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

NCT06713616 | Recruiting Phase 3 DMC FDA Drug

• 2 other identifiers: 200003712123-005287
• Study Type: interventional
• Target: 400
• Locations: 1 country
• Sites: 6

Brief 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.

Conditions

Depression

Outcome Measures

Primary Outcomes (1)

• Self-Reported Effectiveness

  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 Outcomes (10)

• Clinician-Reported Effectiveness

  baseline until end of treatment (4 weeks)

• Response

  baseline until end of treatment (4 weeks)

• Remission

  baseline until end of treatment (4 weeks)

• Suicidal Ideation and Behavior

  baseline until end of treatment (4 weeks)

• Level of Disability

  baseline until end of treatment (4 weeks)

Study Arms (2)

Racemic Ketamine

EXPERIMENTAL

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

Spravato (Esketamine)

EXPERIMENTAL

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)

Interventions

Racemic ketamine DRUG

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.

Racemic Ketamine

Spravato (Esketamine) DRUG

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.

Spravato (Esketamine)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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
• 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 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.

Sponsors & Collaborators

• Yale University: lead
• Patient-Centered Outcomes Research Institute: collaborator

Study Sites (6)

Mood Institute

Milford, Connecticut, 06461, United States

RECRUITING

Yale School of Medicine

New Haven, Connecticut, 06512, United States

RECRUITING

Emory University

Atlanta, Georgia, 30322, United States

RECRUITING

University of Michigan

Ann Arbor, Michigan, 48104, United States

ACTIVE NOT RECRUITING

LifeStance Health

Moore, Oklahoma, 73160, United States

RECRUITING

Houston Center for Advanced Psychiatric Treatment

Bellaire, Texas, 77401, United States

RECRUITING

MeSH Terms

Conditions

Depression

Interventions

Esketamine

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior

Study Officials

• Samuel Wilkinson, MD

  Samuel.Wilkinson@yale.edu

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Cindy Voghell

CONTACT

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Psychiatry

Model Details: This study is a randomized phase 3 drug treatment study. Subjects will be randomized, in randomly varying blocks of no more than 8 at each site, to receive either esketamine (Spravato®) or intravenous ketamine. This study is unblinded.

Study Record Dates

• First Submitted: November 27, 2024
• First Posted: December 3, 2024
• Study Start: January 27, 2025
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): December 31, 2030
• Last Updated: May 5, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (6)