Sequential Therapy for the Treatment of Severe Bipolar Depression.
Condition: Bipolar Depression; Suicidal Ideas; Suicidal Ideation; Suicide, Attempted
MeSH terms: Depression; Depressive Disorder; Suicide; Bipolar Disorder; Suicidal Ideation; Suicide, Attempted
Study type: Interventional
Phase: Phase 2

Summary: 
      NeuroRx is developing NRX-101, a fixed-dose combination oral capsule composed of
      d-cycloserine (DCS) and lurasidone for the maintenance of remission from Severe Bipolar
      Depression with Acute Suicidal Ideation (C-SSRS level 4 or 5) or Behavior (ASIB) in following
      initial stabilization. Patients with Severe Bipolar Depression and ASIB will be recruited in
      both inpatient and outpatient settings and, following informed consent, will be given an
      intravenous infusion of ketamine 0.5mg/kg over 40 minutes. Those who exhibit a satisfactory
      clinical response to ketamine will be randomly allocated to NRX-101 or to lurasidone alone
      (the comparator group). This study is conducted as a feasibility study for a pivotal phase
      2b/3 clinical trial and the primary outcomes for this phase 2 study were blood levels of
      NRX-101, in order to confirm pharmaco-kinetics with remission from depression, as measured by
      BISS-derived MADRS and relapse as secondary outcomes.
    

Detailed description: 
      NeuroRx is developing NRX-101, a fixed-dose combination oral capsule composed of
      D-cycloserine (DCS) and lurasidone for the maintenance of remission from Severe Bipolar
      Depression with Acute Suicidal Ideation or Behavior (ASIB) in adults with Bipolar Depression
      following initial stabilization with ketamine. In recent years, intravenous and intranasal
      ketamine have demonstrated rapid and potent effects in achieving remission from both
      depression and suicidal ideation in both bipolar depression and major depressive disorder.
      However ketamine is will understood to induce hallucination and other dissociative side
      effects, to be addictive and have high abuse potential, and to have potential neurotoxic
      effects. Moreover, ketamine can only be administered in a monitored hospital or clinic
      setting. NRX-101 was developed with the objective of seeking a safe, non-hallucinogenic,
      non-addictive, oral medication that might maintain the effects of ketamine in patients with
      severe depression and acute suicidal ideation and which might be considered as initial
      therapy for patients with depression and non-acute suicidal ideation. The D-cycloserine
      component of NRX-101 is believed to act by inhibiting the brain's NMDA receptor and raising
      levels of glutamate/glutamine (Glx) in the anterior cingulate cortex. Increased Glx, as
      measured by magnetic resonance spectroscopy, has been associated with clinical improvement
      following electroconvulsive therapy (ECT) and following administration of IV ketamine.

      The proposed oral combination product is intended to be administered as part of a sequential
      therapy consisting of the following 2 components:

        1. an initial, one-time intravenous (iv) infusion of ketamine (0.5 mg/kg administered over
           40 min), followed one day later by

        2. twice daily oral capsules of NRX 101 (DCS + lurasidone), dosing of which is initiated 1
           day after ketamine administration, titrated over 5 days to a maintenance dose and
           continued for up to 6 weeks. Each NRX-101 oral capsule contains DCS (237.5 or 175.0 mg)
           and lurasidone (8.25, 16.5, or 33.0 mg). It is anticipated that subjects entering the
           study will be receiving concurrent disorder-directed treatment with other approved
           medications. This treatment regime will be maintained upon entry into the study.
           However, any use of lurasidone, quetiapine, or olanzapine will be stopped at study
           entry, so as to avoid either duplication with study drug (groups 1 and 2) or undermining
           of the control group.

      The clinical efficacy goal is to provide extended relief from symptoms associated with
      Severed Bipolar Depression and ASIB in adults with Bipolar Disorder, after initial
      stabilization with iv ketamine in a clinic, emergency department, or inpatient setting.

      The proposed NRX-101 product takes advantage of a unique synergistic confluence of combining
      two active pharmaceutical ingredients (DCS and lurasidone) that respectively inhibit the NMDA
      and the D2/5-HT2A receptors in the brain. NMDA receptor antagonists, most notably ketamine,
      have been shown in many studies to rapidly reduce depressive and suicidal ideation. However,
      numerous studies have demonstrated the potential of NMDA antagonists to cause hallucination
      and other dissociative side effects. Similarly, D2/5HT2A receptor antagonists, such as
      lurasidone have demonstrated antidepressant effects in bipolar depression, but have
      demonstrated a propensity to cause akathisia in some patients. The goals of combining these
      drugs into a single course of treatment is to maximize the beneficial effects of the specific
      subcomponents while overcoming potential treatment-limiting side effects associated with
      those subcomponents.

      Beneficial effects of the proposed dosage regimen include 1) well-documented pharmacodynamic
      effects of ketamine in treating both persistent depressive symptoms and suicidal ideation in
      bipolar disorder (McCloud, 2015; Naughton, 2014; Newport, 2015; Price, 2014), 2)
      well-documented pharmacodynamic effects of oral DCS against persistent symptoms of depression
      (Heresco-Levy, 2013) and 3) the FDA-approved efficacy of lurasidone in treatment-resistant
      depression (Sunovion Pharmaceuticals, 2013). Due to the synergistic effects, the proposed
      NRX-101 combination capsule is also expected to avoid or minimize the significant undesired
      adverse effects associated with the usage of these drugs as single agents (eg, negative
      consequences of repeated use of ketamine (JHP Pharmaceuticals, 2012), potential
      psychotomimetic effects of long-term treatment with DCS alone (Kantrowitz, 2010) and
      potential akathisia and susceptibility for increased suicidality associated with lurasidone
      alone (Sunovion Pharmaceuticals, 2013).

      The risk of ASIB is higher in bipolar depression than other psychiatric disorder and the
      majority of currently available antidepressants are contraindicated for patients with bipolar
      depression. NeuroRx believes that the proposed NRX-101 treatment regimen (ketamine
      administration followed by NRX-101) will demonstrate superiority over ketamine followed by
      lurasidone in maintaining remission from depression and in delaying the time to documented
      relapse from depression and suicidality in bipolar disorder, providing a new treatment option
      for patients with Severe Bipolar Depression and ASIB.

      There is currently no FDA-approved product for the treatment of ASIB. NeuroRx proposes that
      NRX-101 will fulfill an urgent medical need for safe and effective treatment for ASIB.

      Patients with Severe Bipolar Depression and ASIB will be recruited in inpatient settings and,
      following informed consent, will be given an intravenous infusion of either ketamine 0.5mg/kg
      over 40 minutes or normal saline (placebo). Those who exhibit a satisfactory clinical
      response to ketamine will be randomly allocated to NRX-101 or to lurasidone along (the
      comparator group). The primary outcome variable for this phase 2 study will be blood level
      (pharmacokinetic) exposure of NRX-101 and its D-cycloserine component with remission from
      depression, as measured on the MADRS scale and relapse as secondary endpoints. Relapse is
      defined as return of either depression or suicidality OR the need to alter therapy, which
      might include re-hospitalization, additional antidepressant medication, or electroconvulsive
      therapy (ECT).
    

Intervention name(s): NRX-101 Oral Capsule; Lurasidone Oral Capsule; Ketamine Intravenous Infusion; Saline Solution Intravenous Infusion
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Prospective Randomized Factorial Design Study as per arm/group descriptions; Prospective Randomized Factorial Design Study as per arm/group descriptions; Randomized administration of Ketamine or Placebo in a 3 to 1 ratio; Randomized administration of Ketamine or Placebo in a 3 to 1 ratio
Other intervention name(s): D-cycloserine + Lurasidone Fixed Dose Combination; Lurasidone Fixed Dose Combination
Intervention MeSH terms: Cycloserine; Ketamine; Lurasidone Hydrochloride
Allocation: Randomized
Intervention model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: d-cycloserine; lurasidone; ketamine; randomized controlled trial