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Intramuscular Ketamine Versus Aripiprazole and Escitalopram in the Treatment of Resistant Depression (KETProject)

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ClinicalTrials.gov Identifier: NCT04234776
Recruitment Status : Enrolling by invitation
First Posted : January 21, 2020
Last Update Posted : January 21, 2020
Sponsor:
Information provided by (Responsible Party):
Ricardo Alberto Moreno, M.D., Ph.D., University of Sao Paulo

Tracking Information
First Submitted Date  ICMJE October 7, 2019
First Posted Date  ICMJE January 21, 2020
Last Update Posted Date January 21, 2020
Actual Study Start Date  ICMJE April 3, 2018
Estimated Primary Completion Date June 3, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 15, 2020)
  • Change in depressive symptoms [ Time Frame: 3 times a week in once month (Phase II) ]
    Montomery-Åsberg Depression Rating Scale ([0-60] higher scores: worse outcome). No improvement: MADRS ≤ 25% Partial response: MADRS ≥ 25% and < 50% Response: MADRS ≥ 50% Remission: MADRS ≤10
  • Change in depressive symptoms [ Time Frame: Once a week in six months (Phase III) ]
    Montgomery-Åsberg Depression Rating Scale ([0-60] higher scores: worse outcome). Recovery: Maintenance ≥ 6-8 months Relapse: Full return of symptoms once remission has occurred or worsening ≤ 75% with lower percentage of improvement (HAM-D inclusion criteria)
  • Change in depressive symptoms [ Time Frame: Once a week in once month (Phase IV) ]
    Montgomery-Åsberg Depression Rating Scale ([0-60] higher scores: worse outcome). Relapse: Full return of symptoms once remission has occurred or worsening ≤ 75% with lower percentage of improvement (HAM-D inclusion criteria).
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: January 15, 2020)
  • Depression symptoms [ Time Frame: Through study completion, an average of 1 year. ]
    Hamiltom Depression Ratins Scale (HAM-D [0-50] higher scores: worse outcome).
  • Clinical impressions-S [ Time Frame: Through study completion, an average of 1 year. ]
    Clinical Global Impression Scale (CGI [0-7] higher scores: worse outcome).
  • Clinical impressions-I [ Time Frame: Through study completion, an average of 1 year. ]
    Clinical Global Impression Scale (CGI [0-7] higher scores: worse outcome).
  • Electrocardiographic monitoring [ Time Frame: 3 times a week in once month (Fase II) and once a week in six months (Phase III) ]
    P wave, PR interval, QRS complex, J-point, ST segment, T wave, Corrected QT interval and U wave Rhythm (irregular rhythm: worse outcome).
  • Blood Pressure (BP [mmHg]). [ Time Frame: 3 times a week in once month (Fase II) and once a week in six months (Phase III) ]
    BP low <90/60 (systolic/diastolic) mmHg and high >140/90 mmHg ( (systolic/diastolic).
  • Heart rate (HR [bpm]). [ Time Frame: 3 times a week in once month (Fase II) and once a week in six months (Phase III) ]
    Anormal HR <60 bpm or >100 bpm.
  • Digital pulse oximetry (%). [ Time Frame: 3 times a week in once month (Fase II) and once a week in six months (Phase III) ]
    Low oxygen saturation <95%.
  • Respiratory rate (RR [cycles/min]) [ Time Frame: 3 times a week in once month (Fase II) and once a week in six months (Phase III) ]
    Anormal RR <10 cycles/min or >20 cycles/min.
  • Suicide risk 1 [ Time Frame: Through study completion, an average of 1 year. ]
    Montgomery-Åsberg Depression Rating Scale (item 10 [0-6] higher scores: worse outcome).
  • Suicide risk 2 [ Time Frame: Through study completion, an average of 1 year. ]
    Hamilton Depression Rating Scale (item 3 [0-4] higher scores: worse outcome).
  • General side effects [ Time Frame: 3 times a week in once month (Phase II) and once a week in six months (Phase III) ]
    Ugvalg for Kliniske Undersgelser-Side Effect Rating Scale (UKU-SERS [48 specific symptoms).
  • Hypo/maniac symptoms [ Time Frame: 3 times a week in once month (Phase II) and once a week in six months (Phase III) ]
    Young Mania Rating Scale (YOUNG [0-58] higher scores: worse outcome).
  • Dissociative symptoms [ Time Frame: 3 times a week in once month (Phase II) and once a week in six months (Phase III) ]
    Clinician-Administered Dissociative State Scale (CADSS [0-108] higher scores: worse outcome)
  • Psychotic symptoms [ Time Frame: 3 times a week in once month (Phase II) and once a week in six months (Phase III) ]
    Brief Psychiatric Rating Scale (item 12 [0-6] higher scores: worse outcome).
  • Depression thoughts [ Time Frame: Through study completion, an average of 1 year. ]
    Depression Thoughts Scale (EPD [1-78] higher scores: worse outcome)
  • Stimate intelligence quocient [ Time Frame: Through study completion, an average of 1 year. ]
    Wechsler Abreviated Scale of Intelligence (WASI [70-160 percentille] higher scores: better outcomes).
  • Intelligence quocient [ Time Frame: Through study completion, an average of 1 year. ]
    Wechsler Scale of Intelligence (WAIS III [70-155 percentille] higher scores: better outcomes).
  • Attention [ Time Frame: Through study completion, an average of 1 year. ]
    Trial Making Test (5-95 percentille, higher scores: better outcomes).
  • Memory [ Time Frame: Through study completion, an average of 1 year. ]
    Rey figures (10-100 percentille, higher scores: better outcomes)
  • Executive functions 1 [ Time Frame: Through study completion, an average of 1 year. ]
    Wisconsin Test (50->80 score, higher scores: better outcomes).
  • Executive functions 2 [ Time Frame: Through study completion, an average of 1 year. ]
    Stroop Color Word Test (5-95 percentille, higher scores: better outcomes)
  • Verbal fluency 1 [ Time Frame: Through study completion, an average of 1 year. ]
    Verbal Fluency Test (FAS [10-90 percentille], higher scores: better outcomes))
  • Verbal fluency 2 [ Time Frame: Through study completion, an average of 1 year. ]
    The Rey Auditory-Verbal Learning Test (RAVLT [5-95 percentille], higher scores: better outcomes).
  • Functional recovery 1 [ Time Frame: Through study completion, an average of 1 year. ]
    World Health Organization Quality of Life (WHOQOL-brief [4 domains, 26 questions higher scores: better outcome]).
  • Functional recovery 2 [ Time Frame: Through study completion, an average of 1 year. ]
    Sheehan Disability Scale (SDS [0-30] higher scores: worse outcome).
  • Body Mass Index (BMI) [ Time Frame: Through study completion, an average of 1 year. ]
    Weight and height (kg/m2).
  • Clinical and psychiatric features 1 [ Time Frame: Through study completion, an average of 1 year. ]
    Disease intensity (HAM-D [% of patients], moderate or severe)
  • Clinical and psychiatric features 2 [ Time Frame: Through study completion, an average of 1 year. ]
    Number of episodes (questionnaire [incidence])
  • Clinical and psychiatric features 3 [ Time Frame: Through study completion, an average of 1 year. ]
    Current episode duration (questionnaire [years])
  • Clinical and psychiatric features 4 [ Time Frame: Through study completion, an average of 1 year. ]
    Suicide attempts (questionnaire [% of pacients])
  • Clinical and psychiatric features 5 [ Time Frame: Through study completion, an average of 1 year. ]
    History of physical abuse (questionnaire [% of pacients])
  • Clinical and psychiatric features 6 [ Time Frame: Through study completion, an average of 1 year. ]
    History of sexual abuse (questionnaire [% of pacients])
  • Clinical and psychiatric features 7 [ Time Frame: Through study completion, an average of 1 year. ]
    Psychiatric hospitalizations (questionnaire [% of pacients])
  • Clinical and psychiatric features 8 [ Time Frame: Through study completion, an average of 1 year. ]
    Clinical comorbidities (questionnaire [% of patients]).
  • Clinical and psychiatric features 9 [ Time Frame: Through study completion, an average of 1 year. ]
    Family history of depression (questionnaire [% of patients])
  • Clinical and psychiatric features 10 [ Time Frame: Through study completion, an average of 1 year. ]
    Family history of bipolar disorders (questionnaire [% of patients)
  • Clinical and psychiatric features 11 [ Time Frame: Through study completion, an average of 1 year. ]
    Family history of other mental disorders (questionnaire [% of patients]).
  • Epidemiological features 1 [ Time Frame: Through study completion, an average of 1 year. ]
    Age (questionnaire [years]).
  • Epidemiological features 2 [ Time Frame: Through study completion, an average of 1 year. ]
    Gender (questionnaire [% of patients]; male/female)
  • Epidemiological features 3 [ Time Frame: Through study completion, an average of 1 year. ]
    Marital status (questionnaire [% of patients] single, married, separated, divorced or widower).
  • Epidemiological features 4 [ Time Frame: Through study completion, an average of 1 year. ]
    Ethnicity (questionnaire [% of patients])
  • Epidemiological features 5 [ Time Frame: Through study completion, an average of 1 year. ]
    Religion (questionnaire [% of patients] protestant, pentecostal or neopentecostal, spiritism, afro-brazilian, no religion or atheism and others]).
  • Epidemiological features 6 [ Time Frame: Through study completion, an average of 1 year. ]
    Occupation (questionnaire [% of patients])
  • Epidemiological features 7 [ Time Frame: Through study completion, an average of 1 year. ]
    Education (questionnaire [years])
  • Epidemiological features 8 [ Time Frame: Through study completion, an average of 1 year. ]
    Individual income (questionnaire [dollars]).
  • Epidemiological features 9 [ Time Frame: Through study completion, an average of 1 year. ]
    Family income (questionnaire [dollars]).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Intramuscular Ketamine Versus Aripiprazole and Escitalopram in the Treatment of Resistant Depression
Official Title  ICMJE Intramuscular Ketamine Versus Escitalopram and Aripiprazole in Acute and Maintenance Treatment of Patients With Treatment-resistant Depression
Brief Summary The treatment of resistant depression should be optimized aiming at complete remission of symptoms, a complex condition due to several factors. Approximately 1/3 of patients with depressive disorders do not even respond to available antidepressants. Consequently, new molecules with robust action, fast effects and sustained improvement are currently being researched worldwide. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has emerged as a promising alternative due to its involvement in neurogenesis, synaptogenesis and consequent rapid improvement of depressive and suicidal symptoms with traditional intravenous (IV) use in sub dose (0.5 mg / kg). The therapeutic response of IV use has been short and requires monitoring in a hospital setting. There are no studies evaluating response to long-term ketamine use. Recent research has focused on identifying other routes of ketamine use such as intranasal and intramuscular (IM). The use of ketamine IM, despite the fact that there are few studies and small samples, can demonstrate efficacy in acute treatment and maintenance of depression, as well as low profile of side effects, greater accessibility potential, reduced costs and risks, patient comfort and possible expansion of resistant depression treatment capabilities in different settings.
Detailed Description Compare the response of ketamine IM versus active control in treatment-resistant depression (TRD [primary outcome]) and find safety and tolerability of ketamine IM, evaluate changes in life quality, cognition and suicidal risk (secondary outcomes)
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Subjects will receive IM ketamine or IM saline applications as randomized. Applications will occur three times a week. It will be 4 weeks of IM application (12 initial applications). Injections will occur into the subjects' glutes (0.75 mg / kg). The ketamine group will use 2 placebo tablets and the parallel group escitalopram 15 mg and aripiprazole 5 mg. Thereafter, participants will receive weekly ketamine doses over 6 months as maintenance treatment. Research members will be submitted to Structured Clinical Interview for the DSM for diagnostic categorization and will be evaluated from other scales. Vital signs will be checked continuously for a period of 2 hours with each infusion. Patients will be observed in a quiet, comfortable room and subjected to medical monitoring for 2 hours. They will leave the environment in the company of a competent adult.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Depressive Disorder
Intervention  ICMJE
  • Drug: Ketamine
    (0,75 mg/kg) saline solution (15 mg) Escitalopram (5 mg) Aripiprazole
    Other Names:
    • Active comparator (escitalopram plus aripiprazole)
    • Placebo
  • Diagnostic Test: Cognition
    Composite tools
  • Other: Suicide risk
    MADRS (10) and HAM-D (3)
  • Other: Depression thoughts
    EPD
  • Other: Quality of life and disability
    Quality of life and disability
  • Other: Clinical and epidemiological factors
    Variables and categories
  • Device: Safety of ketamine IM
    Vital signs
  • Other: Tolerability of ketamine IM
    UKU-SERS, YOUNG, CADSS and BPRS-12.
Study Arms  ICMJE
  • Experimental: Rapid-acting antidepressant
    Subjects eligible to participate in the study will receive IM ketamine and will use 2 placebo tablets as randomized.
    Interventions:
    • Drug: Ketamine
    • Diagnostic Test: Cognition
    • Other: Suicide risk
    • Other: Depression thoughts
    • Other: Quality of life and disability
    • Other: Clinical and epidemiological factors
    • Device: Safety of ketamine IM
    • Other: Tolerability of ketamine IM
  • Active Comparator: Comparator
    Subjects eligible to participate in the study will receive IM saline and will use escitalopram 15 mg and aripiprazole 5 mg as randomized
    Interventions:
    • Drug: Ketamine
    • Diagnostic Test: Cognition
    • Other: Suicide risk
    • Other: Depression thoughts
    • Other: Quality of life and disability
    • Other: Clinical and epidemiological factors
    • Device: Safety of ketamine IM
    • Other: Tolerability of ketamine IM
Publications *

*   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 Enrolling by invitation
Estimated Enrollment  ICMJE
 (submitted: January 15, 2020)
88
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 3, 2021
Estimated Primary Completion Date June 3, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Diagnosis of TRD, according to clinical evaluation and confirmed by SCID-IV (Structured Clinical Interview for the DSM);
  2. Moderate to severe intensity of the disease;
  3. Female patients in fertile conditions should be using a clinically accepted contraceptive method (oral contraceptive and/or condom);

    a. Blood test will be requested at the diagnostic stage and in case of clinical doubt as to the patient's gestational status,

  4. Literate and able to understand the tasks requested;
  5. With clinical comorbidities, however compensated;
  6. Patients and/or legal representatives should understand the nature of the study and sign the Informed Consent Form.

Exclusion Criteria:

  1. Imminent risk of suicide;
  2. Patients with psychoactive substance dependence;
  3. Intellectual deficit and psychotic symptoms;
  4. Bipolar spectrum disorders and other primary psychiatric diagnoses;
  5. Allergic to ketamine;
  6. Glaucoma;
  7. Treatment with reversible MAOI (monoamine oxidase inhibitor) in the week prior to visit 0;
  8. Treatment with irreversible MAOI in two weeks prior to visit 0;
  9. Fluoxetine treatment within 4 weeks prior to visit 0;
  10. Treatment with others antidepressants;
  11. Treatment with antipsychotics, lithium, benzodiazepines or other psychotropic drugs within 7 days prior to visit 0;

    a. Lorazepam and zolpidem may be used;

  12. Patients who become pregnant will be excluded from the study and referred for obstetric care.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 40 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Brazil
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04234776
Other Study ID Numbers  ICMJE rampty2805
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Ricardo Alberto Moreno, M.D., Ph.D., University of Sao Paulo
Study Sponsor  ICMJE University of Sao Paulo
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Ricardo A Moreno, MD, PhD Department and Institute of Psychiatry, University of Sao Paulo
PRS Account University of Sao Paulo
Verification Date December 2019

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