A clinical study to determine safety, tolerability and efficacy of drug called Evenamide which is taken orally, in patients with long standing schizophrenia getting inadequate benefit from their current antipsychotic medication.
Scientific Title of Study
A Phase II, prospective, multi-center, randomized, 4-week, double-blind, placebo-controlled study, designed to determine the safety, tolerability, EEG effects and efficacy of oral doses of 30 mg bid of evenamide (NW-3509) in patients with chronic schizophrenia who are symptomatic on their current second-generation antipsychotic (aripiprazole, clozapine, quetiapine, olanzapine, paliperidone, or risperidone) medication.
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
2020-006062-36
EudraCT
NW-3509/008A/II/2020; Version 1.1, dated 18 Dec 2020
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
Patriot House, 4th Floor 3 BSZ Marg, New Delhi Patriot House, 4th Floor 3 BSZ Marg, New Delhi Central DELHI 110002 India
Phone
09868167119
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
Patriot House, 4th Floor 3 BSZ Marg, New Delhi Patriot House, 4th Floor 3 BSZ Marg, New Delhi
DELHI 110002 India
Phone
09868167119
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
Patriot House, 4th Floor 3 BSZ Marg, New Delhi Patriot House, 4th Floor 3 BSZ Marg, New Delhi
DELHI 110002 India
Phone
09868167119
Fax
Email
shiv.issar@clinirx.com
Source of Monetary or Material Support
Newron Pharmaceuticals SpA
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 BSZ Marg, New Delhi-110002
Department of Psychiatry, No. 11, Subburam Street, Gandhi Nagar, Madurai-625020
Madurai Madurai TAMIL NADU
9443772233
vikhram@ahanahospitals.in
Dr Gundugurti Prasad Rao
Asha Hospital
Department of Psychiatry, Road No.14, Banjara Hills, Hyderabad-500034
Hyderabad Hyderabad TELANGANA
9985900005
Prasad40@gmail.com
Dr Prashant Chaudhari
Chembur Hospital and ICCU
C-408, XLNC Chambers first floor Opposite IDBI Bank,
Near Diamond Garden, Sion Trombay Road, Chembur Mumbai-Â 400071 Mumbai MAHARASHTRA
9096983370
drprashantchaudhari100@gmail.com
Dr Sanjay Phadke
Deenanath Mangeshkar Hospital Research Center
Department of Psychiatry, Near Mhatre Briddge, Erandwane, -411004
Pune Pune MAHARASHTRA
9823262786
sanjay_phadke@hotmail.com
Dr Ankur Sachdeva
ESIC Medical College and Hospital
Department of Psychiatry, NH-3, NIT. Faridabad-121001. Haryana Faridabad HARYANA
9899528355
drankur.rml@gmail.com
Dr Radhika Reddy
Help Hospitals Private Limited
Department of Psychiatry, Help Hospitals Private Limited., D. No: 27-29-23, Behind Victoria Museum, Governorpet, Vijayawada-520002 Vizianagaram ANDHRA PRADESH
9848229798
rrvemireddy@yahoo.com
Dr PN Suresh Kumar
IQRAA Psychiatric Care and Rehabilitation Centre
Department of Psychiatry, IQRAA International Hospital and Research center, Near Vyapar Bhavan, Civil Station (PO), Eranhipalam-673020
Kozhikode Kozhikode KERALA
9447218825
drpnsuresh@gmail.com
Dr Shrikant Nimbhorkar
Kingsway Hospitals
44, Kingsway, Near Kasturchand Park,Nagpur, Maharashtra, India-440001 Nagpur MAHARASHTRA
8600877750
dr.shrikantnimbhorkar@gmail.com
Dr Nilesh Shah
Lokmanya Tilak Municipal Medical College & General Hospital
Department of Psychiatry, OPD 21, Department of Psychiatry, New OPD building, 2nd floor, Sion, Mumbai – 400022, Maharashtra, India Mumbai MAHARASHTRA
9821788658
drnilshah@hotmail.com
Dr Bhalchandra Kalmegh
Medipoint Hospital
3rd floor, 241/1, New D.P. Road, Aundh, Pune- 411007, Maharashtra, INDIA Pune MAHARASHTRA
Ethics Committee - Help Hospitals Private Limited, D. No: 27-29-23, Behind Victoria Museum, Governorpet, Vijayawada, Andhra Pradesh, India. ECR/1356/Inst/TN/2020
Approved
Ethics Committee Asha Hospital
Approved
Ethics committee, Radianz Healthcare and Research
Approved
Institute Ethics Committee, PGIMER
Submittted/Under Review
Institutional Ethics Committee for ESIC Faridabad
Approved
Institutional Ethics Committee, Deenanath Mangeshkar Hospital and Research Centre
Submittted/Under Review
Institutional ethics committee, IQRAA International Hospital and Research center
Approved
Institutional Ethics Committee, New Healthcare Nursing Home
Approved
Institutional Ethics Committee, Sri Ramachandra Medical College and Research Institute
Submittted/Under Review
Institutional Ethics Committee, Topiwala National Medical College & B.Y.L Nair Charitable Hospital
Approved
Institutional Ethics Committee- Pondicherry Institute of Medical Sciences
Approved
Kingsway hospitals Ethics Committee
Approved
LTMMC and GH, staff and research society
Approved
Penta-med Ethics Committee
Approved
Yash Society’s Sujata Birla Hospital Ethics Committee
Approved
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition: F20-F29||Schizophrenia, schizotypal, delusional, and other non-mood psychotic disorders,
Intervention / Comparator Agent
Type
Name
Details
Intervention
NW3509
Fixed oral doses of 15 and 30 mg BID orally for 28 days therapy of NW-3509 (Evenamide)
Comparator Agent
Placebo
Placebo BID orally for 28 days therapy of NW-3509 (Evenamide)
Inclusion Criteria
Age From
18.00 Year(s)
Age To
99.00 Year(s)
Gender
Both
Details
Demographics
2. Female subjects must have a negative pregnancy test at the screening visit and at baseline and must not be lactating.
- If of childbearing potential, the subject must use a highly effective method of contraception (i.e., a method that can achieve a failure rate of less than 1percent per year when used consistently and correctly) during the trial, from at least 28 days before the first dose until the final follow-up visit. Highly effective methods of contraception include-
- A woman is considered to be of non-childbearing potential if she meets one of the following criteria:
-is post-menopausal (the last menstrual period was at least 12 months ago, and FSH at screening confirms post-menopausal status),
-has no uterus, ovaries or fallopian tubes.
- Women who are taking hormone replacement therapy (HRT) must use contraception (as described above) during the trial.
- Sexual abstinence is not an acceptable method of contraception.
3. Male subjects who are not sterilized must agree to not have sex without using a condom, if their partner is a woman of childbearing potential, during the trial (from the first dose until the final follow-up visit). Male subjects must also agree not to attempt to father a child and must not donate sperm from the first dose until the final follow-up visit.
4. Body mass index (BMI) of at least 17.5 and less than 35.
Psychiatric
5. Has a current diagnosis of schizophrenia in accordance with DSM-5. Other Axis-I disorders may be present only as lifetime diagnoses if they are not relevant to the current episode of schizophrenia.
6. Has been treated with antipsychotics for at least 2 years.
7. Has a total score on the PANSS more than equal to 70 and less than equal to 85.
8. Has a Clinical Global Impression – Severity of disease (CGI-S) rating of moderately, moderately severely, or severely ill (score of 4, 5 or 6).
9. Needs antipsychotic treatment and is currently receiving a stable dose (minimally for 4 weeks prior to screening) of aripiprazole, clozapine, quetiapine, olanzapine, paliperidone, or risperidone (at least 2 mg risperidone dose-equivalent).
10. Current symptoms have been stably present for at least one month.
Patients must be symptomatic enough to benefit from addition of another antipsychotic while on their current antipsychotic; in general, these patients will have PANSS scores between 70 and 85 and a CGI-S of 4, 5 or 6.
Procedural
11. Patient has provided written informed consent prior to participating in the study.
12. Patient is able to take oral medication and is willing to complete all protocol-defined aspects of the study.
13. Patient resides at home or in a residential care facility with a caregiver who is available to ensure compliance with dosing and scheduled office visits. For US only: Caregiver is defined as someone who has at least 5 contacts with the patient each week, of which at least 2 are face-to-face.
14. 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.
15. If taking clozapine, patient agrees to blood monitoring (venipuncture for measuring ANC) weekly during their first 6 months of clozapine treatment, every 2 weeks from 6 to 12 months, and every 4 weeks after 12 months of treatment.
ExclusionCriteria
Details
Psychiatric
1. DSM-5 diagnosis of schizophreniform disorder (295.40), schizoaffective disorder (295.70), or other primary psychiatric diagnosis, such as bipolar disorder or major depressive disorder. (Comorbid 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. A history of nicotine or caffeine dependence is acceptable
3. Severity of current episode of psychosis requires that the patient be hospitalized. Patients who are chronically hospitalized or in psychiatric day-care, whose hospitalization is for logistic reasons and not due to the severity of their illness, will be eligible for the study.
4. Severity of psychosis is rated very severe (CGI-S of 7).
5. History or current diagnosis of other psychiatric (Axis I diagnosis) or behavioral disorders that may interfere with the conduct or interpretation of the study.
6. 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.
7. “Treatment resistant†defined significant persistent symptoms of schizophrenia after adequate doses of two standard antipsychotic medications (from two different chemical classes, including at least one atypical antipsychotic) following 6 weeks of treatment with each at adequate doses. Treatment resistant patients on clozapine for at least 6 months will be permitted if they have shown minimal improvement in the Investigator’s judgement.
8. Patient is currently in remission and/or experiencing transient mild breakthrough symptoms for which additional adjunctive treatment would not likely provide benefit.
9. History of neuroleptic malignant syndrome, priapism.
10. History of severe tardive dyskinesia; or current moderate or severe tardive dyskinesia.
Medical Status
11. Abnormal epileptiform phenomena (3 per second spike and slow wave discharges) observed on screening EEG.
12. 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., respiratory, liver or kidney disease; malignancy).
13. A disability that may prevent the subject from completing all study requirements (e.g., blindness, deafness, severe language difficulty).
14. 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.
15. History or current diagnosis of any neurodegenerative illness, dementia or 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).
16. History or current diagnosis of epilepsy or seizure disorder (other than febrile seizures in childhood).
17. Loss of 500 ml or more of blood during the 3-month period before study enrollment, e.g. as a donor.
18. Prior surgery or current medical condition which might interfere with the absorption, distribution, metabolism or excretion of the study drug, e.g. 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
19. A current diagnosis of severe or unstable 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)], congestive heart failure, myocardial infarction, coronary artery bypass surgery, or percutaneous transluminal coronary angioplasty.
20. 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).
21. Vital signs (supine) outside the following ranges (measured after 5 minutes supine):
a. Systolic blood pressure below 100 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);
22. History of myocardial infarction, coronary artery bypass surgery, or percutaneous transluminal coronary angioplasty.
Laboratory abnormalities
23. 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.
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); as identified by any of the following:
a. Hepatitis B: hepatitis B surface antigen (HBsAg) or with isolated anti-HBc (HBsAg negative, anti-HBc positive, and anti-HBs negative);
b. Hepatitis C: antibody to hepatitis C positive and HCV RNA positive.
25. Positive results from the HIV serology.
26. 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, depending 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. Clinically significant hypothyroidism or hyperthyroidism, unless stabilized by medication for at least 3 months before screening.
Concomitant therapy
28. Patients treated with anticholinergic drugs whose dose is not stable at baseline.
29. If receiving benzodiazepine therapy, this treatment has not been stabilized for at least 2 months. The lowest dose possible should be used. Occasional prn use is permitted.
30. Treatment with tri- and tetra-cyclic antidepressants, MAO inhibitors, and metoclopramide.
31. Treatment with SSRIs that are moderate/potent inhibitors of CYP2D6 (e.g. fluoxetine).
32. 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.
33. Current treatment with sodium channel blockers (e.g. Class I antiarrhythmic agents, anticonvulsants, local anesthetics) or mood stabilizers (e.g. lithium, carbamazepine, oxcarbazepine, lamotrigine).
34. Exposure to any investigational drug within 5 weeks or 5 half-lives (whichever is longer) prior to screening.
35. A known exaggerated pharmacological sensitivity or hypersensitivity to drugs similar to evenamide
36
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Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Double Blind Double Dummy
Primary Outcome
Outcome
TimePoints
Safety: To evaluate safety and tolerability of evenamide (30mg bid), achieved with 15 mg bid, compared to placebo, in patients with schizophrenia who are being treated with stable doses aripiprazole, clozapine, quetiapine, olanzapine, paliperidone or risperidone.
Efficacy: To evaluate efficacy of evenamide at 30 mg bid, achieved with 15 mg bid, compared to placebo, based on improvements in symptoms of schizophrenia, as assessed by the PANSS total score.
28 Days
Secondary Outcome
Outcome
TimePoints
To evaluate the efficacy of 30mg bid of evenamide, achieved after a 1-week titration starting with 15 mg bid, compared to placebo, based on improvements in symptoms of schizophrenia, as assessed by the Clinical Global Impression - Severity of illness (CGI-S).
28 days
Target Sample Size
Total Sample Size="100" Sample Size from India="60" Final Enrollment numbers achieved (Total)= "291" Final Enrollment numbers achieved (India)="112"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
17.8 Study Documentation and Publication of Study Results
Study Documentation
All unpublished documentation (including the protocol, Case Report Form and Investigator’s Brochure) given to the Investigator is strictly confidential. All recipients must agree not to disclose the information herein contained to any person not connected with the study without the prior written authorization of Newron Pharmaceuticals. The submission of these documents to the IRB/IEC is expressly permitted. The involved parties agree that the results of this study will be used in their original form and/or in a global report for submission to governmental and regulatory authorities of any country.
All information communicated to the investigator(s) by Newron is the exclusive property of Newron Pharmaceuticals S.p.A. The Principal Investigator will ensure this information shall be kept strictly confidential by him/her or any other person connected with the study and shall not be disclosed to any third party without the prior written consent of Newron.
Publication of Results
Any formal presentation or publication of the data from this trial will be considered as a joint publication by the Investigator(s) and Newron. Authorship will be determined by a Publication Committee consisting of the lead investigator(s) from the trial, representatives from Newron, and an external consultant with expertise in the field. For multi-center studies, it is mandatory that the first publication is based on data from all centers, analyzed as stipulated in the protocol by a statistician designated by Newron. Investigators participating in this study agree not to present or publish data gathered from a single center or sub-group of centers before the full initial publication, unless agreed to by all other investigators and Newron. Authorship of any publications resulting from pooled data will include members of each of the contributing centers, as well as Newron personnel.
Newron will form a study publication committee to coordinate and develop a publication policy and help in its implementation. The publication committee will be comprised of the Principal Investigator(s), a representative of Newron and an external consultant. Members of the publication committee cannot serve as first authors of more than one primary publication.
Any publication, abstract, or paper of any information or material relating to or arising out of the present clinical study shall be sent to Newron for review at least sixty (60) days before presentation at any congress, or publication of the final form(s) by any journal. Newron will inform the Investigator of any changes or deletions necessary to preserve Newron’s confidential and proprietary technical information. All rights and interests worldwide in any inventions, know-how or other intellectual or industrial property rights, which arise during the course and/or as a result of the present clinical study or which arise from the information or materials supplied under this Agreement, shall be assigned to, vest in and remain the property of Newron Pharmaceuticals S.p.A.