Home » Trials » SLCTR/2020/023


A pilot, open-label, rater-blinded, randomized, parallel-group, multi-center study to evaluate the safety, tolerability and preliminary efficacy of three add-on fixed doses of evenamide in patients with treatment-resistant schizophrenia (TRS) not responding adequately to their stable, therapeutically active dose of a single antipsychotic medication

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SLCTR Registration Number

SLCTR/2020/023


Date of Registration

16 Nov 2020

The date of last modification

Nov 17, 2020



Application Summary


Scientific Title of Trial

A pilot, open-label, rater-blinded, randomized, parallel-group, multi-center study to evaluate the safety, tolerability and preliminary efficacy of three add-on fixed doses of evenamide in patients with treatment-resistant schizophrenia (TRS) not responding adequately to their stable, therapeutically active dose of a single antipsychotic medication


Public Title of Trial

A clinical study using Evenamide (orally taken new drug with out masking its strenghth) to determine its safety, tolerability and efficacy in patients with treatment resistant schizophrenia, not befitting adequately from their current antipsychotic medication


Disease or Health Condition(s) Studied

schizophrenia


Scientific Acronym

N/A


Public Acronym

N/A


Brief title

A clinical study to determine safety, tolerability and efficacy of drug called Evenamide which is taken orally, in patients with treatment resistant schizophrenia with inadequate benefit from their current antipsychotic medication


Universal Trial Number

U1111-1260-3605


Any other number(s) assigned to the trial and issuing authority

CTRI/2020/09/027537 -CTRI 2020-000437-41-EudraCT


Trial Details


What is the research question being addressed?

What is the safety, tolerability and preliminary efficacy of Evenamide given in three add-on fixed doses in patients with treatment-resistant schizophrenia (trs) who are not responding adequately to their stable, therapeutically active dose of a single antipsychotic medication


Type of study

Interventional


Study design

Allocation

Randomized controlled trial


Masking

Masking not used


Control

Uncontrolled


Assignment

Parallel


Purpose

Treatment


Study Phase

Phase 2


Intervention(s) planned

Study Sites • Colombo North Teaching Hospital This is a 6-week, open-label, randomized,rater blinded multi-center study designed to evaluate the safety, tolerability and preliminary efficacy of fixed doses of evenamide of 7.5 mg bid, 15 mg bid and 30 mg bid as add-on treatment in patients with treatment-resistant schizophrenia on a stable therapeutic dose of an antipsychotic. A minimum of 150 patients will be allocated equally to each of the three treatment groups (50 patients per group). Doses will be initiated in a stepwise fashion. Initially, only the 7.5 mg bid and 15 mg bid doses will be evaluated with a 1:1 randomization scheme. After 50 patients (25 patients in each treatment group) have been treated at these doses, key safety data from these patients will be reviewed by an independent safety monitoring board (ISMB). If this review of the data indicates there are no safety issues, the 30 mg bid dose group will be initiated, and an additional 100 patients will be randomly assigned (1:1:2) to the 7.5, 15 and 30 mg bid treatment groups, with 25, 25 and 50 patients, respectively, enrolled in each group. However, if a decision is made not to include the 30 mg bid dose group in the study, an additional 100 patients will be randomly assigned (1:1) to the 7.5 and 15 mg twice daily treatment groups for a total of 150 patients enrolled, with approximately 75 in each group. Intervention1: NW3509: Fixed oral doses of 7.5, 15 mg BID orally for 6 weeks therapy of NW-3509 (Evenamide)


Inclusion criteria

  1. Age 18 years or older
  2. Male or female not of childbearing potential unless using adequate contraception as determined by their Health Care Provider.

  3. Meets current DSM-5 criteria for schizophrenia. Other psychiatric disorders may be present only as lifetime diagnoses if they are not relevant to the current episode of schizophrenia.

  4. Has been diagnosed with schizophrenia within the past 10 years.

  5. Has shown treatment-resistance according to psychiatric history, with the last failed treatment documented in the patient’s clinical records.

  6. Has a Clinical Global Impression – Severity of disease (CGI-S) rating of moderately ill to severely ill (score of 4 to 6 [scale 1-7]).

  7. Has a PANSS total score ? 70 at screening and baseline.

  8. Has a score of 4 (moderate) or more on at least 2 of the following 4 PANSS symptoms of psychosis: P2 (Conceptual Disorganization), P3 (Hallucinatory Behavior), P6 (Suspiciousness/Persecution) and G9 (Unusual Thought Content); and a total score of at least 20 on the combined total of the PANSS symptom items: P1 (Delusions), P2 (Conceptual Disorganization), P3 (Hallucinatory Behavior), P4 (Excitement), P6 (Suspiciousness/Persecution), P7 (Hostility), and G9 (Unusual thought content).

  9. Has a Global Assessment of Functioning (GAF) scale total score ? 50.

  10. Is in need of anti-psychotic treatment and is currently receiving mono-therapy at a stable dose (minimally for 4 weeks prior to screening) at a minimal recommended therapeutic or higher dose of one antipsychotic (atypical or typical, other than clozapine).

  11. Current level of schizophrenic symptoms has been present for at least one month, but not exceeding one year.

  12. Patient is cooperative, able to take oral medication, able to understand the instructions and willing to complete all aspects of the study, and is capable of doing so.

  13. Patient is residing with a caregiver at his/her home, or is either in a residential care facility or residing alone, with a caregiver available to help ensure compliance with dosing and scheduled office visits in either situation.

  14. Patient has provided written informed consent prior to participating in the study.

  15. Patient agrees to be hospitalized overnight if required for trial purposes or if the investigator deems it necessary to ensure the safety of the patient.


Exclusion criteria

  1. DSM-5 diagnosis of schizophreniform disorder, schizoaffective disorder, 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 criteria, with a severity of ‘moderate’ or ‘severe’, or patient is currently abusing drugs or alcohol or has done so in the past year.

  3. Severity of current episode of psychosis requires that the patient be hospitalized. (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. Has a PANSS total score > 90 or a CGI-S rating of 7 (among the most extremely ill patients).

  5. History or current diagnosis of other psychiatric or behavioral disorders that may interfere with the conduct or interpretation of the study.

  6. Known suicidal risk, or a suicide attempt within the past 2 years, as assessed by the CDSS and/or by psychiatric history.

  7. History of neuroleptic malignant syndrome, priapism or moderate or severe tardive dyskinesia.

  8. 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 bias the assessment of the clinical or mental status of the patient to a significant degree or put the patient at special risk (e.g., liver or kidney disease, severe uncontrolled asthma, malignancy).

  9. Insulin-dependent diabetes mellitus. Patients with non-insulin-dependent diabetes will be eligible if the following criteria are satisfied: a. Diabetes is considered well controlled, with no changes in treatment regimen for at least 4 weeks prior to screening, b. Diabetes is not newly diagnosed at screening.

  10. 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).

  11. History or current diagnosis of epilepsy or seizure disorder, or occurrence of a seizure within the past year, or repeated drug-induced seizures (other than febrile seizures in childhood).

  12. Prior surgery or current medical condition which might 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, inflammatory bowel disease.

  13. Any clinically significant ECG abnormality, including a disorder of rate, rhythm, or conduction, or other morphological changes, or a QTcF interval prolongation (Fridericia’s correction formula) on the ECG (>450 msec for males; >470 msec for females). The 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.

  14. Vital signs (supine) 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

  15. 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 and/or antibody to Hepatitis C).

  16. Positive results from the HIV serology.

  17. Positive results of the 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.

  18. History of or current treatment with clozapine for psychosis.

  19. Requires treatment with an anticholinergic drug, and the dose is not stable.

  20. Receiving benzodiazepine therapy, unless the dose has been stabilized for at least 2 months, excluding occasional prn dosing. Doses of benzodiazepines should not be reduced or stopped during the study, unless clinically necessary. PRN dosing should employ the lowest safe and effective dose possible. Any changes in the dose of a benzodiazepine should be performed under close medical supervision.

  21. Treatment with agents influencing dopamine, norepinephrine or serotonin neurotransmission (e.g. tri- and tetra-cyclic antidepressants, MAO inhibitors, metoclopramide). Treatment with SSRIs and SNRIs that are moderate/potent inhibitors of CYP2D6 (e.g. fluoxetine) will not be permitted; however, patients on a stable dose of an SSRI or SNRI that is a weak inhibitor of CYP2D6 (e.g. escitalopram), for at least 4 weeks before screening, will be eligible.

  22. Treatment with drugs capable of inducing/inhibiting hepatic enzyme metabolism (e.g. barbiturates, carbamazepine, phenylbutazone, phenytoin, primidone, rifampicin) four weeks prior to baseline or during the study.

  23. Current treatment with sodium channel blockers (e.g. Class I antiarrhythmic agents, anticonvulsants, local anesthetics) or mood stabilizers (e.g. lithium, carbamazepine, oxcarbazepine, lamotrigine); Valproic acid will be permitted, if used as maintenance treatment.

  24. Exposure to any investigational drug within 5 weeks or 5 half-lives (whichever is longer) prior to screening.

  25. A known exaggerated pharmacological sensitivity or hypersensitivity to drugs similar to evenamide (e.g. lamotrigine, carbamazepine, oxcarbazepine, topiramate, etc.), or any components of the evenamide capsules.

  26. Electroconvulsive therapy (ECT) or treatment with a transcranial magnetic stimulation (TMS) device within 6 months prior to screening.

  27. Patient is female and of childbearing potential, pregnant or breastfeeding. For inclusion, female patients must be post-menopausal (age 50 or older and confirmed amenorrhea for >12 months), surgically sterilized, or using adequate contraception, as determined by their Health Care Provider.

  28. Patients with a reasonable likelihood of non-compliance with the protocol, or any other reason that, in the Investigator’s opinion, would prohibit the inclusion of the patient in the study.



Primary outcome(s)

1.

Safety Evaluation: Safety will be assessed by the following: • Adverse events (AEs) • Vital signs systolic/diastolic blood pressure, pulse, body temperature, respiratory rate, body weight, BMI, waist circumference) • Laboratory evaluations Haematology: Hematocrit, hemoglobin, RBC count, WBC count, differential WBC count, platelets

Blood Chemistry Sodium, Potassium, Chloride, Bicarbonate, Calcium, Glucose, BUN, Creatinine, total bilirubin, Albumin triglycerides, AST, ALT, alkaline phosphatase, GGT, LDH, total cholesterol, HDL, LDL, VLDL, CPK, total protein

Urinalysis pH, specific gravity, Protein, glucose, ketones, RBC, WBC, casts, Nitrites, bilirubin, hemoglobin

Serum prolactin

• ECG • Special Diagnostic Tests (evaluated at Screening and/or Baseline) Thyroid function: TSH, free triiodothyronine (T3), and free thyroxine (T4) (Screening) - Virology: Hepatitis B and C; HIV (Screening) - Urine drug screen (Screening, Baseline and final visit) - Alcohol breath test (Baseline) - Serum prolactin (Baseline and final visit) - Serum/urine pregnancy test (Screening, Baseline and final visit)

• Physical Examination

General appearance, skin, neck (including thyroid), eyes and ears, nose, mouth, throat, lungs, heart, abdomen, back, lymph nodes, extremities

• Neurological Examination: Evaluation of the mental status, cranial nerves, muscle strength and tone, reflexes, the sensory system, coordination and gait

• A standard eye examination: Visual acuity (Snellen chart), visual field, eye muscles, pupillary response, fundus, tonometry, eyelids, cornea, conjunctiva, sclera and iris will be performed. The examination should be performed by a physician at the site who has the appropriate experience and training. If a clinically significant abnormality is noted that requires expert follow-up, an Ophthalmologist or Optometrist should be consulted.

• Seizure checklist

• Extrapyramidal Symptom Rating Scale - Abbreviated version (ESRS-A)

• Calgary Depression Scale for Schizophrenia (CDSS).

[

06 weeks

]

Secondary outcome(s)

1.

1.Preliminary efficacy of three fixed doses of evenamide Assessed by: - PANSS - CGI-S - CGI-S

2.Determine the effect of evenamide on daily functioning -Based on changes in the Strauss Carpenter level of functioning (LOF)

[

06 weeks

]

Target number/sample size

Globally 150, Locally 30


Countries of recruitment

India


Anticipated start date

2020-11-15


Anticipated end date

2021-03-20


Date of first enrollment


Date of study completion


Recruitment status

Pending


Funding source

Newron Pharmaceuticals S.p.A.


Regulatory approvals

Pending, Conditional approval received



State of Ethics Review Approval


Status

Approved


Date of Approval

2020-08-06


Approval number

P/24/05/2020


Details of Ethics Review Committee

Name: University of Kelaniya
Institutional Address:Ethics- Review Committee, Faculty of Medicine, University of Kelaniya
Telephone:011-2961267
Email: ercmed@kln.ac.lk

Contact & Sponsor Information


Contact person for Scientific Queries/Principal Investigator

Prof Shehan Williams
Consultant Psychiatrist
Colombo North Teaching Hospital, Ragama

+94774301303

shehan@kln.ac.lk

Contact Person for Public Queries

Prof Shehan Williams
Consultant Psychiatrist
Colombo North Teaching Hospital, Ragama

+94774301303

shehan@kln.ac.lk


Primary study sponsor/organization

Dr Ravi Anand
Chief Medical Officer
Newron Pharmaceuticals S.p.A Via Ludovico Ariosto 21, 20091 Bresso (Milano), Italy
+39-02-6103461

ravi@anand.ch

Secondary study sponsor (If any)







Trial Completion details


Do the investigators plan to share identified individual clinical trial participant-level data (IPD)?

No


IPD sharing plan description

N/A


Study protocol available


Protocol version and date

Not Available


Protocol URL

Not Available


Results summary available

No


Date of posting results


Date of study completion


Final sample size


Date of first publication


Link to results


Brief summary of results