Major Depressive EpisodePhase 3KOMETNCT07839338
A Study Comparing Oral Ketamine With Oral Midazolam for the Treatment of Major Depressive Episodes
A Phase 3 study testing Oral ketamine and Oral midazolam in people with Major Depressive Episode, run by Jawaharlal Institute of Postgraduate Medical Education & Research at 5 sites in India.
Trial summary
Patients with depression are acutely distressed, often suicidal, and unable to meet the demands of everyday life. If proven effective in a rigorously conducted multicenter randomized controlled trial (RCT), oral ketamine would provide an affordable and scalable, intervention suitable for integration into routine… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Major Depressive Episode
- What is being tested?
- Oral ketamine and Oral midazolam
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 220 participants
- Where
- 5 sitesIndia
- Study dates
- Oct 2026to Oct 2029
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Consenting adult outpatients or inpatients with at least moderately severe major depressive episode (MDE), denoted by HAM- D more than or equal to 20, associated with major depressive disorder or bipolar disorder, with diagnosis confirmed using a structured diagnostic interview.
Who cannot join
- Patients with co-morbid obsessive-compulsive disorder or intellectual disability disorder or co-morbid substance dependence other than nicotine or patients concurrently receiving neuromodulation treatments or those with psychotic symptoms. Patients with current or ongoing suicide risk, such as active suicidal ideation with a specific plan or some intent in the last 3 days, will be excluded if they are treated as outpatients. Patients in whom, in the subjective opinion of the PI, the MDE symptoms appear to be significantly driven by acute life events or circumstances. Patients with abnormalities of concern detected in the electrocardiogram, or with uncontrolled hypertension or those with ongoing pregnancy or lactation
Trial locations and contacts
5 sites in 1 country. Contact the study team or a site near you to ask about taking part.
5 sites in 1 country
India5 sites
NIMHANS
Bangalore, Karnataka
Suhas Satish, +91 8884493142, suhas.academic@gmail.com
AIIMS, Bhubaneswar
Bhubaneswar, Odisha
Susanta K Padhy, +91 9463895852, psych_susanta@aiimsbhubaneswar.edu.in
MGM Medical College, Mumbai
Mumbai, Maharashtra
Sagar Karia, +91 9594530457, karia777@yahoo.com
Jawaharlal Institute of Postgraduate Medical Education and Research
Puducherry, Puducherry
Vikas Menon, MD, +91 8098158528, drvmenon@gmail.com
Kasturba Medical College
Udupi, Karnataka
Samir K Praharaj, +91 8971026304, samirpsyche@yahoo.co.in
About this study
Official title: A Randomized, Double-blind, Active Placebo-controlled, Multicenter Trial of Efficacy and Safety of Adjunctive Oral Ketamine vs Oral Midazolam for Major Depressive Episodes
Patients with depression are acutely distressed, often suicidal, and unable to meet the demands of everyday life. If proven effective in a rigorously conducted multicenter randomized controlled trial (RCT), oral ketamine would provide an affordable and scalable, intervention suitable for integration into routine psychiatric services.This study will establish an indigenous, cost-effective therapeutic strategy that could improve accessibility, hasten therapeutic response, and inform treatment guidelines, if found to be safe and effective.
Read the detailed description
Background: Conventional antidepressant treatment for major depressive episodes typically requires 3-6 weeks of drug use before meaningful clinical improvement is noted. Consequently, patients have to put their lives and responsibilities on hold while waiting for a therapeutic response.
Problem statement and rationale: There is a distinct need for a safe, acceptable, and effective, rapidly acting antidepressant in MDE to limit the impact on daily life. As an inexpensive, generic medication administered through a convenient route, oral ketamine has the potential to overcome the logistical barriers associated with existing ketamine formulations. If proven effective in a rigorous multicenter randomized controlled trial (RCT), oral ketamine would provide an affordable, scalable, and pragmatic intervention suitable for integration into routine psychiatric services.
Objectives- Primary: To assess the efficacy of adjunctive oral ketamine vs oral midazolam on clinical depression ratings at the end of study week 3- primary endpoint assessed using Hamilton Depression rating scale.
Secondary:
To assess the efficacy of adjunctive oral ketamine vs oral midazolam on clinical depression ratings at study day 2, day 7, and end of study weeks 2 and 4 and suicide ideation ratings at study day 2, study day 7, end of study week 2, week 3, and week 4.
To assess the efficacy of adjunctive oral ketamine vs oral midazolam on between-group response and remission rates, self-rated functioning, and self-rated quality of life at the end of study week 2, week 3, and week 4.
To compare psychophysiological and adverse effects between groups during each treatment session until the end (at 2 hours) and to compare adverse effects between groups at study day 2, day 7, and the end of study week 2, week 3, and week 4.
Methodology: This study uses a randomized, double-blind, active-placebo controlled, multicenter, RCT design to compare the efficacy and safety of repeated dosing with adjunctive oral ketamine vs oral midazolam in patients with moderate to severe MDE. Safety and efficacy endpoints will be assessed by separate outcome raters.
Expected outcomes: This study will establish an indigenous, cost-effective therapeutic strategy that could improve accessibility, hasten therapeutic response, and inform treatment guidelines, if found to be safe and effective.
- Conditions
- Major Depressive Episode
- Being tested
- Oral ketamine, Oral midazolam
- Keywords
- oral ketamine, major depressive episodes, oral midazolam
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Oral ketamineDrug
Nine sessions of oral ketamine
Oral midazolamDrug
Nine sessions of oral midazolam
| Study group | Role | What they receive |
|---|---|---|
| Oral midazolam | Placebo comparator | The comparator arm will receive flexibly-dosed oral midazolam (5-7.5mg across all nine sessions, guided based on psychophysiological response to preserve the integrity of blinding), which will also be administered in approximately 200 mL of water, and sipped across 20-30 minutes Receives: Drug: Oral midazolam |
| Oral ketamine | Experimental | In the first session, oral ketamine will be administered as a fixed 150 mg dose diluted in approximately 200 mL water and sipped across 20-30 minutes. In sessions 2-9 for oral ketamine, the dose will be lowered to 100-125mg in those who do not tolerate 150mg. If patients tolerate the first session well, the dose of ketamine will be increased to 175mg in the second session. If there is a negligible benefit and the intervention is tolerated, the dose of ketamine will be increased to 200 mg in the third session.
Further increase in ketamine will be done in the last week to 250mg, if deemed necessary, due to suboptimal response. Participants will remain nil per oral from one hour before until two hours after each session. Blood pressure and pulse rate will be monitored every 15 minutes for one hour or until normalization. Benzodiazepines such as clonazepam will be permitted for anxiety or agitation Receives: Drug: Oral ketamine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Hamilton Depression Rating Scale (HAM-D)
Endpoint HAM-D scores. Minimum 0 and maximum 52. Higher scores denote worse outcomes.
Measured: End of study week 3 (±2 days)
Secondary outcomes (7)
Hamilton Depression Rating Scale (HAM-D)
Endpoint HAM-D scores. Minimum 0 and maximum 52. Higher scores denote worse outcomes.
Measured: Study day 2 (± 1 day), day 7 (± 1 day), and the end of study weeks 2 (± 1 day) and week 4 (±2 days)
Montgomery-Asberg Depression Rating Scale (MADRS)
Endpoint MADRS scores. Minimum 0 and maximum 60. Higher scores denote worse outcomes.
Measured: End of study day 2 (± 1 day), day 7 (± 1 day), end of study week 2 (±1 day), week 3 (± 2 days), and week 4 (± 2 days)
Patient Health Questionnaire (PHQ)-9
Endpoint PHQ scores. Minimum 0 and maximum 27. Higher scores denote worse outcomes.
Measured: End of study day 2 (± 1 day), day 7 (± 1 day), end of study week 2 (±1 day), week 3 (± 2 days), and week 4 (± 2 days)
Hamilton Depression Rating Scale (HAM-D)/Montgomery-Asberg Depression Rating Scale (MADRS)
Response and remisssion rates. HAM-D-Minimum 0 and maximum 52. MADRS-Minimum 0 and maximum 60.For both scales, higher scores denote worse outcomes.
Measured: End of study week 2 (±1 day), week 3 (± 2 days), and week 4 (± 2 days)
Visual Analogue Scale for self-rated functioning & quality of life
Percentage change from baseline. Scores range from 0 to 100. Higher scores denote better outcome.
Measured: End of study week 2 (±1 day), week 3 (± 2 days), and week 4 (± 2 days)
Intrasession adverse effects checklist
Proportion and frequency of adverse effects. Checklist used for adverse effects.
Measured: During each treatment session until the end (at 2 hours)
Systematic assessment for treatment-emergent effects (SAFTEE) checklist
Proportion and frequency of adverse effects. Checklist used for the systematic assessment of side effects in clinical trials
Measured: At study day 2 (± 1 day), day 7 (± 1 day), end of study week 2 (±1 day), week 3 (± 2 days), and week 4 (± 2 days)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Sep 2026
- Study startOct 2026 (estimated)
- Primary completionOct 2029 (estimated)
- Study completionOct 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Major Depressive EpisodeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 220 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Jawaharlal Institute of Postgraduate Medical Education & Research
- Sponsor type
- Other government
- Collaborators
- Indian Council of Medical Research
- Responsible party
- Principal investigator, Dr. Vikas Menon, Jawaharlal Institute of Postgraduate Medical Education & Research
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07839338
- Sponsor's protocol ID
- JIP-IECIS-6/0826/89
- Acronym
- KOMET
- Status last verified
- Sep 2026
- First submitted
- 18 Sep 2026
- Last updated
- 1 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Kaur S, Parmar C, Gaur V, Chauhan A, Andrade C. The efficacy of oral ketamine in severely depressed patients at high risk of suicide. Asian J Psychiatr. 2023 Aug;86:103678. doi: 10.1016/j.ajp.2023.103678. Epub 2023 Jun 12.
PubMed 37352755Kumar PS, Menon V, Andrade C. A randomised, open-label, pragmatic pilot comparison of oral and intravenous ketamine in treatment-resistant depression. Asian J Psychiatr. 2024 Sep;99:104171. doi: 10.1016/j.ajp.2024.104171. Epub 2024 Jul 23.
PubMed 39068714Silberbauer LR, Eggerstorfer B, Michenthaler P, Reichel S, Stimpfl T, Vanicek T, Naderi-Heiden A, Kasper S, Lanzenberger R, Gryglewski G. Oral ketamine for the treatment of major depressive and bipolar disorder, a randomized controlled trial and meta-analysis. J Affect Disord. 2026 Feb 1;394(Pt A):120466. doi: 10.1016/j.jad.2025.120466. Epub 2025 Oct 14.
PubMed 41101490
Study at a glance
From the registry record, last updated by the sponsor on 1 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized, Double-blind, Active Placebo-controlled, Multicenter Trial of Efficacy and Safety of Adjunctive Oral Ketamine vs Oral Midazolam for Major Depressive Episodes
- ClinicalTrials.gov ID
- NCT07839338
- Acronym / sponsor ID
- KOMET / JIP-IECIS-6/0826/89
- Conditions
- Major Depressive Episode
- Keywords
- oral ketamine, major depressive episodes, oral midazolam
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 220 participants (estimated)
- Lead sponsor
- Jawaharlal Institute of Postgraduate Medical Education & ResearchOther government
- Collaborators
- Indian Council of Medical Research
- Study start
- Oct 2026 (estimated)
- Primary completion
- Oct 2029 (estimated)
- Study completion
- Oct 2029 (estimated)
- First posted
- 24 Sep 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Patients with depression are acutely distressed, often suicidal, and unable to meet the demands of everyday life. If proven effective in a rigorously conducted multicenter randomized controlled trial (RCT), oral ketamine would provide an affordable and scalable, intervention suitable for integration into routine psychiatric services.This study will establish an indigenous, cost-effective therapeutic strategy that could improve accessibility, hasten therapeutic response, and inform treatment guidelines, if found to be safe and effective.
Detailed description
Background: Conventional antidepressant treatment for major depressive episodes typically requires 3-6 weeks of drug use before meaningful clinical improvement is noted. Consequently, patients have to put their lives and responsibilities on hold while waiting for a therapeutic response.
Problem statement and rationale: There is a distinct need for a safe, acceptable, and effective, rapidly acting antidepressant in MDE to limit the impact on daily life. As an inexpensive, generic medication administered through a convenient route, oral ketamine has the potential to overcome the logistical barriers associated with existing ketamine formulations. If proven effective in a rigorous multicenter randomized controlled trial (RCT), oral ketamine would provide an affordable, scalable, and pragmatic intervention suitable for integration into routine psychiatric services.
Objectives- Primary: To assess the efficacy of adjunctive oral ketamine vs oral midazolam on clinical depression ratings at the end of study week 3- primary endpoint assessed using Hamilton Depression rating scale.
Secondary:
To assess the efficacy of adjunctive oral ketamine vs oral midazolam on clinical depression ratings at study day 2, day 7, and end of study weeks 2 and 4 and suicide ideation ratings at study day 2, study day 7, end of study week 2, week 3, and week 4.
To assess the efficacy of adjunctive oral ketamine vs oral midazolam on between-group response and remission rates, self-rated functioning, and self-rated quality of life at the end of study week 2, week 3, and week 4.
To compare psychophysiological and adverse effects between groups during each treatment session until the end (at 2 hours) and to compare adverse effects between groups at study day 2, day 7, and the end of study week 2, week 3, and week 4.
Methodology: This study uses a randomized, double-blind, active-placebo controlled, multicenter, RCT design to compare the efficacy and safety of repeated dosing with adjunctive oral ketamine vs oral midazolam in patients with moderate to severe MDE. Safety and efficacy endpoints will be assessed by separate outcome raters.
Expected outcomes: This study will establish an indigenous, cost-effective therapeutic strategy that could improve accessibility, hasten therapeutic response, and inform treatment guidelines, if found to be safe and effective.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Oral midazolam | Placebo comparator | Drug: Oral midazolamThe comparator arm will receive flexibly-dosed oral midazolam (5-7.5mg across all nine sessions, guided based on psychophysiological response to preserve the integrity of blinding), which will also be administered in approximately 200 mL of water, and sipped across 20-30 minutes |
| Oral ketamine | Experimental | Drug: Oral ketamineIn the first session, oral ketamine will be administered as a fixed 150 mg dose diluted in approximately 200 mL water and sipped across 20-30 minutes. In sessions 2-9 for oral ketamine, the dose will be lowered to 100-125mg in those who do not tolerate 150mg. If patients tolerate the first session well, the dose of ketamine will be increased to 175mg in the second session. If there is a negligible benefit and the intervention is tolerated, the dose of ketamine will be increased to 200 mg in the third session. Further increase in ketamine will be done in the last week to 250mg, if deemed necessary, due to suboptimal response. Participants will remain nil per oral from one hour before until two hours after each session. Blood pressure and pulse rate will be monitored every 15 minutes for one hour or until normalization. Benzodiazepines such as clonazepam will be permitted for anxiety or agitation |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Consenting adult outpatients or inpatients with at least moderately severe major depressive episode (MDE), denoted by HAM- D more than or equal to 20, associated with major depressive disorder or bipolar disorder, with diagnosis confirmed using a structured diagnostic interview.
Key exclusion criteria (1 listed)
- Patients with co-morbid obsessive-compulsive disorder or intellectual disability disorder or co-morbid substance dependence other than nicotine or patients concurrently receiving neuromodulation treatments or those with psychotic symptoms. Patients with current or ongoing suicide risk, such as active suicidal ideation with a specific plan or some intent in the last 3 days, will be excluded if they are treated as outpatients. Patients in whom, in the subjective opinion of the PI, the MDE symptoms appear to be significantly driven by acute life events or circumstances. Patients with abnormalities of concern detected in the electrocardiogram, or with uncontrolled hypertension or those with ongoing pregnancy or lactation
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Oral ketamineNine sessions of oral ketamine | Drug | Oral ketamine |
| Oral midazolamNine sessions of oral midazolam | Drug | Oral midazolam |
Primary outcome
Hamilton Depression Rating Scale (HAM-D)
Time frame: End of study week 3 (±2 days)
Endpoint HAM-D scores. Minimum 0 and maximum 52. Higher scores denote worse outcomes.
7 secondary outcomes
Hamilton Depression Rating Scale (HAM-D)
Time frame: Study day 2 (± 1 day), day 7 (± 1 day), and the end of study weeks 2 (± 1 day) and week 4 (±2 days)
Montgomery-Asberg Depression Rating Scale (MADRS)
Time frame: End of study day 2 (± 1 day), day 7 (± 1 day), end of study week 2 (±1 day), week 3 (± 2 days), and week 4 (± 2 days)
Patient Health Questionnaire (PHQ)-9
Time frame: End of study day 2 (± 1 day), day 7 (± 1 day), end of study week 2 (±1 day), week 3 (± 2 days), and week 4 (± 2 days)
Hamilton Depression Rating Scale (HAM-D)/Montgomery-Asberg Depression Rating Scale (MADRS)
Time frame: End of study week 2 (±1 day), week 3 (± 2 days), and week 4 (± 2 days)
Visual Analogue Scale for self-rated functioning & quality of life
Time frame: End of study week 2 (±1 day), week 3 (± 2 days), and week 4 (± 2 days)
Intrasession adverse effects checklist
Time frame: During each treatment session until the end (at 2 hours)
Systematic assessment for treatment-emergent effects (SAFTEE) checklist
Time frame: At study day 2 (± 1 day), day 7 (± 1 day), end of study week 2 (±1 day), week 3 (± 2 days), and week 4 (± 2 days)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Oct 2026.
- Background: PubMed 37352755Kaur S, Parmar C, Gaur V, Chauhan A, Andrade C. The efficacy of oral ketamine in severely depressed patients at high risk of suicide. Asian J Psychiatr. 2023 Aug;86:103678. doi: 10.1016/j.ajp.2023.103678. Epub 2023 Jun 12.
- Background: PubMed 39068714Kumar PS, Menon V, Andrade C. A randomised, open-label, pragmatic pilot comparison of oral and intravenous ketamine in treatment-resistant depression. Asian J Psychiatr. 2024 Sep;99:104171. doi: 10.1016/j.ajp.2024.104171. Epub 2024 Jul 23.
- Background: PubMed 41101490Silberbauer LR, Eggerstorfer B, Michenthaler P, Reichel S, Stimpfl T, Vanicek T, Naderi-Heiden A, Kasper S, Lanzenberger R, Gryglewski G. Oral ketamine for the treatment of major depressive and bipolar disorder, a randomized controlled trial and meta-analysis. J Affect Disord. 2026 Feb 1;394(Pt A):120466. doi: 10.1016/j.jad.2025.120466. Epub 2025 Oct 14.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Oral ketamine and Oral midazolam in people with Major Depressive Episode, run by Jawaharlal Institute of Postgraduate Medical Education & Research at 5 sites in India.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 1 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in India. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Vikas Menon, MD (+91 8098158528, drvmenon@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Hamilton Depression Rating Scale (HAM-D) (time frame: End of study week 3 (±2 days)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07839338, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Oct 2026.