Long-Term Maintenance With Ketamine and Esketamine for Reduction of Suicide in High-Risk Patients With Depression

Study Overview
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Brief Summary
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The study will consist of a 24-week-long trial examining outcomes in patients with Major Depressive Disorder and suicidal ideation who will receive intravenous (IV) ketamine and intranasal (IN) esketamine, compared to a large sample of matched historical controls. Patients will be recruited from an inpatient psychiatric unit. Eligible patients who provided informed consent will be enrolled in the study that will include a eight IV ketamine treatments, 13 esketamine treatment visits, seven long assessment visits, five short assessment visits, and daily surveys. The study will examine the feasibility, tolerability, and efficacy of repeated IV ketamine followed by esketamine, as well as predictors of treatment response.

Official Title
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Long-Term Maintenance With Ketamine and Esketamine for Reduction of Suicide in High-Risk Patients With Depression

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: Ketamine
* Drug: Esketamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inpatient at a psychiatric unit at MGH Male and female, 18-70 years of age Diagnosis of Major Depressive Disorder, single or recurrent, based on DSM-5 criteria, and currently experiencing a major depressive episode (MDE) at least eight weeks in duration, prior to screening Current suicidal ideation In good general health, as ascertained by medical history, physical examination, clinical laboratory evaluations, and/or ECG A status of non-childbearing potential or use of an acceptable form of birth control Access to a mobile phone or computer with internet connection Ability to read, understand, and provide written and dated informed consent prior to screening Has a treating psychiatrist, either prior to admission or at discharge from the inpatient unit Exclusion Criteria: Any history of previous treatment with IV ketamine Pregnant or breastfeeding A status of childbearing potential and is not willing to use birth control during the study Unstable medical illness Current diagnosis of a moderate to severe substance use disorder, within the last six months prior to screening based on DSM-5 criteria History of bipolar disorder, or any psychotic symptoms in the current or previous depressive episodes An Axis I or Axis II Disorder, which at screening is clinically predominant to their MDD or has been predominant to their MDD at any time within six months prior to screening (i.e., eating disorder, OCD, PTSD) Currently receiving ECT treatment Currently receiving frequent or high dose benzodiazepines, opiates, barbiturates, or other CNS depressant medications Has dementia, delirium, amnestic, or any other primary cognitive disorder Has a clinically significant abnormality on the screening physical examination that might affect safety, study participation, or confound interpretation of study results Inability to consent to or comply with the study procedures. Other medical issues that might affect safety, study participation, or confound interpretation of study results Inability to comply with study safety procedures, including having reliable escorts to and from visits

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Intervention Model: Single Group Assignment
Interventional Model Description: A total of 100 participants will be enrolled in the study to receive intravenous ketamine and intranasal esketamine. Participants will be compared against matched historical control subjects identified through electronic medical records.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Ketamine and Esketamine Treatment<br>All study subjects will receive intravenous (IV) ketamine and intranasal (IN) esketamine treatment. | Drug: Ketamine<br>* Study participants will start treatment including two ketamine infusion visits per week during the acute phase, for up to eight ketamine infusion visits. Participants will then be transitioned to maintenance with intranasal esketamine.<br>Drug: Esketamine<br>* After one month from the eighth ketamine infusion visit, participants will initiate weekly esketamine for 12 weeks, for a total of 13 esketamine treatments. The esketamine visits will happen as per standard of care at the clinic and as instructed by the SPRAVATO Risk Evaluation and Mitigation Strategy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility - Retention | For examining the feasibility of treatment with ketamine and esketamine, descriptive analyses will be conducted to assess participants' retention across study visits. | 24 weeks | 
| Feasibility - Drop-out Rates | For examining the feasibility of treatment with ketamine and esketamine, descriptive analyses will be conducted to assess participants' drop-out rates across participation in the study. | 24 weeks | 
| Tolerability - Cognitive Function and Side Effects | In regard to tolerability, the investigators will closely monitor cognitive functions and side effects during the administration of ketamine and esketamine. | Weeks 0, 1, 2, 3, 4, 8, and 12-24 | 
| Tolerability - Dosage of Treatment | In regard to tolerability, the investigators will record the Necessary Clinical Adjustments (NCAs) for dosage of ketamine and esketamine treatments. | Change between weeks 0, 4, 6, 8, 10, 12, 14, 16, 20, 22, and 24 | 
| Tolerability - Frequency of Treatment | In regard to tolerability, the investigators will record the Necessary Clinical Adjustments (NCAs) for the frequency of ketamine and esketamine administration. | Change between weeks 0, 4, 6, 8, 10, 12, 14, 16, 20, 22, and 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy - Treatment Response | Descriptive analyses will be performed for percentage of responders (defined as 35% improvement on the QIDS-16) at the end of the IV ketamine acute phase, after the eighth ketamine infusion, and across the esketamine maintenance phase. | Weeks 4, 8, and 12-24 | 
| Efficacy - Trajectory of Suicidal Ideation | The change in participants' suicidal ideation will be examined over time and compared to historical controls. | 24 weeks | 
| Efficacy - Trajectory of Depression | The change in participants' depression will be examined over time and compared to historical controls. | 24 weeks | 
| Efficacy - Hospital Readmission Rates | The change in participants' hospital readmission rates will be examined over time and compared to historical controls. | 24 weeks | 
| Efficacy - Prevalence of Suicidal Behavior | The occurrence of suicidal behavior (gestures, attempts, and completed suicide) among participants will be examined over time and compared to historical controls. | 24 weeks | 
| Efficacy - Healthcare Utilization | The change in participants' healthcare utilization rates will be examined over time and compared to historical controls. | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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depression, suicidal ideation