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PCORI Comparative Effectiveness Study-Esketamine (Spravato) vs. Ketamine-Equivalence Study | Clinical Trials | Clareo Health

RECRUITINGPHASE3

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

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

NCT06713616•Yale University

View on ClinicalTrials.gov

Summary

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.

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).

Eligibility

Age

18 - No limit years

Sex

ALL

Healthy Volunteers

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)
•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.
+5 more criteria

Locations (6)

Mood Institute

Milford, Connecticut, United States

Yale School of Medicine

New Haven, Connecticut, United States

Emory University

Atlanta, Georgia, United States

University of Michigan

Ann Arbor, Michigan, United States

LifeStance Health

Moore, Oklahoma, United States

Houston Center for Advanced Psychiatric Treatment

Bellaire, Texas, United States

Key Dates

Start Date

January 27, 2025

Primary Completion Date

December 31, 2030

Completion Date

December 31, 2030

Last Updated

February 17, 2026

Enrollment

400

ESTIMATED participants

Conditions

Depression

Interventions

Racemic ketamine

DRUG

Spravato (Esketamine)

DRUG

Contacts

Cindy Voghell

CONTACT

203-737-4784 Cynthia.Voghell@yale.edu

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Data Source & Attribution

This clinical trial information is sourced from ClinicalTrials.gov, a service of the U.S. National Institutes of Health.

ClinicalTrials.gov last update: February 17, 2026Data synced to Clareo: March 29, 2026

Modifications: This data has been reformatted for display purposes. Eligibility criteria have been parsed into inclusion/exclusion sections. Location data has been geocoded to enable distance-based search. For the authoritative and most current information, please visit ClinicalTrials.gov.

Neither the United States Government nor Clareo Health make any warranties regarding the data. Check ClinicalTrials.gov frequently for updates.

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

Inclusion Criteria

Exclusion Criteria

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