Clinical TrialTreatment-Resistant Depression (TRD)KetamineEsketamineRecruiting

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

Phase III, randomised, open-label, non-inferiority study (n=400) comparing IV racemic ketamine (up to 60 mg per infusion, max 8 lifetime doses) versus intranasal esketamine (56–84 mg per dose) for treatment-resistant depression.

Target Enrollment
400 participants
Study Type
Phase III interventional
Design
Randomized

Detailed Description

Multi-site, randomised, open-label, non-inferiority Phase III trial comparing intravenous racemic ketamine versus intranasal esketamine in patients with treatment-resistant depression; planned n=400, 1:1 allocation.

Primary outcomes are symptom improvement (effectiveness), acceptability, and tolerability; the study will also examine predictors of differential treatment response.

Ketamine administered as 40-minute IV infusions (max 60 mg per infusion, lifetime limit 8 doses); esketamine dosed per FDA label (56–84 mg) with allowance for dose reduction to 28 mg if needed.

Study Protocol

Preparation

sessions

Dosing

8 sessions
40 min each

Integration

sessions

Study Arms & Interventions

Racemic ketamine

experimental

Intravenous racemic ketamine infusions (per-site dosing; max 60 mg per infusion, lifetime limit 8 doses).

Interventions

  • Ketamine60 mg
    via IV• up to 8 doses• 8 doses total

    Infused over 40 minutes; per-protocol max 60 mg per day; total lifetime limit 8 doses.

Esketamine (Spravato)

experimental

Intranasal esketamine per FDA label (56–84 mg dosing with allowance for dose reduction).

Interventions

  • Esketamine56 - 84 mg
    via Inhalation• per label

    56–84 mg per dose; may be reduced to 28 mg for tolerability; dosing per Spravato prescribing information.

Participants

Ages
18 – 99
Sexes
Male & Female

Inclusion Criteria

  • Provision of signed and dated informed consent form
  • 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
  • Female participants must be either not of childbearing potential OR of childbearing potential and practising a highly effective method of contraception and agree to remain on it while receiving study intervention and until 1 week after last dose; agree not to donate eggs during the study

Exclusion Criteria

  • Diagnosis of bipolar disorder or psychotic disorder (e.g., schizophrenia, schizoaffective disorder)
  • Other psychiatric comorbidities permitted if depression is predominant
  • 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 excipients
  • Known family history of ketamine use disorder
  • Prior known ketamine use disorder or subjects for whom participation would result in more than 8 lifetime exposures to ketamine
  • Uncontrolled hypertension (>145/90 at screening; pre-treatment BP up to 150/95 allowed for white-coat effect on treatment visits 1-8)
  • Known cardiovascular or cerebrovascular conditions that increase risk with ketamine or esketamine (including space-occupying CNS lesions) and ECG abnormalities that increase risk
  • Conditions where an acute rise in blood pressure poses serious risk
  • Arteriovenous malformation
  • Positive urine toxicology at screening (except prescribed substances); recent cannabis use may be allowed based on clinical evaluation
  • Positive alcohol breathalyzer or clinical intoxication at screening
  • Unable to arrange transport home after treatment sessions or unwilling to refrain from driving/operating machinery until next day

Study Details

Locations

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

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