Treatment Resistant DepressionPhase 2NCT01920555

Double-Blind, Placebo-Controlled Trial of Ketamine Therapy in Treatment-Resistant Depression (TRD)

A Phase 2 study testing Ketamine in people with Treatment Resistant Depression, run by Massachusetts General Hospital at 6 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

This study is looking at the efficacy, durability, safety, and tolerability of multiple single doses of Ketamine vs. active placebo for treating patients with treatment resistant depression who are taking an antidepressant that is not working for them. Read more about this study

Who is it for?: Ages 18 to 70 years
Conditions the study is for: Treatment Resistant Depression
What is being tested?: Ketamine
Type of treatment: Injection or infusion
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 99 participants
Where: 6 sitesUnited States
Study dates: Dec 2014to Feb 2017
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 70 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Male or female, 18-70 years old.
Able to read, understand, and provide written, dated informed consent prior to screening.
Diagnosed with Major Depressive Disorder (MDD), single or recurrent, and currently experiencing a Major Depressive Episode (MDE) of at least eight weeks in duration, prior to screening.
Has a history of TRD during the current MDE.
Meet the threshold on the total MADRS score of greater than or equal to 20 at both screening and baseline visits (Day -7/-28 and Day 0), as confirmed by the remote centralized MGH CTNI rater between the screen visit and the baseline visit.
In good general health

Show all 10Show fewer

For female participants, status of non-childbearing potential or use of an acceptable form of birth control
Body mass index between 18-35 kg/m2
Concurrent psychotherapy will be allowed if the type and frequency of the therapy has been stable for at least three months prior to screening and is expected to remain stable during participation in the study
Concurrent hypnotic therapy will be allowed if the therapy has been stable for at least 4 weeks prior to screening and if it is expected to remain stable during the course of the subject's participation in the study.

Who cannot join

Female of childbearing potential who is not willing to use one of the specified forms of birth control during the study
Female that is pregnant or breastfeeding
Female with a positive pregnancy test at screening or baseline
History during the current MDE of failure to achieve a satisfactory response to >7 treatment courses of a therapeutic dose of an antidepressant therapy of at least 8 weeks duration during the current episode
Total MADRS score of <20 at the screen or baseline visits, or as assessed by the remote, independent MGH CTNI rater and reported to the site
Current diagnosis of a Substance Use Disorder (Abuse or Dependence) with the exception of nicotine dependence, at screening or within 6 months prior to screening

Show all 43Show fewer

Current Axis I disorder that is the principal focus of treatment and MDD the secondary focus of treatment for the past 6 months or more
History of bipolar disorder, schizophrenia or schizoaffective disorders, or any history of psychotic symptoms in the current or previous depressive episodes
History of eating disorders within five years of screening
Any Axis I or Axis II Disorder, which at screening is clinically predominant to their MDD or has been predominant at any time within 6 months prior to screening
Subject is considered at significant risk for suicidal behavior during the course of their participation in the study
Has failed to respond to electroconvulsive therapy (ECT) during the current depressive episode
Has received vagus nerve stimulation (VNS) at any time prior to screening
Has dementia, delirium, amnestic, or any other cognitive disorder
Has a clinically significant abnormality on the screening physical examination
Participation in any clinical trial with an investigational drug or device within the past month or concurrent to study participation
Current episode of:
Hypertension, Stage 1 as defined by a systolic blood pressure ≥140mmHg or diastolic blood pressure ≥90 mmHg at screening on two of three measurements (standing and supine) at least 15 minutes apart.
Hypertension, Stage 1 as defined by a systolic blood pressure ≥155 mmHg or diastolic blood pressure ≥99 mmHg at the Baseline Visit (Visit 1) within 1.5 hours prior to randomization on two of three measurements (standing and supine) at least 15 minutes apart.
Recent myocardial infarction (within one year) or a history of myocardial infarction.
Syncopal event within the past year.
Congestive heart failure (CHF) New York Heart Association Criteria >Stage 2
Angina pectoris.
Heart rate <50 or >105 beats per minute at screening or randomization (Baseline Visit).
QTcF (Fridericia-corrected) ≥450 msec at screening or randomization (Baseline Visit).
Current history of hypertension, or on antihypertensives for the purpose of lowering blood pressure, who have either had an increase in antihypertensive dose or increase in the number of antihypertensive drugs used to treat hypertension over the last 2 months.
Chronic lung disease excluding asthma.
Lifetime history of surgical procedures involving the brain or meninges, encephalitis, meningitis, degenerative central nervous system disorder, epilepsy, mental retardation, or any other disease/procedure/accident/intervention associated with significant injury to or malfunction of the central nervous system, or a history of significant head trauma within the past 2 years
Presents with any of the following lab abnormalities:
Thyroid stimulating hormone outside of the normal limits and clinically significant as determined by the investigator. Free thyroxine (T4) levels may be measured if TSH level is high. Subject will be excluded if T4 level is clinically significant.
Patients with diabetes mellitus fulfilling any of the following criteria:
Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >8.5% at screening ii. Admitted to hospital for treatment of diabetes mellitus or diabetes mellitus related illness in the past 12 weeks iii. Not under physician care for diabetes mellitus iv. Has not been on the same dose of oral hypoglycaemic drug(s) and/or diet for the 4 weeks prior to screening. For thiazolidinediones (glitazones) this period should not be less than 8 weeks.
Any other clinically significant abnormal laboratory result (as determined after evaluation by study investigator and MGH CTNI medical monitor) at the time of the screening exam.
History of hypothyroidism and has been on a stable dosage of thyroid replacement medication for less than 2 months prior to screening. (Subjects on a stable dosage of thyroid replacement medication for at least 2 months or more prior to screening are eligible for enrollment.)
History of hyperthyroidism which was treated (medically or surgically) less than six months prior to screening
Any current or past history of any physical condition which in the investigator's opinion might put the subject at risk or interfere with study results interpretation
History of positive screening urine test for drugs of abuse at screening
Patients with exclusionary laboratory values, or requiring treatment with exclusionary concomitant medications
Patients on exclusionary concomitant psychotropic medications, the half-life of which would not allow sufficient time for patients to have been free of the medication post-taper for five half-lives within the maximum screening period (28 days).
Patient who have participated in studies of ketamine or AZD6765 or other NMDA receptor antagonists for depression and received active treatment.
Patients with narrow angle glaucoma
Patients with a lifetime history of PCP/Ketamine drug use
Liver Function Tests higher than 2.5 times upper limit of normal

Trial locations and contacts

6 sites in 1 country.

City, postcode or hospital

6 sites in 1 country

United States6 sites

Massachusetts General Hospital
Boston, Massachusetts, 02114
University of Texas Southwestern
Dallas, Texas, 75390
Baylor College of Medicine
Houston, Texas, 77030
Yale University
New Haven, Connecticut, 06520
Mount Sinai School of Medicine
New York, New York, 10029
Stanford University
Palo Alto, California, 94304

Other trials in United States

About this study

Read the detailed description

The primary objective is to investigate whether all doses (0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg, and 1.0 mg/kg) of ketamine are superior to active placebo (midazolam 0.045 mg/kg) therapy in the acute treatment of patients with treatment resistant depression within 72 hours (Day 3), when added to ongoing and stable antidepressant therapy.

Conditions: Treatment Resistant Depression
Being tested: Ketamine, Placebo Midazolam
Keywords: Depression, Treatment Resistant Depression, Ketamine, Antidepressant, MDD, Major Depression
Medical subject headings: Depressive Disorder, Treatment-Resistant, Depression, Depressive Disorder, Major

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

KetamineDrug
Dose of Ketamine will be 0.1 mg/kg - one single infusion
KetamineDrug
Dose of Ketamine will be 0.2 mg/kg - one single infusion
KetamineDrug
Dose of Ketamine will be 0.5 mg/kg - one single infusion
KetamineDrug
Dose of Ketamine will be 1.0 mg/kg - one single infusion
Placebo MidazolamDrug
Dose of Midazolam (active placebo) will be 0.045 mg/kg - one single infusion

Study groups in NCT01920555
Study group	Role	What they receive
Ketamine 0.1mg	Active comparator	Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion Receives: Drug: Ketamine
Ketamine 0.2mg	Active comparator	Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion Receives: Drug: Ketamine
Ketamine 0.5mg	Active comparator	Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion Receives: Drug: Ketamine
Ketamine 1.0mg	Active comparator	Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion Receives: Drug: Ketamine
Midazolam (Active Placebo)	Placebo comparator	Patients in this arm will receive 0.045 mg/kg of midazolam - one single infusion Receives: Drug: Placebo Midazolam

What is being measured

The primary outcome is the main question the study is designed to answer.

Hamilton Rating Scale for Depression - 6 Items
The HAMD6 is a 6-item clinician-rated scale, where clinicians rate the presence of depression symptoms (i.e., depressed mood, guilt, work and interests, psychomotor retardation, psychic anxiety, somatic symptoms) on a 5-point scale, where 0 = not present, and 1-4 represent increasingly severe symptoms. One item (i.e., somatic symptoms) is rated on only a 3-point scale, ranging from 0-2. The possible scale range is 0-22, where higher values represent more severe depression. This instrument is completed with a structured interview guide by the clinician based on his/her assessment of the patient's symptoms. This structured interview has been validated for use with time frames shorter than one week. In this study, the HAMD6 was used to assess symptoms occurring in the past 24 hours.
Measured: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1, & 3

Secondary outcomes (9)

Montgomery-Asberg Depression Rating Scale (MADRS)
The MADRS is a 10-item clinician-rated scale measuring depression severity. Symptoms are rated on a 7-point scale, where 0 = "not present", and 1-6 represent increasing severity. Values 2, 4, and 6 have specific anchoring text (e.g., 2="Difficulties in starting activities." 4="Difficulties in starting simple routine activities which are carried out with effort, 6="Complete lassitude. Unable to do anything without help.") Values 1, 3, and 5 do not have specific text. The possible scale range is 0-60, where higher values represent higher severity. In this study, the MADRS was used to rate symptoms occurring in the past 3 days.
Measured: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0 and 3.
Clinical Global Impressions-Severity (CGI-S)
The CGI-S is a clinician rated single-item scale: "How depressed is the patient at this time?", rated on a 7-point response scale: 1 = Normal, not at all depressed, 2 = Borderline depressed, 3 = Mildly depressed, 4 = Moderately depressed. 5 = Markedly depressed, 6 = severely depressed, 7 = Among the most severely depressed patients. When rating patients, clinicians were asked to consider the past 24 hours.
Measured: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Clinical Global Impressions-Improvement (CGI-I) Scale
The CGI-I is a clinician rated single-item scale: "Compared to the patient's condition at admission, how much has the patient changed?", rated on a 7-point response scale: 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, and 7 = Very much worse. In this case, "admission" referred to the CGI-S screening assessments performed between Day -28 an -7, one conducted during the screening visit, and a second rating conducted by a remote, independent rater.
Measured: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Symptoms of Depression Questionnaire (SDQ)
The SDQ is a 44-item self-report scale, which aims to measure depression more comprehensively by including the assessment of symptoms in the anxiety-depression spectrum, including symptoms of irritability, anger attacks, and anxiety. Items are rated on an 6-point Likert scale, where participants are asked to rate if a specific symptom (e.g. "How has your mood been over the past 24 hours?") is normal for him or her (score = 2), what is better than normal (score = 1), and what is worse than normal (scores = 3-6). The total scale score is calculated by averaging across the items, resulting in a possible range from 1 to 6. Higher scores indicate greater depression severity. When rating, patients were asked to consider their symptoms during the past 24 hours.
Measured: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Clinical Positive Affect Scale (CPAS)
The CPAS is a 16-item self-report scale to assess the level to which participants experience persistent distress due to feeling that they have not returned to their normal or premorbid state. Items (e.g., "I look forward to things") are rated on a 5-point scale (0=not at all, 1=very much less than normal, 2=much less than normal, 3=slightly less than normal, 4=same as best or normal self). The possible scale range is 0 to 64, with higher scores indicating greater recovery from depression. Patients were asked to rate their experience of the past 24 hours.
Measured: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Snaith-Hamilton Pleasure-Scale (SHAPS)
The SHAPS is a 14-item self-report scale to measure hedonic tone. Items (e.g., "I would enjoy reading a book, magazine, or newspaper.") are rated on a 4-point scale (1=strongly disagree, 2=disagree, 3=agree, 4=strongly agree). Either of the 'disagree' responses scores 1 point, and either of the 'agree' responses scores 0 points, for a total scale range of 0-14. Higher scores indicate greater inability to experience pleasure. Patients were asked to rate their experience of the past 24 hours.
Measured: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Clinician-Administered Dissociative States Scale (CADSS) Scores During Infusion
The CADSS is a 23-item self-report scale for the assessment of dissociative states. It is a reliable, valid self-report instrument. The severity of each dissociative symptom ranges from 0 (not present) to 4 (extreme). The total score is calculated by summing across items, with a total possible range of 0-92. The CADSS was administered right before infusion, and 40, 80 minute and 120 minutes after the start of infusion. The timeframe is "at this moment".
Measured: Day 0/baseline at 0, 40, 80, and 120 minutes
Number of Participants Reporting Suicidal Ideation/Behavior on the Columbia Suicide Severity Rating Scale (C-SSRS)
The Columbia Suicide Severity Rating Scale (C-SSRS): The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was developed in the National Institute of Mental Health Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events through any treatment. It is a clinical interview providing a summary of both ideation and behavior that can be administered during any evaluation or risk assessment to identify the level and type of suicidality present. The C-SSRS can also be used during treatment to monitor for clinical worsening or improvement. It contains 5 rating scale questions (yes/no) for suicidal ideation increasing severity and 5 rating scale questions (yes/no) for suicidal behavior of increasing severity. The time frame is for both lifetime and the past six months for the Baseline/Screening scale and since the last visit for the Since Last Visit scale.
Measured: Screening Visit and Days 0, 1, 3, 5, 7, 14 and 30 combined
Number of Participants With Abnormal and Clinically Significant CBC and Chemistry Labs by Treatment
1. CBC
2. Chemistry (Total bilirubin, AST, ALT, GGT, ALK Phosphatase, Creatinine, BUN/Urea, Glucose, Uric Acid)
Testing was performed by study site laboratories and used institutional normal lab value ranges.
Measured: Day 3 and Early Termination Visit (approximately 3 weeks following intervention)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Dec 2014Feb 2017

First posted12 Aug 2013 (estimated)
Study startDec 2014
Primary completionJan 2017
Study completionFeb 2017

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (12)Papers the sponsor has linked to this study.
Other trials for Treatment Resistant DepressionStudies of the same condition, open and under way.
More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 99 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01920555
Sponsor's protocol ID: RAP-003
Other IDs: 271201100006I-0-27100007-1
Status last verified: May 2018
First submitted: 8 Aug 2013
Last updated: 19 Jun 2018
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

HAMILTON M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960 Feb;23(1):56-62. doi: 10.1136/jnnp.23.1.56. No abstract available.
PubMed 14399272
Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol. 1967 Dec;6(4):278-96. doi: 10.1111/j.2044-8260.1967.tb00530.x. No abstract available.
PubMed 6080235
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979 Apr;134:382-9. doi: 10.1192/bjp.134.4.382.
PubMed 444788
Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Heath, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration; 1976.
Nierenberg AA, Bentley KH, Farabaugh AH, Fava M, Deckersbach T. The absence of depressive symptoms is not the presence of wellness: validation of the Clinical Positive Affect Scale. Aust N Z J Psychiatry. 2012 Dec;46(12):1165-72. doi: 10.1177/0004867412459810. Epub 2012 Sep 18.
PubMed 22990434
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007 Jul;164(7):1035-43. doi: 10.1176/ajp.2007.164.7.1035.
PubMed 17606655
Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995 Jul;167(1):99-103. doi: 10.1192/bjp.167.1.99.
PubMed 7551619
Bremner JD, Krystal JH, Putnam FW, Southwick SM, Marmar C, Charney DS, Mazure CM. Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS). J Trauma Stress. 1998 Jan;11(1):125-36. doi: 10.1023/A:1024465317902.
PubMed 9479681
Feeney A, Hoeppner BB, Freeman MP, Flynn M, Iosifescu DV, Trivedi MH, Sanacora G, Mathew SJ, DeBattista C, Ionescu DF, Cusin C, Papakostas GI, Jha MK, Fava M. Effect of Concomitant Benzodiazepines on the Antidepressant Effects of Ketamine: Findings From the RAPID Intravenous Ketamine Study. J Clin Psychiatry. 2022 Nov 14;84(1):22m14491. doi: 10.4088/JCP.22m14491.
PubMed 36383742
Feeney A, Hock RS, Freeman MP, Flynn M, Hoeppner B, Iosifescu DV, Trivedi MH, Sanacora G, Mathew SJ, Debattista C, Ionescu DF, Fava M, Papakostas GI. The effect of single administration of intravenous ketamine augmentation on suicidal ideation in treatment-resistant unipolar depression: Results from a randomized double-blind study. Eur Neuropsychopharmacol. 2021 Aug;49:122-132. doi: 10.1016/j.euroneuro.2021.04.024. Epub 2021 Jun 3.
PubMed 34090255
Freeman MP, Hock RS, Papakostas GI, Judge H, Cusin C, Mathew SJ, Sanacora G, Iosifescu DV, DeBattista C, Trivedi MH, Fava M. Body Mass Index as a Moderator of Treatment Response to Ketamine for Major Depressive Disorder. J Clin Psychopharmacol. 2020 May/Jun;40(3):287-292. doi: 10.1097/JCP.0000000000001209.
PubMed 32332464
Fava M, Freeman MP, Flynn M, Judge H, Hoeppner BB, Cusin C, Ionescu DF, Mathew SJ, Chang LC, Iosifescu DV, Murrough J, Debattista C, Schatzberg AF, Trivedi MH, Jha MK, Sanacora G, Wilkinson ST, Papakostas GI. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry. 2020 Jul;25(7):1592-1603. doi: 10.1038/s41380-018-0256-5. Epub 2018 Oct 3.
PubMed 30283029

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 19 Jun 2018. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Double-Blind, Placebo-Controlled Trial of Ketamine Therapy in Treatment-Resistant Depression (TRD)
ClinicalTrials.gov ID: NCT01920555
Acronym / sponsor ID: RAP-003
Conditions: Treatment Resistant Depression
Keywords: Depression, Treatment Resistant Depression, Ketamine, Antidepressant, MDD, Major Depression
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 99 participants (actual)
Lead sponsor: Massachusetts General HospitalUniversity, hospital or other
Collaborators: National Institute of Mental Health (NIMH), Baylor College of Medicine, Icahn School of Medicine at Mount Sinai, Stanford University, University of Texas, Yale University
Study start: Dec 2014
Primary completion: Jan 2017 (actual)
Study completion: Feb 2017 (actual)
First posted: 12 Aug 2013 (estimated)
Results: Posted 17 Apr 2018

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 5

Arm	Type	Receives
Ketamine 0.1mg	Active comparator	Drug: KetaminePatients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion
Ketamine 0.2mg	Active comparator	Drug: KetaminePatients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion
Ketamine 0.5mg	Active comparator	Drug: KetaminePatients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion
Ketamine 1.0mg	Active comparator	Drug: KetaminePatients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion
Midazolam (Active Placebo)	Placebo comparator	Drug: Placebo MidazolamPatients in this arm will receive 0.045 mg/kg of midazolam - one single infusion

Who may qualify

Ages: 18 to 70 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (10 listed)

Male or female, 18-70 years old.
Able to read, understand, and provide written, dated informed consent prior to screening.
Diagnosed with Major Depressive Disorder (MDD), single or recurrent, and currently experiencing a Major Depressive Episode (MDE) of at least eight weeks in duration, prior to screening.
Has a history of TRD during the current MDE.
Meet the threshold on the total MADRS score of greater than or equal to 20 at both screening and baseline visits (Day -7/-28 and Day 0), as confirmed by the remote centralized MGH CTNI rater between the screen visit and the baseline visit.

Key exclusion criteria (43 listed)

Female of childbearing potential who is not willing to use one of the specified forms of birth control during the study
Female that is pregnant or breastfeeding
Female with a positive pregnancy test at screening or baseline
History during the current MDE of failure to achieve a satisfactory response to >7 treatment courses of a therapeutic dose of an antidepressant therapy of at least 8 weeks duration during the current episode
Total MADRS score of <20 at the screen or baseline visits, or as assessed by the remote, independent MGH CTNI rater and reported to the site

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
KetamineDose of Ketamine will be 0.1 mg/kg - one single infusion	Drug	Ketamine 0.1mg
KetamineDose of Ketamine will be 0.2 mg/kg - one single infusion	Drug	Ketamine 0.2mg
KetamineDose of Ketamine will be 0.5 mg/kg - one single infusion	Drug	Ketamine 0.5mg
KetamineDose of Ketamine will be 1.0 mg/kg - one single infusion	Drug	Ketamine 1.0mg
Placebo MidazolamDose of Midazolam (active placebo) will be 0.045 mg/kg - one single infusion	Drug	Midazolam (Active Placebo)

Primary outcome

Hamilton Rating Scale for Depression - 6 Items
Time frame: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1, & 3
The HAMD6 is a 6-item clinician-rated scale, where clinicians rate the presence of depression symptoms (i.e., depressed mood, guilt, work and interests, psychomotor retardation, psychic anxiety, somatic symptoms) on a 5-point scale, where 0 = not present, and 1-4 represent increasingly severe symptoms. One item (i.e., somatic symptoms) is rated on only a 3-point scale, ranging from 0-2. The possible scale range is 0-22, where higher values represent more severe depression. This instrument is completed with a structured interview guide by the clinician based on his/her assessment of the patient's symptoms. This structured interview has been validated for use with time frames shorter than one week. In this study, the HAMD6 was used to assess symptoms occurring in the past 24 hours.

9 secondary outcomes

Montgomery-Asberg Depression Rating Scale (MADRS)
Time frame: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0 and 3.
Clinical Global Impressions-Severity (CGI-S)
Time frame: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Clinical Global Impressions-Improvement (CGI-I) Scale
Time frame: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Symptoms of Depression Questionnaire (SDQ)
Time frame: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Clinical Positive Affect Scale (CPAS)
Time frame: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Snaith-Hamilton Pleasure-Scale (SHAPS)
Time frame: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Clinician-Administered Dissociative States Scale (CADSS) Scores During Infusion
Time frame: Day 0/baseline at 0, 40, 80, and 120 minutes
Number of Participants Reporting Suicidal Ideation/Behavior on the Columbia Suicide Severity Rating Scale (C-SSRS)
Time frame: Screening Visit and Days 0, 1, 3, 5, 7, 14 and 30 combined
Number of Participants With Abnormal and Clinically Significant CBC and Chemistry Labs by Treatment
Time frame: Day 3 and Early Termination Visit (approximately 3 weeks following intervention)

Results and safety

Results posted to the registry on 17 Apr 2018, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Ketamine 0.1mg	18	14
Ketamine 0.2mg	20	16
Ketamine 0.5mg	22	21
Ketamine 1.0mg	20	17
Midazolam (Active Placebo)	19	18

Primary outcome: Hamilton Rating Scale for Depression - 6 Items

Time frame: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1, & 3. Mean (Standard Deviation). Unit: units on a scale

Measure	Ketamine 0.1mg n = 18	Ketamine 0.2mg n = 20	Ketamine 0.5mg n = 22	Ketamine 1.0mg n = 20	Midazolam 0.045mg n = 19
Day 0	12.5555556 (1.8221585)	12.7500000 (2.4894514)	12.5909091 (1.4690162)	12.6315789 (2.0872770)	13.0526316 (2.2967050)
Day 1	7.5000000 (4.3204938)	9.2631579 (3.6944719)	5.8636364 (4.4859087)	6.9000000 (4.5061362)	10.6666667 (3.3606722)
Day 3	6.8000000 (4.6167397)	8.4736842 (4.9818384)	5.9047619 (4.3000554)	7.2000000 (3.8196170)	9.0555556 (4.5435439)

Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg: Mean Difference (Final Values): -3.18 (95% CI -5.93 to -0.43), p = 0.14, Mixed Models Analysis
Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg: Mean Difference (Final Values): -1.13 (95% CI -3.75 to 1.49), p = 0.79, Mixed Models Analysis
Ketamine 0.1mg vs Ketamine 0.2mg vs Ketamine 0.5mg vs Ketamine 1.0mg vs Midazolam 0.045mg: Mean Difference (Final Values): -4.79 (95% CI -7.35 to -2.24), p <0.01, Mixed Models Analysis

Population analysed: Several subjects dropped out of the study in between Day 0, Day 1 and Day 3.

9 secondary outcomes are reported in the full results.

Adverse events

Time frame: Number of patients with adverse events post infusion (treatment) up to 30 days.. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Ketamine 0.1mg	0 of 18 (0%)	17 of 18 (94.4%)	0 of 18
Ketamine 0.2mg	1 of 20 (5%)	18 of 20 (90%)	0 of 20
Ketamine 0.5mg	0 of 22 (0%)	14 of 22 (63.6%)	0 of 22
Ketamine 1.0mg	0 of 20 (0%)	17 of 20 (85%)	0 of 20
Midazolam (Active Placebo)	0 of 19 (0%)	10 of 19 (52.6%)	0 of 19

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 19 Jun 2018.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 14399272HAMILTON M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960 Feb;23(1):56-62. doi: 10.1136/jnnp.23.1.56. No abstract available.
Background: PubMed 6080235Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol. 1967 Dec;6(4):278-96. doi: 10.1111/j.2044-8260.1967.tb00530.x. No abstract available.
Background: PubMed 444788Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979 Apr;134:382-9. doi: 10.1192/bjp.134.4.382.
BackgroundGuy W, editor. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Heath, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration; 1976.
Background: PubMed 22990434Nierenberg AA, Bentley KH, Farabaugh AH, Fava M, Deckersbach T. The absence of depressive symptoms is not the presence of wellness: validation of the Clinical Positive Affect Scale. Aust N Z J Psychiatry. 2012 Dec;46(12):1165-72. doi: 10.1177/0004867412459810. Epub 2012 Sep 18.
Background: PubMed 17606655Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007 Jul;164(7):1035-43. doi: 10.1176/ajp.2007.164.7.1035.
Background: PubMed 7551619Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995 Jul;167(1):99-103. doi: 10.1192/bjp.167.1.99.
Background: PubMed 9479681Bremner JD, Krystal JH, Putnam FW, Southwick SM, Marmar C, Charney DS, Mazure CM. Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS). J Trauma Stress. 1998 Jan;11(1):125-36. doi: 10.1023/A:1024465317902.
Derived from this study: PubMed 36383742Feeney A, Hoeppner BB, Freeman MP, Flynn M, Iosifescu DV, Trivedi MH, Sanacora G, Mathew SJ, DeBattista C, Ionescu DF, Cusin C, Papakostas GI, Jha MK, Fava M. Effect of Concomitant Benzodiazepines on the Antidepressant Effects of Ketamine: Findings From the RAPID Intravenous Ketamine Study. J Clin Psychiatry. 2022 Nov 14;84(1):22m14491. doi: 10.4088/JCP.22m14491.
Derived from this study: PubMed 34090255Feeney A, Hock RS, Freeman MP, Flynn M, Hoeppner B, Iosifescu DV, Trivedi MH, Sanacora G, Mathew SJ, Debattista C, Ionescu DF, Fava M, Papakostas GI. The effect of single administration of intravenous ketamine augmentation on suicidal ideation in treatment-resistant unipolar depression: Results from a randomized double-blind study. Eur Neuropsychopharmacol. 2021 Aug;49:122-132. doi: 10.1016/j.euroneuro.2021.04.024. Epub 2021 Jun 3.
Derived from this study: PubMed 32332464Freeman MP, Hock RS, Papakostas GI, Judge H, Cusin C, Mathew SJ, Sanacora G, Iosifescu DV, DeBattista C, Trivedi MH, Fava M. Body Mass Index as a Moderator of Treatment Response to Ketamine for Major Depressive Disorder. J Clin Psychopharmacol. 2020 May/Jun;40(3):287-292. doi: 10.1097/JCP.0000000000001209.
Derived from this study: PubMed 30283029Fava M, Freeman MP, Flynn M, Judge H, Hoeppner BB, Cusin C, Ionescu DF, Mathew SJ, Chang LC, Iosifescu DV, Murrough J, Debattista C, Schatzberg AF, Trivedi MH, Jha MK, Sanacora G, Wilkinson ST, Papakostas GI. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry. 2020 Jul;25(7):1592-1603. doi: 10.1038/s41380-018-0256-5. Epub 2018 Oct 3.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Maurizio Fava, MD principal investigator

Massachusetts General Hospital

6 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ketamine in people with Treatment Resistant Depression, run by Massachusetts General Hospital at 6 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 43 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Jun 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 17 Apr 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Hamilton Rating Scale for Depression - 6 Items (time frame: A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1, & 3). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01920555, which also lists 12 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Jun 2018.