Effects of TAK-063 on Preventing Ketamine-Induced Brain Activity Changes as Well as Psychotic-Like Symptoms in Healthy Male Adults

• ClinicalTrials.gov Identifier: NCT01892189
• Recruitment Status: Completed
• First Posted: July 4, 2013
• Results First Posted: January 12, 2017
• Last Update Posted: January 12, 2017
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

Tracking Information

• First Submitted Date: June 20, 2013
• First Posted Date: July 4, 2013
• Results First Submitted Date: November 11, 2016
• Results First Posted Date: January 12, 2017
• Last Update Posted Date: January 12, 2017
• Study Start Date: August 2013
• Actual Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 11, 2016)

Ketamine-Induced Brain Activity in Regions of Interest During Resting State [ Time Frame: Day 1: 4 hours post TAK-063 dose or placebo ]

Ketamine model was used to enhance the sensitivity to detect an effect of phosphodiesterase 10a (PDE10a) inhibition by TAK-063 by ketamine using neuroimaging battery tests. Ketamine induced robust blood oxygen level-dependent(BOLD) functional magnetic resonance imaging(fMRI) response while maintaining minimal accompanying psychotomimetic symptoms. The regions of interest include:left anterior cingulate cortex,right anterior cingulate cortex,left posterior cingulate cortex,right posterior cingulate cortex,left striatum,right striatum,left amygdala,right amygdala,left substantia nigra,right substantia nigra,left thalamus,right thalamus,left ventrolateral prefrontal cortex,right ventrolateral prefrontal cortex,left dorsolateral prefrontal cortex,right dorsolateral prefrontal cortex,left hippocampus,right hippocampus,left subgenual cingulate/Ba25,right subgenual cingulate/Ba25,left paracingulate gyrus/Ba32, and right paracingulate gyrus/Ba32.

Original Primary Outcome Measures (submitted: June 30, 2013)

Ketamine-induced brain activity in regions of interest during Resting State [ Time Frame: 4 hours post-dose ]

Brain activity will be measured by functional magnetic resonance imaging (fMRI) blood-oxygen-level-dependent (BOLD). Areas of interest in brain activity are defined as the Anterior Cingulate Cortex, Posterior Cingulate Cortex, Striatum, Amygdala, Substantia Nigra, Thalamus, and Ventrolateral Prefrontal Cortex.

Current Secondary Outcome Measures (submitted: November 11, 2016)

• Cmax: Maximum Observed Plasma Concentration for TAK-063 and TAK-063 Metabolite (M-I) [ Time Frame: Day 1: pre-dose and at multiple time points (up to 24 hours) postdose ]
• Tmax: Time to Reach Cmax for TAK-063 and TAK-063 M-I [ Time Frame: Day 1: pre-dose and at multiple time points (up to 24 hours) postdose ]
• AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-063 and TAK-063 M-I [ Time Frame: Day 1: Pre-dose and at multiple time points (up to 24 hours) post-dose ]
• Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) [ Time Frame: Baseline up to 14 days after last dose of study drug (Day 32) ]
• Percentage of Participants Who Meet the Takeda Global Research and Development Center, Inc. (TGRD) Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post Dose [ Time Frame: Baseline up to 14 days after last dose of study drug (Day 32) ]
  The percentage of participants with any markedly abnormal standard safety laboratory values collected throughout study.
• Percentage of Participants Who Meet the TGRD Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Post Dose [ Time Frame: Baseline up to 14 days after last dose of study drug (Day 32) ]
  The percentage of participants who meet markedly abnormal criteria designated by TGRD. Vital signs included oral temperature, respiration, blood pressure and pulse (beats per minute).
• Percentage of Participants Who Meet the TGRD Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Post Dose [ Time Frame: Baseline up to 14 days after last dose of study drug (Day 32) ]
  The percentage of participants who meet markedly abnormal criteria designated by TGRD measured throughout study.

Original Secondary Outcome Measures (submitted: June 30, 2013)

• Cmax: Maximum Observed Plasma Concentration Pharmacokinetic Parameter for TAK-063 and TAK-063 metabolite M-I [ Time Frame: Day 1 ]
  Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
• Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) Pharmacokinetic Parameter for TAK-063 and TAK-063 metabolite M-I [ Time Frame: Day 1 ]
  Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.
• AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration Pharmacokinetic Parameter for TAK-063 and TAK-063 metabolite M-I [ Time Frame: Day 1 ]
  (AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC[0-tlqc]).
• Percentage of participants who experience at least one treatment emergent adverse event (TEAE) [ Time Frame: Up to 30 days after last dose of TAK-063 ]
  A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug (AE start date ≥ first dose date) and within 30 days after receiving the last dose of study drug (AE start date - last dose date ≤30).
• Percentage of participants with markedly abnormal safety laboratory tests [ Time Frame: 14 days after last dose of TAK-063. ]
  The percentage of participants with any markedly abnormal standard safety laboratory values after the dose of TAK-063.
• Percentage of participants with markedly abnormal vital sign measurements [ Time Frame: 14 days after last dose of TAK-063. ]
  The percentage of participants who meet markedly abnormal criteria for vital signs after the dose of TAK-063.
• Percentage of participants with markedly abnormal criteria for safety electrocardiogram (ECG) parameters [ Time Frame: 14 days after last dose of TAK-063. ]
  The percentage of participants who meet markedly abnormal criteria after the dose of TAK-063.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Effects of TAK-063 on Preventing Ketamine-Induced Brain Activity Changes as Well as Psychotic-Like Symptoms in Healthy Male Adults
• Official Title: A Randomized, Investigator and Subject-Blind, Placebo-Controlled, Single-Dose, 3-Period, Incomplete Block Cross-Over Study to Evaluate the Effects of Single Oral Administration of TAK-063 on Preventing Ketamine-Induced Brain Activity Changes as Well as Psychotic-Like Symptoms in Healthy Male Adults
• Brief Summary: The purpose of this study is to determine whether ketamine-induced brain activity changes are modulated by TAK-063 administration using neuroimaging battery tests.

Detailed Description

The drug being tested in this study is called TAK-063. This study will look at brain activity changes and treatment of psychotic-like symptoms induced by ketamine, in people who take TAK-063.

The study will enroll approximately 27 participants. Participants will be randomly assigned to one of treatment sequences-which will remain undisclosed to the participants during the study (unless there is an urgent medical need). Participants will receive the following study medications by the end of the study:

• Ketamine intravenous infusion (IV) AND
• Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient AND
• Two doses of TAK-063 at one of three dose levels All participants will be asked to take 3 tablets and will receive a ketamine IV on the first day of 3 separate study periods. Participants will then be assessed for brain activity changes and other symptoms. This single-center trial will be conducted in the United States. The overall time to participate in this study is up to 7 weeks. Participants will make 6 visits to the clinic.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Basic Science

Condition

• Ketamine-Induced Brain Activity Changes
• Psychotic-like Symptoms

Intervention

• Drug: Ketamine
  Ketamine intravenous administration.
  Other Name: Ketalar™
• Drug: TAK-063
  TAK-063 tablets
• Drug: TAK-063 Placebo
  TAK-063 placebo-matching tablets

Study Arms

• Experimental: Sequence 1: Placebo + TAK-063 3 mg + TAK-063 30 mg

  Period 1, Day 1: TAK-063 placebo-matching tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight; Period 2, Day 1: TAK-063 3 milligram (mg), orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight; Period 3, Day 1: TAK-063 30 mg tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight.

  Period 1 & 2 are followed by 7 day washout period.

  Interventions:

  • Drug: Ketamine
  • Drug: TAK-063
  • Drug: TAK-063 Placebo
• Experimental: Sequence 2: TAK-063 3 mg + TAK-063 30 mg + Placebo

  Period 1, Day 1: TAK-063 3 mg tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight; Period 2, Day 1: TAK-063 30 mg tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight; Period 3, Day 1: TAK-063 placebo-matching tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight.

  Period 1 & 2 are followed by 7 day washout period.

  Interventions:

  • Drug: Ketamine
  • Drug: TAK-063
  • Drug: TAK-063 Placebo
• Experimental: Sequence 3: TAK-063 30 mg + Placebo + TAK-063 3 mg

  Period 1, Day 1: TAK-063 30 mg tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight; Period 2, Day 1: TAK-063 placebo-matching tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight; Period 3, Day 1: TAK-063 3 mg tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight.

  Period 1 & 2 are followed by 7 day washout period.

  Interventions:

  • Drug: Ketamine
  • Drug: TAK-063
  • Drug: TAK-063 Placebo
• Experimental: Sequence 4: Placebo + TAK-063 3 mg + TAK-063 300 mg

  Period 1, Day 1: TAK-063 placebo-matching tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight; Period 2, Day 1: TAK-063 3 mg tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight; Period 3, Day 1: TAK-063 300 mg (participants enrolled before protocol amendment 3) or 10 mg (participants enrolled after protocol amendment 3), tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight.

  Period 1 & 2 are followed by 7 day washout period.

  Interventions:

  • Drug: Ketamine
  • Drug: TAK-063
  • Drug: TAK-063 Placebo
• Experimental: Sequence 5: TAK-063 3 mg + TAK-063 300 mg+ Placebo

  Period 1, Day 1: TAK-063 3 mg tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight; Period 2, Day 1: TAK-063 300 mg (participants enrolled before protocol amendment 3) or 10 mg (participants enrolled after protocol amendment 3), tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight; Period 3, Day 1: TAK-063 placebo-matching tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight.

  Period 1 & 2 are followed by 7 day washout period

  Interventions:

  • Drug: Ketamine
  • Drug: TAK-063
  • Drug: TAK-063 Placebo
• Experimental: Sequence 6: TAK-063 300 mg + Placebo + TAK-063 3 mg

  Period 1, Day 1: TAK-063 300 mg (participants enrolled before protocol amendment 3) or 10 mg (participants enrolled after protocol amendment 3), tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight; Period 2, Day 1: TAK-063 placebo-matching tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight; Period 3, Day 1: TAK-063 3 mg tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight.

  Period 1 & 2 are followed by 7 day washout period.

  Interventions:

  • Drug: Ketamine
  • Drug: TAK-063
  • Drug: TAK-063 Placebo
• Experimental: Sequence 7: Placebo + TAK-063 30 mg + TAK-063 300 mg

  Period 1, Day 1: TAK-063 placebo-matching tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight:

  Period 2, Day 1: TAK-063 30 mg tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight; Period 3, Day 1: TAK-063 300 mg (participants enrolled before protocol amendment 3) or 10 mg (participants enrolled after protocol amendment 3), tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight.

  Period 1 & 2 are followed by 7 day washout period

  Interventions:

  • Drug: Ketamine
  • Drug: TAK-063
  • Drug: TAK-063 Placebo
• Experimental: Sequence 8: TAK-063 30 mg + TAK-063 300 mg + Placebo

  Period 1, Day 1: TAK-063 30 mg tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight; Period 2, Day 1: TAK-063 300 mg (participants enrolled before protocol amendment 3) or 10 mg (participants enrolled after protocol amendment 3), tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight; Period 3, Day 1: TAK-063 placebo-matching tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight.

  Period 1 & 2 are followed by 7 day washout period.

  Interventions:

  • Drug: Ketamine
  • Drug: TAK-063
  • Drug: TAK-063 Placebo
• Experimental: Sequence 9: TAK-063 300 mg + Placebo + TAK-063 30 mg
  Period 1, Day 1: TAK-063 300 mg (participants enrolled before protocol amendment 3) or 10 mg (participants enrolled after protocol amendment 3), tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight; Period 2, Day 1: TAK-063 placebo-matching tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight; Period 3, Day 1: TAK-063 30 mg tablets, orally, single dose and ketamine, intravenous administration according to a bolus infusion adjusted to the participant's weight. Period 1 & 2 are followed by 7 day washout period
  Interventions:

  • Drug: Ketamine
  • Drug: TAK-063
  • Drug: TAK-063 Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 30, 2013): 27
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: August 2014
• Actual Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. In the opinion of the investigator, participant is capable of understanding and complying with protocol requirements.
2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
3. Is a healthy adult male.
4. Speaks English as their first language.
5. Is aged 18 to 45 years, inclusive, at the time of informed consent and first dose of study drug.
6. Weighs at least 50 kg and has a body mass index (BMI) between 18 and 32 kilogram per metre square (kg/m^2), inclusive at Screening.
7. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 12 weeks after last dose.
8. Has a normal magnetic resonance imaging (MRI) scan and electroencephalogram (EEG) measurement at Screening.

Exclusion Criteria:

1. Has received any investigational compound or ketamine within 30 days prior to Day 1 of Period 1.
2. Has received TAK-063 in a previous clinical study or as a therapeutic agent.
3. Is an immediate family member, study site employee, or in a dependent relationship with a study site employee who is involved in the conduct of this study (e.g., spouse, parent, child, sibling) or may consent under duress.
4. Has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, endocrine disease, or psychiatric disorder, or other abnormality (including MRI or EEG), which may impact the ability of the participant to participate or potentially confound the study results.
5. Has a known hypersensitivity to any component of the formulation of TAK-063 or ketamine.
6. Has a contraindication for ketamine.
7. Has a positive result for drugs or alcohol at Screening or Check-in (Day -1 of Period 1).
8. Has a history of drug or alcohol abuse or dependence (as defined by Diagnostic & Statistical Manual of Mental Disorders, fourth Edition [DSM-IV]) within 1 year prior to the screening visit or is unwilling to agree to abstain from alcohol and drugs throughout the study.
9. Has taken any excluded medication, supplements, or food products listed in the Excluded Medications and Dietary Products.
10. Has evidence of current cardiovascular, central nervous system (CNS), hepatic, hematopoietic disease, renal dysfunction, metabolic or endocrine dysfunction, serious allergy, asthma hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding in the participant's medical history, physical examination, or safety laboratory tests giving reasonable suspicion of a disease that would contraindicate taking TAK-063 or ketamine or a similar drug in the same class, or that might interfere with the conduct of the study. This includes, but is not limited to, peptic ulcer disease, seizure disorders, and cardiac arrhythmias.
11. Has current or recent (within 6 months) gastrointestinal disease that would be expected to influence the absorption of drugs (ie, a history of malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis frequent [more than once per week] occurrence of heartburn, or any surgical intervention [e.g., cholecystectomy]).
12. Has a history of cancer, except basal cell carcinoma which has been in remission for at least 5 years prior to Day 1 of Period 1.
13. Has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV), or a known history of human immunodeficiency virus infection at Screening.
14. Has used nicotine-containing products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days prior to Check-in (Day -1 of Period 1) or cotinine test is positive at Screening or Check-in (Day -1 of Period 1).
15. Has poor peripheral arterial/venous access or recent wrist trauma.
16. Has donated or lost 450 mL or more of his or her blood volume (including plasmapheresis), or had a transfusion of any blood product within 3 months prior to Day 1 of Period 1.
17. Has a Screening and/or Check-in (Day -1 of Period 1) abnormal (clinically significant) electrocardiogram (ECG). Participant has a supine blood pressure outside the ranges of 90 to 140 mm Hg for systolic and 50 to 90 mm Hg for diastolic, if out of range may be repeated once for eligibility determination at the Screening Visit or Check-in (Day -1 of Period 1).
18. Has a resting heart rate outside the range 50 to 90 beats per minute (bpm), if out of range may be repeated once for eligibility determination at the Screening Visit and/or Check-in (Day -1 of Period 1).
19. Has a QT interval with Fridericia correction method (QTcF) greater than (>) 430 milliseconds (ms) or PR outside the range 120 to 220 ms, if out of range may be repeated once for eligibility determination within a maximum of 5 minutes, at the Screening Visit and/or Check-in (Day -1 of Period 1).
20. Has abnormal Screening laboratory values that suggest a clinically significant underlying disease or participant with the following lab abnormalities: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >1.5 upper limit of normal (ULN).
21. Has a history of Axis I/II mental disorders according to DSM-IV Axis I/II such as depression, anxiety disorders, bipolar disorder, attention deficit/hyperactivity disorder (ADHD), autism spectrum disorders, anorexia nervosa, bulimia nervosa, and schizophrenia.
22. Has a history of head injury or trauma.
23. Has any condition that would prevent an MRI from accurately or safely being performed (e.g., claustrophobia, cardiac pacemaker, metallic implants or clips), as verified per study site's standard MRI assessment questionnaire.
24. Has a risk of suicide according to the Investigator's clinical judgment (e.g., per Columbia-Suicide Severity Rating Scale [C-SSRS]) or has made a suicide attempt in the previous 6 months prior to Screening.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years to 45 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01892189
• Other Study ID Numbers: TAK-063_102; U1111-1141-2177 ( Other Identifier: World Health Organization )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Takeda
• Study Sponsor: Takeda
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Takeda Development Center Americas, Inc.

• PRS Account: Takeda
• Verification Date: November 2016