EG-501 for Cognitive Impairment in Neuropsychiatric SLE (NPSLE): Efficacy and Safety Study

A Multi-Site, Randomized, Placebo-Controlled, Double-Blind, Phase 2 Clinical Trial of EG-501 for the Treatment of Cognitive Impairment in Systemic Lupus Erythematosus

Neuropsychiatric systemic lupus erythematosus with cognitive impairment (NPSLE-CI) is a serious, disabling, and potentially life-threatening manifestation of SLE, affecting up to 80% of patients with cognitive impairments ("brain fog"), leading to substantial disability, approximately 2 times higher unemployment risk, reduced health-related quality of life (HRQoL), and mortality 2-14 times higher than the general population (standardized mortality ratio, SMR). No approved therapies exist for NPSLE cognitive dysfunction, representing a high-priority unmet need for this FDA-recognized serious condition with major functional and psychosocial burden. The objective of this study is to evaluate the safety, tolerability and efficacy of EG-501 in a precise patient subset with NPSLE. Participants will complete a full 14-week clinical trial, receiving either EG-501 or a placebo.

Study Overview

• Status: Completed
• Conditions: Cognitive Impairment; Systemic Lupus Erythematosus (SLE); Neuropsychiatric Systemic Lupus Erythematosus
• Intervention / Treatment: Drug: Placebo; Drug: EG-501

Detailed Description

Protocol EG-501-2.1 is a Phase 2, multi-site, randomized, double-blind, placebo-controlled trial evaluating the efficacy, safety, and tolerability of EG-501 for the treatment of cognitive impairment in systemic lupus erythematosus (SLE). The primary objective was to assess whether a 12-week EG-501 regimen produces a statistically and clinically significant improvement in the Total Scale Index score of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS®), compared with matched placebo, in a precisely defined SLE population with objective cognitive impairment. Fifty-six (56) patients were randomized treatment, 30 to placebo group and 26 to EG-501 group. All but three patients were female. Median age was 44.0 and 45.5 for placebo and EG-501 groups, respectively. With patients recruited only from the US, racial distribution was about 2/3 white, 1/3 black, with ethnicity reflecting largely non-Hispanic demographics.

• Study Type: Interventional
• Enrollment (Actual): 131
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • UT Health Houston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Physician diagnosis of SLE;
2. Report NPSLE symptoms on the screening survey recommended by EULAR guideline but limited to a subset of the psychiatric manifestations questions and using a cut-off score of at least 5, with a minimum of 2.5 being scored on section 1;
3. Score ≤ 85 on the RBANS total index (≤ 1 SD below the normative mean of 100)

Key Exclusion Criteria:

1. Male and female subjects <18 or >69 years;
2. Change in medication that may affect mood or cognition including prednisone, antidepressant medications, analgesics including opioids, or stimulants within the last 4 weeks;
3. Metabolic derangement defined as liver function tests >3x upper limit of normal, or severe renal disease defined as calculated creatinine clearance<30 mL;
4. Severe psychiatric disease including schizophrenia, psychosis, suicidal depression, or substance abuse disorder;
5. Other factors which in the opinion of the investigator could potentially impact the study outcomes (e.g., underlying disease, medications, history)* or prevent the participant from completing the protocol (poor compliance or unpredictable schedule);

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Drug: Placebo; At randomization, subjects will receive one matching placebo capsule twice per day for one week. One matching placebo capsule twice per day will be taken for the next week (Week 2), then one matching placebo capsule in the morning and two capsules at night for one week (Week 3), and finally two capsules twice per day for three weeks (Weeks 4-6). Maximum tolerated number of capsules will be determined at this time and this dose will be continued for an additional six weeks.	Drug: Placebo; The placebo will match the study drug in appearance, dose, and frequency. It will not contain any active drug (EG-501).
Experimental: Drug: EG-501; EG-501/ EG-MNTP-01, Strength: 5 mg or 10 mg, oral capsules At randomization, subjects will receive 5 mg twice per day for one week. Dose will be escalated to 10 mg twice per day for one week, then 10 mg in the morning and 20 mg at night for one week, and finally 20 mg twice per day for three weeks. Maximum tolerated will be determined at this time and this dose will be continued for an additional six weeks.	Drug: EG-501; EG-501/ EG-MNTP-01 is an oral, low-affinity NMDA receptor antagonist.; Other Names: EG-MNTP-01

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Repeatable Battery for Assessment of Neuropsychological Status (RBANS) Total Index Score at endpoint (Visit 4)	RBANS is a widely used psychiatric tool that objectively measures cognitive impairment. It is comprised of 12 subtests and takes approximately 30 minutes. For scoring, the RBANS index scores are converted to classifications including Very Superior (130 and above), Superior (120-129), High Average (110-119), Average (90-109), Low Average (80-89), Borderline (70-79), and Extremely Low (69 and below). A score of Extremely Low equates to severe cognitive impairment. The primary outcome measure will be analyzed using ANCOVA controlling for EG-501 or placebo, baseline RBANS, sex, age, and NMDAR status.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Polysymptomatic Distress Scale	The Polysymptomatic Distress (PSD) scale measures the effect of PSD over a range of pain-related clinical symptoms. The scale was derived from variables used in the 2010 American College of Rheumatology fibromyalgia criteria, modified for use in clinical research, and broadened to be applicable for patients not meeting fibromyalgia diagnostic criteria. The PSD score is calculated by summing two components, the Widespread Pain Index (WPI) and Symptom Severity Scale (SSS). The WPI is a count of painful nonarticular body regions, and the SSS is a symptom severity measure that includes fatigue, sleep, and cognitive problems.	12 weeks
Beck Depression Inventory	The Beck Depression Inventory (BDI) is a 21-item, self-report inventory that measures depression symptoms and attitudes. It takes approximately 10 minutes to complete and requires a fifth to sixth grade reading level to adequately comprehend the questions.	12 weeks
Hospital Anxiety and Depression Scale	The Hospital Anxiety and Depression Scale (HADS) is a self-assessment scale and was developed to detect states of depression, anxiety, and emotional distress among patients who were being treated for a variety of clinical problems. The scale has a total of 14 items, with responses being scored on a scale of 0-3 (3 indicates higher symptom frequencies). Scores for each subscale (anxiety and depression) range from 0 to 21, categorized as follows: normal 0-7, mild 8-10, moderate 11-14, and severe 15-21.	12 weeks
Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2K	SLEDAI-2K is an updated version of the SLEDAI which was originally developed in 1985 as a clinical index to assess lupus disease activity in the preceding 10 days. It is a cumulative and weighted index of 24 different clinical and laboratory variables/disease descriptors, comprising 9 organ systems. The Investigator will assess disease descriptors on the SLEDAI-2K collection sheet (e.g., arthritis, myositis, alopecia, rash, mucosal ulcers, etc.).	12 weeks
RBANS Subscales	Our primary outcome is the RBANS Total Index Score, which is the sum of several subscales/tests. For a secondary outcome, each subscale/test individually to see if there is a trend for any one test in particular will be recorded. The subscales are all scored the same (40 - 160) and include immediate memory, delayed memory, visuospatial/constructional, language, and attention.	12 weeks
Incidence of Treatment-Emergent Adverse Events	The safety of EG-501 as measured by treatment-emergent adverse events will be determined.	12 weeks
Patient Global Impression of Change (PGIC)	Participants will answer the standard question, "Considering all the ways your health affects you, how are you doing since the beginning of your treatment?" Answers include very much worse, much worse, worse, unchanged, improved, much improved, and very much improved.	12 weeks, Endpoint (Visit 4)

Collaborators and Investigators

• Sponsor: Evergreen Therapeutics, Inc.
• Collaborators: Vanderbilt University Medical Center
• Investigators: Principal Investigator: Leslie J. Crofford, M.D., Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): August 23, 2018
• Primary Completion (Actual): August 12, 2025
• Study Completion (Actual): August 12, 2025

Study Registration Dates

• First Submitted: December 2, 2025
• First Submitted That Met QC Criteria: December 10, 2025
• First Posted (Actual): December 15, 2025

Study Record Updates

• Last Update Posted (Actual): December 15, 2025
• Last Update Submitted That Met QC Criteria: December 10, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neuroinflammatory Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Mental Disorders; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Infections; Neurocognitive Disorders; Autoimmune Diseases of the Nervous System; Cognition Disorders; Central Nervous System Viral Diseases; Central Nervous System Infections; Encephalitis; Vasculitis; Vasculitis, Central Nervous System; Meningitis; Meningoencephalitis; Skin and Connective Tissue Diseases; Lupus Erythematosus, Systemic; Cognitive Dysfunction; Lupus Vasculitis, Central Nervous System
• Other Study ID Numbers: EG-501-2.1

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No