Non-inferiority, comparative effectiveness study of intravenous ketamine v. intranasal esketamine for treatment-resistant depression: The EQUIVALENCE trial protocol.

Ketamine is a powerful and rapid-acting antidepressant but has no regulatory authorization for any psychiatric illness. The S-enantiomer of ketamine, esketamine, was approved by the FDA in 2019 as adjunctive therapy for treatment-resistant depression. Substantial controversy exists as to whether there is a significant clinical difference between intravenous (IV) ketamine racemate and intranasal esketamine. The EQUIVALENCE protocol will directly compare these therapies for treatment-resistant depression (TRD). Patients with TRD are randomized (1:1) to receive 8 treatments of IV ketamine or IN esketamine over a 4-week period. The primary outcome is change in depression severity as measured by a patient-reported outcome, the Quick Inventory of Depressive Symptomatology (QIDS) after 4 weeks of treatment. The study is designed as a non-inferiority study, with the FDA-approved therapy, esketamine, considered the standard. With a sample size of 400 total (200 per group), the study is powered to declare non-inferiority within a margin of 1.6 on the QIDS. If IV ketamine is found to be non-inferior to esketamine, a subsequent statistical test will examine whether ketamine is superior. Secondary outcomes include response and remission rates, anxiety severity, quality of life, and patient satisfaction, acceptability, and tolerability. We will also examine whether TRD with anxious distress responds differentially to one treatment or the other and the role that patient preference plays in outcomes. Results of the EQUIVALENCE study will have important implications for patient choice, health insurance coverage policies, and clinical care for TRD.