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RecruitingNCT07184619ENIGMA-TRS 2Updated Sep 10, 2026

Evenamide, a Glutamate Release Modulator, as Add-On to Standard of Care in Subjects With Documented Treatment-Resistant Schizophrenia

A Phase 3 interventional study of Evenamide 15 mg bid and Placebo in Treatment-resistant Schizophrenia, sponsored by Newron Pharmaceuticals SPA. Recruiting at 19 sites in 4 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-09-10.

Sponsored by Newron Pharmaceuticals SPA · Phase 3, Interventional, and Treatment

From the registry’s dates

  • Started Jan 2026; still recruiting 9 months later.
Phase
Phase 3
Study type
Interventional
Enrollment
400
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study summary

This is a prospective, 12-week, randomized, double-blind, placebo-controlled study, designed to evaluate the efficacy, safety, and tolerability of a dose of evenamide of 15 mg bid, compared to placebo, as add-on treatment in patients with documented treatment-resistant schizophrenia (TRS) who have prospectively demonstrated inadequate response to their current stable therapeutic dose of an antipsychotic(s). Approximately 400 patients will be randomized equally (1:1) to each of the two treatment groups in this study.

02

Conditions studied

  • Treatment-resistant Schizophrenia

Keywords

  • evenamide
  • treatment-resistant schizophrenia
  • antipsychotic
  • schizophrenia
  • TRS
  • add-on treatment
03

In context

Schizophrenia, Treatment-Resistant

53 studies on the registry are indexed under Schizophrenia, Treatment-Resistant; 22 are open to participants now.

This study's planned enrollment of 400 is above the median of 60 across 46 interventional studies indexed under Schizophrenia, Treatment-Resistant.

Browse Schizophrenia, Treatment-Resistant studies →

Lead sponsor

Newron Pharmaceuticals SPA is the lead sponsor of 22 studies on the registry; 1 is open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Eligibility criteria

Key Inclusion Criteria:

  • Age - 18 years, or older.
  • If female, the subject has a negative pregnancy test at the screening visit and at baseline, is not lactating, and agrees to use adequate , unless not of .
  • Meets current criteria for schizophrenia.
  • Has shown treatment-resistance to antipsychotics as per TRRIP working group definition (Howes et al., 2017).
  • Currently receiving "standard of care" therapy of a minimal recommended therapeutic dose of one or more antipsychotic(s).
  • Has a Clinical Global Impression - Severity of disease (CGI-S) rating of "mildly ill" to "among the most extremly ill" at baseline.
  • Has a BPRS total score ≥ 45 at screening and baseline.
  • Has a PANSS total score ≥ 70 at baseline.
  • Has a Global Assessment of Functioning (GAF) scale total score ≤ 50.
  • Adherence to prescribed antipsychotic treatment.
  • Patient has provided written prior to participating in the study.

Key Exclusion Criteria:

  • Current DSM-5-TR diagnosis of schizophreniform disorder, schizoaffective disorder, or other primary psychiatric diagnosis, such as bipolar disorder or major depressive disorder
  • History (within three months of study entry) or current diagnosis of "Substance Use Disorder" as defined by the DSM-5-TR criteria.
  • Severity of current episode of psychosis requires that the patient be hospitalized to stabilize the severity of his/her psychotic symptoms. However, these patients may qualify for the study provided their antipsychotic dose has been stable for 6 weeks prior to screening.
  • History or current diagnosis of other psychiatric or behavioral disorders.
  • Known suicidal risk, or a suicide attempt within the past 2 years.
  • History of neuroleptic malignant syndrome or priapism.
  • Disease/medical condition of any type that may impact the patient's safety or interfere with any of the study evaluations.
  • History or current diagnosis of epilepsy or seizure disorder, or occurrence of a seizure within the past year, or repeated drug-induced seizures.
Terms in these criteria, in plain language(4)

Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.

Contraception

Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.

Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.

Childbearing potential

Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).

Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.

DSM diagnostic criteria

The American Psychiatric Association’s manual of mental health diagnoses. DSM-5 (2013, revised as DSM-5-TR in 2022) replaced DSM-IV, and some studies still name the older edition. “Meets DSM criteria for …” means diagnosed by that edition’s diagnostic criteria, usually by a clinician in an interview.

Informed consent

Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.

You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.

05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
400 participants (estimated)

Study arms

  • Experimental
    Evenamide 15 mg bid

    Evenamide capsules 15 mg bid for a total of 12 weeks of add-on treatment

    Drug: Evenamide 15 mg bid

  • Placebo comparator
    Placebo

    Matching placebo capsules bid for a total of 12 weeks of add-on treatment

    Drug: Placebo

Interventions

  • Evenamide capsules 15 mg bid for a total of 12 weeks of add-on treatment

  • DrugPlacebo

    Matching placebo capsules bid for a total of 12 weeks of add-on treatment

06

What researchers measure

Primary outcomes

  1. Change from baseline to endpoint (Week 12) on the total score of the Positive and Negative Syndrome Scale (PANSS).

    Efficacy measured by the mean change from baseline to endpoint of Positive and Negative Syndrome Scale \[PANSS\] total score: a 30-item scale that was designed to assess various symptoms of schizophrenia each rated on a 7-point scale that ranges from 1 (absent) to 7 (extreme psychopathology).

    Time frame: From Baseline to Week 12

  2. Incidence of treatment-emergent adverse events (TEAEs), AEs leading to discontinuation (ADOs), and serious AEs (SAEs).

    Safety and tolerability of a dose of evenamide of 15 mg bid, compared to placebo. The assessment of safety and tolerability will be based primarily on the incidence of treatment-emergent adverse events (TEAEs), AEs leading to discontinuation (ADOs), and serious AEs (SAEs).

    Time frame: From Baseline to 30-day Safety Follow up (12 Weeks of treament + 30-day safety follow up)

Secondary outcomes

  1. Change from baseline to endpoint (Week 12) on the Clinical Global Impression - Severity of illness (CGI-S) score.

    Efficacy measured by the mean change from baseline to endpoint on the Clinical Global Impression Severity of Illness (CGI-S) scale: a 7-point scale ranging from 1 (no symptoms) to 7 (very severe) to assess the severity of a subject's condition.

    Time frame: From Baseline to Week 12

  2. Proportion of patients rated as 'improved' on the CGI-C at endpoint (Week 12).

    Efficacy measured by Clinical Global Impression of Change \[CGI-C\]: a 7-point scale, ranging from 1 (very much improved) to 7 (very much worse), with a score of 4 indicating "no change". Patients with ratings of 1,2 or 3 are considered as 'improved'.

    Time frame: Week 12

  3. Change from baseline to endpoint (Week 12) on the Positive Symptoms sub-scale score of the PANSS.

    Efficacy measured by the mean change from baseline to endpoint on the Positive subscale score of the PANSS: a 7-item subscale designed to assess positive symptoms of schizophrenia each rated on a 7-point scale that ranges from 1 (absent) to 7 (extreme psychopathology).

    Time frame: From Baseline to Week 12

  4. Change from baseline to endpoint (Week 12) on the Personal and Social Performance (PSP) scale.

    Efficacy measured by the mean change from baseline to endpoint on the PSP scale: a 100-point single-item rating scale subdivided into 10 equal intervals that designed to assess the routine social functioning of patients with psychiatric disorders.

    Time frame: From Baseline to Week 12

  5. Change from baseline to endpoint (Week 12) on the Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form scale (Q-LES-Q-SF).

    Efficacy measured by the mean change from baseline to endpoint on the total score of the Quality of Life Enjoyment and Satisfaction Questionnaire: a 16-item scale, each rated from 1 (very poor) to 5 (very good).

    Time frame: From Baseline to Week 12

Other outcomes

  1. Change from baseline to endpoint (Week 12) on the Negative Symptoms sub-scale score of the PANSS.

    Efficacy measured by the mean change from baseline to endpoint on the Positive subscale score of the PANSS: this is a 7-item subscale that was designed to assess negative symptoms of schizophrenia each rated on a 7-point scale that ranges from 1 (absent) to 7 (extreme psychopathology).

    Time frame: From Baseline to Week 12.

  2. Change from baseline to endpoint (Week 12) on the Calgary Depression Scale for Schizophrenia (CDSS).

    Efficacy measured by the mean change from baseline to endpoint on the CDSS: a 9-item, observer-rated, semi-structured, goal-directed interview, validated for diagnosing depression in patients with schizophrenia. Each item is scored between "Absent" (0) to "Severe" (3), based on operational criteria.

    Time frame: From Baseline to Week 12

  3. Change from baseline to endpoint (Week 12) on the Global Assessment of Functioning (GAF) scale.

    Efficacy measured by the mean change from baseline to endpoint on the GAF scale ranging from 0 (inadequate information) to 100 (superior functioning), and is divided into 10-point ranges of functioning.

    Time frame: From Baseline to Week 12.

  4. Change from baseline to endpoint (Week 12) on the Medication Satisfaction Questionnaire (MSQ).

    Efficacy measured by the mean change from baseline to endpoint on the Medication Satisfaction Questionnaire (MSQ) which is a single-item, 7-point scale for patients with schizophrenia to rate their satisfaction with their antipsychotic medication ranging from "extremely dissatisfied" (1) to "extremely satisfied" (7).

    Time frame: From Baseline to Week 12

  5. Change from baseline to endpoint (Week 12) on the Cognitive Test Battery.

    Efficacy measured by the mean change from baseline on the scores of the Cognitive Test Battery. This includes: the Digit Symbol Substitution test, Trail Making Test (Parts A and B), d2 Test of Attention, and verbal fluency measures.

    Time frame: From Baseline to Week 12

07

Study locations

10 of 19 sites recruiting
  • UCLA DGSOM, UCLA Health, UCLA Semel Institute
    Los Angeles, California 90095, United States
    Suspended

    Not enrolling at this site.

  • University of Miami, Miller School of Medicine; Jackson Behavioral Health Hospital
    Miami, Florida 33136, United States
    Suspended

    Not enrolling at this site.

  • Grady Behavioral Health Center, -Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine
    Atlanta, Georgia 30322, United States
    Suspended

    Not enrolling at this site.

  • Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine
    Baltimore, Maryland 21224, United States
    Suspended

    Not enrolling at this site.

  • Manhattan Psychiatric Center, The Nathan Kline Institute for Psychiatric Research
    New York, New York 10035, United States
    Suspended

    Not enrolling at this site.

  • Fundación para el Estudio y Tratamiento de las Enfermedades Mentales
    Buenos Aires, Buenos Aires F.D. 1133, Argentina
    Active, not recruiting

    Not enrolling at this site.

  • Help Hospital
    Vijayawada, Andhra Pradesh 520002, India
    Recruiting
  • Gauhati Medical College and Hospital
    Guwahati, Assam 781032, India
    Recruiting
  • Masina Hospital Trust
    Mumbai, Maharashtra 400027, India
    Recruiting
  • All India Institute Of Medical Sciences
    Nagpur, Maharashtra 441108, India
    Not yet recruiting
  • New Manak Healthcare Hospital
    Navi Mumbai, Maharashtra 400706, India
    Recruiting
  • Ahana Hospitals LLP
    Madurai, Tamil Nadu 625020, India
    Recruiting
  • All India Institute of Medical Sciences
    Bībīnagar, Telangana 508126, India
    Not yet recruiting
  • Udyan Health Care
    Lucknow, Uttar Pradesh 226012, India
    Recruiting
  • Seth Sukhlal Karnani Memorial Hospital
    Kolkata, West Bengal 700025, India
    Not yet recruiting
  • Kuala Lumpur Hospital
    Kuala Lumpur, Kuala Lumpur 50586, Malaysia
    Recruiting
  • Hospital Tuanku Fauziah
    Kangar, 01000, Malaysia
    Recruiting
  • Sentosa Hospital
    Kuching, 93250, Malaysia
    Recruiting
  • Sultan Abdul Halim Hospital
    Sungai Petani, 08000, Malaysia
    Recruiting
08

References and documents

Publications

  • Anand R, Turolla A, Chinellato G, Sansi F, Roy A, Hartman R. Efficacy and safety of evenamide, a glutamate modulator, added to a second-generation antipsychotic in inadequately/poorly responding patients with chronic schizophrenia: Results from a randomized, double-blind, placebo-controlled, phase 3, international clinical trial. Neuropharmacology. 2025 Mar 15;266:110275. doi: 10.1016/j.neuropharm.2024.110275. Epub 2024 Dec 19. PubMed 39708914 ↗
  • Anand R, Turolla A, Chinellato G, Roy A, Hartman RD. Therapeutic Effect of Evenamide, a Glutamate Inhibitor, in Patients With Treatment-Resistant Schizophrenia (TRS): Final, 1-Year Results From a Phase 2, Open-Label, Rater-Blinded, Randomized, International Clinical Trial. Int J Neuropsychopharmacol. 2024 Dec 28;28(1):pyae061. doi: 10.1093/ijnp/pyae061. PubMed 39661380 ↗
  • Anand R, Turolla A, Chinellato G, Roy A, Hartman RD. Phase 2 Results Indicate Evenamide, A Selective Modulator of Glutamate Release, Is Associated With Clinically Important Long-Term Efficacy When Added to an Antipsychotic in Patients With Treatment-Resistant Schizophrenia. Int J Neuropsychopharmacol. 2023 Aug 29;26(8):523-528. doi: 10.1093/ijnp/pyad035. PubMed 37349110 ↗

Individual participant data

Plan to share: Undecided

09

Timeline

Tracking since Sep 25, 2026
ElapsedEstimatedEstimated, not yet reached

Started Jan 2026 (actual). Primary completion is estimated for Mar 2027, 14 months after the start.

How these figures are worked out, and which studies are left out of them.

Registered
Sep 18, 2025
First posted
Sep 22, 2025
StartActual
Jan 23, 2026
Primary completionEst.
Mar 31, 2027
CompletionEst.
Mar 31, 2027
Last update
Sep 10, 2026
What these dates mean
Start.
When the first participant enrolled; while estimated, when the study expects to open to recruitment.
Primary completion.
When the last participant was examined or treated to collect data for the study's main question, its primary outcome. A study that stopped early gives the date its data collection stopped.
Completion.
When the last participant's last visit took place, for every outcome, secondary ones and side effects included: the end of the study. Often later than primary completion, sometimes the same day.
Actual and Est.
Actual means the registry says the date has happened. Est. (estimated) is a date the sponsor plans or expects. It can still move, and the sponsor is expected to change it to actual once it has passed.
No changes since tracking began. The registry record was last updated on Sep 10, 2026, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
10

Registry details

Key details

Study ID
NCT07184619
Responsible party
Sponsor
First posted
Sep 22, 2025
Start date
Jan 23, 2026
Primary completion
Mar 31, 2027 (estimated)
Completion
Mar 31, 2027 (estimated)
Last update
Sep 10, 2026

Study contacts

Newron Pharmaceuticals
Contact
info@newron.com
+39 02 610 3461
Ravi Anand, MD
study director · Newron Pharmaceuticals

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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Studies of the drug tested here: Evenamide

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