A Randomized, Double-blind, Placebo-Controlled, 3-Period Crossover Study Followed by 1 Open-label Comparator Period to Evaluate Central Pharmacodynamic Activity of TAK-653 in Healthy Volunteers Using Transcranial Magnetic Stimulation

TAK-653 is an alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)
type glutamate receptor positive allosteric modulator in clinical development
as a potential therapeutic for patients with treatment-resistant depression.
The TRD field has recently been rejuvenated by the finding that ketamine, an
N-methyl-d-aspartate (NMDA) glutamate receptor open channel blocker, has
rapid-onset antidepressant properties in the TRD population and in rodent
models of depression (eg, reduction of submissive behavior model). The
rationale for an AMPA receptor potentiator to treat TRD follows from the
observation that the antidepressant actions of ketamine in rodents are blocked
with the coadministration of the AMPA receptor blocker NBQX. In addition,
ketamine administration causes an increase in extracellular cortical glutamate,
which can act on downstream AMPA receptors.A current hypothesis on the
mechanisms of the rapid-acting antidepressant effect of ketamine posits that
increased AMPA receptor function is a key element in this mechanism. Taken
together, these data suggest that by directly potentiating AMPA receptors,
TAK-653 may act as a rapid onset antidepressant without the psychotomimetic
side effects associated with ketamine administration. TMS is a noninvasive
neurostimulation method. Noninvasive brain stimulation techniques like TMS
offer an opportunity to study mechanisms of cortical physiology at the systems
level of the human brain [2]. The combination of brain stimulation with
CNS-active drugs might help assessing the effects of these drugs on brain
physiology. Combined with electroencephalography (EEG) and/or electromyography
(EMG), both cortical excitability and the modulatory effects of CNS-penetrant
drugs can be quantified. Given the absence of evidence for human target
engagement or PD activity of TAK-653, the goal
of this study is to leverage a translatable preclinical finding to assess PD
activity in healthy subjects. Of specific interest is to determine whether low
doses of TAK-653 modulate CNS activity. Based on these data, the study
described herein will determine if doses and exposures of TAK-653 correlate
with PD effects in TMS-evoked muscle evoked potentials and EEG signals.

The primary objective of the study is to determine whether TAK-653, in
comparison to placebo, increases CNS excitability, assessed with TMS-evoked MEP
in healthy subjects.
Next to that, the study has the following goals:
- To determine whether TAK-653, in comparison to placebo, modulates responses
evoked with paired TMS pulses that capture intracortical circuitry modulation.
- To determine whether ketamine increases CNS excitability assessed with
TMS-evoked MEP in healthy subjects.
- To determine the safety and tolerability of TAK-653 when administered as
single dose in healthy subjects assessing responses evoked by TMS.

A randomized, double blind, placebo-controlled, 3-period cross-over study
followed by one open label comparator period. The study will include 4
treatment periods, treatment period 1, 2 and 3 are 1 day in duration, period 4
is 2 days in duration, alternating with 3 washout periods of at least 10 days
(not to exceed 15 days).

Test:
TAK-653 0.5 mg
TAK-653 6 mg
Matching placebo

Open label periode:
Ketamine 0.5 mg/kg

This phase 1 trial has been designed to mitigate the known risks associated
with AMPA receptor potentiators as a class and the potential risks based on the
nonclinical toxicity data and preliminaryclinical data for TAK-653. In
addition, this trial has been designed to mitigate the known clinical
risks of ketamine. As this trial will be conducted in healthy subjects, there
is no expected clinical benefit to trial participants. The principal
mitigations for these potential risks include the maintenance of an appropriate
safety margin based on nonclinical study use of low doses that yield low drug
exposure, appropriate selection of the trial population, the prespecified
safety monitoring procedures, and the selection of the trial facility, where
close monitoring can be performed and rapid institution of appropriate care can
be given. The potential risks associated with AMPA receptor potentiators as a
class, the potential risk based on nonclinical toxicity data, and the known
clinical risks of ketamine can be monitored clinically and/or with laboratory
tests and have been considered when determining the stopping rules for this
clinical trial. In addition to the potential risks associated with study drug
administration, there is minimal risk associated with trial procedures
including scheduled, periodic phlebotomy (limited to <500 mL) and noninvasive
procedures including vital sign assessments, electrocardiograms (ECGs), and TMS
assessment. Overall, the benefit-risk profile is considered appropriate for
this trial.