Is evenamide efficacious, safe and tolerable as an add-on therapy in patients with Treatment Resistant Schizophrenia not currently controlled by the patient’s current antipsychotic medication(s)?

1. Study settings: • Colombo North Teaching Hospital • National Hospital Galle

2. Recruitment: Only patients who are determined to be suitable for enrolment in the trial by the Principal Investigator supported by the IEAC and meet all of the inclusion criteria and none of the exclusion criteria at baseline will be eligible for randomization into the treatment phase.

3. Method of generating randomization sequence: Computer generated randomization Method of allocation concealment: Centralized Blinding

Following baseline evaluations and when the patient has been confirmed to be eligible for inclusion, approximately 600 patients (approximately 200/group) with documented Treatment Resistant Schizophrenia (TRS) will be randomized equally (1:1:1) to evenamide 15 mg bid, evenamide 30 mg bid, or a matching placebo bid orally, for a treatment duration of 12 weeks.

1. Patients assigned to evenamide 15 mg bid and evenamide 30 mg bid will continue to receive the same strength of study medication till 52 weeks of treatment.

2. Half of the participants (50%) initially assigned to the placebo group will have the opportunity to receive evenamide during the study starting from the subsequent timepoints: 10% of them at Week 12, 15% at Week-26 and 25% at Week 34. The random assignment of the timing of the switch to evenamide, as well as the dose to be administered, for the placebo-treated patients will be performed at baseline at the time of their randomization to treatment and will be managed by an Interactive Web Response System (IWRS).

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. 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 (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 enrolment 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 and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision) 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, 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 (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 (Appendix 5, available on request) 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. Clinical Global Impression–Severity (CGI-S) scale rating of mildly ill to severely ill (score of 3 to 6 [scale 1-7]) at baseline evaluation.
   
   
9. Brief Psychiatric Rating Scale (BPRS) (18-item, scores of 1-7) total score ? 45 at screening and baseline.
   
   
10. Positive and Negative Syndrome Scale (PANSS) total score ? 70 at the baseline assessment.
    
    
11. 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. A score of 5 (moderately severe) or more on at least one, or 4 (moderate) or more at baseline on at least two of the following 4 core symptoms of psychosis: conceptual disorganization, hallucinatory behaviour, 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
    
    
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.
    
    
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 enrolment in each country. Patients receiving low doses of clozapine in addition to their primary antipsychotic are not included in this restriction.

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 (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. 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.

4. Brief Psychiatric Rating Scale (BPRS) total score has improved by more than 20% from screening to baseline.

5. Clinical Global Impression–Severity (CGI-S) scale 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 behavioural disorders that may interfere with the conduct or interpretation of the study.

8. Has known suicidal risk. Patients who have exhibited suicidal behaviour 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 Columbia-Suicide Severity Rating Scale (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 Behaviour items being exclusionary.

9. Has a history of neuroleptic malignant syndrome or priapism.

Medical

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 diarrhoea, or conditions associated with total or partial obstruction of the urinary tract.

Cardiovascular

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).

Laboratory abnormalities

20..Has clinically significant abnormalities in routine laboratory examinations (haematology; 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 of the protocol 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.

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 (see Appendix 5 of 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 anaesthetics) or mood stabilizers specifically excluded by the protocol (see Appendix 5). 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.

General

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.