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Glutamatergic Mechanisms of Psychosis and Target Engagement (SA1)

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ClinicalTrials.gov Identifier: NCT04589208
Recruitment Status : Recruiting
First Posted : October 19, 2020
Last Update Posted : January 25, 2021
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Joshua Kantrowitz, New York State Psychiatric Institute

Tracking Information
First Submitted Date  ICMJE October 13, 2020
First Posted Date  ICMJE October 19, 2020
Last Update Posted Date January 25, 2021
Actual Study Start Date  ICMJE January 1, 2021
Estimated Primary Completion Date December 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 14, 2020)
  • PhBOLD [ Time Frame: Compare within day changes in phBOLD in response to infusion of ketamine, as measured by resting state fMRI. Calculated by post-pre changes, with higher values indicating higher response. Two scans will be completed, 7 days apart ]
    Pharmacological Blood-oxygen-level Dependent (phBOLD) Response to ketamine
  • Brief Psychiatric Rating Scale (BPRS) [ Time Frame: Compare within day changes in BPRS in response to infusion of ketamine, as measured by the clinical scale. Calculated by post-pre changes, with higher values indicating higher response. Two scans will be completed, 7 days apart ]
    Clinical rating scale assessing common psychiatric symptoms
Original Primary Outcome Measures  ICMJE
 (submitted: October 13, 2020)
  • PhBOLD [ Time Frame: Compare changes in phBOLD in response to infusion of ketamine, as measured by resting state fMRI. Calculated by post-pre changes, with higher values indicating higher response. Two scans will be completed, 7 days apart ]
    Pharmacological Blood-oxygen-level Dependent (phBOLD) Response to ketamine
  • Brief Psychiatric Rating Scale (BPRS) [ Time Frame: Compare changes in BPRS in response to infusion of ketamine, as measured by the clinical scale. Calculated by post-pre changes, with higher values indicating higher response. Two scans will be completed, 7 days apart ]
    Clinical rating scale assessing common psychiatric symptoms
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Glutamatergic Mechanisms of Psychosis and Target Engagement (SA1)
Official Title  ICMJE Glutamatergic Mechanisms of Psychosis and Target Engagement (SA1)
Brief Summary

50 healthy volunteers (HV) will participate in 2 identical ketamine-induced pharmacoBOLD (phBOLD) sessions at least 7 days apart. On both days, clinical assessments will be performed following removal of the subject from the scanner.

HV will be discharged home after clearance by the study physician. This study will assign ketamine doses in successive 10 subject cohorts. The ketamine dose for the 1st cohort will start at 0.08 mg/kg. For subsequent cohorts, the bolus will be successively reduced or increased by 0.02 mg/kg (n=10/dose) to determine the lowest dose of ketamine that still produces a robust phBOLD response.

The study will be subject and rater blind, i.e. subjects and raters, will be blinded to the treatment (ketamine dose) group.

The study physician will be aware of the ketamine dose, and ketamine dose will be the same for both sessions.

Subjects will not be told what the exact ketamine dose they will receive, but it will be based on their weight and will be no higher than 0.08 mg/kg.

Detailed Description

Schizophrenia (Sz) is associated with psychotic symptoms, such as hearing voices and paranoid beliefs that remain partially or fully refractory to standard antipsychotic medications for ~2/3 of patients. Alternative, glutamatergic approaches for treatment development have been proposed but have not yet led to FDA-approved medications. Moreover, several glutamate-targeted medications, such as pomaglumetad (POMA), have failed in pivotal clinical trials despite robust effectiveness in preclinical models. A major barrier to effective glutamatergic treatment development is the absence of validated measures for target engagement that can identify effective compounds and guide dose selection. Target" refers to a factor that an intervention is intended to modify, leading to improvement in symptoms, and target engagement biomarkers are a measure of the ability of the intervention to "engage" the target.

As part of the recently completed NIMH multicenter FAST-PS initiative (IRB protocol 6925 and 7285), we evaluated ketamine-induced pharmacoBOLD (phBOLD) in healthy volunteers (HV) as a potential target engagement biomarker for development of metabotropic glutamate (mGluR2/3) agonists, as a prelude to planned studies in Sz. BOLD imaging indirectly measures brain energy, as a proxy for glutamate target engagement.

The present study will (1) build on these initial positive results to develop phBOLD for use in Sz, (2) optimize ketamine dosing to further increase sensitivity of the phBOLD approach, and (3) explore mechanisms of psychosis. The present study will enable a personalized medicine approach to target engagement and dose evaluation in Sz, while, in parallel, evaluating mechanisms in Sz.

The structure of this grant requires successful completion of Specific Aim (SA) 1 over the first 18 months prior to initiation of SA2 and SA3. We will amend the PSF and consent to include a full description of SA's 2 and 3 prior to its initiation.

In FAST-PS, we selected a high dose of ketamine (0.23 mg/kg) in order to produce robust pharmacological effects. Under SA1, we will titrate this dose downward in HV in order to identify doses that produce reduced psychotomimetic effects, but nevertheless sufficiently robust phBOLD effects.

50 HV will participate in 2 identical phBOLD sessions at least 7 days apart. In total, MRI scans will last approximately 45 minutes, including pre and post ketamine scan. The design is based on our published study(Javitt, Carter et al. 2018). On both days, clinical assessments will be performed following removal of the subject from the scanner.

HV will be discharged home after clearance by the study physician. Although we expect all HV to tolerate ketamine challenge, in the case that a subject does not tolerate it well, we have the capability of admitting a HV subject to an inpatient unit for monitoring and treatment if necessary.

SA1 will assign ketamine doses in successive 10 subject cohorts. The ketamine dose for the 1st cohort will start at 0.08 mg/kg. For subsequent cohorts, the bolus will be successively reduced or increased by 0.02 mg/kg (n=10/dose) to determine the lowest dose of ketamine that still produces a robust phBOLD response.

The study will be subject and rater blind, i.e. subjects and raters, will be blinded to the treatment (ketamine dose) group.

The study physician will be aware of the ketamine dose, and ketamine dose will be the same for both sessions.

Subjects will not be told what the exact ketamine dose they will receive, but it will be based on their weight and will be no higher than 0.08 mg/kg.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description:
Single blind (rater, participant will be unaware of dose). Subjects will be assigned ketamine doses in 10 subject cohorts
Masking: None (Open Label)
Masking Description:

The study will be subject and rater blind, i.e. subjects and raters, will be blinded to the treatment (ketamine dose) group.

The study physician will be aware of the ketamine dose, and ketamine dose will be the same for both sessions.

Subjects will not be told what the exact ketamine dose they will receive, but it will be based on their weight and will be no higher than 0.08 mg/kg.

Primary Purpose: Other
Condition  ICMJE Healthy
Intervention  ICMJE Drug: Ketamine Hydrochloride
We will assign ketamine doses in successive 10 subject cohorts. The ketamine dose for the 1st cohort will start at 0.08 mg/kg. For subsequent cohorts, the bolus will be successively reduced or increased by 0.02 mg/kg (n=10/dose) to determine the lowest dose of ketamine that still produces a robust phBOLD response
Study Arms  ICMJE Experimental: Ketamine
ketamine
Intervention: Drug: Ketamine Hydrochloride
Publications * Not Provided

*   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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 13, 2020)
50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 1, 2023
Estimated Primary Completion Date December 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Age between 18-55
  2. Medically healthy, as assessed by study physician
  3. Capable of understanding the study procedures and able to provide informed consent
  4. Eligible men and women must agree to use a reliable method of birth control (for example, use of oral contraceptives or Norplant; a reliable barrier method of birth control diaphragms with contraceptive jelly; cervical caps with contraceptive jelly; condoms with contraceptive foam; intrauterine devices; partner with vasectomy; or abstinence) during the study. Women who are post-menopausal or otherwise not of childbearing potential are also eligible.

Exclusion Criteria:

  1. Current or past Axis I psychiatric history (including Substance Use Disorder/Alcohol Use Disorder, with the exception of nicotine use disorder)
  2. Positive urine toxicology
  3. History of recreational ketamine use, recreational PCP use, or an adverse reaction to ketamine. Subjects who have participated in prior research ketamine studies will be eligible. Subjects can have infusions not more frequently than biweekly, and not more than 1/month on average, therefore subjects entering the study will need to wait one month if they had a single infusion and 6 weeks if they have had two closely spaced infusions.
  4. History of first-degree relative with schizophrenia
  5. Pregnancy or breast-feeding. This exclusion criterion applies only to females of child-bearing potential (not surgically sterilized and between menarche and 1 year postmenopausal). Must test negative for pregnancy at the time of screening based on a serum pregnancy test.
  6. History of violence, including any history of using a gun, knife, or other weapon with intent to harm someone, as well as a more than one physical fight without a weapon after the age of 18 years old (not including fights that happen during sports competition).
  7. Presence or positive history of significant medical illness, including renal problems (GFR<60), high blood pressure (defined as systolic blood pressure (SBP) > 140 or diastolic blood pressure (DBP) > 90), low blood pressure (SBP < 100, DBP < 60), orthostatic blood pressure at baseline (change in mean arterial pressure [1/3 systolic + 2/3 diastolic] of > 20%), cardiac illness, or clinically significant abnormal screening labs, as determined by the site physician.
  8. Subjects with suicidal ideation with intent or plan (indicated by affirmative answers to items 4 or 5 of the Suicidal Ideation section of the baseline C-SSRS) in the 6 months prior to screening or subjects who represent a significant risk of suicide in the opinion of the investigator.
  9. Presence or positive history of neurological illness, including seizures, mental retardation or any other disease/procedure/accident/intervention associated with significant injury to or malfunction of the central nervous system (CNS), or history of significant head injury.
  10. Metal implants, pacemaker, other metal (e.g., shrapnel or surgical prostheses) or paramagnetic objects contained within the body which may present a risk to the subject or interfere with the MR scan.
  11. Medicinal patch, unless removed prior to the MR scan
  12. Claustrophobia
  13. Currently taking any psychotropic medication, including antidepressant medications, benzodiazepines, antipsychotic medications, mood stabilizers, anti-epileptic medications, and stimulants. We will exclude any subject who requires treatment with any psychotropic medication from one of these classes.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Marlene Carlson 6467748436 Marlene.Carlson@nyspi.columbia.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04589208
Other Study ID Numbers  ICMJE 8063
R01MH123142-01A1 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: NIMH Data Archive:
Supporting Materials: Study Protocol
Time Frame: after publication
Access Criteria: Qualified reseaerchers
URL: https://nda.nih.gov/
Responsible Party Joshua Kantrowitz, New York State Psychiatric Institute
Study Sponsor  ICMJE New York State Psychiatric Institute
Collaborators  ICMJE National Institute of Mental Health (NIMH)
Investigators  ICMJE Not Provided
PRS Account New York State Psychiatric Institute
Verification Date January 2021

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