM-5 criteria for moderate or severe substance use disorder in the 6 months prior to screening, OR in the investigator's opinion, is at risk of withdrawal from substance use (e.g., opiate or alcohol dependent), OR has a lifetime history of ketamine, phencyclidine (PCP), lysergic acid diethylamide, or 4-methylenedioxy-methamphetamine hallucinogen-related use disorders. Nicotine use disorder is permitted.

• The subject has a positive urine test for PCP, cocaine, or amphetamines (inclusive of amphetamine, methamphetamine [mAMP], and 3, 4-methylenedioxy-methamphetamine [MDMA]) at screening.

• The subject has positive hepatitis B, hepatitis C, or HIV results at screening.

• The subject has any history of using ketamine or esketamine for any psychiatric treatment.

• The subject has known or suspected intolerance or hypersensitivity to the investigational product(s), closely related compounds, or any ingredients.

• In the investigator's opinion, the subject has any clinically significant laboratory abnormality including an abnormality that indicates clinically significant hematologic, hepatobiliary, or renal disease. NOTE: All abnormal liver function tests at screening must be reviewed with the medical monitor. Any other lab abnormalities of potential clinical significance should be discussed with the medical monitor.

• The subject has received an investigational product, including vaccines, within 30 days prior to the first dose of study drug.

• The subject was previously enrolled in the current study. Subjects previously screened for, but not randomized in, the current study may be rescreened with approval from the study medical monitor.

• The subject does not meet or is not willing to comply with the requirements related to prohibited and restricted medications and therapies, as well as required washout periods prior to participation. Prohibited medications and therapies include, but are not limited to, monoamine oxidase inhibitors (MAOIs), opioids or drugs with activity at the opioid receptor, psychostimulants, lamotrigine, N-methyl- D-aspartate (NMDA) receptor modulators, magnesium, ECT therapy, transcranial magnetic stimulation (TMS) or any medication/therapy that might confound the results of safety assessments conducted in the study. Subjects who have received any of these prohibited medications within 2 weeks of screening are excluded from the study. Potent cytochrome p450 (CYP) 3A4 inhibitors, including nefazodone and fluvoxamine, are not permitted within 1 week of first dose and until at least 1 day after the last dose. Potent CYP 3A4 inducers, including St. John's wort, are not permitted within 30 days of first dose and until at least 1day after the last dose. Subjects who have recently discontinued lithium or calcium channel blockers within 3 months prior to screening are also excluded.

• The subject is an employee of the sponsor, clinical research organization (CRO), or research site personnel directly affiliated with this study or their immediate family member defined as a spouse, parent, child, or sibling, whether biological or legally adopted.

• The subject has pending legal charges or is on probation.

• The subject, in the investigator's opinion, is considered unsuitable or unlikely to comply with the study protocol for any reason.

• The subject is legally incapacitated, has been involuntarily hospitalized in the past year, or has another significant mental health issue, physical issue, or life circumstance that could interfere with the conduct or interpretation of study evaluations.

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Suicidal Behavior
• Suicidal Ideation
• Suicide

Intervention

Drug:
• Placebo
Identical bi-dose nasal spray devices will be used for placebo, which will be labelled prior to shipment to maintain the blind at the site. Placebo will consist of purified water USP, with denatonium benzoate NF (a bittering agent to simulate the bitter taste of ketamine in SLS-002), and benzalkonium chloride NF. Each spray will deliver 0.1 mL of placebo solution.
• SLS-002
The investigational product (SLS-002) is ketamine hydrochloride (HCl) for intranasal (IN) administration. The IN formulation to be used in this study is 15% weight per volume (w/v) ketamine HCl. SLS-002 consists of United States Pharmacopeia (USP)-grade ketamine HCl, 150mg/mL, in purified water USP, with benzalkonium chloride National Formulary (NF) as an antimicrobial preservative. It will be administered using a bi-dose nasal delivery device. Two sprays (0.1 mL per spray) for a total of 0.2 mL (30 mg) of ketamine HCl will be administered from each device, 1 spray per nostril. Three devices will be used to deliver a 90 mg dose per treatment; 3 x 15% w/v ketamine HCl.

Other:
• Standard of care
Standard of care treatment will be determined by the study physician based on clinical judgement and practice guidelines.

Locations

Country	Name	City	State
United States	Johns Hopkins Hospital	Baltimore	Maryland

Sponsors (2)

Lead Sponsor	Collaborator
Johns Hopkins University	Seelos Therapeutics, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at 24 Hours Following Initial Dose	The MADRS is a 10-item scale designed to assess severity of depression. Questions address apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Items are scored on a scale ranging from 0 to 6 with 2-point intervals and a total score ranging from 0 to 60, with higher MADRS scores indicating more severe depression.	Baseline and 24 hours post first dose
Secondary	Change From Baseline in Clinical Global Impression of Severity for Suicidal Ideation and Behavior (CGIS-SI/B) Scale at 24 Hours Following Initial Dose	The CGIS-SI/B scale is a 5-item clinician-rated measure of suicidality-specific symptom severity, originally deployed in the International Suicide Prevention Trial. Clinicians rate the most severe level of suicidality experienced by the subject during the specified recall period, with response reported on a 5-point Likert-type scale ranging from 1 (not at all suicidal) to 5 (among the most extremely suicidal).	Baseline and 24 hours post first dose
Secondary	Change From Baseline in Patient Global Impression of Severity for Suicidal Ideation and Behavior (PGIS-SI/B) Scale at 24 Hours Following Initial Dose	The PGIS-SI/B is a 5-point, patient-rated scale for assessing the subject's view of the general severity of their illness, which is rated on a single-item Likert-type scale ranging from 1 (not present) to 5 (extremely severe).	Baseline and 24 hours post first dose
Secondary	Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Day 16	The MADRS is a 10-item scale designed to assess severity of depression. Questions address apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Items are scored on a scale ranging from 0 to 6 with 2-point intervals and a total score ranging from 0 to 60, with higher MADRS scores indicating more severe depression.	Baseline and Day 16
Secondary	Change From Baseline in Clinical Global Impression of Severity for Suicidal Ideation and Behavior (CGIS-SI/B) Scale at Day 16	The CGIS-SI/B scale is a 5-item clinician-rated measure of suicidality-specific symptom severity, originally deployed in the International Suicide Prevention Trial. Clinicians rate the most severe level of suicidality experienced by the subject during the specified recall period, with response reported on a 5-point Likert-type scale ranging from 1 (not at all suicidal) to 5 (among the most extremely suicidal).	Baseline and Day 16
Secondary	Change from Baseline in Sheehan-Suicidality Tracking Scale Clinically Meaningful Change Measure (S-STS CMCM) Total Score at 24 Hours Following Initial Dose	The S-STS CMCM is a clinician-rated outcome measure which assesses suicidal ideation or behavior on multiple patient and clinician-rated items. It includes 13 suicidality items that are rated on a Likert-type scale ranging from "not at all" (0) to "extremely" (4), yielding a total score ranging from 0 to 52.	Baseline and 24 hours post first dose