A Randomized, Double-Blind Controlled Comparison of NRX-101 vs. Placebo for Adults Being Treated With Transcranial Magnetic Stimulation for Treatment Resistant Depression

NCT07227103 | Not Yet Recruiting Phase 2 DMC FDA Drug FDA Device

• 1 other identifier: NRX-101_004
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

Major depressive disorder (MDD) is a significant public health problem and leading cause of worldwide disability. Treatment resistance is common in MDD, however, for these individuals, targeted noninvasive brain stimulation is an alternative. Repetitive transcranial magnetic stimulation (rTMS) and more recently, theta-burst stimulation (TBS), are the noninvasive brain stimulation modalities with the largest evidence base in MDD. Although efficacious, an unacceptable proportion of patients do not significantly improve, and several aspects of the TMS parameter space are under investigation to enhance clinical outcomes. DCS has been shown in a randomized trial of more than double the percent response and remission from traditional TMS. When the AMPA one day (ONE-D) TMS protocol was combined with DCS, the measured response rate was 87% at one week. This trial will compare response and remission at six weeks following Transcranial Magnetic Stimulation + D-cycloserine vs. TMS+placebo.

Conditions

Treatment Resistant Depression

Outcome Measures

Primary Outcomes (2)

• MADRS Depression

  Montgomery Asberg Depression Rating Scale Total Score

  6 weeks

• CGI-SS Suicidality

  Clinical Global Impression Suicidality Scale

  6 weeks

Secondary Outcomes (4)

• Percent Response

  Six weeks

• Percent Remission from Depression

  Six weeks

• Percent Remission from Suicidality

  Six weeks

• Percent Improvement on EMOBOT

  Six weeks

Study Arms (2)

Transcranial Magnetic Stimulation plus NRX-101

EXPERIMENTAL

Participants are treated with ONE-D TMS plus NRX-101 175mg DCS/8.5mg Lurasidone once daily for five days

Device: ONE-D TMS; Drug: NRX-101

Transcranial Magnetic Stimualtion

PLACEBO COMPARATOR

Participants are treated with ONE-D TMS plus placebo once daily for five days

Device: ONE-D TMS

Interventions

ONE-D TMS DEVICE

One Day TMS Protocol performed with the AMPA TMS Device 30 Theta burst pulses delivered as per protocol

Also known as: One Day TMS Protocol performed with the AMPA TMS Device

Transcranial Magnetic Stimualtion; Transcranial Magnetic Stimulation plus NRX-101

NRX-101 DRUG

D-cycloserine 175mg + Lurasidone 8.5mg

Transcranial Magnetic Stimulation plus NRX-101

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• to 65 years of age, inclusive, at Screening.
• Scheduled for Transcranial Magnetic Stimulation by a treating physician.
• Able to understand and provide written and dated informed consent prior to Screening.
• Deemed likely to comply with the study protocol, including communication of adverse events (AEs) and other clinically important information, including adherence to the text messaging component of the trial.
• Will follow medical directions for psychiatric care, as appropriate, per the standard of care.
• Resides in a stable living situation. A stable living situation will be defined as a minimum of 3 months at the same address with a reasonable expectation that the situation will continue such that the patient's ability to participate in the study will not be affected. Please note that housing in a shelter of any kind will not be deemed stable housing.
• Previously diagnosed with treatment-resistant depression according to the criteria defined in the DSM-V and having failed treatment with at least two Selective Serotonin Reuptake Inhibitor (SSRI) drugs.
• Has an identified reliable informant/care partner that is willing to provide information and/or supportive care as necessary.
• No active suicidality (without the intention to act) as evidenced by a score of 3 or less on the Columbia Suicide Severity Rating Scale.
• A total score greater than or equal to 25 on the 10 items of the MADRS.
• No co-morbidities as ascertained by medical history, physical examination (including measurement of vital signs), clinical laboratory evaluations, and electrocardiogram (ECG) which might interfere with compliance or the ability to assess efficacy or safety.
• If female, a status of non-childbearing potential or use of an acceptable form of birth control per the following criteria, and agrees to continue use of the same method of birth control for the duration of study participation:
• a. Non-childbearing potential: 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 b. Childbearing potential, and meets the following criteria: i. Use of any form of hormonal birth control for at least 2 months prior to Screening, on hormone replacement therapy that started prior to 12 months of amenorrhea, using an intrauterine device (IUD) for at least 1 month prior to Screening, in a monogamous relationship with a partner who has had a vasectomy, or sexually abstinent.
• ii. Negative urinary pregnancy test at Screening, confirmed by a second negative urinary pregnancy test at Day 1, prior to receiving study treatment.
• Body mass index (BMI) between 18-40 kg/m2; BMI up to 45 kg/m2 is allowed with Medical Monitor review and approval.

You may not qualify if:

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• 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 prior to randomization.
• Current DSM-5 diagnosis of moderate or severe substance use disorder (except marijuana or tobacco use disorder) within the 12 months prior to Screening. (Note: Substance use disorder cannot be the precipitant for study entry).
• A lifetime history of
• phencyclidine (PCP)/ketamine drug abuse, or
• failed use of ketamine for depression or suicidality.
• 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, eating disorder not otherwise specified (NOS), or other specified feeding and eating disorders (OSFED) within 3 years of Screening.
• Has dementia, delirium, amnestic, or any other cognitive disorder.
• Current major psychiatric disorder, diagnosed at Screening with the MINI 7.0.2 which is the primary focus of treatment, with bipolar disorder as the secondary focus of treatment, within the past 6 months.
• Estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m2 using the Cockcroft-Gault formula.
• A clinically significant abnormality on the Screening physical examination that may affect safety or study participation, or that may confound interpretation of study results according to the study clinician.
• Current episode of:

Sponsors & Collaborators

• NeuroRx, Inc.: lead
• AMPA Health, Inc.: collaborator

Study Sites (1)

Cohen and Associates

Sarasota, Florida, 34239, United States

Location

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Central Study Contacts

Rebecca S Cohen, MD

CONTACT

9144049688; rcohen@hopetherapeutics.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Matched drug and placebo capsules
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: November 9, 2025
• First Posted: November 12, 2025
• Study Start: March 1, 2026
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): March 31, 2027
• Last Updated: November 12, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share

Locations

US (1)