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Efficacy of Repeated Ketamine Infusions for Treatment-resistant Depression

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ClinicalTrials.gov Identifier: NCT02360280
Recruitment Status : Completed
First Posted : February 10, 2015
Results First Posted : December 3, 2019
Last Update Posted : December 3, 2019
Sponsor:
Collaborators:
Mayo Clinic
University of Minnesota
Information provided by (Responsible Party):
VA Office of Research and Development

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Treatment-resistant Depression
Interventions Drug: ketamine
Drug: midazolam
Enrollment 62
Recruitment Details Recruitment from April 2015 through October 2018
Pre-assignment Details Four subjects were enrolled but not assigned to treatment. They voluntarily decided to decline participation for logistical issues.
Arm/Group Title Six Ketamine Infusions Single Ketamine Infusion Preceded by 5 Midazolam Infusions
Hide Arm/Group Description

Six infusions of 0.5 mg/Kg of ketamine hydrochloride solution over 2 weeks.

ketamine: sedative

Single infusion of 0.5 mg/Kg of ketamine hydrochloride solution preceded by midazolam 0.045 mg/kg over 2 weeks.

ketamine: sedative

midazolam: sedative

Period Title: Overall Study
Started 28 30
Completed 25 29
Not Completed 3 1
Reason Not Completed
Withdrawal by Subject             2             0
Adverse Event             0             1
Lost to Follow-up             1             0
Arm/Group Title Six Ketamine Infusions Single Ketamine Infusion Preceded by 5 Midazolam Infusions Total
Hide Arm/Group Description

Six infusions of 0.5 mg/Kg of ketamine hydrochloride solution over 2 weeks.

ketamine: sedative

Single infusion of 0.5 mg/Kg of ketamine hydrochloride solution preceded by midazolam 0.045 mg/kg over 2 weeks.

ketamine: sedative

midazolam: sedative

Total of all reporting groups
Overall Number of Baseline Participants 25 29 54
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 25 participants 29 participants 54 participants
54.4  (13.8) 51.2  (12.5) 52.7  (13.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants 29 participants 54 participants
Female
3
  12.0%
5
  17.2%
8
  14.8%
Male
22
  88.0%
24
  82.8%
46
  85.2%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 25 participants 29 participants 54 participants
White 21 25 46
Black/African American 3 1 4
Other 1 3 4
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 25 participants 29 participants 54 participants
25
 100.0%
29
 100.0%
54
 100.0%
MADRS   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 25 participants 29 participants 54 participants
34.88  (7.79) 33.82  (5.11) 34.32  (6.41)
[1]
Measure Description: The Montgomery-Asberg Depression Rating Scale (MADRS) has 10-items which are based on mood symptoms over the past 7 days. Each items is scored 0 (normal) to 6 (severe depression) with overall score ranges from 0 (normal) to 60 (severe depression).
IDS-C   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 25 participants 29 participants 54 participants
36.8  (3.9) 39.8  (7.3) 38.4  (6.1)
[1]
Measure Description: The Inventory of Depressive Symptomatology-Clinician Rated (IDS-C) is a 30-item questionnaire designed to assess the severity of depressive symptoms.The seven-day period prior to assessment is the usual time frame for assessing symptom severity. Ranges are 0-11=None, 12-23=Mild, 24-36=Moderate, 37-46=Severe, 47-84=Very Severe.
BAI   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 25 participants 29 participants 54 participants
12.32  (13.62) 10.57  (6.88) 11.31  (10.42)
[1]
Measure Description: Beck Anxiety Inventory (BAI) contains 21 questions, each answer being scored on a scale value of 0 (not at all) to 3 (severely). Higher total scores indicate more severe anxiety symptoms. 0-7: minimal anxiety; 8-15: mild anxiety; 16-25: moderate anxiety; 26-63: severe anxiety.
CGI   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 25 participants 29 participants 54 participants
5.32  (0.56) 5.14  (0.64) 5.22  (0.60)
[1]
Measure Description: The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness at the time of rating 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.
NRS   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 25 participants 29 participants 54 participants
3.16  (2.49) 3.37  (2.09) 3.27  (2.26)
[1]
Measure Description: The NRS for pain is a unidimensional measure of pain intensity in the last 24 hours. An 11-point numeric scale with 0 representing one pain extreme (e.g., "no pain") and 10 representing the other pain extreme (e.g., "pain as bad as you can imagine" and "worst pain imaginable").
1.Primary Outcome
Title Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Score After 12 Days of Treatment
Hide Description Average difference in the Montgomery-Asberg Depression Rating Scale (MADRS) score change between groups. The MADRS has 10-items which are based on mood symptoms over the past 7 days. Each items is scored 0 (normal) to 6 (severe depression) with overall score ranges from 0 (normal) to 60 (severe depression).
Time Frame 13 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Six Ketamine Infusions Single Ketamine Infusion Preceded by 5 Midazolam Infusions
Hide Arm/Group Description:

Six infusions of 0.5 mg/Kg of ketamine hydrochloride solution over 2 weeks.

ketamine: sedative

Single infusion of 0.5 mg/Kg of ketamine hydrochloride solution preceded by midazolam 0.045 mg/kg over 2 weeks.

ketamine: sedative

midazolam: sedative

Overall Number of Participants Analyzed 25 29
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
21.0
(17.2 to 24.8)
17.2
(13.2 to 21.2)
2.Secondary Outcome
Title Antidepressant Response Defined as >50% Decrease in MADRS Baseline Score
Hide Description Comparing the number of subjects that achieve response between groups as defined above.
Time Frame 13 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Six Ketamine Infusions Single Ketamine Infusion Preceded by 5 Midazolam Infusions
Hide Arm/Group Description:

Six infusions of 0.5 mg/Kg of ketamine hydrochloride solution over 2 weeks.

ketamine: sedative

Single infusion of 0.5 mg/Kg of ketamine hydrochloride solution preceded by midazolam 0.045 mg/kg over 2 weeks.

ketamine: sedative

midazolam: sedative

Overall Number of Participants Analyzed 25 29
Measure Type: Count of Participants
Unit of Measure: Participants
19
  76.0%
20
  69.0%
3.Secondary Outcome
Title Remission Defined as MADRS Score Equal or Less Than 9
Hide Description Comparing the number of subjects that achieve remission between groups as defined above
Time Frame 13 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Six Ketamine Infusions Single Ketamine Infusion Preceded by 5 Midazolam Infusions
Hide Arm/Group Description:

Six infusions of 0.5 mg/Kg of ketamine hydrochloride solution over 2 weeks.

ketamine: sedative

Single infusion of 0.5 mg/Kg of ketamine hydrochloride solution preceded by midazolam 0.045 mg/kg over 2 weeks.

ketamine: sedative

midazolam: sedative

Overall Number of Participants Analyzed 25 29
Measure Type: Count of Participants
Unit of Measure: Participants
12
  48.0%
11
  37.9%
4.Secondary Outcome
Title Time From Post-infusion Response to Occurrence of Relapse Defined as <50% of Baseline MADRS Score
Hide Description The length of time from post-infusion response until relapse (defined as >50% of MADRS baseline score) assessed for up to 6 months.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The overall number of participants in each intervention corresponds to the total number of subjects that achieve response at the end of six infusions.
Arm/Group Title Six Ketamine Infusions Single Ketamine Infusion Preceded by 5 Midazolam Infusions
Hide Arm/Group Description:

Six infusions of 0.5 mg/Kg of ketamine hydrochloride solution over 2 weeks.

ketamine: sedative

Single infusion of 0.5 mg/Kg of ketamine hydrochloride solution preceded by midazolam 0.045 mg/kg over 2 weeks.

ketamine: sedative

midazolam: sedative

Overall Number of Participants Analyzed 19 20
Median (95% Confidence Interval)
Unit of Measure: weeks
6.00
(0 to 16.81)
2.00
(0 to 4.92)
Time Frame The time frame of data collection was 3 years and 8 months (from April 2015 through December 2018). Each participant was assessed for up to 28 weeks.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Six Ketamine Infusions Single Ketamine Infusion Preceded by 5 Midazolam Infusions
Hide Arm/Group Description

Six infusions of 0.5 mg/Kg of ketamine hydrochloride solution over 2 weeks.

ketamine: sedative

Single infusion of 0.5 mg/Kg of ketamine hydrochloride solution preceded by midazolam 0.045 mg/kg over 2 weeks.

ketamine: sedative

midazolam: sedative

All-Cause Mortality
Six Ketamine Infusions Single Ketamine Infusion Preceded by 5 Midazolam Infusions
Affected / at Risk (%) Affected / at Risk (%)
Total   0/25 (0.00%)   0/29 (0.00%) 
Hide Serious Adverse Events
Six Ketamine Infusions Single Ketamine Infusion Preceded by 5 Midazolam Infusions
Affected / at Risk (%) Affected / at Risk (%)
Total   1/25 (4.00%)   1/29 (3.45%) 
Nervous system disorders     
Recurrent headaches   1/25 (4.00%)  1/29 (3.45%) 
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Six Ketamine Infusions Single Ketamine Infusion Preceded by 5 Midazolam Infusions
Affected / at Risk (%) Affected / at Risk (%)
Total   17/25 (68.00%)   8/29 (27.59%) 
Cardiac disorders     
Increased in blood pressure   6/25 (24.00%)  5/29 (17.24%) 
Ear and labyrinth disorders     
Ringing in ears   0/25 (0.00%)  1/29 (3.45%) 
Eye disorders     
Blurred vision   0/25 (0.00%)  2/29 (6.90%) 
Gastrointestinal disorders     
Nausea   5/25 (20.00%)  2/29 (6.90%) 
Constipation   1/25 (4.00%)  1/29 (3.45%) 
Dry mouth   0/25 (0.00%)  1/29 (3.45%) 
General disorders     
General malaise   7/25 (28.00%)  2/29 (6.90%) 
Nervous system disorders     
Dizziness   1/25 (4.00%)  3/29 (10.34%) 
Tremors   1/25 (4.00%)  0/29 (0.00%) 
Sleeping too much   4/25 (16.00%)  3/29 (10.34%) 
Poor concentration   5/25 (20.00%)  2/29 (6.90%) 
Headaches   6/25 (24.00%)  4/29 (13.79%) 
Psychiatric disorders     
Insomnia   4/25 (16.00%)  3/29 (10.34%) 
Restlessness   3/25 (12.00%)  0/29 (0.00%) 
Anxiety   5/25 (20.00%)  7/29 (24.14%) 
Decreased energy   7/25 (28.00%)  5/29 (17.24%) 
Fatigue   6/25 (24.00%)  4/29 (13.79%) 
Renal and urinary disorders     
Frequent urination   0/25 (0.00%)  1/29 (3.45%) 
Reproductive system and breast disorders     
Loss of sexual desire   4/25 (16.00%)  3/29 (10.34%) 
Trouble achieving orgasm   1/25 (4.00%)  2/29 (6.90%) 
Trouble with erections   0/25 (0.00%)  2/29 (6.90%) 
Respiratory, thoracic and mediastinal disorders     
Respiratory distress   1/25 (4.00%)  1/29 (3.45%) 
Skin and subcutaneous tissue disorders     
Increased perspiration   0/25 (0.00%)  1/29 (3.45%) 
Itching   1/25 (4.00%)  1/29 (3.45%) 
Indicates events were collected by systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Paulo R. Shiroma
Organization: Minneapolis VA Medical Center
Phone: 612-467-2264
EMail: paulo.shiroma@va.gov
Layout table for additonal information
Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT02360280    
Other Study ID Numbers: CLNA-018-14S
First Submitted: January 29, 2015
First Posted: February 10, 2015
Results First Submitted: October 21, 2019
Results First Posted: December 3, 2019
Last Update Posted: December 3, 2019