Ignite Creation Date:
2024-05-06 @ 9:44 AM
Last Modification Date:
2024-10-26 @ 12:19 PM
Study NCT ID:
NCT03065335
Status:
RECRUITING
Last Update Posted:
2024-07-12
First Post:
2017-02-24
Brief Title:
Neuropharmacologic Imaging and Biomarker Assessments of Response to Acute and Repeated-Dosed Ketamine Infusions in Major Depressive Disorder
Sponsor:
National Institute of Mental Health NIMH
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Neuropharmacologic Imaging and Biomarker Assessments of Response to Acute and Repeated-Dosed Ketamine Infusions in Major Depressive Disorder
Status:
RECRUITING
Status Verified Date:
2024-10-17
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:
Background
Most medications that treat depression take weeks or months to work Researchers want to develop fast-acting treatments One dose of ketamine has a rapid antidepressant effect For most people this lasts a week or less Repeated doses of ketamine may help maintain this effect
Objective
Main Study To study the effects of ketamine in treating depression
Ketamine Metabolites Substudy To study how ketamine effects brain chemistry
To study how ketamine effects the brain This is done by looking at metabolites which are created when a drug is broken down
Eligibility
Main Study People ages 18-65 with major depressive disorder and healthy volunteers
Ketamine Metabolites Substudy Healthy volunteers ages 18-65
Design
Main Study
Participants will be screened in another study with
Medical and psychiatric history
Psychiatric and physical exam
Blood urine and heart tests
Participants will be inpatients at NIH for 4 phases totaling 14-20 weeks
Phase I 2-7 weeks
Gradually stop current medications
MRI Participants lie and perform tasks in a machine that takes pictures of the body
Mood and thinking tests
Blood and urine tests
Sleep test Monitors on the skin record brain waves breathing heart rate and movement during sleep
Transcranial magnetic stimulation A coil on the scalp gives an electrical current that affects brain activity
Stress tests Electrodes on the skin measure reactions to loud noises or electric shocks
Phase I tests are repeated in Phases II and III and in the final visit
Phase II 4-5 weeks
4 weekly IV infusions of ketamine or a placebo during an MRI or MEG For the MEG a cone over the head records brain activity
Phase III optional
8 infusions of ketamine over 4 weeks
Phase IV optional
Symptoms monitoring for 4 weeks
Participants will have a final visit They will be offered standard treatment at NIH for up to 2 months
Ketamine Metabolites Substudy
Participants will be screened in another study with
Medical and psychiatric history
Psychiatric and physical exam
Blood urine and heart tests
Participants will be inpatients at NIH for 4 days
Study Procedures
Mood and thinking tests
Blood and urine tests
1 infusion of ketamine
Spinal tap and spinal catheter Used to get samples of cerebrospinal fluid CSF This is a fluid that moves around and within the brain and spinal cord Studying CSF will help us learn how ketamine effects brain chemistry
Most medications that treat depression take weeks or months to work Researchers want to develop fast-acting treatments One dose of ketamine has a rapid antidepressant effect For most people this lasts a week or less Repeated doses of ketamine may help maintain this effect
Objective
Main Study To study the effects of ketamine in treating depression
Ketamine Metabolites Substudy To study how ketamine effects brain chemistry
To study how ketamine effects the brain This is done by looking at metabolites which are created when a drug is broken down
Eligibility
Main Study People ages 18-65 with major depressive disorder and healthy volunteers
Ketamine Metabolites Substudy Healthy volunteers ages 18-65
Design
Main Study
Participants will be screened in another study with
Medical and psychiatric history
Psychiatric and physical exam
Blood urine and heart tests
Participants will be inpatients at NIH for 4 phases totaling 14-20 weeks
Phase I 2-7 weeks
Gradually stop current medications
MRI Participants lie and perform tasks in a machine that takes pictures of the body
Mood and thinking tests
Blood and urine tests
Sleep test Monitors on the skin record brain waves breathing heart rate and movement during sleep
Transcranial magnetic stimulation A coil on the scalp gives an electrical current that affects brain activity
Stress tests Electrodes on the skin measure reactions to loud noises or electric shocks
Phase I tests are repeated in Phases II and III and in the final visit
Phase II 4-5 weeks
4 weekly IV infusions of ketamine or a placebo during an MRI or MEG For the MEG a cone over the head records brain activity
Phase III optional
8 infusions of ketamine over 4 weeks
Phase IV optional
Symptoms monitoring for 4 weeks
Participants will have a final visit They will be offered standard treatment at NIH for up to 2 months
Ketamine Metabolites Substudy
Participants will be screened in another study with
Medical and psychiatric history
Psychiatric and physical exam
Blood urine and heart tests
Participants will be inpatients at NIH for 4 days
Study Procedures
Mood and thinking tests
Blood and urine tests
1 infusion of ketamine
Spinal tap and spinal catheter Used to get samples of cerebrospinal fluid CSF This is a fluid that moves around and within the brain and spinal cord Studying CSF will help us learn how ketamine effects brain chemistry
Detailed Description:
Objective
The current protocol has a two-fold purpose In the pharmacodynamic imaging phase we will investigate the neuropharmacodynamics of acute intravenous ketamine administration in patients with major depressive disorder MDD and healthy volunteers HV using functional MRI fMRI and electrophysiological modalities electroencephalography EEG and magnetoencephalography MEG We will also investigate if specific signatures from functional neuroimaging transcranial magnetic stimulation TMS associated evoked potentials TMS-EP sleep EEG S-EEG and psychophysiologic responses can be used to classify specific subpopulations of patients with MDD preliminary findings from such an approach may be important in forging further studies identifying those who will respond to ketamine infusions In the repeat-dosing phase we will expand upon our previous findings of the immediate efficacy of glutamatergic modulators by investigating the safety and efficacy of repeated dose administrations of ketamine in MDD patients We will include all MDD patients regardless of antidepressant response to single infusions of ketamine to allow for potential identification of patients who are able to attain andor maintain a response over a series of infusions To reduce any potential biases due to partial blinding all patients will be randomized into groups to receive ketamine at either 05 mgkg or 01 mgkg an active comparator
Study Population
The study consists of 50 patients with treatment-resistant MDD between 18 and 65 years old and 50 agegender matched HVs Within the MDD group 25 patients will be enrolled into each group in the repeat-dosing phase An addition 50 HVs will participate in the Ketamine Metabolites Substudy
Study Design
This study is a Phase I Clinical Trial that comprises four phases
Phase I includes screening medication taper as needed medication-free period and baseline assessments including optional TMS-EP S-EEG the None Predictive Unpredictive NPU-threat test non-brain imaging cognitive tasks and blood samples for plasma neurochemicals and peripheral blood biomarkers
In Phase II all subjects will receive an alternating series of placebo and ketamine infusions once per week for a total of 4 infusions 2 ketamine 2 placebo Concurrently with each infusion subjects will be administered either resting-state fMRI with simultaneous EEG or resting state MEG recording thus each subject receives fMRIEEG and MEG for both a placebo and ketamine infusion Participants may also undergo optional sEEG non-brain imaging cognitive tasks TMS-EP and NPU
Phase III involves MDD patients whose depression symptoms relapsed after the final infusion in Phase II Patients whose symptoms did not relapse may receive an additional one-week washout Subjects will be randomized to receive ketamine at 05 or 01 mgkg twice weekly for 4 weeks total of 8 infusions Participants may undergo optional fMRI S-EEG MEG non-brain imaging cognitive tasks TMS-EP pupillometry and NPU at time points between infusions Clinical rating scales will assess depression symptomology and blood will be drawn for pharmacokinetics testing and biomarker analyses
Phase IV includes patients who completed Phase III and who are responders These patients will be followed up for an additional 4 weeks or until relapse to determine durability of response The final study day will include rating scales medical evaluations blood tests and an additional sMRI to assess structural changes that may have occurred due to repeated ketamine infusions
The protocol includes a substudy evaluating ketamine metabolites in Ketamine Metabolites Substudy Only HVs will be enrolled in this substudy Subjects will undergo a single infusion of ketamine concurrently with serial peripheral blood collection Some participants may also undergo serial CSF collection during the ketamine infusion Clinical rating scales cognitive tasks MEG S-EEG CSF andor blood draws for pharmacokinetics testing and biomarker analyses will be done
Outcome Measures
The primary outcome measure of Phase II is the pharmacodynamic fMRI and MEG responses to ketamine compared to placebo Secondary outcome measures include the difference in Montgomery-Asberg Depression Rating Scale MADRS score from baseline to 24 hours between the placebo and ketamine infusion correlations between an antidepressant response and TMS-EP S-EEG neuroimaging cognitive and NPU measures In Phase II the HVs acts as another level of control to identify a potential neuropharmacodynamic signature associated with an antidepressant response to ketamine
The primary outcome measure for Phase III is the difference or change in MADRS from baseline to the end of 4 weeks of twice-weekly infusions Secondary outcome measures include cognitive TMS-EP S-EEG and NPU-threat test measures
Other outcome measures for both Phase II and III include clinical rating scales neurocognitive tests ketamine levels plasma neurochemicals and peripheral blood biomarkers Additional outcomes in Phase III are baseline and post-repeated dose infusion MRI scans and neurocognitive test results Rating scales are the outcomes measures of Phase IV Subjects will continue Phase IV for 4 weeks or until relapse
The current protocol has a two-fold purpose In the pharmacodynamic imaging phase we will investigate the neuropharmacodynamics of acute intravenous ketamine administration in patients with major depressive disorder MDD and healthy volunteers HV using functional MRI fMRI and electrophysiological modalities electroencephalography EEG and magnetoencephalography MEG We will also investigate if specific signatures from functional neuroimaging transcranial magnetic stimulation TMS associated evoked potentials TMS-EP sleep EEG S-EEG and psychophysiologic responses can be used to classify specific subpopulations of patients with MDD preliminary findings from such an approach may be important in forging further studies identifying those who will respond to ketamine infusions In the repeat-dosing phase we will expand upon our previous findings of the immediate efficacy of glutamatergic modulators by investigating the safety and efficacy of repeated dose administrations of ketamine in MDD patients We will include all MDD patients regardless of antidepressant response to single infusions of ketamine to allow for potential identification of patients who are able to attain andor maintain a response over a series of infusions To reduce any potential biases due to partial blinding all patients will be randomized into groups to receive ketamine at either 05 mgkg or 01 mgkg an active comparator
Study Population
The study consists of 50 patients with treatment-resistant MDD between 18 and 65 years old and 50 agegender matched HVs Within the MDD group 25 patients will be enrolled into each group in the repeat-dosing phase An addition 50 HVs will participate in the Ketamine Metabolites Substudy
Study Design
This study is a Phase I Clinical Trial that comprises four phases
Phase I includes screening medication taper as needed medication-free period and baseline assessments including optional TMS-EP S-EEG the None Predictive Unpredictive NPU-threat test non-brain imaging cognitive tasks and blood samples for plasma neurochemicals and peripheral blood biomarkers
In Phase II all subjects will receive an alternating series of placebo and ketamine infusions once per week for a total of 4 infusions 2 ketamine 2 placebo Concurrently with each infusion subjects will be administered either resting-state fMRI with simultaneous EEG or resting state MEG recording thus each subject receives fMRIEEG and MEG for both a placebo and ketamine infusion Participants may also undergo optional sEEG non-brain imaging cognitive tasks TMS-EP and NPU
Phase III involves MDD patients whose depression symptoms relapsed after the final infusion in Phase II Patients whose symptoms did not relapse may receive an additional one-week washout Subjects will be randomized to receive ketamine at 05 or 01 mgkg twice weekly for 4 weeks total of 8 infusions Participants may undergo optional fMRI S-EEG MEG non-brain imaging cognitive tasks TMS-EP pupillometry and NPU at time points between infusions Clinical rating scales will assess depression symptomology and blood will be drawn for pharmacokinetics testing and biomarker analyses
Phase IV includes patients who completed Phase III and who are responders These patients will be followed up for an additional 4 weeks or until relapse to determine durability of response The final study day will include rating scales medical evaluations blood tests and an additional sMRI to assess structural changes that may have occurred due to repeated ketamine infusions
The protocol includes a substudy evaluating ketamine metabolites in Ketamine Metabolites Substudy Only HVs will be enrolled in this substudy Subjects will undergo a single infusion of ketamine concurrently with serial peripheral blood collection Some participants may also undergo serial CSF collection during the ketamine infusion Clinical rating scales cognitive tasks MEG S-EEG CSF andor blood draws for pharmacokinetics testing and biomarker analyses will be done
Outcome Measures
The primary outcome measure of Phase II is the pharmacodynamic fMRI and MEG responses to ketamine compared to placebo Secondary outcome measures include the difference in Montgomery-Asberg Depression Rating Scale MADRS score from baseline to 24 hours between the placebo and ketamine infusion correlations between an antidepressant response and TMS-EP S-EEG neuroimaging cognitive and NPU measures In Phase II the HVs acts as another level of control to identify a potential neuropharmacodynamic signature associated with an antidepressant response to ketamine
The primary outcome measure for Phase III is the difference or change in MADRS from baseline to the end of 4 weeks of twice-weekly infusions Secondary outcome measures include cognitive TMS-EP S-EEG and NPU-threat test measures
Other outcome measures for both Phase II and III include clinical rating scales neurocognitive tests ketamine levels plasma neurochemicals and peripheral blood biomarkers Additional outcomes in Phase III are baseline and post-repeated dose infusion MRI scans and neurocognitive test results Rating scales are the outcomes measures of Phase IV Subjects will continue Phase IV for 4 weeks or until relapse
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
True
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 17-M-0060 | None | None | None |