Ignite Creation Date:
2024-07-17 @ 11:35 AM
Last Modification Date:
2024-10-26 @ 3:34 PM
Study NCT ID:
NCT06488586
Status:
RECRUITING
Last Update Posted:
2024-07-10
First Post:
2024-06-26
Brief Title:
IV Ketamine Vs in Esketamine for MDD TRD
Sponsor:
Gustavo Vazquez
Organization:
Queens University
Study Overview
Official Title:
In Esketamine and IV Ketamine Multi-site Observational Study Assessing the Effectiveness and Tolerability of Two Novel Therapies for Treatment-resistant Depression
Status:
RECRUITING
Status Verified Date:
2024-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The goal of this observational study is to learn about the comparative acute effects of ketamine vs esketamine in participants over the age of 18 for the treatment of their severe depression and suicidal ideations
Participants are already taking antidepressants andor antipsychotics as part of their regular medical care for depression
Participants are already taking antidepressants andor antipsychotics as part of their regular medical care for depression
Detailed Description:
This is a multi-center observational prospective cohort study in Providence Care Hospital in Kingston ON Envision Mind Care in Edmonton AB Center for Addiction and Mental Health in Toronto ON the University of British Columbia in Vancouver BC and Sunnybrook Health Sciences Center in Toronto ON Canada This study presents real-world clinical data from patients receiving either IV ketamine or IN esketamine for the management of MDD-TRD Participants consisted of adult outpatients 18-75 years old with unipolar depression experiencing major depressive episodes as determined by the DSM5 and characterized as MDD-TRD diagnosed with major depressive disorder as outlined by the DSM5 and experienced at least two previous failed antidepressant treatments of adequate dose and duration for the current episode
IV ketamine or IN esketamine are provided as standard-of-care add-on treatments and free of charge to patients Only medications that have the potential to interact with either ketamine or esketamine such as benzodiazepines naltrexone lamotrigine gabapentin and pregabalin are discontinued prior to the start of the treatment and for the duration of treatment The tapering and discontinuation processes follow the standard-of-care clinical practices and are monitored by the most responsible physician for each patient Patients with psychosis main diagnosis of personality disorder uncontrolled hypertension substance abuse currently pregnant or breastfeeding or who had a previous negative reaction to ketamine or esketamine are ineligible to receive IV ketamine or IN esketamine
Approval to perform this study was obtained through the Health Sciences Research Ethics Board at Queens University TRAQ 6031789 All participants provide voluntary written informed consent for collecting analyzing and presenting aggregate data This study follows the standards set by the Declaration of Helsinki and data management complies with US federal Health Insurance Portability and Accountability Act HIPAA regulations pertaining to the confidentiality of patient records
After obtaining informed consent from the participants Investigators observe participant acute treatment course receiving either IV ketamine or IN esketamine treatment recording any potential side effects during and after administration and changes in the severity of participant depressive symptoms In the participating clinical centers both IV ketamine and IN esketamine treatments consist of bi-weekly sessions for four weeks following standard-of-care clinical guidelines The decision of delivering IV ketamine or IN esketamine is determined between the patient and the most responsible physician responsible for administering the treatment Insurance coverage for IN esketamine and patient preference for mode of administration IV vs IN are major determinant factors Since IN esketamine is approved by Health Canada this is the preferred treatment if a patient has the appropriate insurance coverage otherwise IV ketamine is offered for free as its cost is covered by the academic center providing the treatment
For IV ketamine treatment ketamine is administered at 05mgkg over 40 minutes For IN esketamine treatment esketamine is administered as a nasal spray two sprays per nostril 56mg total for the first treatment and three sprays per nostril 84mg for the rest of the acute series All treatments are administered at the academic center under the supervision of a mental health care professional Patients are asked to come fasting at least two hours prior to treatment and to remain resting in the treatment room throughout the dosing session Throughout each dosing session blood pressure oxygen levels and onset duration and severity of common side effects are recorded by nursing staff andor physicians Patients are discharged after a minimum of 30 minutes post administration provided that the vital signs return to baseline and that the patient is calm alert and oriented
The primary outcome of this study is to determine and compare the clinical effectiveness of IV ketamine and IN esketamine on the management of depressive symptoms using the Montgomery and Åsberg Depression Rating Scale MADRS Treatment response is determined as a total score reduction of 50 or more from baseline partial response to a score reduction between 25 and 50 from baseline score and remission to a post-treatment MADRS total score of 10 points or less
Baseline depression symptoms are measured in the week before the first IV ketamine or IN esketamine session Then progression of depression symptoms through the treatment course is assessed once per week up to 24 hours after the 2nd 4th 6th and 8th study endpoint session Measurements are performed by an independent trained assessor not directly involved in the treatment of the patients virtually or in-person
The secondary outcome of this study is to determine and compare the effectiveness of IV ketamine and IN esketamine in the reduction of suicidal ideation SI and determine the tolerability of these treatments in terms of side effect frequency and severity The item 10 Q10 of the MADRS is used to track changes in SI response is defined as a reduction in Q10 score from baseline to treatment endpoint and remission as a score of 0 at treatment endpoint 232526 Tolerability of the treatments is regularly assessed during and up to 24 hours after the infusion by the clinic staff and trained independent raters respectively The assessments include the tracking of depersonalization symptoms using the 6-item Clinician Administered Dissociative Symptom Scale CADSS-6 27 dropping out of the treatment and common side effects associated with these treatments using a checklist changes in heart rate and blood pressure anxiety lightheadedness drowsiness dizziness blurred vision nausea and headaches Alterations in the vitals above or below the baseline for each patient are recorded based on severity as mild medium or severe following validated clinical guidelines
Statistical analysis
The sample size was determined considering the effect size for reduction in depression symptoms for IV ketamine and IN esketamine treatments found in the literature Cohens D167 for IV ketamine and Cohens D124 for IN esketamine a power of 08 and a significance level of p005 Based on these values Investigators would need a sample size of 24 patients for either treatment to observe a significant effect in a paired sample t-test The calculations of this study were carried out on IBM SPSS Statistics for Mac version 24 IBM Corp Armonk NY USA at a significance level of pamplt005 and applying a per-protocol only treatment completers and an intention to treat ITT approach for completeness of the analysis and to support the real-world clinical approach of this study Multiple imputation is applied to address the missing data points either due to missing assessment questionnaires or patient dropout The pattern of missing data was random and Investigators applied a Mersenne Twister algorithm to generate random numbers This approach conducted 5 multiple imputation iterations using linear regression as the imputation method Investigators considered the pooled result from the 5 multiple imputation iterations
For both per-protocol and ITT assessments Investigators analyze the MADRS and CADSS-6 data using descriptive statics and linear regression to compare score changes across different timepoints and between IV ketamine and IN esketamine For linear regression Investigators identify the slope and y-intercept coefficient and used correlation coefficient R2 and P-P plots to determine the goodness of fit of the regression model Effect size is calculated using Cohens D d with 95 confidence interval 95 CI Side effect burden is reported in terms of frequency of each side effect and severity ie mild medium or severe
The impact of age and biological sex on treatment response and side effects is analyzed using one-way and two-way multivariate analysis of variance MANOVA For this assessment Investigators assume multivariate normality homogeneity of covariance matrices and linearity and employ Wilks Lambda to test for between-group differences in the multivariate analysis Post-hoc analysis employs the Tukeyamp39s Honest Significant Difference HSD
IV ketamine or IN esketamine are provided as standard-of-care add-on treatments and free of charge to patients Only medications that have the potential to interact with either ketamine or esketamine such as benzodiazepines naltrexone lamotrigine gabapentin and pregabalin are discontinued prior to the start of the treatment and for the duration of treatment The tapering and discontinuation processes follow the standard-of-care clinical practices and are monitored by the most responsible physician for each patient Patients with psychosis main diagnosis of personality disorder uncontrolled hypertension substance abuse currently pregnant or breastfeeding or who had a previous negative reaction to ketamine or esketamine are ineligible to receive IV ketamine or IN esketamine
Approval to perform this study was obtained through the Health Sciences Research Ethics Board at Queens University TRAQ 6031789 All participants provide voluntary written informed consent for collecting analyzing and presenting aggregate data This study follows the standards set by the Declaration of Helsinki and data management complies with US federal Health Insurance Portability and Accountability Act HIPAA regulations pertaining to the confidentiality of patient records
After obtaining informed consent from the participants Investigators observe participant acute treatment course receiving either IV ketamine or IN esketamine treatment recording any potential side effects during and after administration and changes in the severity of participant depressive symptoms In the participating clinical centers both IV ketamine and IN esketamine treatments consist of bi-weekly sessions for four weeks following standard-of-care clinical guidelines The decision of delivering IV ketamine or IN esketamine is determined between the patient and the most responsible physician responsible for administering the treatment Insurance coverage for IN esketamine and patient preference for mode of administration IV vs IN are major determinant factors Since IN esketamine is approved by Health Canada this is the preferred treatment if a patient has the appropriate insurance coverage otherwise IV ketamine is offered for free as its cost is covered by the academic center providing the treatment
For IV ketamine treatment ketamine is administered at 05mgkg over 40 minutes For IN esketamine treatment esketamine is administered as a nasal spray two sprays per nostril 56mg total for the first treatment and three sprays per nostril 84mg for the rest of the acute series All treatments are administered at the academic center under the supervision of a mental health care professional Patients are asked to come fasting at least two hours prior to treatment and to remain resting in the treatment room throughout the dosing session Throughout each dosing session blood pressure oxygen levels and onset duration and severity of common side effects are recorded by nursing staff andor physicians Patients are discharged after a minimum of 30 minutes post administration provided that the vital signs return to baseline and that the patient is calm alert and oriented
The primary outcome of this study is to determine and compare the clinical effectiveness of IV ketamine and IN esketamine on the management of depressive symptoms using the Montgomery and Åsberg Depression Rating Scale MADRS Treatment response is determined as a total score reduction of 50 or more from baseline partial response to a score reduction between 25 and 50 from baseline score and remission to a post-treatment MADRS total score of 10 points or less
Baseline depression symptoms are measured in the week before the first IV ketamine or IN esketamine session Then progression of depression symptoms through the treatment course is assessed once per week up to 24 hours after the 2nd 4th 6th and 8th study endpoint session Measurements are performed by an independent trained assessor not directly involved in the treatment of the patients virtually or in-person
The secondary outcome of this study is to determine and compare the effectiveness of IV ketamine and IN esketamine in the reduction of suicidal ideation SI and determine the tolerability of these treatments in terms of side effect frequency and severity The item 10 Q10 of the MADRS is used to track changes in SI response is defined as a reduction in Q10 score from baseline to treatment endpoint and remission as a score of 0 at treatment endpoint 232526 Tolerability of the treatments is regularly assessed during and up to 24 hours after the infusion by the clinic staff and trained independent raters respectively The assessments include the tracking of depersonalization symptoms using the 6-item Clinician Administered Dissociative Symptom Scale CADSS-6 27 dropping out of the treatment and common side effects associated with these treatments using a checklist changes in heart rate and blood pressure anxiety lightheadedness drowsiness dizziness blurred vision nausea and headaches Alterations in the vitals above or below the baseline for each patient are recorded based on severity as mild medium or severe following validated clinical guidelines
Statistical analysis
The sample size was determined considering the effect size for reduction in depression symptoms for IV ketamine and IN esketamine treatments found in the literature Cohens D167 for IV ketamine and Cohens D124 for IN esketamine a power of 08 and a significance level of p005 Based on these values Investigators would need a sample size of 24 patients for either treatment to observe a significant effect in a paired sample t-test The calculations of this study were carried out on IBM SPSS Statistics for Mac version 24 IBM Corp Armonk NY USA at a significance level of pamplt005 and applying a per-protocol only treatment completers and an intention to treat ITT approach for completeness of the analysis and to support the real-world clinical approach of this study Multiple imputation is applied to address the missing data points either due to missing assessment questionnaires or patient dropout The pattern of missing data was random and Investigators applied a Mersenne Twister algorithm to generate random numbers This approach conducted 5 multiple imputation iterations using linear regression as the imputation method Investigators considered the pooled result from the 5 multiple imputation iterations
For both per-protocol and ITT assessments Investigators analyze the MADRS and CADSS-6 data using descriptive statics and linear regression to compare score changes across different timepoints and between IV ketamine and IN esketamine For linear regression Investigators identify the slope and y-intercept coefficient and used correlation coefficient R2 and P-P plots to determine the goodness of fit of the regression model Effect size is calculated using Cohens D d with 95 confidence interval 95 CI Side effect burden is reported in terms of frequency of each side effect and severity ie mild medium or severe
The impact of age and biological sex on treatment response and side effects is analyzed using one-way and two-way multivariate analysis of variance MANOVA For this assessment Investigators assume multivariate normality homogeneity of covariance matrices and linearity and employ Wilks Lambda to test for between-group differences in the multivariate analysis Post-hoc analysis employs the Tukeyamp39s Honest Significant Difference HSD
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None