Sequential Therapy for the Treatment of Severe Bipolar Depression. (STABIL-B)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02974010|
Recruitment Status : Completed
First Posted : November 28, 2016
Results First Posted : May 25, 2021
Last Update Posted : May 25, 2021
|First Submitted Date ICMJE||November 22, 2016|
|First Posted Date ICMJE||November 28, 2016|
|Results First Submitted Date ICMJE||December 13, 2020|
|Results First Posted Date ICMJE||May 25, 2021|
|Last Update Posted Date||May 25, 2021|
|Actual Study Start Date ICMJE||January 15, 2018|
|Actual Primary Completion Date||August 31, 2018 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||BDM Score (BISS-derived MADRS) Change From Baseline at Day 42 [ Time Frame: Day 42 ]
The study will measure the difference on BISS-derived MADRS score between NRX-101 and lurasidone (comparator) groups. The Bipolar Inventory of Symptom Scale (BISS) is a validated 42-item clinician-rated scale (21 items each for the depression and mania subscales) in which each item is rated on a 0-4 severity scale where higher values indicate worse severity. BISS-derived MADRS (BDM): MADRS is a 10-item clinician-rated scale, with each item rated on a 0-6 severity scale, where a higher number indicates worse severity. Responses to each question are equally weighted and summed. The BDM has a minimum score of 0 and a maximum of 40, where higher scores indicate a worse severity, therefore decreases in average BDM are considered a better outcome. Data are presented as mean change from baseline (end of stage 1, Day 1) using LOCF
|Original Primary Outcome Measures ICMJE
||Relapse [ Time Frame: Six weeks ]
Relapse is ascertained as return to baseline in either depression or suicidality as determined by the treating physician and adjudicated by an independent review committee or by the need to institute a new treatment plan for the patient.
|Current Secondary Outcome Measures ICMJE||Not Provided|
|Original Secondary Outcome Measures ICMJE
||Measures of depression and suicidality on psychometric scales [ Time Frame: Six weeks ]
Study arms will be compared using mean scores on a series of psychometric scales over six weeks.
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Sequential Therapy for the Treatment of Severe Bipolar Depression.|
|Official Title ICMJE||Sequential Therapy (NRX-100 Followed by NRX-101) for the Treatment of Acute Suicidal Ideation and Behavior in Bipolar Depression: the STABIL-B Study|
|Brief 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.|
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:
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).
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 2|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Study Arms ICMJE||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Actual Study Completion Date ICMJE||November 20, 2019|
|Actual Primary Completion Date||August 31, 2018 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Inclusion Criteria:A subject will be eligible for inclusion in this study only if all of the following criteria apply:
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
|Ages ICMJE||18 Years to 65 Years (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT02974010|
|Other Study ID Numbers ICMJE||NRX 101-001|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Current Responsible Party||NeuroRx, Inc.|
|Original Responsible Party||Same as current|
|Current Study Sponsor ICMJE||NeuroRx, Inc.|
|Original Study Sponsor ICMJE||Same as current|
|PRS Account||NeuroRx, Inc.|
|Verification Date||May 2021|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP