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Clinical Trial Details (PDF Generation Date :- Fri, 01 Oct 2021 07:22:25 GMT)

CTRI Number CTRI/2020/02/023099 [Registered on: 03/02/2020] - Trial Registered Prospectively Last Modified On 02/08/2021 Post Graduate Thesis No Type of Trial Interventional Type of Study Drug Study Design Randomized, Parallel Group, Placebo Controlled Trial Public Title of Study A clinical study to determine safety, tolerability and efficacy of drug called Evenamide which is taken orally, in patients with long standing getting inadequate benefit from their current . Scientific Title of A Phase II, prospective, multi-center, randomized, 4-week, double-blind, placebo-controlled, Study multiple-dose study, designed to determine the safety, tolerability, EEG effects and preliminary efficacy of fixed oral doses of 7.5 and 15 mg bid of evenamide (NW-3509) in patients with chronic schizophrenia who are symptomatic on their current second-generation antipsychotic (, , , , , or ) medication. Secondary IDs if Any Secondary ID Identifier 104.708 Other NW-3509/008/II/2019 Amendment 2, 23 Protocol Number December 2019 Details of Principal Details of Principal Investigator Investigator or overall Name Shiv Issar Trial Coordinator (multi-center study) 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 9868167119 Fax Email [email protected] Details Contact Details Contact Person (Scientific Query) Person (Scientific Name Shiv Issar Query) 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 9868167119 Fax Email [email protected] Details Contact Details Contact Person (Public Query) Person (Public Query) Name Shiv Issar Designation Head, Clinical and RA Affiliation CliniRx Research Pvt Ltd

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Address Patriot House, 4th Floor 3 BSZ Marg, New Delhi Patriot House, 4th Floor 3 BSZ Marg, New Delhi Central DELHI 110002 India Phone 9868167119 Fax Email [email protected] Source of Monetary or Source of Monetary or Material Support Material Support > Newron Pharmaceuticals SpA Via Ludovico Ariosto 21 20091 Bresso (Milano) Italy Primary Sponsor Primary Sponsor Details Name Newron Pharmaceuticals SpA Address Via Ludovico Ariosto 21 20091 Bresso (Milano) Italy Type of Sponsor Pharmaceutical industry-Global Details of Secondary Name Address Sponsor CliniRx Research Pvt Ltd Patriot House, 4th Floor, 3 BSZ Marg, New Delhi-110002 Countries of List of Countries Recruitment India United States of America Sites of Study Name of Principal Name of Site Site Address Phone/Fax/Email Investigator Dr Vikhram Ahana Hospital LLP Department of 9443772233 Ramasubramanian Psychiatry, No. 11, Subburam Street, vikhram@ahanahospita Gandhi Nagar, ls.in Madurai-625020 Madurai TAMIL NADU Dr Gundugurti Prasad Asha Hospital Department of 9985900005 Rao Psychiatry, Road No.14, Banjara Hills, [email protected] Hyderabad-500034 Hyderabad TELANGANA Dr Ranjive Mahajan Dayanand Medical Department of 9872655006 College & Hospital Psychiatry, Research & Development Centre, [email protected] Dayanand Medical College and Hospital, Tagore Nagar, Civil Lines - 141001 Ludhiana PUNJAB Dr Sanjay Phadke Deenanath Mangeshkar Department of 9823262786 Hospital Research Psychiatry, Near Center Mhatre Briddge, sanjay_phadke@hotma Erandwane, -411004 il.com Pune MAHARASHTRA Dr Radhika Reddy Help Hospitals Private Department of 9848229798 Limited Psychiatry, Help Hospitals Private [email protected]

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Limited., D. No: m 27-29-23, Behind Victoria Museum, Governorpet, Vijayawada, Andhra Pradesh, India. Pincode-520002 Vizianagaram ANDHRA PRADESH Dr PN Suresh Kumar IQRAA Psychiatric Care Department of 9447218825 and Rehabilitation Psychiatry, IQRAA Centre International Hospital [email protected] and Research center, Near Vyapar Bhavan, Civil Station (PO), Eranhipalam-673020 Kozhikode KERALA Dr Supriya Hegde Mangala Hospital and Department of 9845338287 Mangala Kidney Psychiatry, Mangala Foundation Hospital and Mangala [email protected] Kidney Foundation, m Vajra Hills, Kadri Road -575003 Mangalore Mysore KARNATAKA Dr Vijay Kumar KG National Institute of Department of 9985900005 Mental Health and Psychiatry, Hosur Neurosciences Road, Wilson Garden,B [email protected] engaluru-560029, India Bangalore KARNATAKA Dr Sandeep Grover Post Graduate Institute Department of 9316138997 of Medical Education Psychiatry, Nehru and Research Hospital, Department of drsandeepg2002@yaho Psychiatry, Cobalt o.com Block, PGIMER, 160012-Chandigarh Patiala PUNJAB Dr Sanjeev Saoji Saoji Tupkari Hospital Department of 9822957746 Psychiatry 4, Vijay Nagar, Garkheda Road, [email protected] -431005 m Aurangabad MAHARASHTRA Dr Ramanathan Sri Ramachandra Department of 9841019910 Sathianathan Hospital Psychiatry, Sri Ramachandra sathianathen6@yahoo. University, No:1 com Ramachandra Nagar, Porur – 600116 Chennai TAMIL NADU Dr Johnson Pradeep St Johns Medical Department of 9632175933 College hospital, Psychiatry, St Johns Department of Medical College & drjohnsonpradeep@gm Psychiatry Hospital, St Johns ail.com National Academy of

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health Science, Sarjapur Main Road, 560034 Bangalore KARNATAKA Dr Umesh Nagapurkar Sujata Birla Hospital Department of 9823146088 and Medical Research Psychiatry, Opposite Centre Bytco College, Nashik [email protected] Road m Nashik MAHARASHTRA Details of Ethics Name of Committee Approval Status Date of Approval Is Independent Ethics Committee Committee? Drug Trial Ethics Approved 18/02/2020 No Committee, Dayanand Medical College and Hospital Ethics Committee - Approved 14/07/2020 No Help Hospitals Private Limited, D. No: 27-29-23, Behind Victoria Museum, Governorpet, Vijayawada, Andhra Pradesh, India. ECR/1356/Inst/TN/2020 Ethics committee Asha Approved 25/02/2020 No Hospital, Ethics committee, Approved 02/01/2020 No Radianz Healthcare and Research Institute Ethics Approved 14/05/2020 No Committee, PGIMER Institutional Ethics Approved 20/01/2020 No Committee, Deenanath Mangeshkar Hospital and Research Centre Institutional ethics Approved 18/12/2019 No committee, IQRAA International Hospital and Research center Institutional Ethics Approved 28/11/2019 No Committee, Sri Ramachandra Medical College and Research Institute Institutional Ethics Approved 26/05/2020 No Committee, St. John’s Medical College Hospital, Mangala Institutional Approved 23/12/2019 No Ethics Committee, Mangala Hospital and Mangala Kidney Foundation NIMHANS Ethics Submittted/Under No Date Specified No Committee, Review

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Administrative Block, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore, Karnataka-560029, India Saoji Tupkari Hospital Approved 27/02/2020 No Ethics Committee Yash Society’s Sujata Approved 06/06/2020 No Birla Hospital Ethics Committee Regulatory Clearance Status Date Status from DCGI Approved/Obtained 31/12/2019 Health Condition / Health Type Condition Problems Studied Patients Other schizophrenia Intervention / Type Name Details Comparator Agent Intervention NW3509 Fixed oral doses of 7.5 and 15 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 Inclusion Criteria Age From 18.00 Year(s) Age To 99.00 Year(s) Gender Both Details Psychiatric
4. 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. [see Exclusion criteria below]
5. Has been treated with for at least 2 years.
6. Has a total score on the PANSS < 80.
7. Has a Clinical Global Impression – Severity of disease (CGI-S) rating of mildly, moderately or moderately severely ill (score of 3, 4 or 5).
8. 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).
9. Current symptoms have been stably present for at least one month.
Procedural
10. Patient has provided written informed consent prior to participating in the study.
11. Patient is able to take oral medication and is willing to complete all protocol-defined aspects of the study.
12. 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.
13. 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.
14. 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. Exclusion Criteria Exclusion Criteria

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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 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 or has done so in the past year. A history of nicotine or caffeine dependence is acceptable 3. Severity of current episode of 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 severe or higher (CGI-S of 6 or greater). 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. A “yes” response on the C-SSRS Suicidal Ideation Item 4 or Item 5, or a “yes” response on any of the five C-SSRS Suicidal Behavior items, at screening, or a suicide attempt within the past 6 months, excludes the patient from the study. 7. “Treatment resistant” defined significant persistent symptoms of schizophrenia after adequate doses of two standard antipsychotic (from two different chemical classes, including at least one ) 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. History of neuroleptic malignant syndrome, priapism. 9. History of severe tardive dyskinesia; or current moderate or severe tardive dyskinesia. Medical Status 10. Abnormal epileptiform phenomena (3 per second spike and slow wave discharges) observed on screening EEG. 11. 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); 12. A disability that may prevent the subject from completing all study requirements (e.g., blindness, deafness, severe language difficulty); 13. Insulin-dependent diabetes mellitus. Patients with non-insulin-dependent diabetes will be eligible if the following criteria are satisfied: Method of Generating Computer generated randomization Random Sequence Method of Centralized Concealment Blinding/Masking Double Blind Double Dummy Primary Outcome Outcome Timepoints To evaluate the safety and tolerability (including 28 Days EEG and ECG effects) of two fixed oral doses of evenamide (7.5 and 15 mg bid [15 and 30

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mg/day]), compared to placebo, in patients with schizophrenia who are being treated with stable doses of antipsychotic medication (aripiprazole, clozapine, quetiapine, olanzapine, paliperidone or risperidone). Secondary Outcome Outcome Timepoints To evaluate evidence for efficacy of evenamide 4 Weeks in a range from 7.5 to 15 mg bid, compared to placebo, based on improvements in symptoms of schizophrenia, as assessed by the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression - Change from baseline (CGI-C) and Severity of illness (CGI-S) Target Sample Size Total Sample Size=120 Sample Size from India=100 Final Enrollment numbers achieved (Total)=138 Final Enrollment numbers achieved (India)=111 Phase of Trial Phase 2 Date of First 03/02/2020 Enrollment (India) Date of First 03/02/2020 Enrollment (Global) Estimated Duration of Years=0 Trial Months=3 Days=0 Recruitment Status of Completed Trial (Global) Recruitment Status of Completed Trial (India) Publication Details None Brief Summary This is a prospective, 4-week, randomized, double-blind, placebo-controlled, study designed to evaluate the safety, tolerability, including effects on EEG recordings, and preliminary efficacy of two fixed oral doses of evenamide of 7.5 mg and 15 mg bid (15 and 30 mg/day) in patients with chronic schizophrenia who are receiving treatment at constant doses of one of the following atypical antipsychotics: aripiprazole, clozapine, quetiapine, olanzapine, paliperidone or risperidone. Approximately 120 patients will be randomized in a 1:1:1 ratio to receive either evenamide 7.5 or 15 mg, or placebo, given bid. Immediately following completion of the 4-week double-blind phase, participants may enter a 48-week open-label extension study (Study NW-3509/009/II/2019) in which all patients will receive treatment with evenamide.

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