Study design

The study was conducted in accordance with the ethical principles as set out in the Declaration of Helsinki and its amendments and in compliance with the approved protocol of the United States Food and Drug Administration (FDA). The protocol ({"type":"clinical-trial","attrs":{"text":"NCT02974010","term_id":"NCT02974010"}}NCT02974010) and its associated Informed Consent Agreement were reviewed and approved by the central Institutional Review Board (IRB) of this study, Schulman IRB (now Advarra, Inc). Participants were evaluated to ensure that they were capable of understanding the nature of this study and its potential risks, discomforts, and benefits. All participants provided written informed consent.

This was a multi-center, double-blind, twostage, parallel randomized trial to evaluate the efficacy of ketamine, compared to saline, in the rapid improvement of patients with severe BD and ASIB (Stage 1) and the efficacy of NRX-101, compared to lurasidone, in maintaining the improvement achieved in Stage 1 (Stage 2). There were separate randomizations for Stage 1 and Stage 2.

This study was originally designed for a larger sample size but was terminated prior to full enrollment to accommodate a Special Protocol Agreement (SPA) with FDA wherein the primary endpoint scale was changed from the Bipolar Inventory of Symptoms Scale (BISS)-derived Montgomery-Åsberg Depression Rating Scale (MADRS) (BDM) to the traditional MADRS 10-item scale. This request was made by FDA to facilitate post-hoc comparison of NRX-101 results with placebo results already on file at FDA. The FDA additionally requested a separation of Stage 1 and Stage 2 for the SPA protocol. This study enrolled, randomized, and treated 22 patients prior to its early termination.