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

NCT03792672 | Completed Phase 1 Results FDA Drug

• 4 other identifiers: TAK-653-1003U1111-1224-54302018-004206-26NL68394.056.18
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Healthy Volunteers

Keywords

Drug Therapy

Outcome Measures

Primary Outcomes (2)

• 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 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

  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

  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

  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

  Baseline, 2.5 hours post ketamine dose, and 24 hours post ketamine dose

Study Arms (6)

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.

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.

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.

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.

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.

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.

Drug: TAK-653; Drug: Placebo; Drug: Ketamine

Interventions

TAK-653 DRUG

TAK-653 tablets.

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

Placebo DRUG

TAK-653 placebo-matching tablets.

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

Ketamine DRUG

Ketamine intravenous infusion.

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

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Neurocrine Biosciences: lead
• Takeda: collaborator

Study Sites (1)

CHDR

Leiden, Netherlands

Location

Related Publications (1)

• 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.

  PMID: 36153330 DERIVED

MeSH Terms

Interventions

Ketamine

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

medicalinformation@tpna.com

1-877-825-3327

Study Officials

• Medical Director

  Millennium Pharmaceuticals, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: The study is double blind in Treatment Periods 1, 2, and 3 and open-label in Treatment Period 4.
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: The study is a randomized, crossover 6 sequence study in Treatment Periods 1, 2, and 3.

Study Record Dates

• First Submitted: January 2, 2019
• First Posted: January 3, 2019
• Study Start: February 11, 2019
• Primary Completion: May 15, 2019
• Study Completion: June 18, 2019
• Last Updated: March 19, 2021
• Results First Posted: July 2, 2020

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will share

Locations

NL (1)