Glutamatergic Mechanisms: Aim2

Healthy Clinical Trial

Official title: Glutamatergic Mechanisms of Psychosis and Target Engagement: Aim2

Status Suspended

Clinical Trial Summary

This is a randomized, double-blind, and placebo controlled. 120 HV will be randomized to one of three ketamine arms, delivered in a bolus dose over one minute: low (0.086 mg/kg), medium (0.125 mg/kg), and high (0.23 mg/kg).

Within each ketamine arm, subjects will be randomized to 4 days of TS-134 20 mg or placebo in a 5:3 ratio (25 TS-134:15 placebo). Following an outpatient Screening Period (up to 31 days), eligible subjects will undergo an up to 5-day inpatient Treatment Period. During the study, each subject will undergo a total of two ketamine sessions: a first session during the Screening Period and a second session on Day 4 of the Treatment Period, conducted at least 7 days apart. All randomized subjects will be dosed with TS-134 or placebo daily in a fed state for 4 days during the study, titrated to 20 mg over the first 2 days.

Clinical Trial 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 and a parallel industry sponsored project, 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 structure of the R01 grant funding this protocol was split into three studies, specific aim (SA) 1, 2 and 3. In FAST-PS, a high dose of ketamine (0.23 mg/kg) was used in order to produce robust pharmacological effects.

Under SA1, which was conducted under IRB 8063, this dose was titrated downward in across two phBOLD sessions in HV in order to determine the lowest dose of ketamine that still produces a phBOLD response of Cohen's d≥1.5, hypothesizing that this dose would provide the best signal to noise for use in SA2. The study was conducted in groups of 10 subject per dose cohort, and the analysis supports using a low dose of 0.086 mg/kg for SA2.

SA2 experiments are modeled after our preliminary TS-134 studies. SA2 will be randomized, double-blind, and placebo controlled. 120 HV will be randomized to one of three ketamine arms: low, medium, and high. Based on SA1, the low dose will be 0.086 mg/kg. The medium dose, 0.125 mg/kg, is based the previously published mGluR2/3 target engagement study and the high dose is equal to 0.23 mg/kg, the same as in the FAST-PS study.

Within each ketamine arm, subjects will be randomized to 4 days of TS-134 20 mg or placebo in a 5:3 ratio (25 TS-134:15 placebo). Following an outpatient Screening Period (up to 31 days), eligible subjects will undergo an up to 5-day inpatient Treatment Period. During the study, each subject will undergo a total of two ketamine sessions: a first session during the Screening Period and a second session on Day 4 of the Treatment Period, conducted at least 7 days apart. All randomized subjects will be dosed with TS-134 or placebo daily in a fed state for 4 days during the study, titrated to 20 mg over the first 2 days. As before, subjects' general health and safety status will be confirmed by a phone call following discharge from the Treatment Period. Primary outcomes will be (1) suppression of the phBOLD response and (2) psychiatric symptoms after 4 days of TS-134, relative to ketamine screening session effects.

In parallel, we will evaluate sLASER MRS to interrogate the glutamate system . These additional measures will be collected at baseline, pre ketamine.

For up to the 1st 20 subjects, we will not randomize to low dose, and subjects will only receive either high or medium dose. ;

Related Conditions & MeSH terms

• Healthy

• NCT number: NCT05401227
• Study type: Interventional
• Source: New York State Psychiatric Institute
• Status: Suspended
• Phase: Phase 1
• Start date: October 15, 2022
• Completion date: August 15, 2026