A Study to Evaluate Central Nervous System (CNS) Pharmacodynamic Activity of TAK-653 in Healthy Participants Using Transcranial Magnetic Stimulation (TMS)

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

The primary purpose of this study is to determine whether TAK-653, in comparison to placebo, increases CNS excitability, assessed with TMS-evoked motor-evoked potential (MEP) in healthy participants.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: TAK-653; Drug: Placebo; Drug: Ketamine

Detailed Description

The drug being tested in this study is called TAK-653. This study is designed to evaluate the central pharmacodynamic activity of TAK-653 using TMS. The study will enroll approximately 24 participants to yield 22 participants that complete treatment periods 1, 2, and 3. Participants will be randomly assigned to 1 of the 6 sequences to receive TAK-653 0.5 mg low dose or TAK-653 6 mg high dose or Placebo in double-blind treatment periods 1, 2, and 3, followed by Ketamine 0.5 mg/kg in open-label Treatment period 4.

All participants will receive one dose of TAK-653 (0.5 or 6 mg), or Placebo or Ketamine on Day 1 of each treatment period.

This single center trial will be conducted in the Netherlands. The overall time to participate in this study is 15 weeks. Participants will make 5 visits to the clinic. A washout period of minimum 10 days will be maintained between the doses in treatment periods 1 to 3. Follow-up phone call will be made on Day 14.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Leiden, Netherlands
    • CHDR

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Must be judged to be in good health by the investigator, based on clinical evaluations including laboratory safety tests, medical history, physical examination, 12-lead electrocardiogram (ECG), and vital sign measurements performed at the screening visit and before the first dose of study drug.
2. Must be male or female (of nonchildbearing potential) aged 18 to 55 years, inclusive, at the screening visit.
3. Must have a body mass index (BMI) greater than or equal to (>=) 18.5 and less than or equal to (<=) 30.0 kilogram per square meter (kg/m^2) at the screening visit.

Exclusion Criteria:

1. Has a positive alcohol or drug screen.
2. Had major surgery or donated or lost 1 unit of blood (approximately 500 milliliter [mL]) within 4 weeks before the screening visit.
3. Has a history of alcohol consumption exceeding 2 standard drinks per day on average (1 glass is approximately equivalent to the following: beer [354 mL/12 ounce (oz)], wine [118 mL/4 oz], or distilled spirits [29.5 mL/1 oz] per day).
4. Who regularly smoke more than 5 cigarettes daily or equivalent and unable or unwilling not to smoke during the in-house period.
5. Consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per day.
6. Has a previous or current clinically significant psychiatric disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5) including substance use disorder.
7. Has a history of intracranial mass lesion, hydrocephalus and/or head injury or trauma.
8. Has metal objects in brain or skull.
9. Has a cochlear implant or deep brain stimulation device.
10. Has a history of epilepsy, seizures, or convulsions.
11. Has a family history of epilepsy, seizures, or convulsions.
12. Has abnormal sleeping patterns (example, working night shifts)
13. Has an rMT of more than 75% of the maximum stimulator output, measured using TMS-electromyogram (EMG) during screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TAK-653 6 mg + TAK-653 0.5 mg + Placebo + Ketamine 0.5 mg/kg; TAK-653 6 milligram (mg) high dose tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 milligram per kilogram (mg/kg), intravenous infusion, once on Day 1 of Treatment Period 4. A washout of 10 to 15 days will be maintained between each treatment period.	Drug: TAK-653; TAK-653 tablets.; Drug: Placebo; TAK-653 placebo-matching tablets.; Drug: Ketamine; Ketamine intravenous infusion.
Experimental: TAK-653 6 mg + Placebo + TAK-653 0.5 mg + Ketamine 0.5 mg/kg; TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, intravenous infusion, once on Day 1 of Treatment Period 4. A washout of 10 to 15 days will be maintained between each treatment period.	Drug: TAK-653; TAK-653 tablets.; Drug: Placebo; TAK-653 placebo-matching tablets.; Drug: Ketamine; Ketamine intravenous infusion.
Experimental: TAK-653 0.5 mg + TAK-653 6 mg + Placebo + Ketamine 0.5 mg/kg; TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, intravenous infusion, once on Day 1 of Treatment Period 4. A washout of 10 to 15 days will be maintained between each treatment period.	Drug: TAK-653; TAK-653 tablets.; Drug: Placebo; TAK-653 placebo-matching tablets.; Drug: Ketamine; Ketamine intravenous infusion.
Experimental: TAK-653 0.5 mg + Placebo + TAK-653 6 mg + Ketamine 0.5 mg/kg; TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, intravenous infusion, once on Day 1 of Treatment Period 4. A washout of 10 to 15 days will be maintained between each treatment period.	Drug: TAK-653; TAK-653 tablets.; Drug: Placebo; TAK-653 placebo-matching tablets.; Drug: Ketamine; Ketamine intravenous infusion.
Experimental: Placebo + TAK-653 0.5 mg + TAK-653 6 mg + Ketamine 0.5 mg/kg; TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, intravenous infusion, once on Day 1 of Treatment Period 4. A washout of 10 to 15 days will be maintained between each treatment period.	Drug: TAK-653; TAK-653 tablets.; Drug: Placebo; TAK-653 placebo-matching tablets.; Drug: Ketamine; Ketamine intravenous infusion.
Experimental: Placebo + TAK-653 6 mg + TAK-653 0.5 mg + Ketamine 0.5 mg/kg; TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, intravenous infusion, once on Day 1 of Treatment Period 4. A washout of 10 to 15 days will be maintained between each treatment period.	Drug: TAK-653; TAK-653 tablets.; Drug: Placebo; TAK-653 placebo-matching tablets.; Drug: Ketamine; Ketamine intravenous infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Peak-to-Peak Amplitude of Motor-evoked Potential (MEP) Obtained With Single-pulse Transcranial Magnetic Stimulation (TMS) for TAK-653 at 2.5 Hours Post TAK-653 Dose	TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Single-pulse TMS was used to determine peak-to-peak amplitude of MEP at a stimulation intensity of 120 percent (%) of baseline resting motor threshold (rMT). rMT was defined as the minimum stimulus intensity to evoke an MEP. Change in peak-to peak amplitude of MEP was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 versus (vs.) matched oral placebo.	Baseline, 2.5 hours post TAK-653 dose
Change From Baseline in Resting Motor Threshold (rMT) Obtained With Single-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose	The rMT was defined as the minimum stimulus intensity to evoke an MEP. Single-pulse TMS was used to determine rMT. A lower rMT value indicated greater neuronal excitability. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in rMT was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 vs. matched oral placebo.	Baseline, 2.5 hours post TAK-653 dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Magnitude of Long Intracortical Inhibition (LICI) Obtained With Paired-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose	LICI was TMS stimulation paradigm that capture modulation of cortical excitation-inhibition balance with pairs of TMS pulses at stimulation intensity conditioning pulse and test pulse of 120% of baseline rMT. rMT was defined as the minimum stimulus intensity to evoke an MEP. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in LICI was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 vs. matched oral placebo.	Baseline, 2.5 hours post TAK-653 dose
Change From Baseline in Magnitude of Short Intracortical Inhibition (SICI) Obtained With Paired-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose	SICI was TMS stimulation paradigm that capture modulation of cortical excitation-inhibition balance with pairs of TMS pulses at stimulation intensity conditioning pulse 80% of baseline rMT and test pulse of 120% of baseline rMT. rMT was defined as the minimum stimulus intensity to evoke an MEP. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in SICI was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 vs. matched oral placebo.	Baseline, 2.5 hours post TAK-653 dose
Change From Baseline in rMT Obtained With Single-pulse TMS to Assess the Effect of Ketamine at 2.5 Hours and 24 Hours Post-dose of Ketamine	The rMT was defined as the minimum stimulus intensity to evoke an MEP. Single-pulse TMS was used to determine rMT. A lower rMT value indicated greater neuronal excitability. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in rMT was be assessed by TMS after treatment with 0.5 mg/kg Ketamine.	Baseline, 2.5 hours post ketamine dose, and 24 hours post ketamine dose
Change From Baseline in in Peak-to-Peak Amplitude of MEP Obtained With Single-pulse TMS to Assess the Effect of Ketamine at 2.5 Hours and 24 Hours Post Dose of Ketamine	TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Single-pulse TMS was used to determine peak-to-peak amplitude of MEP at a stimulation intensity of 120% of baseline rMT. rMT was defined as the minimum stimulus intensity to evoke an MEP. Change in peak-to peak amplitude of MEP was be assessed by TMS after treatment 0.5 mg/kg Ketamine.	Baseline, 2.5 hours post ketamine dose, and 24 hours post ketamine dose

Collaborators and Investigators

• Sponsor: Neurocrine Biosciences
• Collaborators: Takeda

Publications and helpful links

General Publications

• Dijkstra F, O'Donnell P, Klaassen E, Buhl D, Asgharnejad M, Rosen L, Zuiker R, van Gerven J, Jacobs G. Central nervous system effects of TAK-653, an investigational alpha-amino-3-hydroxy-5-methyl-4-isoxazole receptor (AMPAR) positive allosteric modulator in healthy volunteers. Transl Psychiatry. 2022 Sep 24;12(1):408. doi: 10.1038/s41398-022-02148-w.

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2019
• Primary Completion (Actual): May 15, 2019
• Study Completion (Actual): June 18, 2019

Study Registration Dates

• First Submitted: January 2, 2019
• First Submitted That Met QC Criteria: January 2, 2019
• First Posted (Actual): January 3, 2019

Study Record Updates

• Last Update Posted (Actual): March 19, 2021
• Last Update Submitted That Met QC Criteria: March 17, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Drug Therapy
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Ketamine
• Other Study ID Numbers: TAK-653-1003; U1111-1224-5430 (Other Identifier: WHO); 2018-004206-26 (EudraCT Number); NL68394.056.18 (Registry Identifier: CCMO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No