PCORI Comparative Effectiveness Study-Esketamine (Spravato) vs. Ketamine-Equivalence Study

April 29, 2026 updated by: Samuel Wilkinson, Yale University

Comparative Effectiveness of Racemic Ketamine Versus Esketamine (Spravato®) for Depression

The purpose of this study is to compare the relative effectiveness, acceptability, and side effects of ketamine delivered through an IV (a drip into the arm) which is not currently FDA approved for use in the treatment of treatment-resistant depression (TRD) and Esketamine (Spravato®), taken as a nasal spray which has received FDA approval for use in the treatment of treatment-resistant depression (TRD) in the treatment of patients with treatment-resistant depression (TRD). The study will look at the following:

  • How well the treatment helps with symptoms of depression (effectiveness),
  • How comfortable and willing people are to use the treatment (acceptability), and
  • How well people can deal with any side effects from the treatment (tolerability).

The study will also examine factors that may predict which treatment works better for certain patients.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This non-inferiority, multi-site, comparative effectiveness study will utilize a randomized design. Individuals with treatment resistant depression (TRD) will be randomized (1:1) to Spravato® or IV ketamine. This 5-year multisite comparative effectiveness study will enroll 400 total patients (~200 per group).

Study Type

Interventional

Enrollment (Estimated)

400

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Connecticut
      • Milford, Connecticut, United States, 06461
        • Recruiting
        • Mood Institute
        • Contact:
        • Principal Investigator:
          • Lisa Harding, MD
      • New Haven, Connecticut, United States, 06512
        • Recruiting
        • Yale School of Medicine
        • Contact:
        • Principal Investigator:
          • Samuel Wilkinson, MD
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Recruiting
        • Emory University
        • Contact:
          • Brandon Kitay, MD
          • Phone Number: 404-712-6939
    • Michigan
      • Ann Arbor, Michigan, United States, 48104
        • Active, not recruiting
        • University of Michigan
    • Oklahoma
    • Texas
      • Bellaire, Texas, United States, 77401
        • Recruiting
        • Houston Center for Advanced Psychiatric Treatment
        • Contact:
          • Sandhya Prashad, MD
        • Contact:
        • Principal Investigator:
          • Sandhya Prashad, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Provision of signed and dated informed consent form
  • Stated willingness to comply with all study procedures and availability for the duration of the study
  • Adults ages 18 or older
  • Diagnosis of major depressive disorder that is refractory to two or more antidepressant trials
  • Moderate or severe depression based on an initial MADRS score ≥ 25
  • Judged appropriate for ketamine or esketamine by clinician, independent of potential study participation

  • A female participant must be:

    a. Not of childbearing potential*, OR b. Of childbearing potential and practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly) and agrees to remain on a highly effective method while receiving study intervention and until 1 week after last dose - the end of relevant systemic exposure. The investigator will evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of drug. Acceptable methods of contraception are: i. combined (estrogen and progestogen containing) hormonal or progestogen-only hormonal contraception associated with inhibition of ovulation (oral, transdermal, or intravaginal) ii. intrauterine device (IUD) iii. intrauterine hormone-releasing system (IUS) iv. bilateral tubal occlusion/ligation v. male partner with a bilateral vasectomy with documented aspermia or a bilateral orchiectomy vi. male or female condom with spermicide, diaphragm, or sponge with spermicide (Note: Use of condom as the sole method of contraception is not considered to be a highly effective method of contraception).

  • A female participant must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study * We will consider women to be of childbearing potential if they are within 2 years of menopause (within 3 years since last menstrual period) and have not had a hysterectomy, bilateral oophorectomy, or other definitive surgical intervention.

Exclusion Criteria:

  • Diagnosis of bipolar disorder or psychotic disorder (i.e., schizophrenia, schizoaffective disorder)
  • Other psychiatric comorbidities are permitted so long as depression is the predominant diagnosis
  • Active or recent (within 12 months) substance use disorder (other than nicotine)
  • Pregnant or lactating women
  • Intracerebral hemorrhage or aneurysmal vascular disease
  • Hypersensitivity to ketamine, esketamine or any of the excipients
  • Known family history of ketamine use disorder
  • Prior known ketamine use disorder as well as subjects for whom study participations will result in more than 8 lifetime exposures to ketamine (e.g., prior exposure to ketamine, prior recreational use with ketamine). Prior esketamine exposure is also exclusionary.
  • Uncontrolled hypertension, as demonstrated by a blood pressure of greater than 145 / 90 at screening visit. (Pre-treatment blood pressure will be permitted to be 150 / 95 to allow for "whitecoat" hypertension on treatment visits 1-8.)
  • Known cardiovascular and cerebrovascular conditions that are associated with an increased risk related to ketamine or esketamine administration (including space-occupying CNS lesions). This includes those prospective participants who undergo EKG and are shown to have an abnormality that would put them at increased risk related to treatment.
  • Known condition for which an acute rise in blood pressure would pose a serious risk.
  • Arteriovenous malformation
  • Positive urine toxicology at screening visit, except for substances that are prescribed (i.e., benzodiazepines, stimulants). Given the extended length of time between exposure and negative toxicology screen, a positive screen for THC will not be exclusionary unless the pattern of use and clinical evaluation are indicative of cannabis use disorder. Cannabis used within 24 hours of dosing is exclusionary.
  • Positive alcohol breathalyzer at screening or clinical signs of intoxication
  • The patient is unable to arrange for someone to drive them home after each treatment session; patients who are unwilling to refrain from driving and operating machinery on treatment days until the next day following sleep will be excluded.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Racemic Ketamine
Ketamine will be given intravenously. Per FDA guidance, the max dose of ketamine will be 60mg per day, with a total lifetime limit of 8 doses. Ketamine will be infused over 40 minutes.
Drug: Racemic ketamine
Ketamine will be given intravenously. Per FDA guidance, the max dose of ketamine will be 60mg per day, with a total lifetime limit of 8 doses. Ketamine will be infused over 40 minutes.
Experimental: Spravato (Esketamine)
Spravato® (Esketamine) will be given intranasally. For esketamine, the dose will be between 56 and 84mg, according to the FDA label for the drug. Allowances will be made for patients who have difficulty tolerating these doses to be dosed at 28mg in subsequent treatment sessions.
Drug: Spravato (Esketamine)
Spravato® (Esketamine) will be given intranasally. For esketamine, the dose will be between 56 and 84mg, according to the FDA label for the drug. Allowances will be made for patients who have difficulty tolerating these doses to be dosed at 28mg in subsequent treatment sessions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Self-Reported Effectiveness
Time Frame: 30 days
defined as the change in depression severity after 8 treatments, as assessed by the 16-item, patient-reported outcome, Quick Inventory of Depression Symptomatology (QIDS-SR16), at the end of one-month of treatment. Scale ranges from 0 - 27 with higher scores indicating worse depression.
30 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinician-Reported Effectiveness
Time Frame: baseline until end of treatment (4 weeks)
change in Montgomery-Asberg Depression Rating Scale (MADRS) score. Scale ranges from 0-60 with higher scores indicating worse depression.
baseline until end of treatment (4 weeks)
Response
Time Frame: baseline until end of treatment (4 weeks)
defined as a ≥50% decrease from baseline to end of week 4 on the Quick Inventory of Depression Symptomatology (QIDS-SR16). The proportion and number of participants with response will be compared between groups.
baseline until end of treatment (4 weeks)
Remission
Time Frame: baseline until end of treatment (4 weeks)
defined as a total score of ≤ 5 on the Quick Inventory of Depression Symptomatology (QIDS-SR16). The proportion and number of participants with remission will be compared between groups.
baseline until end of treatment (4 weeks)
Suicidal Ideation and Behavior
Time Frame: baseline until end of treatment (4 weeks)
The Columbia-Suicide Severity Scale Rating (C-SSRS) will be collected to examine any comparative differences in suicidal ideation. Scale ranges from 0-5 (for suicidal ideation) with higher scores indicating worse ideation. Scale for behavior measures counts of suicide behaviors.
baseline until end of treatment (4 weeks)
Level of Disability
Time Frame: baseline until end of treatment (4 weeks)
The Sheehan Disability Scale (SDS) will be used to assess any changes in patient disability levels associated with the treatments. The SDS is a patient rated discretized analog measure of functional disability in work, social and family life. Score for each subscale ranges from 0-10, with higher scores indicating worse disability.
baseline until end of treatment (4 weeks)
Quality of Life
Time Frame: baseline until end of treatment (4 weeks)
defined as changes in quality of life, as assessed by the Quality of Life in Depression Scale (QLDS). The QLDS will assess changes in the quality-of-life factors in relation to antidepressant treatments. The score ranges from 0-34, with higher scores indicating worse quality of life.
baseline until end of treatment (4 weeks)
Utilization of Healthcare Resources
Time Frame: end of treatment (4 weeks)
Measure using the Health Resource Utilization Questionnaire to track all cause healthcare utilization by assessing patients visits to all forms of healthcare providers and settings and tracking the use of other health related resources. In specific, group comparisons on specific types of patient visits (e.g., therapy visits, hospitalizations, ED visits) will be made. The scale measures counts of healthcare visits.
end of treatment (4 weeks)
Acceptability
Time Frame: end of treatment (4 weeks after baseline)
The 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9) will be used as the key secondary outcome measure. The TSQM-9 is a validated tool for assessing patient satisfaction with treatment and covers the domains of effectiveness, convenience, and global satisfaction. Each domain is scored from 0-100 with lower scores indicating lower satisfaction. Behavioral measures will be used to assess treatment acceptability by comparing dropout rates and missed visits between the two treatment options.
end of treatment (4 weeks after baseline)
Patient and Clinician Global Severity and Improvement
Time Frame: baseline until end of treatment (4 weeks)
Global improvement of depression will be assessed with the Clinician and Patient Global Impression-Severity/Improvement indices. These are simple measures for clinicians and patients to provide information on overall depression severity and improvement with treatment. The scale ranges from 1-7 with higher scores indicating worse depression.
baseline until end of treatment (4 weeks)
Tolerability and Safety
Time Frame: baseline until end of treatment (4 weeks)
Tolerability will be based on group comparison of number of patients who experience adverse events of special interest. These include vomiting, dysphoric reactions, and clinically meaningful elevations in blood pressure and/or heart rate during the treatment session.
baseline until end of treatment (4 weeks)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Yale University

Collaborators

Patient-Centered Outcomes Research Institute

Investigators

  • Principal Investigator: Samuel Wilkinson, MD, Samuel.Wilkinson@yale.edu

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 27, 2025

Primary Completion (Estimated)

December 31, 2030

Study Completion (Estimated)

December 31, 2030

Study Registration Dates

First Submitted

November 27, 2024

First Submitted That Met QC Criteria

November 27, 2024

First Posted (Actual)

December 3, 2024

Study Record Updates

Last Update Posted (Actual)

May 5, 2026

Last Update Submitted That Met QC Criteria

April 29, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2000037121
  • 23-005287 (Other Grant/Funding Number: PCORI)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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