Comparing the effectiveness of nasal Esketamine and IV Ketamine for treating depression

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

This study is testing whether a nasal spray called Esketamine works better than IV Ketamine for people with treatment-resistant depression and how well patients tolerate each option.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 400 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Yale University (Academic / other)
• Locations: 6 sites (Milford, Connecticut and 5 other locations)
• Trial ID: NCT06713616 on ClinicalTrials.gov

What this trial studies

This study aims to compare the effectiveness, acceptability, and side effects of two treatments for treatment-resistant depression (TRD): Esketamine (Spravato), a nasal spray, and IV ketamine, which is not yet FDA approved for this use. It will involve a randomized design where 400 patients will be enrolled and assigned to receive either treatment over a 5-year period. The study will assess how well each treatment alleviates depression symptoms, how acceptable they are to patients, and how manageable the side effects are. Additionally, it will explore factors that may predict which treatment is more effective for specific patients.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 or older with major depressive disorder that has not responded to two or more antidepressant trials.

Not a fit: Patients who do not have treatment-resistant depression or who are not suitable for ketamine or esketamine treatment may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could provide valuable insights into effective treatment options for patients with treatment-resistant depression.

How similar studies have performed: Other studies have shown promising results with ketamine and esketamine for depression, indicating that this comparative approach is relevant and potentially impactful.

Eligibility criteria

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.

Where this trial is running

Milford, Connecticut and 5 other locations

• Mood Institute — Milford, Connecticut, United States (Recruiting)
• Yale School of Medicine — New Haven, Connecticut, United States (Recruiting)
• Emory University — Atlanta, Georgia, United States (Recruiting)
• University of Michigan — Ann Arbor, Michigan, United States (Active_not_recruiting)
• LifeStance Health — Moore, Oklahoma, United States (Recruiting)
• Houston Center for Advanced Psychiatric Treatment — Bellaire, Texas, United States (Recruiting)

Study contacts

• Principal investigator: Samuel Wilkinson, MD — [e-mail]
• Study coordinator: Cindy Voghell

Conditions Depression