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CTRI Number  CTRI/2023/11/059499 [Registered on: 03/11/2023] Trial Registered Prospectively
Last Modified On: 02/08/2024
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 Study to Evaluate the Efficacy and Safety of Ketamine in Treatment Resistant Depression 
Scientific Title of Study   A Phase III, Randomized, Double Blind, Placebo Controlled, Parallel Group, Comparative, Multi-Centre Clinical Study to Evaluate the Efficacy and Safety of Ketamine Subcutaneous Injection as an Adjunct Treatment to on-going Antidepressant Therapy in Patients with Treatment Resistant Depression (TRD) 
Trial Acronym  NIL 
Secondary IDs if Any  
Secondary ID  Identifier 
TML/KET/01;Version 3.1; 09.05.2023  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Modification(s)  
Name  Dr Balaji More 
Designation  Vice President- Medical Services 
Affiliation  Themis Medicare Limited 
Address  Themis Medicare Limited 11-12 Udyog Nagar Goregaon West Mumbai Mumbai Suburban MAHARASHTRA

Mumbai
MAHARASHTRA
400104
India 
Phone  8452959225  
Fax    
Email  balaji.more@themismedicare.com  
 
Details of Contact Person
Scientific Query
Modification(s)  
Name  Dr Aditi Datta 
Designation  Managing Director  
Affiliation  Biosite Research Private Limited. 
Address  1st Floor, Ajmera Nucleus, 424C, Next to Mahindra Tech Park, Shanthipura, Electronic City Phase 2, Bengaluru, Karnataka 560100

Bangalore
KARNATAKA
560100
India 
Phone  8035104561  
Fax    
Email  aditi.datta@biositeindia.com  
 
Details of Contact Person
Public Query  
Name  Sangameshwar Iyer 
Designation  Company Secretary 
Affiliation  Themis Medicare Limited  
Address  Themis Medicare Limited 11/12 Udyog Nagar Goregaon (West) Mumbai Mumbai (Suburban) MAHARASHTRA

Mumbai
MAHARASHTRA
400104
India 
Phone  9769692460  
Fax    
Email  sangameshwar.iyer@themismedicare.com  
 
Source of Monetary or Material Support  
Themis Medicare Limited 11/12, Udyog Nagar, S. V. Road, Goregaon (W), Mumbai – 400104, Maharashtra, India  
 
Primary Sponsor  
Name  Themis Medicare Limited 
Address  11/12, Udyog Nagar, S. V. Road, Goregaon (W), Mumbai – 400104, Maharashtra, India 
Type of Sponsor  Pharmaceutical industry-Indian 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study
Modification(s)  
No of Sites = 8  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Susanta Kumar Padhy  AIIMS, Bhubaneshwar  AIIMS, Sijua, Patrapada,Bhubaneswar-751019
Khordha
ORISSA 		 8054831604

susanta.pgi30@yahoo.in 
Dr Parlin Mansukhlal Dadhaniya  Anand Multispeciality Hospital and Research Centre  Department of Psychiatry; Room number 1, 4th Floor, Sarthak Mall, Mahatma Mandir Road, Sargasan Cross Road, Sargasan, Gandhinagar-382421
Gandhinagar
GUJARAT 		 9427371747

parlin30dadhania@yahoo.in 
Dr Narendra Kumar M S  Department of Psychiatry, KR Hospital, Mysore  Department of Psychiatry, KR Hospital attached to Mysore Medical College and Research lnstitute, Irwin Road, Mysuru 570001, Karnataka, India.
Mysore
KARNATAKA 		 9481818612

drheggere@gmail.com 
Dr Nilesh Shah  Department of Psychiatry, Sion Hospital.  OPD 21,Department of Psychiatry, 2nd floor, Sion Hospital, Mumbai, 400022
Mumbai
MAHARASHTRA 		 9821788658

drnilshah@hotmail.com 
Dr Nishanth Vemana  Excel Hospital  Department of Psychiatry; Room number 103, 1st Floor, 1-5-56/29, Old Alwal Rd, Beside Bharat Petroleum, Near IG Statue,Banda Basti, Old Alwal , Secunderabad, Telengana, 500010
Hyderabad
TELANGANA 		 9440664042

vemananishanth12@gmail.com 
Dr Partha Kundu  IPGME & R and SSKM Hospital  Department of Psychiatry: Ground floor, Unit head office -01, IPGME&R and SSKM Hospital, 244, A.J.C Bose Road, Kolkata-700020
Kolkata
WEST BENGAL 		 9051386220

drparthakundu@gmail.com 
Dr Rajendra Someshwar Anand  Kanoria Hospital Research Centre  Department of Psychiatry; Room number 10, Ground Floor, Airport-Gandhinagar Highway, Village:Bhat, Dist:Gandhinagar - 382428, Gujarat
Gandhinagar
GUJARAT 		 9824017400

drrajendraanand@yahoo.com 
Dr Asish Mukhopadhyay  Nil Ratan Sircar Medical College & Hospital  Department of Psychiatry; Room number 1; 3rd floor OPD budling, Nil Ratan Sircar Medical College & Hospital, 138, AJC Bose Road, Kolkata-700014.
Kolkata
WEST BENGAL 		 9830476643

asish47@gmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 9  
Name of Committee  Approval Status 
Anand Ethics Committee, Anand Multispeciality Hospital and Research Centre  Approved 
Excel Hospital Institutional Ethics Committee  Approved 
Institutional Ethics Committee  Approved 
Institutional Ethics Committee Lokmanya Tilak  Submittted/Under Review 
Institutional Ethics Committee, Nil Ratan Sircar Medical College & Hospital  Approved 
Institutional Ethics Committee, AIIMS  Submittted/Under Review 
Institutional Ethics Committee, St. John’s Medical College Hospital  Approved 
IPGME & R Research Oversight Committee  Approved 
Kanoria Ethics Committee  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: F332||Major depressive disorder, recurrent severe without psychotic features,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  Ketamine Solution 50 mg/mL PFS  Subjects will receive either Ketamine Solution 50 mg/mL Prefilled Syringe for Subcutaneous Injection at a dose of 0.5 mg/kg of body weight or equivalent volume of matching placebo as a single dose on Day 1 and Day 4 of every week up to 6 weeks or till significant improvement whichever is earlier 
Comparator Agent  Matching Placebo of test product  Subjects will receive either Ketamine Solution 50 mg/mL PFS for Subcutaneous Injection at a dose of 0.5 mg/kg of body weight or equivalent volume of matching placebo as a single dose on Day 1 and Day 4 of every week up to 6 weeks or till significant improvement whichever is earlier volume of matching placebo 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  55.00 Year(s)
Gender  Both 
Details  1. Male and female subjects between 18 to 65 years of age (both inclusive).
2. Subjects of depression who have failed to respond to the treatment with adequate dose and duration (minimum three weeks from initiation of the last antidepressant drug) of at least two different classes of antidepressant medications (TRD), without psychotic features, as assessed by investigator with the Structured Clinical Interview for DSM-5 (Diagnosis of TRD will be made based on patient’s treatment record and clinical interview).
3. Subjects with negative alcohol breath test result and urine screening result for drugs of abuse (including amphetamines, barbiturates, benzodiazepines, marijuana, cocaine and morphine) [Note: If the patient is taking any of these drugs on prescription may be included in the study in spite of a positive screening results for the prescribed drug(s)].
4. Subjects with baseline score of ≥ 22 on the Montgomery and Åsberg Depression Rating Scale (MADRS).
5. Subjects with baseline score of ≤ 9 on Bladder Pain/ Interstitial Cystitis Symptom Score (BPIC-SS),
6. For Female Subjects, of childbearing potential practicing an acceptable method of birth control such as sexual abstinence, a double-barrier method, condom plus spermicide, diaphragm plus spermicide, or vaginal spermicidal suppository; for the duration of the study as judged by the investigator(s)/study physician and agree to follow the same should be used during treatment.
OR
Postmenopausal for at least 1 year.
OR
Surgically sterile (bilateral tubal ligation/bilateral oophorectomy/ hysterectomy has been performed on the Subject).
7. Subjects who can give voluntary, written informed consent to participate in this clinical investigation and from whom IEC/IRB approved written informed consent has been obtained prior to screening.
8. Subjects shall be willing and able to understand and comply with the requirements of the protocol, administer the medication as instructed, return for the required treatment period visits, comply with therapy prohibitions, and be able to complete the study
 
 
ExclusionCriteria 
Details  1. History of previous non-response to esketamine or ketamine in depressive episode.
2. Subjects having any unstable medical or neurological condition as per principal investigator assessment.
3. Subject has suicidal ideation with intent to act during screening phase or on Day 1 (prior to randomization) based on the Columbia-Suicide Severity Rating Scale (C-SSRS) or per Investigator‟s clinical judgment, or has a history of suicidal behaviour within the past year as assessed on the C SSRS; or subject has homicidal ideation/intent at Screening or on Day 1.
4. Subjects with substance abuse or dependence in the 6 months prior to screening.
5. Subjects with any psychotic disorder, bipolar disorder, obsessive compulsive disorder, intellectual disability, autism, cluster B personality disorder, organic disorder, developmental disorder.
6. Subjects with lifetime abuse or dependence on ketamine.
7. Subjects with previous history of non-response to Ketamine, or to all of the oral antidepressant medications.
8. Subjects with history of Vagus Nerve Stimulation (VNS) or deep brain stimulation in current episode of depression.
9. Subjects with history of homicidal ideation/intent.
10. Subjects with QT prolongation ≥450 msec during screening ECG or other significant arrhythmias. 11. Subjects with Other major medical conditions including coronary artery disease, uncontrolled hypertension, hypertensive crisis.
12. Subjects with known case of HIV infection, Hepatitis B, or Hepatitis C Infection.
13. Subjects with known case of Type 1 diabetes or Type 2 diabetes mellitus with HbA1c value greater than 8%.
14. Subjects who have any condition that would compromise compliance with this protocol.
15. Female subjects who are pregnant or lactating or planning to become pregnant during the study period.
16. Female subjects who are not ready to use acceptable contraceptive methods during the study period.
17. Suspected hypersensitivity to Ketamine or any of the ingredients of the formulation.
18. Subjects with any other medical condition that might adversely impact the safety of the study participants or confound the study results.
19. Subjects who have been treated with an investigational drug or investigational device within a period of 30 days prior to study entry.
20. Currently taking prohibited concomitant medications(s) listed and inability/unwillingness to discontinue them for the entire study period.
21. Suspected inability or unwillingness to comply with the study procedures
 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Centralized 
Blinding/Masking   Participant and Investigator Blinded 
Primary Outcome  
Outcome  TimePoints 
Percentage of responders in the test group compared to that in placebo group as assessed by MADRS  Subjects in the Test product arm will receive Ketamine Solution 50 mg/mL PFS for Subcutaneous Injection at a dose of 0.5 mg/kg of body weight upto twice a week (on day 1 & day 4) for up to 6 weeks. Subjects in the Reference product arm will receive Matching Placebo of Ketamine solution upto twice a week (on day 1 & day 4) for up to 6 weeks 
 
Secondary Outcome  
Outcome  TimePoints 
change in depression severity from baseline to study endpoint using MADRS in test group versus
placebo,
Change from baseline to study endpoint in the Patient Health Questionnaire (PHQ-9) score.
Change from baseline to study endpoint in Clinical Global Impression (CGI) Scale
Remission from depression (at end of treatment period), defined as the proportion of participants who had a depression rating of less than or equal to ten on the MADRS.
Number of doses to Clinically Relevant Response (≥ 50% on MADRS)
Number of doses to show at least 25% improvement on MADRS
Change in C-SSRS (Columbia-Suicide Severity Rating Scale) score from baseline to end of treatment
Change from baseline to study endpoint in Brief Psychiatric Rating Scale (BPRS) to assess the
Psychotomimetic effects during the study using Brief Psychiatric Rating Scale (BPRS)
 		 Subjects in the Test product arm will receive Ketamine Solution 50 mg/mL PFS for Subcutaneous Injection at a dose of 0.5 mg/kg of body weight upto twice a week (on day 1 & day 4) for up to 6 weeks. Subjects in the Reference product arm will receive Matching Placebo of Ketamine solution upto twice a week (on day 1 & day 4) for up to 6 weeks 
 
Target Sample Size   Total Sample Size="81"
Sample Size from India="81" 
Final Enrollment numbers achieved (Total)= "81"
Final Enrollment numbers achieved (India)="81" 
Phase of Trial   Phase 3 
Date of First Enrollment (India)   10/11/2023 
Date of Study Completion (India) 25/01/2025 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Date Missing 
Estimated Duration of Trial   Years="1"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)   Not Applicable 
Recruitment Status of Trial (India)  Completed 
Publication Details   N/A 
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Response - NO
Brief Summary  

Despite availability of many antidepressant medications such as MAO inhibitors, TCA, SSRIs and SNRIs, many patients remain resistant to treatment. Treatment Resistant Depression (TRD), defined as patients who in the current depressive episode, had not responded adequately to at least two different classes of antidepressants of adequate dose and duration, is an unmet medical need. Therefore, there is a need for a more effective and rapid-acting antidepressant for the treatment of such patients.

Ketamine has been approved for general anesthesia either alone or in combination with other anesthetics since 1970 in USA and 1971 in India. Multiple clinical studies published over last 25 years indicate that Ketamine can be an useful option in the treatment of Major Depressive Disorder, especially in treatment-resistant depression. Esketamine (S-enantiomer of ketamine) was approved by US FDA and later in EU as a single-use nasal spray device for the treatment of treatment-resistant-depression (TRD) in adults and Depressive symptoms in adults with major depressive disorder (MDD). Based on published data, subcutaneous ketamine administration is effective in controlling symptoms of MDD and TRD and the risk of adverse events is relatively less in comparison to intravenous injection.

This double blind RCT has been designed to assess the efficacy and safety of Ketamine 50 mg/mL Solution in PFS when administered as subcutaneous injection as an add on treatment to the ongoing antidepressant therapy in patients with treatment   resistant   depression (TRD).

 
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