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

NCT01920555 | Completed Phase 2 Results DMC

• 2 other identifiers: RAP-003271201100006I-0-27100007-1
• Study Type: interventional
• Target: 99
• Locations: 1 country
• Sites: 6

Brief 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.

Conditions

Treatment Resistant Depression

Keywords

Depression; Treatment Resistant Depression; Ketamine; Antidepressant; MDD; Major Depression

Outcome Measures

Primary Outcomes (1)

• 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.

  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)

  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)

  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

  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)

  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)

  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

Study Arms (5)

Ketamine 0.1mg

ACTIVE COMPARATOR

Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion

Drug: Ketamine

Ketamine 0.2mg

ACTIVE COMPARATOR

Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion

Drug: Ketamine

Ketamine 0.5mg

ACTIVE COMPARATOR

Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion

Drug: Ketamine

Ketamine 1.0mg

ACTIVE COMPARATOR

Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion

Drug: Ketamine

Midazolam (Active Placebo)

PLACEBO COMPARATOR

Patients in this arm will receive 0.045 mg/kg of midazolam - one single infusion

Drug: Placebo Midazolam

Interventions

Ketamine DRUG

Dose of Ketamine will be 0.1 mg/kg - one single infusion

Ketamine 0.1mg

Placebo Midazolam DRUG

Dose of Midazolam (active placebo) will be 0.045 mg/kg - one single infusion

Midazolam (Active Placebo)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• National Institute of Mental Health (NIMH): collaborator
• Baylor College of Medicine: collaborator
• Icahn School of Medicine at Mount Sinai: collaborator
• Stanford University: collaborator
• University of Texas: collaborator
• Yale University: collaborator

Study Sites (6)

Stanford University

Palo Alto, California, 94304, United States

Location

Yale University

New Haven, Connecticut, 06520, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Mount Sinai School of Medicine

New York, New York, 10029, United States

Location

University of Texas Southwestern

Dallas, Texas, 75390, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Related Publications (12)

• 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.

  PMID: 14399272 BACKGROUND

• 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.

  PMID: 6080235 BACKGROUND

• 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.

  PMID: 444788 BACKGROUND

• 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.

  BACKGROUND

• 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.

  PMID: 22990434 BACKGROUND

• 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.

  PMID: 17606655 BACKGROUND

• 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.

  PMID: 7551619 BACKGROUND

• 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.

  PMID: 9479681 BACKGROUND

• 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.

  PMID: 36383742 DERIVED

• 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.

  PMID: 34090255 DERIVED

• 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.

  PMID: 32332464 DERIVED

• 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.

  PMID: 30283029 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant; Depression; Depressive Disorder, Major

Interventions

Ketamine

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Results Point of Contact

• Title: Maurizio Fava, MD
• Organization: Massachusetts General Hospital

MFAVA@mgh.harvard.edu

617-724-2513

Study Officials

• Maurizio Fava, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Overall Principal Investigator

Study Record Dates

• First Submitted: August 8, 2013
• First Posted: August 12, 2013
• Study Start: December 1, 2014
• Primary Completion: January 1, 2017
• Study Completion: February 1, 2017
• Last Updated: June 19, 2018
• Results First Posted: April 17, 2018

Record last verified: 2018-05

Locations

US (6)