Healthy VolunteersPhase 1NCT03792672

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

A Phase 1 study testing TAK-653 and Ketamine in people with Healthy Volunteers, run by Neurocrine Biosciences at 1 site in Netherlands.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

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. Read more about this study

Who is it for?: Ages 18 to 55 yearsHealthy volunteers can take part
Conditions the study is for: Healthy Volunteers
What is being tested?: TAK-653 and Ketamine
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 24 participants
Where: 1 siteNetherlands
Study dates: 11 Feb 2019to 18 Jun 2019
Phase: Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 55 years
All sexes
Healthy volunteers accepted
Adult

Who may be able to join

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.
Must be male or female (of nonchildbearing potential) aged 18 to 55 years, inclusive, at the screening visit.
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.

Who cannot join

Has a positive alcohol or drug screen.
Had major surgery or donated or lost 1 unit of blood (approximately 500 milliliter [mL]) within 4 weeks before the screening visit.
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).
Who regularly smoke more than 5 cigarettes daily or equivalent and unable or unwilling not to smoke during the in-house period.
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.
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.

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Has a history of intracranial mass lesion, hydrocephalus and/or head injury or trauma.
Has metal objects in brain or skull.
Has a cochlear implant or deep brain stimulation device.
Has a history of epilepsy, seizures, or convulsions.
Has a family history of epilepsy, seizures, or convulsions.
Has abnormal sleeping patterns (example, working night shifts)
Has an rMT of more than 75% of the maximum stimulator output, measured using TMS-electromyogram (EMG) during screening.

Trial locations and contacts

1 site in 1 country.

Netherlands1 site

CHDR
Leiden

Other trials in Netherlands

About this study

Official title: 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.

Read the 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.

Conditions: Healthy Volunteers
Being tested: TAK-653, Placebo, Ketamine
Keywords: Drug Therapy

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

TAK-653Drug
TAK-653 tablets.
PlaceboDrug
TAK-653 placebo-matching tablets.
KetamineDrug
Ketamine intravenous infusion.

Study groups in NCT03792672
Study group	Role	What they receive
TAK-653 6 mg + TAK-653 0.5 mg + Placebo + Ketamine 0.5 mg/kg	Experimental	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. Receives: Drug: TAK-653; Drug: Placebo; Drug: Ketamine
TAK-653 6 mg + Placebo + TAK-653 0.5 mg + Ketamine 0.5 mg/kg	Experimental	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. Receives: Drug: TAK-653; Drug: Placebo; Drug: Ketamine
TAK-653 0.5 mg + TAK-653 6 mg + Placebo + Ketamine 0.5 mg/kg	Experimental	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. Receives: Drug: TAK-653; Drug: Placebo; Drug: Ketamine
TAK-653 0.5 mg + Placebo + TAK-653 6 mg + Ketamine 0.5 mg/kg	Experimental	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. Receives: Drug: TAK-653; Drug: Placebo; Drug: Ketamine
Placebo + TAK-653 0.5 mg + TAK-653 6 mg + Ketamine 0.5 mg/kg	Experimental	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. Receives: Drug: TAK-653; Drug: Placebo; Drug: Ketamine
Placebo + TAK-653 6 mg + TAK-653 0.5 mg + Ketamine 0.5 mg/kg	Experimental	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. Receives: Drug: TAK-653; Drug: Placebo; Drug: Ketamine

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: Baseline, 2.5 hours post TAK-653 dose

Secondary outcomes (4)

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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline, 2.5 hours post ketamine dose, and 24 hours post ketamine dose

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

11 Feb 201918 Jun 2019

First posted3 Jan 2019
Study start11 Feb 2019
Primary completion15 May 2019
Study completion18 Jun 2019

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Healthy VolunteersStudies of the same condition, open and under way.
More trials run by Neurocrine BiosciencesThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Other
Allocation: Randomised
Intervention model: Crossover
Model description: The study is a randomized, crossover 6 sequence study in Treatment Periods 1, 2, and 3.
Masking: Double blind
Who is masked: Participant, Investigator
Enrolment: 24 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03792672
Sponsor's protocol ID: TAK-653-1003
Other IDs: U1111-1224-5430, 2018-004206-26, NL68394.056.18, 2018
Status last verified: Mar 2021
First submitted: 2 Jan 2019
Last updated: 19 Mar 2021
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes: 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.

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.
PubMed 36153330

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 19 Mar 2021. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: 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
ClinicalTrials.gov ID: NCT03792672
Acronym / sponsor ID: TAK-653-1003
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 24 participants (actual)
Lead sponsor: Neurocrine BiosciencesIndustry (pharma, biotech, devices)
Collaborators: Takeda
Study start: 11 Feb 2019 (actual)
Primary completion: 15 May 2019 (actual)
Study completion: 18 Jun 2019 (actual)
First posted: 3 Jan 2019 (actual)
Results: Posted 2 Jul 2020

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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.

Detailed description

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.

Study design

Primary purpose: Other
Allocation: Randomised
Intervention model: Crossover
Masking: Double blind (participant, investigator)
Number of arms: 6
Model description: The study is a randomized, crossover 6 sequence study in Treatment Periods 1, 2, and 3.

Arm	Type	Receives
TAK-653 6 mg + TAK-653 0.5 mg + Placebo + Ketamine 0.5 mg/kg	Experimental	Drug: TAK-653, Drug: Placebo, Drug: KetamineTAK-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.
TAK-653 6 mg + Placebo + TAK-653 0.5 mg + Ketamine 0.5 mg/kg	Experimental	Drug: TAK-653, Drug: Placebo, Drug: KetamineTAK-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.
TAK-653 0.5 mg + TAK-653 6 mg + Placebo + Ketamine 0.5 mg/kg	Experimental	Drug: TAK-653, Drug: Placebo, Drug: KetamineTAK-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.
TAK-653 0.5 mg + Placebo + TAK-653 6 mg + Ketamine 0.5 mg/kg	Experimental	Drug: TAK-653, Drug: Placebo, Drug: KetamineTAK-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.
Placebo + TAK-653 0.5 mg + TAK-653 6 mg + Ketamine 0.5 mg/kg	Experimental	Drug: TAK-653, Drug: Placebo, Drug: KetamineTAK-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.
Placebo + TAK-653 6 mg + TAK-653 0.5 mg + Ketamine 0.5 mg/kg	Experimental	Drug: TAK-653, Drug: Placebo, Drug: KetamineTAK-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.

Who may qualify

Ages: 18 to 55 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult

Key inclusion criteria (3 listed)

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.
Must be male or female (of nonchildbearing potential) aged 18 to 55 years, inclusive, at the screening visit.
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.

Key exclusion criteria (13 listed)

Has a positive alcohol or drug screen.
Had major surgery or donated or lost 1 unit of blood (approximately 500 milliliter [mL]) within 4 weeks before the screening visit.
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).
Who regularly smoke more than 5 cigarettes daily or equivalent and unable or unwilling not to smoke during the in-house period.
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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
TAK-653TAK-653 tablets.	Drug	Placebo + TAK-653 0.5 mg + TAK-653 6 mg + Ketamine 0.5 mg/kg, Placebo + TAK-653 6 mg + TAK-653 0.5 mg + Ketamine 0.5 mg/kg, TAK-653 0.5 mg + Placebo + TAK-653 6 mg + Ketamine 0.5 mg/kg, TAK-653 0.5 mg + TAK-653 6 mg + Placebo + Ketamine 0.5 mg/kg, TAK-653 6 mg + Placebo + TAK-653 0.5 mg + Ketamine 0.5 mg/kg, TAK-653 6 mg + TAK-653 0.5 mg + Placebo + Ketamine 0.5 mg/kg
PlaceboTAK-653 placebo-matching tablets.	Drug	Placebo + TAK-653 0.5 mg + TAK-653 6 mg + Ketamine 0.5 mg/kg, Placebo + TAK-653 6 mg + TAK-653 0.5 mg + Ketamine 0.5 mg/kg, TAK-653 0.5 mg + Placebo + TAK-653 6 mg + Ketamine 0.5 mg/kg, TAK-653 0.5 mg + TAK-653 6 mg + Placebo + Ketamine 0.5 mg/kg, TAK-653 6 mg + Placebo + TAK-653 0.5 mg + Ketamine 0.5 mg/kg, TAK-653 6 mg + TAK-653 0.5 mg + Placebo + Ketamine 0.5 mg/kg
KetamineKetamine intravenous infusion.	Drug	Placebo + TAK-653 0.5 mg + TAK-653 6 mg + Ketamine 0.5 mg/kg, Placebo + TAK-653 6 mg + TAK-653 0.5 mg + Ketamine 0.5 mg/kg, TAK-653 0.5 mg + Placebo + TAK-653 6 mg + Ketamine 0.5 mg/kg, TAK-653 0.5 mg + TAK-653 6 mg + Placebo + Ketamine 0.5 mg/kg, TAK-653 6 mg + Placebo + TAK-653 0.5 mg + Ketamine 0.5 mg/kg, TAK-653 6 mg + TAK-653 0.5 mg + Placebo + Ketamine 0.5 mg/kg

Primary outcome

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
Time frame: Baseline, 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.
Change From Baseline in Resting Motor Threshold (rMT) Obtained With Single-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose
Time frame: Baseline, 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.

4 secondary outcomes

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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Baseline, 2.5 hours post ketamine dose, and 24 hours post ketamine dose

Results and safety

Results posted to the registry on 2 Jul 2020, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Placebo + TAK-653 0.5 mg + TAK-653 6 mg + Ketamine 0.5 mg/kg	4	4
Placebo + TAK-653 6 mg + TAK-653 0.5 mg + Ketamine 0.5 mg/kg	4	4
TAK-653 0.5 mg + Placebo + TAK-653 6 mg + Ketamine 0.5 mg/kg	4	4
TAK-653 0.5 mg + TAK-653 6 mg + Placebo + Ketamine 0.5 mg/kg	4	4
TAK-653 6 mg + Placebo + TAK-653 0.5 mg + Ketamine 0.5 mg/kg	4	4
TAK-653 6 mg + TAK-653 0.5 mg + Placebo + Ketamine 0.5 mg/kg	4	4

Primary outcome: 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

Time frame: Baseline, 2.5 hours post TAK-653 dose. Mean (Standard Deviation). Unit: microvolt (mcV)

Measure	Placebo n = 24	TAK-653 0.5 mg n = 24	TAK-653 6 mg n = 24
Baseline	898.828 (693.1535)	841.068 (591.1367)	1004.127 (574.5982)
Change at 2.5 Hours Post TAK-653 Dose	-139.117 (829.5901)	17.265 (466.2556)	139.932 (813.9705)

Placebo vs TAK-653 0.5 mg: Least square mean (LSM) difference: 115 (90% CI -128 to 359), p = 0.4278, Mixed Models Analysis
Placebo vs TAK-653 6 mg: LSM difference: 338 (90% CI 90.5 to 585), p = 0.0269, Mixed Models Analysis

Population analysed: The pharmacodynamics (PD) set included of all participants who received study drug and had at least one postdose PD measurement. The PD analysis set included all participants who had completed first 3 treatment periods. Participants who were evaluable for this measure at given time point were included for the assessment.

Primary outcome: Change From Baseline in Resting Motor Threshold (rMT) Obtained With Single-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose

Time frame: Baseline, 2.5 hours post TAK-653 dose. Mean (Standard Deviation). Unit: percentage of maximum stimulator output

Measure	Placebo n = 24	TAK-653 0.5 mg n = 24	TAK-653 6 mg n = 24
Baseline	55.3 (7.46)	55.9 (8.99)	55.3 (8.93)
Change at 2.5 hours post TAK-653 Dose	-0.1 (2.74)	-0.5 (1.74)	-0.3 (1.95)

Placebo vs TAK-653 0.5 mg: LSM difference: -0.388 (90% CI -1.37 to 0.595), p = 0.5089, Mixed Models Analysis
Placebo vs TAK-653 6 mg: LSM difference: -0.209 (90% CI -1.19 to 0.773), p = 0.7208, Mixed Models Analysis

Population analysed: The PD set included of all participants who received study drug and had at least one postdose PD measurement. The PD analysis set included all participants who had completed first 3 treatment periods.

4 secondary outcomes are reported in the full results.

Adverse events

Time frame: Treatment-emergent adverse events are adverse events that started after the first dose of study drug until 14 days after last dose in Treatment Period 4 (up to Day 48). Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Placebo	0 of 24 (0%)	7 of 24 (29.2%)	0 of 24
TAK-653 0.5 mg	0 of 24 (0%)	9 of 24 (37.5%)	0 of 24
TAK-653 6 mg	0 of 24 (0%)	12 of 24 (50%)	0 of 24
Ketamine 0.5 mg/kg	0 of 20 (0%)	20 of 20 (100%)	0 of 20

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 19 Mar 2021.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 36153330Dijkstra 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.
Individual participant dataSharing planned: Yes. 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.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Medical Director study director

Millennium Pharmaceuticals, Inc.

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing TAK-653 and Ketamine in people with Healthy Volunteers, run by Neurocrine Biosciences at 1 site in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 2 Jul 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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 (time frame: Baseline, 2.5 hours post TAK-653 dose). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03792672, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Mar 2021.