| CTRI Number |
CTRI/2024/03/064257 [Registered on: 18/03/2024] Trial Registered Prospectively |
| Last Modified On: |
04/12/2024 |
| 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 examine the effects of oral ketamine in patients with alcohol use disorder |
|
Scientific Title of Study
|
Oral Ketamine in Resistant Alcohol Use Disorder: A Multi-centric Single-blind Randomized Controlled Trial |
| Trial Acronym |
NIL |
|
Secondary IDs if Any
|
| Secondary ID |
Identifier |
| NIL |
NIL |
|
|
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
|
| Name |
Dr Deepak S Ghadigaonkar |
| Designation |
Assistant Professor of Psychiatry |
| Affiliation |
National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru |
| Address |
Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Off Hosur Road, Bengaluru- 560029, Karnataka, India
Bangalore
KARNATAKA
56007629
India |
| Phone |
7022156409 |
| Fax |
|
| Email |
deepak.ghadigaonkar@gmail.com |
|
Details of Contact Person
Scientific Query
|
| Name |
Dr Deepak S Ghadigaonkar |
| Designation |
Assistant Professor of Psychiatry |
| Affiliation |
National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru |
| Address |
Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Off Hosur Road, Bengaluru- 560029, Karnataka, India
Bangalore
KARNATAKA
56007629
India |
| Phone |
7022156409 |
| Fax |
|
| Email |
deepak.ghadigaonkar@gmail.com |
|
Details of Contact Person
Public Query
|
| Name |
Dr Deepak S Ghadigaonkar |
| Designation |
Assistant Professor of Psychiatry |
| Affiliation |
National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru |
| Address |
Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Off Hosur Road, Bengaluru- 560029, Karnataka, India
Bangalore
KARNATAKA
56007629
India |
| Phone |
7022156409 |
| Fax |
|
| Email |
deepak.ghadigaonkar@gmail.com |
|
|
Source of Monetary or Material Support
|
| Indian Council of Medical Research (ICMR), New Delhi is the funding agency. |
| Lokopriya Gopinath Bordoloi Regional Institute of Mental Health (LGBRIMH), Tezpur is a site for the study |
| National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru is a site for the study |
|
|
Primary Sponsor
|
| Name |
Dr Deepak S Ghadigaonkar |
| Address |
Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru- 560029, Karnataka, India |
| Type of Sponsor |
Other [Self] |
|
|
Details of Secondary Sponsor
|
|
|
Countries of Recruitment
|
India |
|
Sites of Study
|
| No of Sites = 2 |
| Name of Principal
Investigator |
Name of Site |
Site Address |
Phone/Fax/Email |
| Dr Diptadhi Mukherjee |
Lokopriya Gopinath Bordoloi Regional Institute of Mental Health (LGBRIMH), Tezpur |
Department of Addiction Medicine, Department of Psychiatry, Lokopriya Gopinath Bordoloi Regional Institute of Mental Health (LGBRIMH), P.O: Tezpur, Dist: Sonitpur, Assam, PIN: 784001
Sonitpur
ASSAM |
9706533435
diptadhimukherjee@gmail.com |
| Dr Deepak S Ghadigaonkar |
National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru |
Centre for Addiction Medicine, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Off Hosur Road, Bengaluru- 560029, Karnataka, India
Bangalore
KARNATAKA |
7022156409
deepak.ghadigaonkar@gmail.com |
|
|
Details of Ethics Committee
|
| No of Ethics Committees= 2 |
| Name of Committee |
Approval Status |
| Institute Ethics Committee (Behavioural Sciences Division), NIMHANS |
Approved |
| Institutional Ethics Committee, LGBRIMH |
Submittted/Under Review |
|
|
Regulatory Clearance Status from DCGI
|
|
|
Health Condition / Problems Studied
|
| Health Type |
Condition |
| Patients |
(1) ICD-10 Condition: F102||Alcohol dependence, |
|
|
Intervention / Comparator Agent
|
| Type |
Name |
Details |
| Intervention |
Oral Ketamine |
For the first session, the patient will remain on an empty stomach for 4 hours before the ketamine dose. A dose of 150 mg ketamine (50 mg/mL, clear solution) will be mixed with 20 mL of drinking water, and the patient will be asked to sip it over 5 minutes. The occurrence of drowsiness within 30 minutes of ingestion of oral ketamine will be taken as a sign of an adequate dose. In case drowsiness is not observed, the dose in the next session will be increased by 50 mg up to a maximum of 250 mg in a session. Following the ingestion, the patient will be observed for 60 minutes, following which he/she can return to the ward accompanied by an attender. Thus, a single session of oral ketamine will last for about an hour, which includes the duration of observation and monitoring.
In subsequent sessions, patients will be asked to come fortnightly such that they have had a light meal 4 hours before receiving ketamine. Patients will receive six fortnightly sessions over three months of follow-up.
The total duration of the treatment in the intervention arm will be three months.
|
| Comparator Agent |
Oral Midazolam |
For the first session, the patient will remain on an empty stomach for 4 hours before the midazolam dose. A dose of 10 mg midazolam (1 mg/mL, clear solution) will be mixed with 20 mL of drinking water, and the patient will be asked to sip it over 5 minutes. The occurrence of drowsiness within 30 minutes of ingestion of oral midazolam will be taken as a sign of an adequate dose. In case drowsiness is not observed, the dose in the next session will be increased by 2.5mg up to a maximum of 15 mg during a session. Following the ingestion, the patient will be observed for 60 minutes, following which he/she can return to the ward accompanied by an attender. Thus, a single session of oral ketamine will last for about an hour, which includes the duration of observation and monitoring. In subsequent sessions, patients will be asked to come fortnightly such that they have had a light meal 4 hours before receiving midazolam. Patients will receive six fortnightly sessions over three months of follow-up.
The total duration of the treatment in the comparator arm will be three months. |
|
|
Inclusion Criteria
|
| Age From |
18.00 Year(s) |
| Age To |
65.00 Year(s) |
| Gender |
Both |
| Details |
1. Either gender.
2. Age between 18 to 65 years.
3. Diagnosis of Alcohol Use Disorder (AUD)- Severe, diagnosed by a psychiatrist per Diagnostic and Statistical Manual 5 TR (DSM-V TR).
4. Severity of Alcohol Dependence Questionnaire (SADQ) score of 31 or more signifying severe dependence.
5. Inadequate response to standard treatment for AUD defined as follows (both criteria should be met):
• Relapse to heavy drinking within three months of discharge in at least one previous admission. This is based on the DSM-5 TR definition of early remission in AUD.
• Failed trials of at least one of the standard or off-label medications (Acamprosate, Baclofen, Topiramate, Naltrexone, Disulfiram) as evidenced by relapse to heavy drinking while on treatment or following non-compliance.
6. Willingness to come for fortnightly sessions and for blood tests.
7. For females of reproductive age, willingness to take effective contraception from the day of signing the consent form until six weeks after treatment discontinuation. |
|
| ExclusionCriteria |
| Details |
1. Currently taking any other relapse prevention medication
2. Uncontrolled hypertension (systolic 140 mm Hg or greater and diastolic 90 mm Hg or greater).
3. Body mass index (BMI) more than 30.
4. History or presence of a psychotic illness
5. Current or past history of recreational use of any prescription drug.
6. Current or past history of any other SUD except nicotine and cannabis.
7. Intellectual disability, sensory impairment or uncommunicative patients where obtaining consent and assessment of craving, adverse effects are precluded.
8. Renal impairment defined as estimated Glomerular Filtration Rate (eGFR) less than 60 mL/min/1.73 m2 as calculated using Modification of Diet in Renal Disease formula (MDRD).
9. Severe Alcoholic hepatitis or end-stage liver disease as defined by a MELD score (Model of end-stage liver disease) more than or equal to 21.
10. Unstable angina.
11. History of intracranial mass lesion or glaucoma
12. History of an allergic reaction to ketamine.
13. Pregnant or breastfeeding currently. |
|
|
Method of Generating Random Sequence
|
Permuted block randomization, fixed |
|
Method of Concealment
|
Sequentially numbered, sealed, opaque envelopes |
|
Blinding/Masking
|
Participant Blinded |
|
Primary Outcome
|
| Outcome |
TimePoints |
| Change in the relapse rates in patients receiving oral ketamine against those receiving oral midazolam. The relapse rates will be calculated based on the primary endpoint of a heavy drinking episode within three months of discharge from hospital. The secondary endpoints of time to relapse, number of relapses and treatment discontinuation will be consodered. |
T0 is the time of first treatment session.
T1 is at 2 weeks from T0.
T2 is at 4 weeks from T0.
T3 is at 6 weeks from T0.
T4 is at 8 weeks from T0.
T5 is at 10 weeks from T0.
T6 is at 12 weeks from T0. |
|
|
Secondary Outcome
|
| Outcome |
TimePoints |
| The pharmacokinetic parameters of oral ketamine in adults with a population pharmacokinetic framework as it can handle unbalanced (unequal number of samples given by different subjects), unstructured (variable time of collection of samples with respect to drug administration) and sparse data. |
T0 is the time of first ketamine session. |
| The tolerability and safety of oral ketamine in alcoholo use disorder. This will be assessed using a multimonitor with breathing rate, heart rate, non-invasive blood pressure, and SpO2 probe during the sessions. Other scales used will be: 1) Clinician-Administered Dissociative States Scale (CADSS) before the session and at 30 minutes after ingestion, 2) 4 items positive sub-scale of Brief Psychiatric Rating Scale (BPRS) before and at 60 minutes after ingestion, 3) Observer’s assessment of alertness/sedation scale (OAASS) before, at 30 minutes and at 60 minutes of ingestion, 4) Bladder Pain Interstitial Cystitis Symptom Score (BPICSS) before each session starting with the second session, 5) 5 Item, Likert scale version of Drug Effect Questionnaire (DEQ) at 30 minutes after ingestion in each session, 6) Assessment for vomiting, nausea, retching, 7) Other treatment-emergent adverse event |
T0 is the time of first treatment session.
T1 is at 2 weeks from T0.
T2 is at 4 weeks from T0.
T3 is at 6 weeks from T0.
T4 is at 8 weeks from T0.
T5 is at 10 weeks from T0.
T6 is at 12 weeks from T0. |
| The mediators of change in the drinking behaviour, as assessed for general health and depressive/anxiety symptoms using Hamilton’s depression rating scale (HDRS), State and Trait Anxiety Inventory (STAI), Short Form 12 (SF 12). |
T0 is the time of first treatment session.
T1 is at 2 weeks from T0.
T2 is at 4 weeks from T0.
T3 is at 6 weeks from T0.
T4 is at 8 weeks from T0.
T5 is at 10 weeks from T0.
T6 is at 12 weeks from T0. |
|
|
Target Sample Size
|
Total Sample Size="128"
Sample Size from India="128"
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" |
|
Phase of Trial
|
Phase 2 |
|
Date of First Enrollment (India)
|
01/04/2024 |
| Date of Study Completion (India) |
Applicable only for Completed/Terminated trials |
| Date of First Enrollment (Global) |
Date Missing |
| Date of Study Completion (Global) |
Applicable only for Completed/Terminated trials |
|
Estimated Duration of Trial
|
Years="3"
Months="0"
Days="0" |
Recruitment Status of Trial (Global)
Modification(s)
|
Not Applicable |
| Recruitment Status of Trial (India) |
Open to Recruitment |
|
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
|
Alcohol use disorder (AUD) is responsible for substantial morbidity and mortality in our country. Currently, available pharmacological and psychosocial treatment options fail to benefit a sizeable number of patients. Ketamine has emerged as an effective treatment for resistant depression and has preliminary evidence in AUD. However, currently used protocols are impractical due to the need for an anaesthetist for parenteral ketamine dose and cost-ineffective, patent-protected nasal spray. Ketamine is absorbed when used orally, and there is emerging evidence that metabolites generated during first-pass hepatic metabolism are active.
Therefore, we propose that oral ketamine therapy is a viable option and should be explored. This will be the first study to use oral ketamine for a substance use disorder. We will also provide pharmacokinetic data of oral ketamine in adults, which is currently unavailable.
To evaluate the efficacy and safety of oral doses of ketamine in improving outcome and severity measures of resistant AUD.
Randomized, double-blind, placebo-controlled trial to test the efficacy of orally administered ketamine in preventing relapse to heavy drinking, when used as a maintenance treatment given weekly. We will recruit AUD in-patients (N = 116, 1:1 randomization) who have not responded to treatment and randomize them to receive either ketamine (150-250 mg per oral) or a psychoactive placebo (midazolam 10-15 mg per oral) every week. We will also measure the blood concentration of ketamine and its metabolites to make a population pharmacokinetic model.
At the end of the study, we should be able to provide efficacy, safety and pharmacokinetic data of oral ketamine treatment in AUD. |