Evenamide in patients with treatment-resistant schizophrenia not responding to antipsychotics

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Newron Pharmaceuticals S.p.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

Trial duration

16 Dec 2025 → ongoing

Decision date (initial)

2025-08-25

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Newron Pharmaceuticals S.p.A.

External identifiers

EU CT number

2024-519836-18-00

WHO UTN

U1111-1321-1719

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Primary Efficacy: To evaluate the efficacy of fixed doses of evenamide of 15 mg bid and 30 mg bid, compared to placebo, in patients with treatment-resistant schizophrenia (TRS), based on improvement in symptoms of schizophrenia, as assessed by the change from baseline to endpoint (Week 12) on the total score of the Positive and Negative Syndrome Scale (PANSS).
Primary Safety: To evaluate the safety and tolerability of fixed doses of evenamide of 15 mg bid and 30 mg bid, compared to placebo, in patients with TRS on a stable dose of their current antipsychotic medication. 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).

Secondary objectives 5

1. Key Secondary: To evaluate the efficacy of fixed doses of evenamide of 15 mg bid and 30 mg bid, compared to placebo, in patients with TRS, based on the change from baseline to endpoint (Week 12) on the Clinical Global Impression - Severity of illness (CGI-S).
2. To evaluate the efficacy of fixed doses of evenamide of 15 mg bid and 30 mg bid, compared to placebo, in patients with TRS, based on the proportion of patients with improvement (score of 1, 2 or 3) and mean rating on the Clinical Global Impression – Change from baseline (CGI-C) at endpoint (Week 12).
3. To evaluate the efficacy of fixed doses of evenamide of 15 mg bid and 30 mg bid, compared to placebo, in patients with TRS, based on improvement in positive symptoms of schizophrenia, as assessed by the change from baseline to endpoint (Week 12) on the Positive Symptoms sub-scale score of the PANSS.
4. To determine the effect of fixed doses of evenamide of 15 mg bid and 30 mg bid, compared to placebo, in patients with TRS, on daily functioning, based on the change from baseline to endpoint (Week 12) on the Personal and Social Performance (PSP) scale.
5. To determine the effect of fixed doses of evenamide of 15 mg bid and 30 mg bid, compared to placebo, in patients with TRS, on health-related quality of life, as assessed by the change from baseline to endpoint (Week 12) on the Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form scale (Q-LES-Q-SF).

Conditions and MedDRA coding

treatment-resistant schizophrenia (TRS)

Study design 6 periods

Regulatory references

Scientific advice from competent authorities

Swedish Medical Products Agency, Danish Medicines Agency, Spanish Agency Of Medicines And Medical Devices, European Medicines Agency, National Authority Of Medicines And Health Products, Health Canada, Medicines And Healthcare Products Regulatory Agency

EMA paediatric investigation plan (PIP)

EMEA-002516-PIP03-21

Plan to share IPD

Yes

IPD plan description

Anonymized Individual data patient (IDP) may be requested to Newron Pharmaceuticals S.p.A by anyone who wishes to access the data. Data requestors will need to submit a proposal for how the data will be used. Study data, including anonymized individual patient data, will be made available through a secure portal after approval of the proposal by Newron Pharmaceuticals SpA and signature by the data requestor of a data access agreement.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

1. Age – 18 years, or older, at screening. The suitability of elderly patients (e.g., >80 years of age) for enrolment in the study should be discussed with the Medical Monitor.
2. If female, the subject has a negative pregnancy test at the screening visit and at baseline, and is not lactating.
3. If female and of childbearing potential, the subject agrees to use adequate contraception, as determined by her Health Care Provider or according to local guidelines (Contraception Requirements for Women of Childbearing Potential Enrolled at Sites in the European Union (EU) are provided in Appendix 6 of the protocol). Sexual abstinence is not an acceptable method of contraception. A woman is considered to not be of childbearing potential if she meets one of the following criteria: a. is post-menopausal (the last menstrual period was at least 12 months ago, and FSH at screening confirms post-menopausal status), b. has had a hysterectomy, bilateral oophorectomy, or bilateral salpingectomy. Women who are taking hormone replacement therapy (HRT) must use adequate contraception (as described above) during the trial.
4. Body mass index (BMI) of at least 17.5 and less than 35. Patients with a BMI of less than 17.5, or 35 or higher may be considered for enrollment on a case-by-case basis if, in the Investigator’s opinion, this does not put the patient at any additional risk for participating in the trial. These cases should be discussed with the Medical Monitor and documented in the source records.
5. Currently meets DSM-5-TR diagnostic criteria for schizophrenia, as confirmed by the Mini International Neuropsychiatric Interview (MINI) for Psychotic Disorders Studies 7.0.2. Other psychiatric disorders may be present as lifetime diagnoses if the current episode of schizophrenia is confirmed by the principal investigator (PI). [see Exclusion criteria below]
6. Confirmation of treatment resistance, according to the consensus guidelines from the Treatment Response and Resistance in Psychosis (TRRIP) working group (Howes et al, 2017), by documentation in the medical records that the patient has had no, or inadequate symptomatic relief to at least two antipsychotics, including one second-generation antipsychotic (SGA), despite treatment for at least 6 weeks at adequate doses as specified in the product label.
7. Requires antipsychotic treatment and is currently receiving “standard of care”, consisting of one or more oral (given for at least 6 weeks prior to screening) or depot (given for at least 2 cycles) antipsychotic(s) at a stable therapeutic dose(s), in accordance with the package insert (country specific). Only second-generation antipsychotics listed in Appendix 5 will be permitted as the primary antipsychotic. Other second-generation antipsychotics not on the list, as well as first-generation antipsychotics, will be allowed as secondary antipsychotics. The patient’s current antipsychotic(s) may be the same as one of the two antipsychotics the patient did not benefit from previously. If the minimum therapeutic dose of the primary antipsychotic is not tolerated, the maximum tolerated dose may be used. a. The plasma level of the concomitant primary antipsychotic measured at screening must be equivalent to or greater than the minimum plasma concentration that would correspond to a therapeutic dose of the drug (based on the manufacturer’s recommendation – a list of therapeutic plasma concentration ranges for the allowed second-generation antipsychotics will be provided to investigators). b. For patients receiving more than one antipsychotic, the daily dose of the primary antipsychotic should be within the therapeutic dose range (country specific). It is recommended that the daily dose for the other antipsychotic(s) should be towards the lower end of the proposed therapeutic range, according to the country-specific package insert, or lower, unless clinically justified. . c. Patients being treated with clozapine as their primary antipsychotic must be on a stable dose for at least 12 weeks before screening, with a plasma concentration of at least 350 ng/mL. Patients may also be receiving concomitant treatment with mood stabilizers, antidepressants and/or anxiolytics, as allowed by the protocol.
8. Has a CGI-S rating of mildly ill to severely ill (score of 3 to 6 [scale 1-7]) at the baseline evaluation.
9. Has a BPRS (18-item, scores of 1-7) total score ≥ 45 at screening and baseline.
10. Has a PANSS total score ≥ 70 or more at the baseline assessment.
11. Has a Global Assessment of Functioning (GAF) scale total score ≤ 50.
12. Adherence to prescribed antipsychotic treatment has been confirmed by the patient’s caregiver from time of screening to baseline and found to be acceptable following review by the Investigator.
13. At the baseline evaluation, the patient has a score of 5 (moderately severe) or more on at least one, or 4 (moderate) or more on at least two of the following 4 core symptoms of psychosis: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content; and a total score of at least 18 on the combined total of the 4 core items and the following 3 additional positive symptoms items: grandiosity, hostility, and excitement (based on the BPRS descriptions using the 1-7 scale).
14. Current symptoms have been relatively stable for at least 3 months prior to screening, i.e., no episode of florid psychosis requiring continuous use of rescue medication, an increase (>30%) in the dose of the current primary antipsychotic treatment, or hospitalization, as determined by the Investigator. Guidelines for management of worsening of the patient’s psychosis during the screening period are provided in Section 11.5, Concomitant Medication - Short-term management of worsening of symptoms of psychosis.
15. Is cooperative, and able to take oral medication, understand study procedures and complete all aspects of the study.
16. Resides with a caregiver, or is either in a residential care facility or residing alone, with a responsible person (e.g., family member, social worker, case worker or nurse), considered reliable by the Investigator, available to provide support to the patient to help ensure compliance with medication dosing, scheduled clinic visits, and protocol procedures. Caregiver” is defined as someone who has at least 3 contacts with the patient each week, of which at least one is face-to-face.
17. Has provided written informed consent.
18. Has been considered eligible by a member of the Independent Eligibility Assessment Committee.
19. If taking clozapine, the patient agrees to blood monitoring (venipuncture for measuring ANC) according to local guidelines. Patients treated with clozapine as their primary antipsychotic will be limited to 30% of the total enrollment in each country. Patients receiving low doses of clozapine in addition to their primary antipsychotic are not included in this restriction.

Exclusion criteria 39

1. Current DSM-5-TR diagnosis of schizophreniform disorder (295.40), schizoaffective disorder (295.70), or other primary psychiatric diagnosis, such as bipolar disorder or major depressive disorder (Depression will be assessed at screening and baseline using the Calgary Depression Scale for Schizophrenia (CDSS); a score of 7 or higher will be exclusionary).
2. History (within three months of study entry) or current diagnosis of ‘Substance Use Disorder’ as defined by the DSM-5-TR criteria, with a severity of ‘moderate’ or ‘severe’, or patient is currently abusing drugs or alcohol or has done so in the past year. A history of nicotine, or caffeine dependence is acceptable. Patients testing positive for THC on the urine drug screen will not be excluded from the study unless there is evidence of toxic psychosis.
3. The patient is currently 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. Patients who are chronically hospitalized and will remain so for the duration of the study, or in psychiatric daycare, whose hospitalization is for logistic reasons and not due to the severity of their illness, will be eligible for the study.
4. BPRS total score has improved by more than 20% from screening to baseline.
5. CGI-S has improved by 1 point or more from screening to baseline.
6. Has a CGI-S rating of 7 (among the most extremely ill patients).
7. Has a history or current diagnosis of other psychiatric or behavioral disorders that may interfere with the conduct or interpretation of the study.
8. Has known suicidal risk. Patients who have exhibited suicidal behavior within the past 6 months, as indicated by an actual attempt, interrupted attempt, aborted attempt, or preparatory acts will be excluded from participating in the trial. In making the assessment of suicidal risk, the Investigator should take into account the ratings on the C-SSRS (based on the past 1 month), with A ‘YES’ response on the Suicidal Ideation Item 4 or Item 5, or a ‘YES’ response on any of the five C-SSRS Suicidal Behavior items being exclusionary.
9. Has a history of neuroleptic malignant syndrome or priapism.
10. Has an advanced, severe, or unstable disease of any type that may interfere with any of the study evaluations, including any medical condition that could be expected to progress, recur, or change to such an extent that it may significantly bias the assessment of the clinical or mental status of the patient or put the patient at special risk (e.g., liver or kidney disease, severe uncontrolled asthma, malignancy).
11. Has a disability that may prevent the subject from completing all study requirements (e.g., blindness, deafness, severe language difficulty).
12. Has insulin-dependent diabetes mellitus. Patients with non-insulin-dependent diabetes will be eligible if the following criteria are satisfied: a. HbA1c < 7.0% at screening, b. Diabetes is considered well controlled, with no changes in treatment regimen for at least 4 weeks prior to screening, c. Diabetes is not newly diagnosed at screening.
13. Has a history or current diagnosis of any neurodegenerative illness, dementia, significant concomitant neurological disease, organic cerebral disease, cerebrovascular disease, focal neurological lesions or history of any trauma resulting in loss of consciousness (during the past 2 years).
14. Has a history or current diagnosis of epilepsy or seizure disorder or has experienced a seizure within the past year or has had repeated drug-induced seizures.
15. Has had a loss of 500 mL or more of blood during the 3-month period before the study, e.g., as a donor.
16. Has had prior surgery or current medical condition which may interfere with the absorption, distribution, metabolism, or excretion of the study drug, e.g., peptic ulceration, gastric or intestinal surgery, impaired renal or hepatic function, cardiovascular abnormalities, inflammatory bowel disease, chronic symptoms of pronounced constipation or diarrhea, or conditions associated with total or partial obstruction of the urinary tract.
17. Has a current diagnosis or history of severe, unstable, or progressive cardiovascular disease, including ischemic heart disease, vasovagal syncope, sick-sinus syndrome, arrhythmia, conduction deficits [e.g., sino-atrial block, second or third degree atrio-ventricular block (PR >0.20)], Brugada syndrome, congestive heart failure, myocardial infarction, coronary artery bypass surgery, or percutaneous transluminal coronary angioplasty.
18. Has a clinically significant ECG abnormality, including a disorder of rate, rhythm, or conduction, or other morphological changes, or a QTcF interval prolongation (Fridericia’s correction) on the ECG (>450 msec for males; >470 msec for females). A 12-lead ECG will be used for determining the suitability of the patient for inclusion in the study (determination made by the Investigator). Values averaged from the 3 ECG measurements at baseline should be used in determining eligibility.
19. Patient’s vital signs (supine) are outside the following ranges (measured after 5 minutes supine): a. Systolic blood pressure (SBP) below 90 or above 150 mmHg; b. Diastolic blood pressure (DBP) below 50 or above 95 mmHg; c. Radial pulse (from vital signs) below 50 or above 100 bpm; d. Orthostatic hypotension (decrease in SBP/DBP from supine to standing position exceeding 30 mmHg).
20. Has clinically significant abnormalities in routine laboratory examinations (hematology; blood chemistry, including electrolytes and liver and kidney function tests; urinalysis), as determined by the Principal Investigator in consultation with the Medical Monitor, at the screening evaluation. Tables of clinically notable values for laboratory parameters in Appendix 2 should be used as a guide in making this determination.
21. Has a Child-Pugh class of B or C, suggestive of impaired liver function, at screening.
22. Has an eGFR < 30 mL/min, suggestive of severely impaired renal function, at screening.
23. Has a history of hepatitis B and/or C, and/or positive serology results, which indicate the presence of hepatitis B and/or C (Hepatitis B surface antigen [HbsAg] and/or antibody to Hepatitis C [HCV]).
24. Has positive HIV serology.
25. Has positive results from drug and alcohol tests at screening and/or baseline. Patients who test positive for drugs of abuse at screening, but have negative test results at baseline, may be eligible, dependent on the type of drug and the likelihood of continued abuse during the study. Possible inclusion of these patients in the study should be discussed with the Medical Monitor.
26. Has clinically significant hypothyroidism or hyperthyroidism, unless stabilized by medication for at least 3 months before screening.
27. Requires treatment with an anticholinergic drug for which the dose is not stable at baseline.
28. Is receiving benzodiazepine therapy, unless the dose has been stabilized for at least 2 months, excluding occasional prn dosing. The lowest possible dose should be used.
29. Is currently being treated with agents influencing dopamine, norepinephrine or serotonin neurotransmission (e.g., tri- and tetra-cyclic antidepressants, MAO inhibitors, metoclopramide). Treatment with SSRIs or SNRIs that are potent inhibitors of CYP2D6 (e.g., fluoxetine, paroxetine, duloxetine) is not recommended; patients on a stable dose of an SSRI that is a weak/moderate inhibitor of CYP2D6 (e.g., escitalopram, venlafaxine), for at least 4 weeks before screening, will be eligible (see Appendix 5 of the protocol).
30. Has been treated with drugs capable of inducing/inhibiting hepatic enzyme metabolism (e.g., barbiturates, carbamazepine, phenylbutazone, phenytoin, primidone, rifampicin) within four weeks prior to baseline or during the study.
31. Is receiving current treatment with sodium channel blockers (e.g., Class I antiarrhythmic agents, anticonvulsants, local anesthetics) or mood stabilizers specifically excluded by the protocol (see Appendix 5 of the protocol). Valproic acid will be permitted, if used as maintenance treatment.
32. Has had exposure to an investigational drug within 5 weeks or 5 half-lives (whichever is longer) prior to screening.
33. Has had an exaggerated pharmacological sensitivity or hypersensitivity to drugs similar to evenamide (e.g., lamotrigine, carbamazepine, oxcarbazepine, topiramate, etc.), or any components of the evenamide or matching placebo capsules.
34. Has been treated with a drug or treatment known to cause major organ system toxicity, e.g., tamoxifen, within 4 weeks, or received radiation therapy or a drug with cytotoxic potential, e.g., chemotherapy, during the past year.
35. Has received electroconvulsive therapy (ECT) or treatment with a transcranial magnetic stimulation (TMS) device within 3 months prior to screening.
36. If female, the patient is of childbearing potential, pregnant or breastfeeding. For inclusion, female patients must be post-menopausal (confirmed amenorrhea for >12 months), surgically sterilized, or using adequate contraception, as determined by their Health Care Provider, or according to local guidelines.
37. Received treatment with evenamide in a prior study.
38. Is an employee of the Sponsor, assigned agent of the Sponsor (e.g., CRO), or the investigational site, or a relative of an employee.
39. Poses a likelihood for non-compliance with the study protocol, or any other reason that, in the Investigator’s opinion, would prohibit the inclusion of the patient in the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Mean changes from baseline to endpoint (Week 12) on the PANSS total score will be compared between the evenamide 30 mg bid and placebo groups using a mixed-effects repeated measures model approach (MMRM), with treatment, region, visit, and treatmentby-visit interaction as fixed effects, and baseline value as covariate, will be used to analyze the mean change from baseline to Week 12 on the PANSS Total Score.

Secondary endpoints 1

1. For the key secondary efficacy endpoint, the mean change from baseline on the CGI-S at endpoint (Week 12) will be compared between the evenamide 30 mg bid dose and placebo groups using the same MMRM approach used for the primary efficacy endpoint, with treatment, region, visit, and treatment-by-visit interaction as fixed effects, and baseline value as covariate

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Newron Pharmaceuticals S.p.A.

Sponsor organisation

Newron Pharmaceuticals S.p.A.

Address

Via Antonio Meucci 3

City

Bresso

Postcode

20091

Country

Italy

Scientific contact point

Organisation

Newron Pharmaceuticals S.p.A.

Contact name

Dr. Ravi Anand

Public contact point

Organisation

Newron Pharmaceuticals S.p.A.

Contact name

Dr. Ravi Anand

Third parties 9

Locations

9 EU/EEA countries · 43 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 104 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications