Bipolar DepressionPhase 3SevereBDNCT03396601
NRX100 vs. Placebo for Rapid Stabilization of Acute Suicidal Ideation and Behavior in Bipolar Depression
A Phase 3 study testing Ketamine Hydrochloride in people with Bipolar Depression and Suicidal Ideation, run by NeuroRx, Inc. at 2 sites in United States.
Trial summary
NMDA antagonist drugs have increasingly been demonstrated to reduce symptoms of depression and suicidal ideation. NeuroRx has developed a sequential therapy consisting of IV NRX-100 (ketamine HCL) for rapid stabilization of symptoms of depression and suicidal ideation followed by oral NRX-101 (fixed dose combination… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Bipolar Depression, Suicidal Ideation
- What is being tested?
- Ketamine Hydrochloride
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 150 participants
- Where
- 2 sitesUnited States
- Study dates
- 25 Jun 2019to 31 Dec 2024
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- A subject will be eligible for inclusion in this study only if all of the following criteria apply:
- 18 to 65 years of age, inclusive, at screening.
- Able to understand and provide written and dated informed consent prior to screening. Deemed likely to comply with study protocol and communicate AEs and other clinically important information, and agree to be hospitalized to complete screening and initiate experimental treatment.
- Resides in a stable living situation, in the opinion of the investigator
- Has an identified reliable informant, in the opinion of the investigator
- Diagnosed with bipolar disorder (BD) according to the criteria defined in the DSM-5. The diagnosis of BD will be made by a psychiatrist and supported by the MINI 7.0.2.
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- Suicidal ideation or behavior as evidenced by an answer of "Yes" to item 4 or item 5 on the C-SSRS.
- A score of greater than or equal to 20 on the 10 items of the BISS that correspond with MADRS (equivalent to MADRS (BDM) total score of 30).
- In good general health, as ascertained by medical history, physical examination (including measurement of seated vital signs), clinical laboratory evaluations, and electrocardiogram
- If female, a status of non-childbearing potential or use of an acceptable form of birth control per the following specific criteria:
- Non-childbearing potential (e.g., physiologically incapable of becoming pregnant, i.e., permanently sterilized [status post hysterectomy, bilateral tubal ligation], or post-menopausal with last menses at least one year prior to screening); or
- Childbearing potential, and meets the following criteria:
- Using any form of hormonal birth control, on hormone replacement therapy started prior to 12 months of amenorrhea, using an intrauterine device (IUD), having a monogamous relationship with a partner who has had a vasectomy, or sexually abstinent.
- Negative urinary pregnancy test at screening, confirmed by a second negative urinary pregnancy test at randomization prior to receiving study treatment.
- Willing and able to continuously use one of the following methods of birth control during the course of the study, defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly: implants, injectable or patch hormonal contraception, oral contraceptives, IUD, double-barrier contraception, sexual abstinence. The form of birth control will be documented at screening and pre-ketamine baseline.
- Body mass index between 18-35kg/m2.
- Concurrent psychotherapy will be allowed if the type and frequency of the therapy (e.g., weekly or monthly) has been stable for at least three months prior to screening and is expected to remain stable for the duration of the study.
- Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, benzodiazepines, or trazodone) will be allowed if the therapy has been stable for at least four weeks prior to screening and if it is expected to remain stable during the course of the subject's participation in the study. Subjects can also continue treatment with benzodiazepines used for anxiety if therapy has been stable for at least four weeks prior to screening and if it is expected to remain stable during the course of the subject's participation in the study.
Who cannot join
- A subject will not be eligible for inclusion in this study if any of the following criteria apply:
- Female of childbearing potential who is not willing to use one of the specified forms of birth control during the study.
- Female who is pregnant or breastfeeding.
- Female with a positive pregnancy test at screening or before oral dosing of investigational product.
- Current DSM-5 diagnosis of moderate or severe substance use disorder (except marijuana or tobacco use disorder) within the 12 months prior to screening. Substance abuse cannot be the precipitant of entry to treatment.
- Subjects with a lifetime history of PCP/ketamine drug use, or failed use of ketamine for depression.
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- History of schizophrenia or schizoaffective disorder, or any history of psychotic symptoms when not in an acute bipolar mood episode.
- History of anorexia nervosa, bulimia nervosa, or eating disorder NOS (OSFED) within five years of screening.
- Has dementia, delirium, amnestic, or any other cognitive disorder.
- Any major psychiatric disorder, including a personality disorder, which is clinically predominant to BD at screening, or has been the primary focus of treatment predominant to BD at any time within six months prior to screening.
- Current major psychiatric disorder, diagnosed at screening with the MINI 7.0.2, that is the primary focus of treatment, with BD as the secondary focus of treatment, within the past six months.
- A clinically significant abnormality on the screening physical examination that might affect safety or study participation, or that might confound interpretation of study results according to the study clinician.
- Current episode of:
- Untreated hypertension, (Stage 1 or greater) as defined by a systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg at screening on two of three measurements at least 15 minutes apart. If untreated due to missing medication dose/s this is not exclusionary.
- Hypertension, Stage 2, as defined by a systolic blood pressure ≥155 mmHg or diastolic blood pressure ≥99 mmHg within 1.5 hours prior to ketamine infusion on two of three measurements at least 15 minutes apart at the pre-ketamine assessment (on Day 0 at Visit 1).
- Recent myocardial infarction (within one year).
- Syncopal event within the past year.
- Congestive heart failure (CHF) New York Heart Association Criteria >Stage 2.
- Angina pectoris.
- Heart rate <50 or >105 beats per minute at screening, pre-ketamine infusion (Day 0) or at randomization (Day 1).
- QTcF ≥450 msec at screening for men, ≥ 470 msec for women, pre-ketamine infusion (Day 0), or at randomization (Day 1), on two of three measurements at least 15 minutes apart.
- History of hypertension, or on antihypertensives for the purpose of lowering blood pressure, with either an increase in antihypertensive dose or increase in the number of antihypertensive drugs used to treat hypertension over the last two months.
- Chronic lung disease, excluding asthma.
- Lifetime history of surgical procedures involving the brain or meninges, encephalitis, meningitis, degenerative central nervous system (CNS) disorder (e.g., Alzheimer's or Parkinson's Disease), epilepsy, mental retardation, or any other disease/procedure/accident/intervention that, according to the screening clinician, is deemed associated with significant injury to or malfunction of the CNS; or history of significant head trauma within the past two years.
- Presents with any of the following lab abnormalities:
- Subjects with diabetes mellitus fulfilling any of the following criteria: i. Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >8.0 % at screening.
- Admitted to hospital for treatment of diabetes mellitus or diabetes mellitus-related illness in the past 12 weeks.
- Not under physician care for diabetes mellitus. iv. Has not been on the same dose of oral hypoglycemic drug(s) and/or diet for the four weeks prior to screening. For thiazolidinediones (glitazones) this period should not be less than eight weeks.
- Any other clinically significant abnormal laboratory result (as determined by the investigator and medical monitor) at the time of the screening.
- Any current or past history of any physical condition which, in the investigator's opinion, might put the subject at risk or interfere with study results interpretation.
- Subjects on exclusionary concomitant psychotropic medications (see Appendix 1) as defined in the study manual.
- At randomization, subjects prescribed more than one agent in each category;
- Approved antidepressants (e.g., SSRIs, SNRIs, TeCAs, fluoxetine), but not 5-HT-2a antagonists (lurasidone, aripiprazole, olanzapine, quetiapine)
- Mood stabilizers (e.g., lithium, carbamazepine, valproic acid)
- Subjects with exclusionary laboratory values (see Table 2).
- Known allergies to lurasidone or Latuda, cycloserine or Seromycin, or the excipients mannitol, croscarmellose sodium, magnesium stearate, silicon dioxide, and/or HPMC (hydroxypropylmethylcellulose).
- Participation in any clinical trial with an investigational drug or device within the past month or concurrent to study participation.
- Study site personnel and/or persons employed by NeuroRx, Inc. or Target Health or by the investigator or study site (i.e., permanent, temporary contract worker, or designee responsible for the conduct of the study), or an immediate family member (i.e., spouse or parent, child, or sibling [biological or legally adopted]) of such persons.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
JP Smith Hospital
Fort Worth, Texas, 76104
Research Centers of America
Hollywood, Florida, 33024
About this study
Official title: Administration of Intravenous NRX100 (Ketamine) vs Placebo Infusion for Rapid Stabilization of Acute Suicidal Ideation and Behavior in Patients With Bipolar Depression
NMDA antagonist drugs have increasingly been demonstrated to reduce symptoms of depression and suicidal ideation. NeuroRx has developed a sequential therapy consisting of IV NRX-100 (ketamine HCL) for rapid stabilization of symptoms of depression and suicidal ideation followed by oral NRX-101 (fixed dose combination of D-cycloserine and lurasidone) for maintenance of stabilization from symptoms of depression and suicidal ideation. This study will test the hypothesis that that NRX-100 is superior to placebo in achieving rapid reduction in symptoms of depression and suicidal ideation in patients with Severe Bipolar Depression and Acute Suicidal Ideation or Behavior within 24 hours of administration.
Read the detailed description
Background and Rationale: NMDA antagonist drugs have increasingly been demonstrated to reduce symptoms of depression and suicidal ideation. Specifically, NRX-100 (ketamine HCl, 0.5 mg/kg IV over 40 minutes) has been shown to induce acute reductions in suicidality and depression in patients with bipolar depression, relative to control. Numerous reports have documented a 50% reduction in the MADRS depression scale and a 75% reduction in suicidality following a single infusion of ketamine in patients with suicidal ideation and depression. While the repeat use of ketamine is not supported and may be contraindicated by the literature, D-cycloserine (DCS), when combined with SSRI antidepressants in patients with treatment resistant depression, and when combined with atypical antipsychotics, in particular lurasidone (NRX-101), has shown separation from control and ability to maintain remission from suicidality and depression over 6 weeks with oral use.
Primary Objective:
- To test the hypothesis that a single infusion of NRX-100 is superior to placebo infusion in the rapid stabilization of patients with severe Bipolar Depression and Acute Suicidal Ideation and Behavior (ASIB).
Secondary Objectives:
- Key secondary: To test the hypothesis that there is a more favorable reduction in the mean change from baseline on the Montgomery Asberg Depression Rating Scale (MADRS) between NRX-100 and saline groups on day 1 and day 2.
Methodology: A multi-center, randomized, double-blind, trial involving a single IV infusion to achieve response by 24 hours. The randomization will be 3:1 favoring NRX-100 (ketamine) infusion (n=105) vs. Saline infusion (n=35). Subjects who respond successfully to treatment will be offered enrollment in a six week followup study of NRX-101 (an oral fixed dose combination of d-cycloserine and lurasidone) vs. standard of care in order to ascertain maintenance of the ketamine effect.
- Conditions
- Bipolar Depression, Suicidal Ideation
- Being tested
- Ketamine Hydrochloride, Placebo
- Medical subject headings
- Bipolar Disorder, Suicidal Ideation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ketamine HydrochlorideDrug
Ketamine HCl will be infused intravenously at a dose of 0.5 mg/kg over 40 minutes
PlaceboDrug
Normal Saline placebo will be infused IV over 40 minutes
| Study group | Role | What they receive |
|---|---|---|
| NRX-100 infusion | Experimental | Infusion of IV NRX-100 (ketamine) Receives: Drug: Ketamine Hydrochloride |
| Saline (placebo) infusion | Experimental | Infusion of IV Saline Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Suicidal Ideation
A score of 3 or less on the Columbia Suicidality Severity Rating Scale (C-SSRS). The scale is scored from 0 to 5 on suicidal ideation.
Measured: 24 hours
Secondary outcomes (1)
Depression
Mean change from baseline on Montgomery Asberg Depression Rating Scale (MADRS) between NRX-100 and saline infusion. The scale consists of 10 items, each scored from 0-6, for a possible total score of 60.
Measured: 24 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jan 2018
- Study start25 Jun 2019
- Primary completion31 Dec 2024 (estimated)
- Study completion31 Dec 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Bipolar DepressionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 150 participants (estimated)
Sponsor and investigators
- Lead sponsor
- NeuroRx, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Target Health Inc.
- Responsible party
- Sponsor
- Investigators
- Martin Brecher, MD, Study director, VP, Clinical Development, NeuroRx, Inc.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03396601
- Sponsor's protocol ID
- NRX100_001
- Acronym
- SevereBD
- Status last verified
- Jan 2024
- First submitted
- 5 Jan 2018
- Last updated
- 19 Jan 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 19 Jan 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Administration of Intravenous NRX100 (Ketamine) vs Placebo Infusion for Rapid Stabilization of Acute Suicidal Ideation and Behavior in Patients With Bipolar Depression
- ClinicalTrials.gov ID
- NCT03396601
- Acronym / sponsor ID
- SevereBD / NRX100_001
- Conditions
- Bipolar Depression, Suicidal Ideation
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 150 participants (estimated)
- Lead sponsor
- NeuroRx, Inc.Industry (pharma, biotech, devices)
- Collaborators
- Target Health Inc.
- Study start
- 25 Jun 2019 (actual)
- Primary completion
- 31 Dec 2024 (estimated)
- Study completion
- 31 Dec 2024 (estimated)
- First posted
- 11 Jan 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
NMDA antagonist drugs have increasingly been demonstrated to reduce symptoms of depression and suicidal ideation. NeuroRx has developed a sequential therapy consisting of IV NRX-100 (ketamine HCL) for rapid stabilization of symptoms of depression and suicidal ideation followed by oral NRX-101 (fixed dose combination of D-cycloserine and lurasidone) for maintenance of stabilization from symptoms of depression and suicidal ideation. This study will test the hypothesis that that NRX-100 is superior to placebo in achieving rapid reduction in symptoms of depression and suicidal ideation in patients with Severe Bipolar Depression and Acute Suicidal Ideation or Behavior within 24 hours of administration.
Detailed description
Background and Rationale: NMDA antagonist drugs have increasingly been demonstrated to reduce symptoms of depression and suicidal ideation. Specifically, NRX-100 (ketamine HCl, 0.5 mg/kg IV over 40 minutes) has been shown to induce acute reductions in suicidality and depression in patients with bipolar depression, relative to control. Numerous reports have documented a 50% reduction in the MADRS depression scale and a 75% reduction in suicidality following a single infusion of ketamine in patients with suicidal ideation and depression. While the repeat use of ketamine is not supported and may be contraindicated by the literature, D-cycloserine (DCS), when combined with SSRI antidepressants in patients with treatment resistant depression, and when combined with atypical antipsychotics, in particular lurasidone (NRX-101), has shown separation from control and ability to maintain remission from suicidality and depression over 6 weeks with oral use.
Primary Objective:
- To test the hypothesis that a single infusion of NRX-100 is superior to placebo infusion in the rapid stabilization of patients with severe Bipolar Depression and Acute Suicidal Ideation and Behavior (ASIB).
Secondary Objectives:
- Key secondary: To test the hypothesis that there is a more favorable reduction in the mean change from baseline on the Montgomery Asberg Depression Rating Scale (MADRS) between NRX-100 and saline groups on day 1 and day 2.
Methodology: A multi-center, randomized, double-blind, trial involving a single IV infusion to achieve response by 24 hours. The randomization will be 3:1 favoring NRX-100 (ketamine) infusion (n=105) vs. Saline infusion (n=35). Subjects who respond successfully to treatment will be offered enrollment in a six week followup study of NRX-101 (an oral fixed dose combination of d-cycloserine and lurasidone) vs. standard of care in order to ascertain maintenance of the ketamine effect.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| NRX-100 infusion | Experimental | Drug: Ketamine HydrochlorideInfusion of IV NRX-100 (ketamine) |
| Saline (placebo) infusion | Experimental | Drug: PlaceboInfusion of IV Saline |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- A subject will be eligible for inclusion in this study only if all of the following criteria apply:
- 18 to 65 years of age, inclusive, at screening.
- Able to understand and provide written and dated informed consent prior to screening. Deemed likely to comply with study protocol and communicate AEs and other clinically important information, and agree to be hospitalized to complete screening and initiate experimental treatment.
- Resides in a stable living situation, in the opinion of the investigator
- Has an identified reliable informant, in the opinion of the investigator
Key exclusion criteria (38 listed)
- A subject will not be eligible for inclusion in this study if any of the following criteria apply:
- Female of childbearing potential who is not willing to use one of the specified forms of birth control during the study.
- Female who is pregnant or breastfeeding.
- Female with a positive pregnancy test at screening or before oral dosing of investigational product.
- Current DSM-5 diagnosis of moderate or severe substance use disorder (except marijuana or tobacco use disorder) within the 12 months prior to screening. Substance abuse cannot be the precipitant of entry to treatment.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ketamine HydrochlorideKetamine HCl will be infused intravenously at a dose of 0.5 mg/kg over 40 minutes | Drug | NRX-100 infusion |
| PlaceboNormal Saline placebo will be infused IV over 40 minutes | Drug | Saline (placebo) infusion |
Primary outcome
Suicidal Ideation
Time frame: 24 hours
A score of 3 or less on the Columbia Suicidality Severity Rating Scale (C-SSRS). The scale is scored from 0 to 5 on suicidal ideation.
1 secondary outcome
Depression
Time frame: 24 hours
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Jan 2024.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Martin Brecher, MD study director
VP, Clinical Development, NeuroRx, Inc.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Ketamine Hydrochloride in people with Bipolar Depression and Suicidal Ideation, run by NeuroRx, Inc. at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 18 inclusion and 38 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 19 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Suicidal Ideation (time frame: 24 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Jan 2024.