DepressionPhase 3NCT06713616
PCORI Comparative Effectiveness Study-Esketamine (Spravato) vs. Ketamine-Equivalence Study
A Phase 3 study testing Racemic ketamine and Spravato (Esketamine) in people with Depression, run by Yale University at 8 sites in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Depression
- What is being tested?
- Racemic ketamine and Spravato (Esketamine)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 400 participants
- Where
- 8 sitesUnited States
- Study dates
- 27 Jan 2025to 31 Dec 2030
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 9Show fewer
- A female participant must be:
- 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.
Who cannot join
- 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
Show all 15Show fewer
- 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.
Trial locations and contacts
8 sites in 1 country. Contact the study team or a site near you to ask about taking part.
8 sites in 1 country
United States8 sites, 6 recruiting
- Active, not recruiting
University of Michigan
Ann Arbor, Michigan, 48104
- Recruiting
Emory University
Atlanta, Georgia, 30322
Brandon Kitay, MD, 404-712-6939
- Recruiting
Houston Center for Advanced Psychiatric Treatment
Bellaire, Texas, 77401
Sandhya Prashad, MD
Sarah Hartigan, (832) 730 - 5196, sarah@sprashadmd.com
- Recruiting
Mood Institute
Milford, Connecticut, 06461
Lisa Harding, MD, 203-701-9737, Trials@DepressionMD.com
Lisa Harding, MD
- Active, not recruiting
LifeStance Health
Moore, Oklahoma, 73160
- Recruiting
Athena Care
Nashville, Tennessee, 37228
Amanda Sparks-Bushnell, MD, 615-861-1000, interventional@athenacare.health
Amanda Sparks-Bushnell, MD
- Recruiting
Yale School of Medicine
New Haven, Connecticut, 06512
Samuel Wilkinson, MD, 203-764-9131, Samuel.Wilkinson@yale.edu
Samuel Wilkinson, MD
- Recruiting
Seattle NTC
Seattle, Washington, 98104
Rebecca Allen, MD, 206-467-6300 ext. 5, Rebecca.Allen@seattlentc.com
Rebecca Allen, MD
About this study
Official title: 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.
Read the 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).
- Conditions
- Depression
- Being tested
- Racemic ketamine, Spravato (Esketamine)
- Medical subject headings
- Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Racemic ketamineDrug
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.
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Spravato (Esketamine) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 30 days
Secondary outcomes (10)
Clinician-Reported Effectiveness
change in Montgomery-Asberg Depression Rating Scale (MADRS) score. Scale ranges from 0-60 with higher scores indicating worse depression.
Measured: baseline until end of treatment (4 weeks)
Response
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.
Measured: baseline until end of treatment (4 weeks)
Remission
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.
Measured: baseline until end of treatment (4 weeks)
Suicidal Ideation and Behavior
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.
Measured: baseline until end of treatment (4 weeks)
Level of Disability
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.
Measured: baseline until end of treatment (4 weeks)
Quality of Life
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.
Measured: baseline until end of treatment (4 weeks)
Utilization of Healthcare Resources
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.
Measured: end of treatment (4 weeks)
Acceptability
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.
Measured: end of treatment (4 weeks after baseline)
Patient and Clinician Global Severity and Improvement
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.
Measured: baseline until end of treatment (4 weeks)
Tolerability and Safety
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.
Measured: baseline until end of treatment (4 weeks)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Dec 2024
- Study start27 Jan 2025
- Primary completion31 Dec 2030 (estimated)
- Study completion31 Dec 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for DepressionStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- None (open label)
- Enrolment
- 400 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Collaborators
- Patient-Centered Outcomes Research Institute
- Responsible party
- Principal investigator, Samuel Wilkinson, Yale University
- Investigators
- Samuel Wilkinson, MD, Principal investigator, Samuel.Wilkinson@yale.edu
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06713616
- Sponsor's protocol ID
- 2000037121
- Other IDs
- 23-005287
- Status last verified
- Jul 2026
- First submitted
- 27 Nov 2024
- Last updated
- 8 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 8 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Comparative Effectiveness of Racemic Ketamine Versus Esketamine (Spravato®) for Depression
- ClinicalTrials.gov ID
- NCT06713616
- Acronym / sponsor ID
- 2000037121
- Conditions
- Depression
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 400 participants (estimated)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Collaborators
- Patient-Centered Outcomes Research Institute
- Study start
- 27 Jan 2025 (actual)
- Primary completion
- 31 Dec 2030 (estimated)
- Study completion
- 31 Dec 2030 (estimated)
- First posted
- 3 Dec 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Racemic Ketamine | Experimental | Drug: Racemic ketamineKetamine 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. |
| Spravato (Esketamine) | Experimental | 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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
Key exclusion criteria (15 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Racemic ketamineKetamine 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)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) |
Primary outcome
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.
10 secondary outcomes
Clinician-Reported Effectiveness
Time frame: baseline until end of treatment (4 weeks)
Response
Time frame: baseline until end of treatment (4 weeks)
Remission
Time frame: baseline until end of treatment (4 weeks)
Suicidal Ideation and Behavior
Time frame: baseline until end of treatment (4 weeks)
Level of Disability
Time frame: baseline until end of treatment (4 weeks)
Quality of Life
Time frame: baseline until end of treatment (4 weeks)
Utilization of Healthcare Resources
Time frame: end of treatment (4 weeks)
Acceptability
Time frame: end of treatment (4 weeks after baseline)
Patient and Clinician Global Severity and Improvement
Time frame: baseline until end of treatment (4 weeks)
Tolerability and Safety
Time frame: baseline until end of treatment (4 weeks)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Sep 2026.
- Individual participant dataSharing planned: No
Related trials for Depression
Not yet recruitingObservational study
Validation of Wearable Core Body Temperature-Based Circadian Rhythm Digital Biomarkers
Mood Disorders, Major Depressive Diorder
RecruitingObservational study
A Prospective Study of Anxiety, Depression, and Bipolar Disorder in People
Anxiety Disorders, Depressive Disorder
RecruitingPhase 3
A Study of Vortioxetine in Japanese Pediatric Patients With Major Depressive Disorder
Major Depressive Disorder
Recruiting
Anticipated Patient and Caregiver Burden
Amyotrophic Lateral Sclerosis
Recruiting
A Study of Brief Behavioral Activation for the Treatment of Depression in Older Adult Cancer Survivors
Survivorship
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Samuel Wilkinson, MD principal investigator
Samuel.Wilkinson@yale.edu
8 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Racemic ketamine and Spravato (Esketamine) in people with Depression, run by Yale University at 8 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 8 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Cindy Voghell (203-737-4784, Cynthia.Voghell@yale.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Self-Reported Effectiveness (time frame: 30 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Sep 2026.