Healthy Volunteers
Conditions
Keywords
Drug Therapy
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.
Interventions
DRUGTAK-653
TAK-653 tablets.
DRUGPlacebo
TAK-653 placebo-matching tablets.
DRUGKetamine
Ketamine intravenous infusion.
Sponsors
Takeda
Neurocrine Biosciences
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Masking description
The study is double blind in Treatment Periods 1, 2, and 3 and open-label in Treatment Period 4.
Intervention model description
The study is a randomized, crossover 6 sequence study in Treatment Periods 1, 2, and 3.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | 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 | 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 | 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. |
Countries
Netherlands
Participant flow
Recruitment details
Participants took part in the study at 1 investigative site in Netherlands from 11 February 2019 to 18 June 2019.
Pre-assignment details
Healthy participants were enrolled in 1 of the 6 treatment sequences of this 3-period crossover study to receive TAK 653 0.5 milligram (mg) (Low dose), TAK-653 6 mg (high dose), placebo in Treatment Periods 1 to 3, and ketamine 0.5 milligram per kilogram (mg/kg) in an open label treatment Period 4.
Participants by arm
| Arm | Count |
|---|---|
| All Participants TAK-653 placebo-matching tablets or TAK-653 0.5 mg low dose tablets or TAK-653 6 mg high dose tablets, orally, once, on Day 1 of respective Treatment Period 1, 2 or 3 and Ketamine 0.5 mg/kg, infusion, intravenously, once on Day 1 of Treatment Period 4. A Washout Period of at least 10 days was maintained between each treatment period. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Treatment Period 4 (2 Days) | Other | 1 | 0 | 0 | 0 | 0 | 0 |
| Washout Period 3 (10 Days) | Physician Decision | 0 | 0 | 1 | 0 | 0 | 0 |
| Washout Period 3 (10 Days) | Withdrawal by Subject | 1 | 0 | 0 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 27.9 years STANDARD_DEVIATION 9 |
| Body Mass Index (BMI) | 23.93 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 2.85 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Height | 181.98 centimeter (cm) STANDARD_DEVIATION 9.88 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 22 Participants |
| Region of Enrollment Netherlands | 24 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 23 Participants |
| Weight | 79.12 kilogram (Kg) STANDARD_DEVIATION 10.81 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 20 |
| other Total, other adverse events | 7 / 24 | 9 / 24 | 12 / 24 | 20 / 20 |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 20 |
Outcome results
Primary
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.
Time frame: Baseline, 2.5 hours post TAK-653 dose
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 | Baseline | 898.828 microvolt (mcV) | Standard Deviation 693.1535 |
| Placebo | 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 | Change at 2.5 Hours Post TAK-653 Dose | -139.117 microvolt (mcV) | Standard Deviation 829.5901 |
| TAK-653 0.5 mg | 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 | Baseline | 841.068 microvolt (mcV) | Standard Deviation 591.1367 |
| TAK-653 0.5 mg | 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 | Change at 2.5 Hours Post TAK-653 Dose | 17.265 microvolt (mcV) | Standard Deviation 466.2556 |
| TAK-653 6 mg | 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 | Baseline | 1004.127 microvolt (mcV) | Standard Deviation 574.5982 |
| TAK-653 6 mg | 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 | Change at 2.5 Hours Post TAK-653 Dose | 139.932 microvolt (mcV) | Standard Deviation 813.9705 |
p-value: 0.427890% CI: [-128, 359]Mixed Models Analysis
p-value: 0.026990% CI: [90.5, 585]Mixed Models Analysis
Primary
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.
Time frame: Baseline, 2.5 hours post TAK-653 dose
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 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 | Baseline | 55.3 percentage of maximum stimulator output | Standard Deviation 7.46 |
| 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 | Change at 2.5 hours post TAK-653 Dose | -0.1 percentage of maximum stimulator output | Standard Deviation 2.74 |
| TAK-653 0.5 mg | Change From Baseline in Resting Motor Threshold (rMT) Obtained With Single-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose | Baseline | 55.9 percentage of maximum stimulator output | Standard Deviation 8.99 |
| TAK-653 0.5 mg | Change From Baseline in Resting Motor Threshold (rMT) Obtained With Single-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose | Change at 2.5 hours post TAK-653 Dose | -0.5 percentage of maximum stimulator output | Standard Deviation 1.74 |
| TAK-653 6 mg | Change From Baseline in Resting Motor Threshold (rMT) Obtained With Single-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose | Baseline | 55.3 percentage of maximum stimulator output | Standard Deviation 8.93 |
| TAK-653 6 mg | Change From Baseline in Resting Motor Threshold (rMT) Obtained With Single-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose | Change at 2.5 hours post TAK-653 Dose | -0.3 percentage of maximum stimulator output | Standard Deviation 1.95 |
p-value: 0.508990% CI: [-1.37, 0.595]Mixed Models Analysis
p-value: 0.720890% CI: [-1.19, 0.773]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, 2.5 hours post ketamine dose, and 24 hours post ketamine dose
Population: 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 Treatment Period 4. Participants who were evaluable for this measure at given time point were included for the assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 | 1150.618 mcV | Standard Deviation 1047.392 |
| Placebo | 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 | Change at 2.5 hours Ketamine Post Dose | -193.897 mcV | Standard Deviation 897.0245 |
| Placebo | 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 | Change at 24 hours Ketamine Post Dose | -295.041 mcV | Standard Deviation 944.4889 |
Secondary
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.
Time frame: Baseline, 2.5 hours post TAK-653 dose
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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: LICI 100 ms | 16.167 percent inhibition | Standard Deviation 27.0976 |
| Placebo | 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: LICI 50 ms | 75.113 percent inhibition | Standard Deviation 97.2865 |
| Placebo | 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 | Change at 2.5 Hours Post TAK-653 Dose: LICI 50 ms | 0.675 percent inhibition | Standard Deviation 54.5725 |
| Placebo | 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 | Change at 2.5 Hours Post TAK-653 Dose: LICI 100 ms | 0.147 percent inhibition | Standard Deviation 29.1567 |
| Placebo | 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: LICI 200 ms | 48.149 percent inhibition | Standard Deviation 33.1815 |
| Placebo | 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 | Change at 2.5 Hours Post TAK-653 Dose: LICI 200 ms | 2.882 percent inhibition | Standard Deviation 21.2459 |
| Placebo | 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: LICI 300 ms | 59.463 percent inhibition | Standard Deviation 31.1596 |
| Placebo | 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 | Change at 2.5 Hours Post TAK-653 Dose: LICI 300 ms | -9.996 percent inhibition | Standard Deviation 27.7151 |
| TAK-653 0.5 mg | 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: LICI 100 ms | 10.430 percent inhibition | Standard Deviation 14.1289 |
| TAK-653 0.5 mg | 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: LICI 300 ms | 56.115 percent inhibition | Standard Deviation 36.8452 |
| TAK-653 0.5 mg | 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 | Change at 2.5 Hours Post TAK-653 Dose: LICI 100 ms | 5.905 percent inhibition | Standard Deviation 18.8939 |
| TAK-653 0.5 mg | 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: LICI 200 ms | 48.934 percent inhibition | Standard Deviation 48.6073 |
| TAK-653 0.5 mg | 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 | Change at 2.5 Hours Post TAK-653 Dose: LICI 200 ms | 9.902 percent inhibition | Standard Deviation 42.5761 |
| TAK-653 0.5 mg | 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: LICI 50 ms | 96.515 percent inhibition | Standard Deviation 113.2728 |
| TAK-653 0.5 mg | 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 | Change at 2.5 Hours Post TAK-653 Dose: LICI 300 ms | 8.618 percent inhibition | Standard Deviation 36.0453 |
| TAK-653 0.5 mg | 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 | Change at 2.5 Hours Post TAK-653 Dose: LICI 50 ms | 18.319 percent inhibition | Standard Deviation 81.4378 |
| TAK-653 6 mg | 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 | Change at 2.5 Hours Post TAK-653 Dose: LICI 50 ms | 19.395 percent inhibition | Standard Deviation 110.087 |
| TAK-653 6 mg | 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 | Change at 2.5 Hours Post TAK-653 Dose: LICI 200 ms | 11.540 percent inhibition | Standard Deviation 30.1594 |
| TAK-653 6 mg | 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: LICI 100 ms | 46.808 percent inhibition | Standard Deviation 149.9806 |
| TAK-653 6 mg | 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 | Change at 2.5 Hours Post TAK-653 Dose: LICI 100 ms | -28.644 percent inhibition | Standard Deviation 142.5618 |
| TAK-653 6 mg | 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: LICI 300 ms | 54.572 percent inhibition | Standard Deviation 30.5543 |
| TAK-653 6 mg | 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: LICI 50 ms | 96.568 percent inhibition | Standard Deviation 111.1657 |
| TAK-653 6 mg | 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: LICI 200 ms | 49.773 percent inhibition | Standard Deviation 37.7173 |
| TAK-653 6 mg | 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 | Change at 2.5 Hours Post TAK-653 Dose: LICI 300 ms | 1.638 percent inhibition | Standard Deviation 32.6843 |
Comparison: LICI 50 ms peak-to-peak amplitudep-value: 0.417490% CI: [-14.8, 42.8]Mixed Models Analysis
Comparison: LICI 50 ms peak-to-peak amplitudep-value: 0.383290% CI: [-25.3, 31.5]Mixed Models Analysis
Comparison: LICI 100 ms peak-to-peak amplitudep-value: 0.936890% CI: [-7.23, 6.58]Mixed Models Analysis
Comparison: LICI 100 ms peak-to-peak amplitudep-value: 0.37990% CI: [-3.32, 10.7]Mixed Models Analysis
Comparison: LICI 200 ms peak-to-peak amplitudep-value: 0.25890% CI: [-3.44, 18.2]Mixed Models Analysis
Comparison: LICI 200 ms peak-to-peak amplitudep-value: 0.152490% CI: [-1.45, 20.2]Mixed Models Analysis
Comparison: LICI 300 ms peak-to-peak amplitudep-value: 0.02290% CI: [5.06, 29.4]Mixed Models Analysis
Comparison: LICI 300 ms peak-to-peak amplitudep-value: 0.192790% CI: [-2.59, 21.8]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, 2.5 hours post TAK-653 dose
Population: 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. Participants who were evaluable for this measure at given time point were included for the assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 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 | Baseline: SICI 2 ms | 43.095 percent inhibition | Standard Deviation 30.7011 |
| 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 | Change at 2.5 Hours Post TAK-653 Dose: SICI 2 ms | 5.052 percent inhibition | Standard Deviation 47.5676 |
| 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 | Baseline: SICI 5 ms | 70.640 percent inhibition | Standard Deviation 49.8699 |
| 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 | Change at 2.5 Hours Post TAK-653 Dose: SICI 5 ms | 14.303 percent inhibition | Standard Deviation 81.6111 |
| TAK-653 0.5 mg | 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 | Change at 2.5 Hours Post TAK-653 Dose: SICI 5 ms | 4.274 percent inhibition | Standard Deviation 30.8966 |
| TAK-653 0.5 mg | 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: SICI 2 ms | 39.159 percent inhibition | Standard Deviation 39.2536 |
| TAK-653 0.5 mg | 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: SICI 5 ms | 59.672 percent inhibition | Standard Deviation 37.7419 |
| TAK-653 0.5 mg | 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 | Change at 2.5 Hours Post TAK-653 Dose: SICI 2 ms | 1.772 percent inhibition | Standard Deviation 35.9158 |
| TAK-653 6 mg | 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 | Change at 2.5 Hours Post TAK-653 Dose: SICI 5 ms | -7.247 percent inhibition | Standard Deviation 52.9205 |
| TAK-653 6 mg | 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 | Change at 2.5 Hours Post TAK-653 Dose: SICI 2 ms | -14.580 percent inhibition | Standard Deviation 37.7311 |
| TAK-653 6 mg | 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: SICI 5 ms | 72.722 percent inhibition | Standard Deviation 62.0484 |
| TAK-653 6 mg | 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: SICI 2 ms | 47.951 percent inhibition | Standard Deviation 42.1139 |
Comparison: SICI 2 ms peak-to-peak amplitudep-value: 0.55990% CI: [-21.8, 10.5]Mixed Models Analysis
Comparison: SICI 2 ms peak-to-peak amplitudep-value: 0.104990% CI: [-32.5, 0.242]Mixed Models Analysis
Comparison: SICI 5 ms peak-to-peak amplitudep-value: 0.223890% CI: [-39.4, 6.06]Mixed Models Analysis
Comparison: SICI 5 ms peak-to-peak amplitudep-value: 0.184790% CI: [-41.3, 4.56]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, 2.5 hours post ketamine dose, and 24 hours post ketamine dose
Population: 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 Treatment Period 4. Participants who were evaluable for this measure at given time point were included for the assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 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 | Baseline | 54.4 percentage of maximum stimulator output | Standard Deviation 9.28 |
| 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 | Change at 2.5 hours Ketamine Post Dose | 0.7 percentage of maximum stimulator output | Standard Deviation 4.18 |
| 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 | Change at 24 hours Ketamine Post Dose | 0.8 percentage of maximum stimulator output | Standard Deviation 3.1 |