CTRI/2025/05/086726招募中3 期
A Phase III, 52-week, prospective, randomized, double-blind, placebo-controlled, parallel-group, multi-center study, with a primary efficacy endpoint at 12 weeks, to determine the efficacy, safety, and tolerability of fixed doses of 15 mg bid and 30 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)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 600
- 试验地点
- 12
- 主要终点
- 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 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.
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 盲法
- Double
入排标准
- 年龄范围
- 18.00 Year(s) 至 80.00 Year(s)（—）
- 性别
- All
入选标准
- •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 example less 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 Contraception Requirements for Women of Childbearing Potential Enrolled at Sites in the European Union are provided in Appendix 6 Sexual abstinence is not an acceptable method of contraception.
- •4 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 must use adequate contraception during the trial 5 Body mass index of at least 17.5 and less than
- •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 Investigators 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 6 Currently meets DSM 5 TR diagnostic criteria for schizophrenia, as confirmed by the Mini International Neuropsychiatric Interview for Psychotic Disorders Studies 7.0.
- •Other psychiatric disorders may be present as lifetime diagnoses if the current episode of schizophrenia is confirmed by the principal investigator 7 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 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 8 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 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.
- •The patients current antipsychotics 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 manufacturers 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 ngmL Patients may also be receiving concomitant treatment with mood stabilizers, antidepressants and anxiolytics, as allowed by the protocol 9 Has a CGI S rating of mildly ill to severely ill score of 3 to 6 scale 1 to 7 at the baseline evaluation 10 Has a BPRS 18 item, scores of 1 to 7 total score more than equal to 45 at screening and baseline 11 Has a PANSS total score less than equal to 70 or more at the baseline assessment 12 Has a Global Assessment of Functioning GAF scale total score more than equal to 50 13 Adherence to prescribed antipsychotic treatment has been confirmed by the patients caregiver from time of screening to baseline and found to be acceptable following review by the Investigator 14 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 to 7 scale 15 Current symptoms have been relatively stable for at least 3 months prior to screening that is 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 patients psychosis during the screening period are provided in Section 11.5, Concomitant Medication Short term management of worsening of symptoms of psychosis Procedural 16 Is cooperative, and able to take oral medication, understand study procedures and complete all aspects of the study 17 Resides with a caregiver,or is either in a residential care facility or residing alone, with a responsible person example, 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 18 Has provided written informed consent 19 Has been considered eligible by a member of the Independent Eligibility Assessment Committee 20 If taking clozapine, the patient agrees to blood monitoring according to local guidelines.
- •Patients treated with clozapine as their primary antipsychotic will be limited to 30 percent 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.
排除标准
- •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 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 or 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 percent 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.
- •Medical Status 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 example liver or kidney disease, severe uncontrolled asthma, malignancy 11 Has a disability that may prevent the subject from completing all study requirements example blindness, deafness, severe language difficulty 12 Has insulin dependent diabetes mellitus 13 Patients with non insulin dependent diabetes will be eligible if the following criteria are satisfied a HbA1c more than 7.0 percent 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 14 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 15 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 16 Has had a loss of 500 mL or more of blood during the 3 month period before the study, example as a donor 17 Has had prior surgery or current medical condition which may interfere with the absorption, distribution, metabolism, or excretion of the study drug, example, 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 18 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 example, sino atrial block, second or third degree atrio ventricular block PR less than 0.20, Brugada syndrome, congestive heart failure, myocardial infarction, coronary artery bypass surgery, or percutaneous transluminal coronary angioplasty.
- •19 Has a clinically significant ECG abnormality, including a disorder of rate, rhythm, or conduction, or other morphological changes, or a QTcF interval prolongation Fridericias correction on the ECG less than 450 msec for males less 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.
- •20 Patients 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 or DBP from supine to standing position exceeding 30 mmHg Laboratory abnormalities 21 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 22 Has a Child Pugh class of B or C, suggestive of impaired liver function, at screening 23 Has an eGFR more than 30 mLmin, suggestive of severely impaired renal function, at screening.
- •24 Has a history of hepatitis B and C, and positive serology results, which indicate the presence of hepatitis B and/or C Hepatitis B surface antigen HbsAg and antibody to Hepatitis C HCV 25 Has positive HIV serology 26 Has positive results from drug and alcohol tests at screening and 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 27 Has clinically significant hypothyroidism or hyperthyroidism, unless stabilized by medication for at least 3 months before screen Concomitant therapy 28 Requires treatment with an anticholinergic drug for which the dose is not stable at baseline.
- •29 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 30 Is currently being treated with agents influencing dopamine, norepinephrine or serotonin neurotransmission example tri and tetra cyclic antidepressants, MAO inhibitors, metoclopramide.
- •Treatment with SSRIs or SNRIs that are potent inhibitors of CYP2D6 example, fluoxetine, paroxetine, duloxetine is not recommended patients on a stable dose of an SSRI that is a weak or moderate inhibitor of CYP2D6 example escitalopram, venlafaxine, for at least 4 weeks before screening, will be eligible see Appendix 5 31 Has been treated with drugs capable of inhibiting hepatic enzyme metabolism example, barbiturates, carbamazepine, phenylbutazone, phenytoin, primidone, rifampicin within four weeks prior to baseline or during the study 32 Is receiving current treatment with sodium channel blockers example, Class I antiarrhythmic agents, anticonvulsants, local anesthetics or mood stabilizers specifically excluded by the protocol see Appendix 5 Valproic acid will be permitted, if used as maintenance treatment 33 Has had exposure to an investigational drug within 5 weeks or 5 half lives whichever is longer prior to screening 34 Has had an exaggerated pharmacological sensitivity or hypersensitivity to drugs similar to evenamide example, lamotrigine, carbamazepine, oxcarbazepine, topiramate, or any components of the evenamide or matching placebo capsules 35 Has been treated with a drug or treatment known to cause major organ system toxicity, example, tamoxifen, within 4 weeks, or received radiation therapy or a drug with cytotoxic potential, example, chemotherapy, during the past year 36 Has received electroconvulsive therapy ECT or treatment with a transcranial magnetic stimulation TMS device within 3 months prior to screening General 37 If female, the patient is of childbearing potential, pregnant or breastfeeding.
- •For inclusion, female patients must be post menopausal confirmed amenorrhea for less than 12 months, surgically sterilized, or using adequate contraception, as determined by their Health Care Provider, or according to local guidelines 38 Received treatment with evenamide in a prior study 39 Is an employee of the Sponsor, assigned agent of the Sponsor example, CRO, or the investigational site, or a relative of an employee 40 Poses a likelihood for non compliance with the study protocol, or any other reason that, in the Investigators opinion, would prohibit the inclusion of the patient in the study.
结局指标
主要结局
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 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.
时间窗: Primary efficacy timepoint of outcome is at 12 weeks
次要结局
- The mean change from baseline on the CGI S at endpoint Week 12 will be compared between the evenamide 30 mg bid dose & placebo groups using the same MMRM approach used for the primary efficacy endpoint, with treatment, region, visit, & treatment by visit interaction as fixed effects, & baseline value as covariate(Secondary efficacy timepoint is at 12 weeks.)
研究者
Shiv Issar
CliniRx Research Pvt. Ltd.
研究点 (12)
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