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Intranasal Ketamine in Ultra-REsistant Depression (SURE-ECT Non Responders) (SURE-ECT)

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ClinicalTrials.gov Identifier: NCT05137938
Recruitment Status : Recruiting
First Posted : November 30, 2021
Last Update Posted : December 29, 2021
Sponsor:
Information provided by (Responsible Party):
Centre for Addiction and Mental Health

Tracking Information
First Submitted Date  ICMJE November 2, 2021
First Posted Date  ICMJE November 30, 2021
Last Update Posted Date December 29, 2021
Actual Study Start Date  ICMJE October 25, 2021
Estimated Primary Completion Date October 25, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 9, 2021)
Change in symptom severity of depression as measured by the Hamilton Rating Scale for Depression - 24 [ Time Frame: 2 months ]
Hamilton Rating Scale for Depression (24-item version); This scale is used to quantify the severity of symptoms of depression Scale range: 0-76 (total score) Lower scores indicate lower severity of depressive symptoms (i.e., better outcome) Higher scores indicate higher severity of depressive symptoms (i.e., worse outcome)
Original Primary Outcome Measures  ICMJE
 (submitted: November 16, 2021)
Improvement in symptom severity of depression as measured by the Hamilton Rating Scale for Depression - 24 [ Time Frame: 2 months ]
Hamilton Rating Scale for Depression (24-item version); This scale is used to quantify the severity of symptoms of depression Scale range: 0-76 (total score) Lower scores indicate lower severity of depressive symptoms (i.e., better outcome) Higher scores indicate higher severity of depressive symptoms (i.e., worse outcome)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 9, 2021)
  • Change in symptom severity of Suicidal Ideation as measured by by the Scale of Suicide Ideation (SSI) [ Time Frame: 2 months ]
    Scale for Suicide Ideation (SSI); This scale is used to assess the presence or absence of suicidal ideation and the degree of severity of suicidal ideas Scale range: 0-38 (total score) Lower scores indicate lower severity of suicidal ideation (i.e., better outcome) Higher scores indicate higher severity of suicidal ideation (i.e., worse outcome)
  • Safety and tolerability as assessed by changes in Blood Pressure (BP) [ Time Frame: 1 month ]
    Assessed through monitoring of systolic and diastolic Blood Pressure (mmHg) on each treatment session before treatment and every 30 minutes within a 2-hour monitoring period.
  • Safety and tolerability as assessed by changes in Heart Rate (BPM) [ Time Frame: 1 month ]
    Assessed through monitoring of Heart Rate (beats per minute) on each treatment session before treatment and every 30 minutes within a 2-hour monitoring period.
  • Safety and tolerability as assessed by changes in O2 Saturation [ Time Frame: 1 month ]
    Assessed through monitoring of Oxygen saturation levels on each treatment session before treatment and every 30 minutes within a 2-hour monitoring period.
  • Safety and Tolerability of IN Ketamine as assessed by monitoring of adverse events [ Time Frame: 2 months ]
    Assessed through monitoring of adverse events, cardiovascular adverse events and/or respiratory distress throughout the trial.
  • Impact of Ketamine on cortical excitation as measured by intracortical facilitation (ICF) [ Time Frame: 1 months ]
    Assessed through administration of neurophysiological paradigms using Transcranial Magnetic Stimulation (TMS) paired with electromyography (EMG) and electroencephalography (EEG).
  • Impact of Ketamine on cortical inhibition as measured by short-interval cortical inhibition (SICI) [ Time Frame: 1 month ]
    Assessed through administration of neurophysiological paradigms using Transcranial Magnetic Stimulation (TMS) paired with electromyography (EMG) and electroencephalography (EEG).
Original Secondary Outcome Measures  ICMJE
 (submitted: November 16, 2021)
  • Improvement in symptom severity of Suicidal Ideation as measured by by the Scale of Suicide Ideation (SSI) [ Time Frame: 2 months ]
    Scale for Suicide Ideation (SSI); This scale is used to assess the presence or absence of suicidal ideation and the degree of severity of suicidal ideas Scale range: 0-38 (total score) Lower scores indicate lower severity of suicidal ideation (i.e., better outcome) Higher scores indicate higher severity of suicidal ideation (i.e., worse outcome)
  • Safety and tolerability as assessed by changes in Blood Pressure (BP) [ Time Frame: 1 month ]
    Assessed through monitoring of systolic and diastolic Blood Pressure (mmHg) on each treatment session before treatment and every 30 minutes within a 2-hour monitoring period.
  • Safety and tolerability as assessed by changes in Heart Rate (BPM) [ Time Frame: 1 month ]
    Assessed through monitoring of Heart Rate (beats per minute) on each treatment session before treatment and every 30 minutes within a 2-hour monitoring period.
  • Safety and tolerability as assessed by changes in O2 Saturation [ Time Frame: 1 month ]
    Assessed through monitoring of Oxygen saturation levels on each treatment session before treatment and every 30 minutes within a 2-hour monitoring period.
  • Safety and Tolerability of IN Ketamine as assessed by monitoring of adverse events [ Time Frame: 2 months ]
    Assessed through monitoring of adverse events, cardiovascular adverse events and/or respiratory distress throughout the trial.
  • Impact of Ketamine on cortical excitation as measured by intracortical facilitation (ICF) [ Time Frame: 1 months ]
    Assessed through administration of neurophysiological paradigms using Transcranial Magnetic Stimulation (TMS) paired with electromyography (EMG) and electroencephalography (EEG).
  • Impact of Ketamine on cortical inhibition as measured by short-interval cortical inhibition (SICI) [ Time Frame: 1 month ]
    Assessed through administration of neurophysiological paradigms using Transcranial Magnetic Stimulation (TMS) paired with electromyography (EMG) and electroencephalography (EEG).
Current Other Pre-specified Outcome Measures
 (submitted: December 9, 2021)
Change in quality of life measures as assessed by the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) [ Time Frame: 1 month ]
World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) (12-item version); This scale is used to assess disability over six domains of functioning: cognition, mobility, self-care, getting along with others, participation in society, and life activities. Scale range: 12-60 (total score) Lower scores indicate lower disability or loss of function (i.e., better outcome) Higher scores indicate higher disability or loss of function (i.e., worse outcome)
Original Other Pre-specified Outcome Measures
 (submitted: November 16, 2021)
Exploratory Measures [ Time Frame: 1 month ]
Improvement in quality of life measures as assessed by the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0)
 
Descriptive Information
Brief Title  ICMJE Intranasal Ketamine in Ultra-REsistant Depression (SURE-ECT Non Responders)
Official Title  ICMJE Safety and Clinical Effects of Intranasal Ketamine in Ultra-REsistant Depression (SURE-ECT Non Responders). Pilot Study
Brief Summary Despite the known efficacy of pharmacotherapy (i.e. antidepressants) and psychotherapeutic interventions in treating depressive disorders, research evidence suggests that 20% to 40% of patients with major depressive disorder (MDD) do not respond adequately to such treatments. These patients are diagnosed with Treatment-Resistant Depression (TRD), and are sometimes treated with convulsive therapy. However, about 10-30% of TRD patients do not respond to convulsive therapy, and are thus diagnosed with Ultra-Resistant Depression (URD). Using an open label pilot study involving subjects, this trial aims to assess the safety, tolerability, and clinical effects of intranasal ketamine (IN) treatment in patients who do not respond to convulsive therapy. Intranasal ketamine (IN) treatment approach has shown promising therapeutic outcomes for patients with TRD, but has not yet been studied on patients with URD.
Detailed Description

Ketamine is a fast-acting anesthetic that can have stimulant effects when taken at low doses. It acts as a non-competitive high-affinity N-methyl-d-aspartate (NMDA) receptor antagonist that stimulates synaptic glutamate release and blocks extra-synaptic NMDA receptors. This mechanism of action mediates excitatory synaptic transmission through the central nervous system and therefore results in robust antidepressant effects. Administering intravenous (IV) ketamine to patients with TRD has shown to produce rapid antidepressant effects. Nevertheless, delivering IV ketamine to patients can be challenging since it requires specialized expertise and equipment. A promising alternative that preserves IV ketamine's rapid onset of therapeutic action while minimizing inconvenience and discomfort is intranasal drug delivery (IN). This current proof-of-concept clinical trial is an open label pilot study on patients with treatment-resistant unipolar depression who did not respond to, or did not tolerate, an acute course of convulsive therapy. Using a combination of Transcranial Magnetic Stimulation (TMS) neurophysiological tools with electromyography (EMG) and electroencephalography (EEG), this trial also aims to explore biomarkers of ketamine's antidepressant effect by examining ketamine's action on NMDA neurotransmission. Investigating the impact of ketamine on cortical excitation and inhibition could provide insight into the role of NMDA receptors in cortical physiology, and therefore determine potential predictors of clinical response for depression.

Objective 1: To test the safety and tolerability of IN ketamine in patients with URD who did not respond to/tolerate an acute course of convulsive therapy

Hypothesis 1: IN ketamine will be safe and well tolerated in patients with URD

Objective 2: To test the clinical effects of IN ketamine patients with URD who did not respond to/tolerate an acute course of convulsive therapy

Hypothesis 2: IN ketamine will result in improvement in depressive symptoms, suicidal ideation, and quality of life measures (compared to scores from baseline)

Objective 3: To investigate the impact of ketamine on cortical excitation via intracortical facilitation (ICF) and cortical inhibition via short-interval cortical inhibition (SICI) paradigms

Hypothesis 3: IN ketamine will result in neurophysiological changes as measured by TMS-EMG and EEG

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
Open label pilot study
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Depression
Intervention  ICMJE Drug: Intranasal Ketamine (IN)
A sterile form of ketamine will be administered intranasally twice weekly for four weeks. Dosing schedule will be determined based on patient's weight using a specialized formula. Patients will be started at the lowest dose during the first treatment session. Dose will be titrated further to therapeutic dose in the following sessions. The dose will be adjusted if patients do not tolerate full therapeutic doses. After receiving the second treatment of each week, participants will be seen by a study physician to determine dosing for the following week. Patients will be monitored by trained personnel for the full duration of the 2 hour supervision period. Vital signs and physical symptoms will be monitored consistently and measurements taken every 30 minutes. Appropriate medications will be provided to manage treatment-related side effects and any adverse events. Labetalol will be used in the management of treatment-related transient hypertension as needed.
Study Arms  ICMJE Experimental: Intranasal Ketamine (IN)
Ketamine will be administered intranasally (IN) using an atomizer (MAD300 by Teleflex, North Carolina, USA).
Intervention: Drug: Intranasal Ketamine (IN)
Publications * Knyahnytska Y, Zomorrodi R, Kaster T, Voineskos D, Trevizol A, Blumberger D. The Safety, Clinical, and Neurophysiological Effects of Intranasal Ketamine in Patients Who Do Not Respond to Electroconvulsive Therapy: Protocol for a Pilot, Open-Label Clinical Trial. JMIR Res Protoc. 2022 Jan 17;11(1):e30163. doi: 10.2196/30163.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 16, 2021)
25
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 25, 2024
Estimated Primary Completion Date October 25, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Individuals with a diagnosis of non-psychotic MDD as confirmed by the Mini-International Neuropsychiatric Interview (MINI)
  2. Individuals meeting criteria for Ultra Resistant Major Depressive Disorder (URD) in current episode

    URD is defined as:

    1. those who received at least eight convulsive therapy treatment sessions and did not respond, or
    2. those who were not able to tolerate convulsive therapy
  3. Individuals scoring 14 and above on the Hamilton Rating Scale for Depression-24 Items (HRSD-24)
  4. Individuals capable to provide consent who are receiving care as outpatients

Exclusion Criteria:

  1. Individuals with history of substance use disorder (i.e. dependence or abuse) within the past month; and lifetime history of ketamine substance use disorder as confirmed by the MINI
  2. Concomitant major unstable medical illness such as poorly controlled high blood pressure or patients diagnosed with enlarged prostate or reporting any other urinary related issues
  3. Pregnancy or the intention to become pregnant and breastfeeding during the study as confirmed by self-report. Female participants of reproductive potential must be willing to use a medically acceptable method of birth control which include highly effective (e.g. approved hormonal contraceptives, intrauterine device, tubal ligation) or double barrier (e.g. male condom with diaphragm, male condom with cervical cap) methods of contraception or abstinence if that is the usual and preferred lifestyle of the participant
  4. Presence of cardiac decompensation/heart failure v)
  5. Diagnosis of any primary psychotic disorder, bipolar disorder, obsessive-compulsive disorder, or post-traumatic stress disorder (current) as confirmed by the MINI
  6. Diagnosis of severe personality disorder as assessed during the initial consultation with a physician at the Temerty Centre prior to study entry
  7. Any significant neurological disorder (e.g., a space occupying brain lesion, a history of stroke, a cerebral aneurysm, a seizure disorder, Parkinson's disease, Huntington's chorea, multiple sclerosis) as assessed through medical history review during the initial consultation with a physician at the Temerty Centre prior to study entry
  8. Individuals presenting with a medical condition, a medication, or a laboratory abnormality that could cause a major depressive episode or significant cognitive impairment in the opinion of the investigator
  9. Individuals requiring a benzodiazepine with a dose equivalent to lorazepam 2 mg/day or higher; being on any anticonvulsant(e.g. Lamotrigine) and/or opioid medication due to the potential of these medications to limit the efficacy of ketamine
  10. Individuals unable to communicate in spoken and written English fluently enough to complete the required study assessments due to a language barrier or a non-correctable clinically significant sensory impairment (i.e., cannot hear or see well enough to complete clinical assessments)
  11. Individuals with cognitive or physical impairment which may potentially interfere with IN ketamine administration and subject's ability to stay in the same place for a 2-hr monitoring supervision as assessed through medical history review during the initial consultation with a physician at the Temerty Centre prior to study entry
  12. Any intracranial implant (e.g., aneurysm clips, shunts, cochlear implants) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed given that we will be using TMS-EMG/EEG
  13. Those unable to secure escort to accompany them back home after ketamine sessions will also be excluded from this study
  14. Any known allergy to the study medication or any component/ingredient of the ketamine preparation
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 21 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Nour Afandi, BSc 416-535-8501 ext 30925 nour.Afandi@camh.ca
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05137938
Other Study ID Numbers  ICMJE 095-2019
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Centre for Addiction and Mental Health
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Centre for Addiction and Mental Health
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Yuliya Knyahnytska, MD, PhD Centre for Addiction and Mental Health
PRS Account Centre for Addiction and Mental Health
Verification Date December 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP