A Study to Investigate Evoked Potentials as Markers of Ketamine-induced Cortical Plasticity in Patients With Major Depressive Disorder

• Sponsor: Janssen Research & Development, LLC (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01957410
• Collaborator: (none)
• Enrollment: 13
• Location: 1
• Arms: 2
• Duration (Months): 19
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

To evaluate if somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) obtained with electroencephalography (EEG) and electromyography (EMG) can be used to detect changes in cortical plasticity in responders to a single IV infusion of ketamine as compared to non-responders.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: Ketamine; Drug: Placebo	Phase 2

Detailed Description

This study will be conducted in patients with Major Depressive Disorder (MDD) and divided into 2 sequential cohorts. Cohort 1 will be conducted in 12 patients at a single center. For each patient, there will be up to 4 sequential phases: a screening phase of up to 6 weeks, an open-label treatment phase of up to 4 weeks, an optional open-label treatment phase of up to 1 week, and a follow-up phase of up to 1 week (if applicable). Cohort 2 will be conducted in 20 patients and will be a multicenter, double-blind (neither physician nor patient knows the treatment that the patient receives), randomized (the study drug is assigned by chance), placebo-controlled (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial) design. For each patient, there will be up to 4 sequential phases: a screening phase of up to 6 weeks, a double-blind treatment phase of up to 4 weeks, an optional open-label treatment phase of up to 1 week, and a follow-up phase of up to 1 week (if applicable). The total study duration for each patient will be maximally about 12 weeks. Participant safety will be monitored throughout the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: An Open-Label and Double-Blind Study to Investigate Evoked Potentials as Markers of Ketamine-induced Cortical Plasticity in Subjects With Major Depressive Disorder
• Study Start Date: Feb 1, 2014
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ketamine Intravenous (IV) Patients will receive a single IV dose of ketamine given as a continuous infusion.	Drug: Ketamine; During Cohorts 1 and 2, a single ketamine 0.5 mg/kg dose will be given as a continuous IV infusion over 40 minutes by use of an electronic syringe infusion pump. The predefined dose and infusion rate/duration should not be adjusted. If a patient is unable to tolerate the study medication, the infusion should be stopped. Within 1 week of completion of the open-label treatment phase, participants can receive a single dose of ketamine 0.5 mg/kg administered as an IV infusion over 40 minutes during an optional open-label treatment phase.
Placebo Comparator: Placebo Intravenous (IV) Patients will receive a single IV dose of placebo given as a continuous infusion.	Drug: Placebo; During Cohort 2, a single placebo dose will be given as a continuous IV infusion over 40 minutes by use of an electronic syringe infusion pump. Within 1 week of completion of the double-blind treatment phase, participants can receive a single dose of ketamine 0.5 mg/kg administered as an IV infusion over 40 minutes during an optional open-label treatment phase.

Outcome Measures

Primary Outcome Measures

1. Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Somatosensory Evoked Potential (SEPs) Amplitudes at 4 Hours Postdose on Day 1 [Baseline and Day 1 (4 hours postdose)]

   SEPs are the electrical signals generated by the nervous system in response to somatosensory stimuli - typically through electrical stimulation of the median nerve. SEPs are read on the skull with electroencephalography (EEG). SEPs was recorded using a 64-channel EEG system at baseline (predose) and regularly after study drug administration. The change from baseline was calculated as post-baseline value minus baseline value for each participant. Since the number of participants at baseline differ from the number of participants at post-baseline measure (that is [i.e.] not all baseline values are paired), the mean change is not equal to the difference between the means at the two time points.

2. Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Motor Evoked Potential (MEPs) Amplitudes at 4 Hours Postdose on Day 1 [Baseline and Day 1 (4 hours postdose)]

   MEPs are generated when stimulation of the brain on the motor cortex (with Transcranial Magnetic Stimulation [TMS]) causes the spinal cord and peripheral muscles to produce neuroelectrical signals. MEPs are typically measured in the hand muscles. The Motor Evoked Response to Transcranial Magnetic Stimulation (TMS MEPs) was evaluated at baseline and regularly after study drug administration. Intracortical inhibition and facilitation was also evaluated using TMS. A figure-of-eight coil with external loop diameters of 9 cm was used to elicit motor responses in the contralateral first dorsal interosseus.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patient must be medically stable

• Patient must meet Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) diagnostic criteria for Major Depressive Disorder (MDD), without psychotic features, based upon clinical assessment and confirmed by the Mini International Psychiatric Interview (MINI)

• Patient must have had an inadequate response to at least 2 antidepressants, one of which is in the current episode of depression

• Patient must have an Inventory of Depressive Symptomatology 30-item Clinician-rated (IDS-C30) total score ≥ 34 at Screening and Day -1

• Women must be postmenopausal, surgically sterile, or, if heterosexually active, practicing a highly effective method of birth control

• Men who are heterosexually active with a woman of childbearing potential must agree to use a double barrier method of birth control and to not donate sperm during the study and for 3 months after receiving the last dose of study drug

Exclusion Criteria:

• Patient has current signs and/or symptoms of liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, or metabolic disturbances

• Patient has a primary DSM-IV diagnosis of current (active) generalized anxiety disorder (GAD), panic disorder, obsessive compulsive disorder (OCD), posttraumatic stress disorder (PTSD), anorexia nervosa, or bulimia nervosa

• Patient has a current diagnosis of bipolar disorder, mental retardation, or cluster b personality disorder (e.g., borderline personality disorders, antisocial personality disorder, etc)

• Patient has a current or prior diagnosis of a psychotic disorder or MDD with psychosis

• Patient has not responded to treatment with electroconvulsive therapy (ECT) in the current episode of depression

• Patient has suicidal ideation with intent to act, or has homicidal ideation/intent, during Screening phase per Investigator's clinical judgment

• Patient has any significant primary sleep disorder

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Durham	North Carolina	United States

Sponsors and Collaborators

• Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT01957410
• Other Study ID Numbers: CR102607; KETIVTRD2004
• First Posted: Oct 8, 2013
• Last Update Posted: Jan 27, 2017
• Last Verified: Dec 1, 2016

• Keywords provided by Janssen Research & Development, LLC: Major Depressive Disorder; Ketamine; Evoked potentials; Somatosensory evoked potentials; Motor evoked potentials; Cortical plasticity
• Additional relevant MeSH terms: Disease; Depressive Disorder; Depression; Depressive Disorder, Major; Ketamine

Study Results

Participant Flow

Recruitment Details	A total of 13 participants were enrolled, treated and completed the study.

Arm/Group Title	Ketamine IV 0.5mg/kg
Arm/Group Description	Participants received a single ketamine 0.5 milligram per kilogram (mg/kg) dose as a continuous Intravenous (IV) infusion over 40 minutes by use of an electronic syringe infusion pump on Day 1. Participants who responded continued the open-label treatment phase through Day 28 or until relapse, whichever occurred first. An additional single IV dose of ketamine 0.5 mg/kg was available during an optional open label treatment phase.
Period Title: Open Label
STARTED	13
COMPLETED	13
NOT COMPLETED	0
Period Title: Open Label
STARTED	13
COMPLETED	13
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Ketamine IV 0.5mg/kg
Arm/Group Description	Participants received a single ketamine 0.5 milligram per kilogram (mg/kg) dose as a continuous Intravenous (IV) infusion over 40 minutes by use of an electronic syringe infusion pump on Day 1. Participants who responded continued the open-label treatment phase through Day 28 or until relapse, whichever occurred first. An additional single IV dose of ketamine 0.5 mg/kg was available during an optional open label treatment phase.
Overall Participants	13
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.9 (11.45)
Gender (Count of Participants)
Female	9 69.2%
Male	4 30.8%
Region of Enrollment (participants) [Number]
USA	13 100%

Outcome Measures

1. Primary Outcome

Title	Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Somatosensory Evoked Potential (SEPs) Amplitudes at 4 Hours Postdose on Day 1
Description	SEPs are the electrical signals generated by the nervous system in response to somatosensory stimuli - typically through electrical stimulation of the median nerve. SEPs are read on the skull with electroencephalography (EEG). SEPs was recorded using a 64-channel EEG system at baseline (predose) and regularly after study drug administration. The change from baseline was calculated as post-baseline value minus baseline value for each participant. Since the number of participants at baseline differ from the number of participants at post-baseline measure (that is [i.e.] not all baseline values are paired), the mean change is not equal to the difference between the means at the two time points.
Time Frame	Baseline and Day 1 (4 hours postdose)

Outcome Measure Data

Analysis Population Description

Efficacy analysis set included all participants who received a dose of ketamine and who had at least 1 postbaseline value of SEP (P40).

Arm/Group Title	Ketamine IV 0.5mg/kg
Arm/Group Description	Participants received a single ketamine 0.5 milligram per kilogram (mg/kg) dose as a continuous Intravenous (IV) infusion over 40 minutes by use of an electronic syringe infusion pump on Day 1. Participants who responded continued the open-label treatment phase through Day 28 or until relapse, whichever occurred first. An additional single IV dose of ketamine 0.5 mg/kg was available during an optional open label treatment phase.
Measure Participants	13
Responders: Baseline (n=9)	1.83 (1.13)
Responders: Day 1, 4 Hours (n=6)	2.58 (1.24)
Responders: Change from Baseline (n=6)	0.47 (1.68)
Non-Responders: Baseline (n=4)	1.70 (1.10)
Non-Responders: Day 1, 4 Hours (n=3)	1.84 (1.48)
Non-Responders: Change from Baseline (n=3)	0.47 (0.43)

2. Primary Outcome

Title	Comparison of Ketamine Responders and Ketamine Non-responders in the Change From Baseline in Motor Evoked Potential (MEPs) Amplitudes at 4 Hours Postdose on Day 1
Description	MEPs are generated when stimulation of the brain on the motor cortex (with Transcranial Magnetic Stimulation [TMS]) causes the spinal cord and peripheral muscles to produce neuroelectrical signals. MEPs are typically measured in the hand muscles. The Motor Evoked Response to Transcranial Magnetic Stimulation (TMS MEPs) was evaluated at baseline and regularly after study drug administration. Intracortical inhibition and facilitation was also evaluated using TMS. A figure-of-eight coil with external loop diameters of 9 cm was used to elicit motor responses in the contralateral first dorsal interosseus.
Time Frame	Baseline and Day 1 (4 hours postdose)

Outcome Measure Data

Analysis Population Description

Efficacy analysis set included all participants who received a dose of ketamine and who had at least 1 postbaseline value of MEP.

Arm/Group Title	Ketamine IV 0.5mg/kg
Arm/Group Description	Participants received a single ketamine 0.5 milligram per kilogram (mg/kg) dose as a continuous Intravenous (IV) infusion over 40 minutes by use of an electronic syringe infusion pump on Day 1. Participants who responded continued the open-label treatment phase through Day 28 or until relapse, whichever occurred first. An additional single IV dose of ketamine 0.5 mg/kg was available during an optional open label treatment phase.
Measure Participants	13
Responders: Baseline (n=9)	0.874 (0.710)
Responders: Day 1, 4 hour (H) (n=9)	1.052 (0.867)
Responders: Change from Baseline (n=9)	0.179 (0.765)
Non-Responders: Baseline (n=4)	1.257 (1.055)
Non-Responders: Day 1, 4H (n=4)	1.197 (1.067)
Non-Responders: Change from Baseline (n=4)	-0.060 (0.088)

Adverse Events

Time Frame	Up to 1 week after the last dose administration (6 weeks)
Arm/Group Title	Ketamine IV 0.5mg/kg
Arm/Group Description	Participants received a single ketamine 0.5 milligram per kilogram (mg/kg) dose as a continuous Intravenous (IV) infusion over 40 minutes by use of an electronic syringe infusion pump on Day 1. Participants who responded continued the open-label treatment phase through Day 28 or until relapse, whichever occurred first. An additional single IV dose of ketamine 0.5 mg/kg was available during an optional open label treatment phase.
All Cause Mortality
	Ketamine IV 0.5mg/kg
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ketamine IV 0.5mg/kg
	Affected / at Risk (%)	# Events
Total	0/13 (0%)
Other (Not Including Serious) Adverse Events
	Ketamine IV 0.5mg/kg
	Affected / at Risk (%)	# Events
Total	10/13 (76.9%)
Gastrointestinal disorders
Nausea	1/13 (7.7%)	1
General disorders
Infusion site bruising	2/13 (15.4%)	2
Infections and infestations
Bacterial vaginosis	1/13 (7.7%)	1
Oral herpes	1/13 (7.7%)	1
Respiratory tract infection	1/13 (7.7%)	1
Urinary tract infection	1/13 (7.7%)	2
Musculoskeletal and connective tissue disorders
Myalgia	1/13 (7.7%)	1
Nervous system disorders
Headache	4/13 (30.8%)	4
Psychiatric disorders
Panic attack	2/13 (15.4%)	3
Respiratory, thoracic and mediastinal disorders
Paranasal sinus discomfort	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
Dermatitis contact	1/13 (7.7%)	1
Rash	1/13 (7.7%)	1

Limitations/Caveats

Study was planned as open label treatment phase (Cohort 1) and double blind treatment phase (Cohort 2). However, study was terminated after completion of Cohort 1.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

A copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested in writing, such publication will be withheld for up to an additional 60 days.