This Phase III study tests how safe and effective Evenamide is when added to regular treatment in people with schizophrenia
Scientific Title of Study
A Phase III, 12-week, prospective, randomized, double-blind, placebo-controlled, parallel-group, multi-center study to determine the efficacy, safety, and tolerability of a dose of 15 mg bid of evenamide as add-on in patients with documented treatment-resistant schizophrenia, which is not adequately controlled by a stable therapeutic dose of the patient’s current antipsychotic medication(s)
Trial Acronym
NIL
Secondary IDs if Any
Secondary ID
Identifier
CT/25/000155
DCGI
NCT07184619
ClinicalTrials.gov
NW-3509/022/III/2024
Protocol Number
Protocol Version 2.1 dated 31 July 2025
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Shiv Issar
Designation
Head, Clinical and RA
Affiliation
CliniRx Research Pvt. Ltd.
Address
CliniRx Research Pvt. Ltd., 4th Floor, BSZ Marg, New Delhi, Delhi-110002
Central DELHI 110002 India
Phone
9868167119
Fax
Email
shiv.issar@clinirx.com
Details of Contact Person Scientific Query
Name
Shiv Issar
Designation
Head, Clinical and RA
Affiliation
CliniRx Research Pvt. Ltd.
Address
CliniRx Research Pvt. Ltd., 4th Floor, BSZ Marg, New Delhi, Delhi-110002
DELHI 110002 India
Phone
9868167119
Fax
Email
shiv.issar@clinirx.com
Details of Contact Person Public Query
Name
Shiv Issar
Designation
Head, Clinical and RA
Affiliation
CliniRx Research Pvt. Ltd.
Address
CliniRx Research Pvt. Ltd., 4th Floor, BSZ Marg, New Delhi, Delhi-110002
DELHI 110002 India
Phone
9868167119
Fax
Email
shiv.issar@clinirx.com
Source of Monetary or Material Support
Newron Pharmaceuticals S.p.A., Via Antonio Meucci, 3 2120091 Bresso (Milano), Italy
Primary Sponsor
Name
Newron Pharmaceuticals SpA
Address
Via Antonio Meucci, 3 20091 Bresso (Milano) Italy
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
Clinirx Research Pvt Ltd
Patriot House, 4th Floor 3, Bahadur Shah Zafar Marg, New Delhi, Delhi (India) - 110002
Countries of Recruitment
Argentina Colombia India Malaysia Sri Lanka United States of America
Clinical Research Unit, Basement, No 7, Subburaman Street, Gandhi Nagar, Madurai- 625020, Tamil Nadu, India Madurai TAMIL NADU
9443772233
vikhram@ahanahospitals.in
Dr Sonakshi Jyrwa
All India Institute of Medical Sciences Nagpur
Department of Psychiatry,OPD building, 3rd floor, Room no- 301 MIHAN, Nagpur, Sumthana, Dahegaon, Maharashtra, 441108, India Nagpur MAHARASHTRA
9953954055
sjdanielle@gmail.com
Dr Deepanjali Medhi
Gauhati Medical College and Hospital
Department of Psychiatry,1st floor, GMC Hospital Road, Bhangagarh, Guwahati -781032, Assam, India Kamrup ASSAM
9435115263
dr.jonali09@gmail.com
Dr Radhika Reddy
Help hospitals Pvt Ltd
Department of Clinical research, First floor, Block C, D.No 27-29-23, Behind Victoria Museum,M.G.Road, Vijayawada 520002, Andhra Pradesh, India Guntur ANDHRA PRADESH
9848229798
rrvemireddy@yahoo.com
Prof Dr Sujit Sarkhel
Institute of Post Graduate Medical Education & Research, Seth Sukhlal Karnani Memorial Hospital
Institute of Psychiatry, Research room, 1st floor- Sleep laboratory, 7, D.L. Khan Road, Kolkata-700025, West Bengal, India Kolkata WEST BENGAL
9836074700
sujitsarkhel@gmail.com
Dr Anu Kant Mital
Masina Hospital Trust
Wellness Center building, Ground Floor, Sant Savta Marg, Byculla (East), Mumbai, Maharashtra 400027, India Mumbai MAHARASHTRA
9820164327
akmital@gmail.com
Dr Prashant Sunil Chaudhari
New Manak Healthcare Hospital
OPD No 2, ground floor, Near Rajiv Gandhi Bridge, sector 8, Nerul West, Nerul, Navi Mumbai, Maharashtra 400706, India Mumbai MAHARASHTRA
9096983370
drprashantchaudhari100@gmail.com
Dr Adarsh Tripathi
Udyan Health Care Pvt Ltd
Room no 7, Basement floor, 730, Udyan-1, Eldeco, (Near Bangla Bazar), Lucknow-226012, Uttar Pradesh, India Lucknow UTTAR PRADESH
Bhartiya Hospital Medical Research Society Ethics Committee
Approved
Ethics Committee Help Hospitals Private Limited
Approved
Ethics Committee, Radianz Healthcare and Research
Approved
Institutional Ethics Committee for Clinical Trial All India Institute of Medical Sciences
Submittted/Under Review
Institutional Ethics Committee, Gauhati Medical College and Hospita
Approved
Institutional Ethics Committee, Masina Hospital
Approved
Institutional Human Ethics Committee, Udyan Health Care Pvt. Ltd
Submittted/Under Review
IPGME and R Research Oversight Committee
Approved
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition: F208||Other schizophrenia,
Intervention / Comparator Agent
Type
Name
Details
Intervention
Evenamide
A fixed dose of evenamide 15 mg, administered orally twice daily for a duration of 12 weeks
Comparator Agent
Placebo
A fixed dose of matching placebo 15 mg, administered orally twice daily for a duration of 12 weeks
Inclusion Criteria
Age From
18.00 Year(s)
Age To
80.00 Year(s)
Gender
Both
Details
The patient must meet the following inclusion criteria to be eligible for enrollment into the study:
Demographics
1. Age – 18 years, or older, at screening. The suitability of elderly patients more than 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. Sexual abstinence is not an acceptable method of contraception.
A woman is considered not to 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 must use adequate contraception 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.
Psychiatric
5. Currently meets DSM-5-TR diagnostic criteria for schizophrenia, as confirmed by the Mini International Neuropsychiatric Interview 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.
6. Confirmation of treatment resistance, according to the consensus guidelines from the Treatment Response and Resistance in Psychosis working group, by documentation in the medical records that the patient has had no, or inadequate symptomatic relief in response to at least two antipsychotics, including one second-generation antipsychotic, 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, in accordance with the package insert. 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 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 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 ‘among the most extremely ill’ score of 3 to 7 scale 1-7 at the baseline evaluation.
9. Has a BPRS 18-item, scores of 1-7 total score more than equal to 45 at screening and baseline.
10. Has a PANSS total score more than equal to 70 at the baseline assessment.
11. Has a Global Assessment of Functioning scale total score less than equal to 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 more than 30 percent 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.
Procedural
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. For US only: “Caregiver” is defined as someone who has regular contacts with the patient each week, of which at least one is face-to-face. For ex-US countries: “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 percent of the total enrollment. Patients receiving low doses of clozapine in addition to their primary antipsychotic are not included in this restriction.
ExclusionCriteria
Details
The presence of any of the following will exclude a patient from study enrollment:
Psychiatric
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; 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 has been 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, 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, provided they meet all of the other criteria.
4. BPRS total score has improved by more than 20 percent from screening to baseline.
5. CGI-S has improved by 1 point or more from screening to baseline.
6. Has a history or current diagnosis of other psychiatric or behavioral disorders that may interfere with the conduct or interpretation of the study.
7. 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.
8. Has a history of neuroleptic malignant syndrome or priapism.
Medical Status
9. 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.
10. Has a disability that may prevent the subject from completing all study requirements e.g., blindness, deafness, severe language difficulty.
11. Has diabetes mellitus that was newly diagnosed at screening or is not well controlled i.e. HbA1c more than equal to 7.0%, or treatment regimen has not been stable for at least 4 weeks prior to screening.
Patients with insulin-dependent diabetes will be eligible only if the following additional criteria are satisfied:
a. No severe episodes of hypoglycemia within the last 6 months,
b. Is compliant with insulin therapy, and has no tolerability issues with injections, no cardiovascular complications, and no other medical conditions that would put the patient at risk, as per the Investigator’s judgment.
12. 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.
13. 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.
14. Has had a loss of 500 mL or more of blood during the 3-month period before the study, e.g., as a donor.
15. 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.
Cardiovascular
16. 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 more than 0.20, Brugada syndrome, congestive heart failure, myocardial infarction, coronary artery bypass surgery, or percutaneous transluminal coronary angioplasty.
17. Has a clinically significant ECG abnormality, including a disorder of rate, rhythm, or conduction, or other morphological changes, or a QTcF interval prolongation on the ECG more than 450 msec for males; more than 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.
18. Patient’s vital signs supine are outside the following ranges measured after 5 minutes supine:
a. Systolic blood pressure below 90 or above 150 mmHg;
b. Diastolic blood pressure 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.
Laboratory abnormalities
19. 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.
20. Has a Child-Pugh class of B or C, suggestive of impaired liver function, at screening.
21. Has an eGFR less than 30 mL/min, suggestive of severely impaired renal function, at screening.
22. Has a history of hepatitis B and/or C and/or demonstration of hepatitis B and/or C antibodies at screening. In both cases, patients will be excluded only if there is evidence of active disease, defined as elevated ALT and AST more than 2x ULN, and/or bilirubin levels more than 1.5x ULN.
23. Has positive HIV serology and a diagnosis of acquired immunodeficiency syndrome, i.e. CD4+ cell count of less than 200 cells per microliter of blood, or any symptoms that may suggest an active infection, such as rash, acute infections, night sweats and chills.
24. Has positive results from drug tests at screening and/or baseline, or alcohol test at 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.
25. Has clinically significant hypothyroidism or hyperthyroidism, unless stabilized by medication for at least 3 months before screening.
26. Genotyping confirms that the patient is a CYP2D6 poor metabolizer.
Concomitant therapy
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 or SNRI that is a weak/moderate inhibitor of CYP2D6 e.g., escitalopram, venlafaxine, for at least 4 weeks before screening, will be eligible.
30. Has been treated with drugs capable of potently 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. 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 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 or treatment with a transcranial magnetic stimulation device within 3 months prior to screening.
General
36. If female, the patient is of childbearing potential, pregnant or breastfeeding. For inclusion, female patients must be post-menopausal confirmed amenorrhea for more than 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.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Double Blind Double Dummy
Primary Outcome
Outcome
TimePoints
Mean changes from baseline to endpoint (Week 12) on the PANSS total score will be compared between the evenamide groups and the placebo group using a mixed-effects repeated measures model approach (MMRM), with treatment, region, visit, and treatment-by-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.
Primary efficacy timepoint of outcome is at 12 weeks.
Secondary Outcome
Outcome
TimePoints
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 15 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.
Secondary efficacy timepoint is at 12 weeks.
Target Sample Size
Total Sample Size="400" Sample Size from India="100" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
Evenamide (NW-3509) is an orally available new chemical entity that specifically blocks voltage-gated sodium channels in a state dependent manner, with a higher affinity for the inactivated state of the channel, and modulates sustained repetitive firing, without inducing impairment of the normal excitability. Evenamide normalizes glutamate release induced by aberrant sodium channel activity, without affecting basal glutamate levels, due to its inhibition of VGSCs. VGSCs play an essential biophysical role, transmitting electrical signals through action potential generation and propagation in the peripheral and central nervous systems. There is growing evidence indicating that gene mutations, changes in gene expression, or inappropriate modulation of these channels can lead to electrical instability of the cell membrane and exaggerate spontaneous activity of neurons, as is observed during pathological states such as epilepsy, pain and psychiatric disorders.
In schizophrenia, VGSC blockers are frequently used as add-on therapy to antipsychotics, with their success being attributed not only to their mood stabilizer effects, but also to their enhancement of the onset of antipsychotic action, increasing the overall efficacy of the antipsychotic drugs. Based on its effect on VGSCs, evenamide used in combination with current neuroleptics should improve their efficacy, allowing a reduction of their dosage, and thereby reducing associated side effects. A4 week, Phase 2a study in patients with schizophrenia has provided preliminary evidence of efficacy, tolerability and safety. A recently completed open label, rater blinded, 1 year, Phase 2or3 study in patients with treatment-resistant schizophrenia has provided evidence of safety, tolerability and efficacy of evenamide at doses up to 30 mg bid added on to a single antipsychotic.