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

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ClinicalTrials.gov Identifier: NCT03792672
Recruitment Status : Completed
First Posted : January 3, 2019
Results First Posted : July 2, 2020
Last Update Posted : March 19, 2021
Sponsor:
Collaborator:
Takeda
Information provided by (Responsible Party):
Neurocrine Biosciences

Tracking Information
First Submitted Date  ICMJE January 2, 2019
First Posted Date  ICMJE January 3, 2019
Results First Submitted Date  ICMJE June 12, 2020
Results First Posted Date  ICMJE July 2, 2020
Last Update Posted Date March 19, 2021
Actual Study Start Date  ICMJE February 11, 2019
Actual Primary Completion Date May 15, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 12, 2020)
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 2, 2019)
Change in Resting Motor Threshold (rMT) Obtained with Single-pulse TMS [ Time Frame: Baseline, at 2 hour 30 minutes post TAK-653 dose ]
The rMT is defined as the minimum stimulus intensity to evoke an MEP.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 12, 2020)
  • 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 ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 2, 2019)
  • Change in Amplitude of MEP Obtained with Single-pulse TMS to Assess the Effect of TAK-653 [ Time Frame: Baseline, at 2 hour 30 minutes ]
    The change in peak-to-peak amplitude of the MEP obtained with single-pulse TMS at a stimulation intensity of 120 percent (%) of baseline rMT, assessing TAK-653 effects over predosing baseline for each treatment period will be determined.
  • Change in Long Intracortical Inhibition (LICI) Obtained with Paired-pulse TMS [ Time Frame: Baseline, Day 1 ]
    LICI are paired-pulse TMS (stimulation intensity conditioning pulse and test pulse: 120% of baseline rMT) paradigms that capture modulation of cortical excitation-inhibition balance with pairs of TMS pulses.
  • Change in Short Intracortical Inhibition (SICI) Obtained with Paired-pulse TMS [ Time Frame: Baseline, Day 1 ]
    SICI are paired-pulse TMS (stimulation intensity: conditioning pulse 80% of baseline rMT; test pulse: 120% of baseline rMT) paradigms that capture modulation of cortical excitation-inhibition balance with pairs of TMS pulses.
  • Change in rMT Obtained with Single-pulse TMS to Assess the Effect of Ketamine [ Time Frame: Baseline, at 24 hours post TAK-653 dose ]
    The rMT is defined as the minimum stimulus intensity to evoke an MEP.
  • Change in Amplitude of MEP Obtained with Single-pulse TMS to Assess the Effect of Ketamine [ Time Frame: Baseline, Day 1 ]
    The change peak-to-peak amplitude of the MEP obtained with single-pulse TMS at a stimulation intensity of 120% of baseline rMT, assessing ketamine effects over predosing baseline for each treatment period will be determined.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Evaluate Central Nervous System (CNS) Pharmacodynamic Activity of TAK-653 in Healthy Participants Using Transcranial Magnetic Stimulation (TMS)
Official Title  ICMJE 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
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
The study is a randomized, crossover 6 sequence study in Treatment Periods 1, 2, and 3.
Masking: Double (Participant, Investigator)
Masking Description:
The study is double blind in Treatment Periods 1, 2, and 3 and open-label in Treatment Period 4.
Primary Purpose: Other
Condition  ICMJE Healthy Volunteers
Intervention  ICMJE
  • Drug: TAK-653
    TAK-653 tablets.
  • Drug: Placebo
    TAK-653 placebo-matching tablets.
  • Drug: Ketamine
    Ketamine intravenous infusion.
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: TAK-653
    • Drug: Placebo
    • Drug: Ketamine
  • 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.
    Interventions:
    • Drug: TAK-653
    • Drug: Placebo
    • Drug: Ketamine
  • 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.
    Interventions:
    • Drug: TAK-653
    • Drug: Placebo
    • Drug: Ketamine
  • 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.
    Interventions:
    • Drug: TAK-653
    • Drug: Placebo
    • Drug: Ketamine
  • 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.
    Interventions:
    • Drug: TAK-653
    • Drug: Placebo
    • Drug: Ketamine
  • 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.
    Interventions:
    • Drug: TAK-653
    • Drug: Placebo
    • Drug: Ketamine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 2, 2019)
24
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE June 18, 2019
Actual Primary Completion Date May 15, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03792672
Other Study ID Numbers  ICMJE TAK-653-1003
U1111-1224-5430 ( Other Identifier: WHO )
2018-004206-26 ( EudraCT Number )
NL68394.056.18 ( Registry Identifier: CCMO )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
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.
Responsible Party Neurocrine Biosciences
Study Sponsor  ICMJE Neurocrine Biosciences
Collaborators  ICMJE Takeda
Investigators  ICMJE
Study Director: Medical Director Millennium Pharmaceuticals, Inc.
PRS Account Neurocrine Biosciences
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP