Study to Determine D-amino Acid Oxidase Brain Enzyme Occupancy of TAK-831 After Single-dose Oral Administration
Study Details
Study Description
Brief Summary
The purpose of this study is to determine the relationship between TAK-831 dose, plasma exposure, extent and duration of brain D-amino acid oxidase (DAO) enzyme occupancy following single oral dosing of TAK-831 in healthy participants.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Detailed Description
The drug being tested in this study is called TAK-831. TAK-831 is a highly selective and potent inhibitor of DAO, a peroxisomal enzyme active towards neutral D-amino acids which potentially effects cerebellar dysfunction. This study will look at the relationship between TAK-831 plasma exposure and the extent and duration of brain DAO enzyme occupancy after single oral dosing of TAK-831 in healthy male participants using [18F]PGM299 radioactive tracer injection and PET imaging.
The study will enroll up to 22 participants in two different sets. Up to 16 participants will be enrolled in Set A. Within that total, up to 5 dose levels of TAK-831 may be evaluated, with up to 6 participants per dose level, although typically, there will be 2 to 3 participants per dose level. All participants in Set A will also receive up to 3 doses of [18F]PGM299. Up to 6 participants will be enrolled in Set B. All participants in Set B will be assigned to single treatment group to receive 2 doses of [18F]PGM299.
All participants in Set A will be asked to take single oral dose of TAK-831 suspension on Day
- In Set A, each of the participant will receive a maximum of 3 PET scans with [18F]PGM299; 1 at baseline 2 following a single oral dose of TAK-831 on Days 1 and 2. In Set B, each of the participant will receive 2 PET scans with [18F]PGM299 on Days 1 and 10. Set B will be conducted after the confirmation of blockade of [18F]PGM299 binding by TAK-831 in 2 to 4 participants of Set A.
This multi-center trial will be conducted in the United Kingdom. The overall time to participate in this study is 62 days. Participants in Set A will make 4 visits to the clinic, and participants in Set B will make 3 visits to the clinic and all will be contacted by telephone on Day 15 (Set A) and Day 12 (Set B) of treatment period for a follow-up assessment.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Set A: TAK-831 100 mg TAK-831 100 milligram (mg), suspension, orally, once on Day 1 and up to 100 megabecquerel (MBq) of Positron Emission Tomography (PET) ligand PGM028299 labeled with [18F] ([18F]PGM299) with a maximal mass up to 12.5 microgram (mcg), injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. |
Drug: TAK-831
TAK-831 oral suspension.
Drug: [18F]PGM299
[18F]PGM299 injection
|
| Experimental: Set A: TAK-831 200 mg TAK-831 200 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. |
Drug: TAK-831
TAK-831 oral suspension.
Drug: [18F]PGM299
[18F]PGM299 injection
|
| Experimental: Set A: TAK-831 250 mg TAK-831 250 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. |
Drug: TAK-831
TAK-831 oral suspension.
Drug: [18F]PGM299
[18F]PGM299 injection
|
| Experimental: Set A: TAK-831 500 mg TAK-831 500 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. |
Drug: TAK-831
TAK-831 oral suspension.
Drug: [18F]PGM299
[18F]PGM299 injection
|
| Experimental: Set B: [18F]PGM299 [18F]PGM299 up to 100 MBq (with a maximal mass up to 12.5 mcg), injection, intravenously, prior to PET imaging on Days 1 and 10. |
Drug: [18F]PGM299
[18F]PGM299 injection
|
Outcome Measures
Primary Outcome Measures
- Total Volume of Distribution (VT) of [18F]PGM299 in the Cerebellar Grey Matter (GM) for Each PET Scan [Set A: Baseline (PET scan 1), 2 hours (PET scan 2) and 26 hours (PET scan 3) post-TAK-831 dose; Set B: Day 1 (PET scan 1) and Day 10 (PET scan 2)]
- Non-displaceable Binding Potential (BPND) of [18F]PGM299 in the Cerebellar GM for Each PET Scan [Set A: Baseline (PET scan 1), 2 hours (PET scan 2) and 26 hours (PET scan 3) post-TAK-831 dose; Set B: Day 1 (PET scan 1) and Day 10 (PET scan 2)]
- D-amino Acid Oxidase (DAO) Occupancy Estimation in the Cerebellar GM [Set A: Baseline (PET scan 1), 2 hours (PET scan 2) and 26 hours (PET scan 3) post-TAK-831 dose; Set B: Day 1 (PET scan 1) and Day 10 (PET scan 2)]
DAO occupancy is calculated as percent difference between baseline and postdose [18F]PGM299 BPND for each participant.
Secondary Outcome Measures
- Set A: EC50- Plasma Concentration of TAK-831 That Corresponds to 50 Percent (%) DAO Brain Enzyme Occupancy in Cerebellum [Set A: Baseline, 2 and 26 hours post-TAK-831 dose]
EC50 was obtained from global VT model. The affinity constant relating plasma concentration of TAK-831 to DAO occupancy (EC50) was estimated by fitting the PET and plasma concentration data (VT, Cp). It was calculated as VT= VsBase (EC50/EC50+Cp) + VND, where Vs Base was the group-level (global) volume of distribution of the specific binding in the target region (cerebellar GM) and VND was the volume of distribution of the non-displaceable component (non-specific bound and free radiotracer) of the target region.
- Set A: Dose of TAK-831 That Corresponds to 50% DAO Brain Enzyme Occupancy in Cerebellum [Set A: At 2 and 26 hours post-TAK-831 dose]
Dose of TAK-831 that corresponds to 50% DAO brain enzyme occupancy in cerebellum at the time of maximum observed plasma concentration (Tmax) of TAK-831 was estimated.
- Set B: Coefficient of Variation (CoV) of [18F]PGM299 Binding in Healthy Human Brain [Set B: Baseline up to Day 10]
CoV was calculated as COV (P)(%) = 100 * mean/ standard deviation, where P was different participant scanned under baseline condition.
- Set A: Plasma Concentrations of TAK-831 During Each Post-TAK-831 Dosing PET Scan Periods [Set A: Days 1 and 2 At time 0 (at tracer injection), 60 minutes after tracer injection and 120 minutes after tracer injection for each post TAK-831 dosing PET scan period]
- Set A: Percent Change From Baseline to Post-TAK-831 Dose in AUEC(0-24)Serine: Area Under the Effect-time Curve From Time 0 to 24 Hours Post-TAK-831 Dose for Dextro-serine (D-serine) and Levo-serine (L-serine) [Set A: Baseline, 24 hours post-TAK-831 dose]
- Set A: Percent Change From Baseline to Post-TAK-831 Dose in AUEC(0-24)Serine: Area Under the Effect-time Curve From Time 0 to 24 Hours Post-TAK-831 Dose for Ratio of D-serine to Total Serine [Set A: Baseline, 24 hours post-TAK-831 dose]
- Set A: Percent Change in Maximum Drug-induced Effect (Emax,Serine) on Change in Plasma Concentrations of D-serine and L-serine [Set A: Baseline, 24 hours post-TAK-831 dose]
- Set A: Percent Change in Maximum Drug-induced Effect (Emax, D: Total Serine Ratio) on the Ratio of D-serine to Total Serine [Set A: Baseline, 24 hours post-TAK-831 dose]
- Set A: Time to Reach the Maximum PD Effect (Time to Emax,Serine) for D-serine and L-serine [Set A: Day -1 At 1, 4 and 12 hours post check-in and Day 1 pre-dose and at multiple time points (up to 24 hours) post-TAK-831 dose]
- Set A: Time to Reach the Maximum PD Effect (Time to Emax,Serine) for Ratio of D-serine to Total Serine [Set A: Day -1 At 1, 4 and 12 hours post check-in and Day 1 pre-dose and at multiple time points (up to 24 hours) post-TAK-831 dose]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Is capable of understanding and complying with protocol requirements.
-
Signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
-
Is in good health as determined by physical examination, electrocardiogram (ECG), and laboratory evaluations.
-
Is a healthy male aged 25 to 55 years, inclusive, at the time of informed consent and first injection of the PET tracer.
-
Weighs at least 45 kilogram (kg) and has a body mass index (BMI) from 18.0 to 30.0 kilogram per square meter (kg/m^2), inclusive, at Screening.
-
Agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 90 days after last dose.
Exclusion Criteria:
-
Has received any investigational compound or device within 3 months or 5 half-lives, whichever is longer, prior to Check-in for Screening.
-
Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in the conduct of this study (example, spouse, parent, child, sibling) or may consent under duress.
-
Has uncontrolled, clinically significant (CS), neurologic (including seizure disorder), cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal (GI), urologic, immunologic, or endocrine disease or psychiatric disorder, or other abnormality, which may impact the ability of the participant to participate or potentially confound the study results.
-
Has a known hypersensitivity to any component of the formulation of TAK-831 or related compounds, or to [18 F]PGM299 or to any of its components.
-
Has a positive urine or breath test result for drugs of abuse (defined as any illicit drug use), ethanol (alcohol), or cotinine at Screening, Check-in for Baseline Imaging/Confinement Period 1, or Check-in for the Treatment/Confinement Period 2 (Day -1) for a participant participating in Set A or at Screening, Check-in for Tracer TEST PET Imaging/Confinement Period 1, or Check-in for RE-TEST PET Imaging/Confinement Period 2 for a participant participating in Set B.
-
Has a history of drug abuse (defined as any illicit drug use) or a history of ethanol (alcohol) abuse within 1 year prior to the screening visit or is unwilling to agree to abstain from ethanol (alcohol) and drugs throughout the study.
-
Has taken any medication, supplements, or food products during the time periods listed in the excluded medications and dietary products table.
-
Intends to donate sperm during the course of this study or for 90 days after the last dose of study medication.
-
Has evidence of current cardiovascular, central nervous system, hepatic, or hematopoietic disease; renal, metabolic or endocrine dysfunction; serious allergy, asthma, hypoxemia, hypertension, or allergic skin rash; or 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-831 or a similar drug in the same class, which might interfere with the conduct of the study. This includes, but is not limited to, peptic ulcer disease and cardiac arrhythmias.
-
Has current or recent (within 6 months) GI disease that would be expected to influence the absorption of drugs (that is, a history of malabsorption), any surgical intervention known to impact absorption (example, bariatric surgery or bowel resection), esophageal reflux, peptic ulcer disease, erosive esophagitis, or frequent (more than once per week) occurrence of heartburn.
-
Has a history of cancer, except basal cell carcinoma that has been in remission for at least 5 years prior to Day 1.
-
Has a positive test result for hepatitis B virus surface antigen (HBsAg), hepatitis C virus (HCV) antibody (HCAB), or human immunodeficiency virus (HIV) infection at Screening.
-
Has used nicotine-containing products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 44 days prior to Check-in for Confinement Period 1. Cotinine test is positive at Screening, or Check-in for Confinement Period 1, or Confinement Period 2.
-
Has poor peripheral venous access.
-
Has an abnormal Allen's test in either upper extremity.
-
Has donated or lost 450 milliliter (mL) or more of his blood volume (including plasmapheresis), or had a transfusion of any blood product within 90 days prior to Confinement Period 1.
-
Has an abnormal CS ECG at Screening, Check-in for Confinement Period 1, or at Check-in for Confinement Period 2. Entry of any participant with an abnormal (not clinically significant [NCS]) ECG must be approved and documented by signature of the coordinating investigator or delegate.
-
Has a supine blood pressure outside the ranges of 100 to 140 millimeter of mercury (mm Hg) for systolic and 50 to 90 mm Hg for diastolic, confirmed with 1 repeat testing within a maximum of 30 minutes, at the Screening Visit, Check-in for Confinement Period 1, or Confinement Period 2.
-
Has a resting heart rate outside the range of 50 to 90 beats/minute, confirmed with 1 repeat testing within a maximum of 30 minutes, at the Screening Visit, Check-in for Confinement Period 1, or Confinement Period 2.
-
Has a Fridericia's Correction Formula (QTcF) - QTcF interval greater than (>) 450 millisecond (msec) or PR outside the range of 120 to 220 msec, confirmed with 1 repeat testing within a maximum of 30 minutes, at the Screening Visit, Check-in for Confinement Period 1, or Confinement Period 2.
-
Has abnormal Screening laboratory values that suggest a CS underlying disease or the following laboratory abnormalities: Alanine Aminotransferase (ALT) and/or Alanine serum transaminase AST >1.5*upper limit of normal (ULN).
-
Has a risk of suicide according to the investigator's clinical judgment (example, per Columbia-Suicide Severity Rating Scale [C-SSRS]) or has made an attempt in the previous 6 months.
-
Has had a seizure or convulsion (lifetime), including absence seizure and febrile convulsion.
-
In the opinion of the investigator, is unlikely to comply with the protocol or is unsuitable for any other reason.
-
Has had previous exposure to ionizing radiation such that, in combination with the exposure from this study, their exposure will be >10 millisievert (mSv) for the previous year.
-
Has a contraindication to medical resonance imaging (MRI) based on the standard MRI screening questionnaire. Contraindications include ferromagnetic foreign bodies (example, shrapnel, ferromagnetic fragments in the orbital area), certain implanted medical devices (example, aneurysm clips, cardiac pacemakers) or claustrophobia.
-
Has findings on screening brain MRI scan that will potentially compromise participant safety or the scientific integrity of the study data, if the participant were to participate in this study.
-
Has prolonged prothrombin time (PT) or activated partial thromboplastin time (PTT) or reduced platelet count (less than [<] 100*10^9/Liter [L]).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | London | United Kingdom |
Sponsors and Collaborators
- Neurocrine Biosciences
- Takeda
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- TAK-831-1003
- 2015-004509-17
- U1111-1176-7493
- 15/LO/1916
Study Results
Participant Flow
| Recruitment Details | Participants took part in the study at 2 investigative sites in the United Kingdom from 21-Mar-2016 to 30-Aug-2016. |
|---|---|
| Pre-assignment Detail | Healthy participants in Set A received up to 100 megabecquerel (MBq) of [18F]PGM299 for 3 PET scans at baseline, 2, and 26 hours post TAK-831. Set A participants also received a single dose of TAK-831 (100 milligram [mg], 200 mg, 250 mg, or 500 mg). Healthy participants in Set B received up 100 MBq of [18F]PGM299 for 2 PET scans on Day 1 and 10. |
| Arm/Group Title | Set A: TAK-831 100 mg | Set A: TAK-831 200 mg | Set A: TAK-831 250 mg | Set A: TAK-831 500 mg | Set B: [18F]PGM299 | Set A: [18F]PGM299 Baseline |
|---|---|---|---|---|---|---|
| Arm/Group Description | TAK-831 100 mg, suspension, orally, once on Day 1 and up to 100 MBq of Positron Emission Tomography (PET) ligand PGM028299 labeled with [18F] ([18F]PGM299) with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 200 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 250 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 500 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | [18F]PGM299 up to 100 MBq (with a maximal mass up to 12.5 mcg), injection, intravenously, prior to PET imaging on Days 1 and 10. | [18F]PGM299 up to 100 MBq with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline only. Participant in this reporting group discontinued from the study and did not receive any TAK-831 dose. |
| Period Title: Overall Study | ||||||
| STARTED | 4 | 2 | 5 | 2 | 6 | 1 |
| COMPLETED | 4 | 2 | 4 | 2 | 5 | 0 |
| NOT COMPLETED | 0 | 0 | 1 | 0 | 1 | 1 |
Baseline Characteristics
| Arm/Group Title | Set A: TAK-831 100 mg | Set A: TAK-831 200 mg | Set A: TAK-831 250 mg | Set A: TAK-831 500 mg | Set B: [18F]PGM299 | Set A: [18F]PGM299 Baseline | Total |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | TAK-831 100 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 200 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 250 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 500 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | [18F]PGM299 up to 100 MBq (with a maximal mass up to 12.5 mcg), injection, intravenously, prior to PET imaging on Days 1 and 10. | [18F]PGM299 up to 100 MBq with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline only. Participant in this reporting group discontinued from the study and did not receive any TAK-831 dose. | Total of all reporting groups |
| Overall Participants | 4 | 2 | 5 | 2 | 6 | 1 | 20 |
| Age (Count of Participants) | |||||||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
4
100%
|
2
100%
|
5
100%
|
2
100%
|
6
100%
|
1
100%
|
20
100%
|
| >=65 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Sex: Female, Male (Count of Participants) | |||||||
| Female |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Male |
4
100%
|
2
100%
|
5
100%
|
2
100%
|
6
100%
|
1
100%
|
20
100%
|
| Race (NIH/OMB) (Count of Participants) | |||||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
1
20%
|
0
0%
|
0
0%
|
0
0%
|
1
5%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
1
20%
|
1
50%
|
4
66.7%
|
0
0%
|
6
30%
|
| White |
3
75%
|
2
100%
|
3
60%
|
1
50%
|
2
33.3%
|
1
100%
|
12
60%
|
| More than one race |
1
25%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
5%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (Count of Participants) | |||||||
| United Kingdom |
4
100%
|
2
100%
|
5
100%
|
2
100%
|
6
100%
|
1
100%
|
20
100%
|
| Smoking Classification (Count of Participants) | |||||||
| Never smoked |
4
100%
|
2
100%
|
3
60%
|
2
100%
|
4
66.7%
|
1
100%
|
16
80%
|
| Ex-smoker |
0
0%
|
0
0%
|
2
40%
|
0
0%
|
2
33.3%
|
0
0%
|
4
20%
|
| Alcohol Classification (Count of Participants) | |||||||
| Never drunk |
0
0%
|
0
0%
|
2
40%
|
1
50%
|
1
16.7%
|
1
100%
|
5
25%
|
| Current drinker |
3
75%
|
2
100%
|
3
60%
|
1
50%
|
3
50%
|
0
0%
|
12
60%
|
| Ex-drinker |
1
25%
|
0
0%
|
0
0%
|
0
0%
|
2
33.3%
|
0
0%
|
3
15%
|
| Caffeine Consumption (Count of Participants) | |||||||
| Caffeine consumption |
4
100%
|
2
100%
|
5
100%
|
2
100%
|
3
50%
|
1
100%
|
17
85%
|
| No caffeine consumption |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
3
50%
|
0
0%
|
3
15%
|
Outcome Measures
| Title | Total Volume of Distribution (VT) of [18F]PGM299 in the Cerebellar Grey Matter (GM) for Each PET Scan |
|---|---|
| Description | |
| Time Frame | Set A: Baseline (PET scan 1), 2 hours (PET scan 2) and 26 hours (PET scan 3) post-TAK-831 dose; Set B: Day 1 (PET scan 1) and Day 10 (PET scan 2) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The set included all participants who had at least 1 technically adequate PET scan. |
| Arm/Group Title | Set A: TAK-831 100 mg | Set A: TAK-831 200 mg | Set A: TAK-831 250 mg | Set A: TAK-831 500 mg | Set B: [18F]PGM299 | Set A: [18F]PGM299 Baseline |
|---|---|---|---|---|---|---|
| Arm/Group Description | TAK-831 100 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 200 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 250 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 500 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | [18F]PGM299 up to 100 MBq (with a maximal mass up to 12.5 mcg), injection, intravenously, prior to PET imaging on Days 1 and 10. | [18F]PGM299 up to 100 MBq with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline only. Participant in this reporting group discontinued from the study and did not receive any TAK-831 dose. |
| Measure Participants | 4 | 2 | 5 | 2 | 6 | 1 |
| Participant 1- PET Scan 1 |
1.211
|
1.247
|
1.349
|
1.683
|
0.658
|
0.863
|
| Participant 1- PET Scan 2 |
0.400
|
0.126
|
0.247
|
0.114
|
1.109
|
NA
|
| Participant 1- PET Scan 3 |
1.467
|
0.543
|
0.58
|
1.182
|
NA
|
NA
|
| Participant 2- PET Scan 1 |
0.663
|
1.585
|
0.743
|
2.095
|
0.884
|
NA
|
| Participant 2- PET Scan 2 |
0.241
|
0.217
|
0.266
|
0.172
|
1.130
|
NA
|
| Participant 2- PET Scan 3 |
0.809
|
0.77
|
0.425
|
0.553
|
NA
|
NA
|
| Participant 3- PET Scan 1 |
1.397
|
NA
|
0.981
|
NA
|
1.504
|
NA
|
| Participant 3- PET Scan 2 |
0.858
|
NA
|
0.189
|
NA
|
1.388
|
NA
|
| Participant 3-PET Scan 3 |
1.078
|
NA
|
0.802
|
NA
|
NA
|
NA
|
| Participant 4- PET Scan 1 |
1.297
|
NA
|
0.853
|
NA
|
1.459
|
NA
|
| Participant 4- PET Scan 2 |
0.592
|
NA
|
0.254
|
NA
|
0.979
|
NA
|
| Participant 4-PET Scan 3 |
1.055
|
NA
|
0.67
|
NA
|
NA
|
NA
|
| Participant 5- PET Scan 1 |
NA
|
NA
|
0.976
|
NA
|
0.895
|
NA
|
| Participant 5- PET Scan 2 |
NA
|
NA
|
NA
|
NA
|
1.077
|
NA
|
| Participant 5- PET Scan 3 |
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
| Participant 6- PET Scan 1 |
NA
|
NA
|
NA
|
NA
|
1.036
|
NA
|
| Participant 6 -PET Scan 2 |
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
| Title | Non-displaceable Binding Potential (BPND) of [18F]PGM299 in the Cerebellar GM for Each PET Scan |
|---|---|
| Description | |
| Time Frame | Set A: Baseline (PET scan 1), 2 hours (PET scan 2) and 26 hours (PET scan 3) post-TAK-831 dose; Set B: Day 1 (PET scan 1) and Day 10 (PET scan 2) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The set included all participants who had at least 1 technically adequate PET scan. |
| Arm/Group Title | Set A: TAK-831 100 mg | Set A: TAK-831 200 mg | Set A: TAK-831 250 mg | Set A: TAK-831 500 mg | Set B: [18F]PGM299 | Set A: [18F]PGM299 Baseline |
|---|---|---|---|---|---|---|
| Arm/Group Description | TAK-831 100 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 200 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 250 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 500 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | [18F]PGM299 up to 100 MBq (with a maximal mass up to 12.5 mcg), injection, intravenously, prior to PET imaging on Days 1 and 10. | [18F]PGM299 up to 100 MBq with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline only. Participant in this reporting group discontinued from the study and did not receive any TAK-831 dose. |
| Measure Participants | 4 | 2 | 5 | 2 | 6 | 1 |
| Participant 1- PET Scan 1 |
10.99
|
7.31
|
6.71
|
8.96
|
3.77
|
5.49
|
| Participant 1- PET Scan 2 |
3.26
|
-0.28
|
0.47
|
-0.20
|
4.99
|
NA
|
| Participant 1- PET Scan 3 |
7.89
|
4.22
|
4.32
|
11.19
|
NA
|
NA
|
| Participant 2- PET Scan 1 |
3.88
|
8.38
|
3.53
|
13.35
|
13.49
|
NA
|
| Participant 2- PET Scan 2 |
1.01
|
0.16
|
0.25
|
0.06
|
5.89
|
NA
|
| Participant 2- PET Scan 3 |
4.39
|
6.06
|
2.17
|
4.59
|
NA
|
NA
|
| Participant 3- PET Scan 1 |
7.22
|
NA
|
4.80
|
NA
|
7.13
|
NA
|
| Participant 3- PET Scan 2 |
5.13
|
NA
|
0.01
|
NA
|
7.46
|
NA
|
| Participant 3-PET Scan 3 |
4.53
|
NA
|
3.53
|
NA
|
NA
|
NA
|
| Participant 4- PET Scan 1 |
7.37
|
NA
|
4.84
|
NA
|
7.48
|
NA
|
| Participant 4- PET Scan 2 |
2.72
|
NA
|
0.37
|
NA
|
4.35
|
NA
|
| Participant 4-PET Scan 3 |
11.13
|
NA
|
3.38
|
NA
|
NA
|
NA
|
| Participant 5- PET Scan 1 |
NA
|
NA
|
3.69
|
NA
|
5.30
|
NA
|
| Participant 5- PET Scan 2 |
NA
|
NA
|
NA
|
NA
|
6.38
|
NA
|
| Participant 5- PET Scan 3 |
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
| Participant 6- PET Scan 1 |
NA
|
NA
|
NA
|
NA
|
8.29
|
NA
|
| Participant 6- PET Scan 2 |
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
| Title | D-amino Acid Oxidase (DAO) Occupancy Estimation in the Cerebellar GM |
|---|---|
| Description | DAO occupancy is calculated as percent difference between baseline and postdose [18F]PGM299 BPND for each participant. |
| Time Frame | Set A: Baseline (PET scan 1), 2 hours (PET scan 2) and 26 hours (PET scan 3) post-TAK-831 dose; Set B: Day 1 (PET scan 1) and Day 10 (PET scan 2) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Due to variability in localization of [18F]PGM299 in both Cerebellar GM and Frontal Cortex GM, DAO occupancy estimation as a percent difference from baseline and post-TAK-831 dosing PET scans in Cerebellar GM based on VT values could not be made. |
| Arm/Group Title | Set A: TAK-831 100 mg | Set A: TAK-831 200 mg | Set A: TAK-831 250 mg | Set A: TAK-831 500 mg | Set A: [18F]PGM299 Baseline |
|---|---|---|---|---|---|
| Arm/Group Description | TAK-831 100 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 200 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 250 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 500 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | [18F]PGM299 up to 100 MBq with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline only. Participant in this reporting group discontinued from the study and did not receive any TAK-831 dose. |
| Measure Participants | 0 | 0 | 0 | 0 | 0 |
| Title | Set A: EC50- Plasma Concentration of TAK-831 That Corresponds to 50 Percent (%) DAO Brain Enzyme Occupancy in Cerebellum |
|---|---|
| Description | EC50 was obtained from global VT model. The affinity constant relating plasma concentration of TAK-831 to DAO occupancy (EC50) was estimated by fitting the PET and plasma concentration data (VT, Cp). It was calculated as VT= VsBase (EC50/EC50+Cp) + VND, where Vs Base was the group-level (global) volume of distribution of the specific binding in the target region (cerebellar GM) and VND was the volume of distribution of the non-displaceable component (non-specific bound and free radiotracer) of the target region. |
| Time Frame | Set A: Baseline, 2 and 26 hours post-TAK-831 dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PET target occupancy set included all participants who received study drug (TAK-831) and had a technically adequate baseline PET scan and at least 1 technically adequate post-TAK-831 dose PET scan. |
| Arm/Group Title | Set A: All Participants |
|---|---|
| Arm/Group Description | Participants received TAK-831 100, 200, 250 or 500 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. |
| Measure Participants | 12 |
| Mean (95% Confidence Interval) [nanogram per milliliter (ng/mL)] |
12.7
|
| Title | Set A: Dose of TAK-831 That Corresponds to 50% DAO Brain Enzyme Occupancy in Cerebellum |
|---|---|
| Description | Dose of TAK-831 that corresponds to 50% DAO brain enzyme occupancy in cerebellum at the time of maximum observed plasma concentration (Tmax) of TAK-831 was estimated. |
| Time Frame | Set A: At 2 and 26 hours post-TAK-831 dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PET target occupancy set included all participants who received study drug (TAK-831) and had a technically adequate baseline PET scan and at least 1 technically adequate post-TAK-831 dose PET scan. |
| Arm/Group Title | Set A: All Participants |
|---|---|
| Arm/Group Description | Participants received TAK-831 100, 200, 250 or 500 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. |
| Measure Participants | 12 |
| Number [mg] |
100
|
| Title | Set B: Coefficient of Variation (CoV) of [18F]PGM299 Binding in Healthy Human Brain |
|---|---|
| Description | CoV was calculated as COV (P)(%) = 100 * mean/ standard deviation, where P was different participant scanned under baseline condition. |
| Time Frame | Set B: Baseline up to Day 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis set included all participants in Set B who had completed technically evaluable test and re-test PET scans. |
| Arm/Group Title | Set B: [18F]PGM299 |
|---|---|
| Arm/Group Description | [18F]PGM299 up to 100 MBq (with a maximal mass up to 12.5 mcg), injection, intravenously, prior to PET imaging on Days 1 and 10. |
| Measure Participants | 5 |
| Number [percentage of CoV] |
30.13
|
| Title | Set A: Plasma Concentrations of TAK-831 During Each Post-TAK-831 Dosing PET Scan Periods |
|---|---|
| Description | |
| Time Frame | Set A: Days 1 and 2 At time 0 (at tracer injection), 60 minutes after tracer injection and 120 minutes after tracer injection for each post TAK-831 dosing PET scan period |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic(PK) set where data at specified time points post-tracer injection was available.PK set included all participants who received study drug(TAK-831)and had at least 1 measurable plasma concentration for TAK-831.Data was reported for Participant 1,2,3 and 4 of each of TAK-831 100,250mg and Participant 1 and 2 of TAK-831 200,500mg arms. |
| Arm/Group Title | Set A: TAK-831 100 mg | Set A: TAK-831 200 mg | Set A: TAK-831 250 mg | Set A: TAK-831 500 mg |
|---|---|---|---|---|
| Arm/Group Description | TAK-831 100 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 200 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 250 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 500 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. |
| Measure Participants | 4 | 2 | 4 | 2 |
| Day 1: pre-tracer dose |
211.250
|
416.500
|
273.750
|
1404.500
|
| Day 1: 60 minutes post-tracer dose |
83.375
|
129.050
|
122.725
|
376.500
|
| Day 1: 120 minutes post-tracer dose |
42.500
|
82.000
|
89.925
|
176.000
|
| Day 2: pre-tracer dose |
4.028
|
7.360
|
11.025
|
23.400
|
| Day 2: 60 minutes post-tracer dose |
3.140
|
5.205
|
9.658
|
28.455
|
| Day 2: 120 minutes post-tracer dose |
3.123
|
5.380
|
8.665
|
33.975
|
| Title | Set A: Percent Change From Baseline to Post-TAK-831 Dose in AUEC(0-24)Serine: Area Under the Effect-time Curve From Time 0 to 24 Hours Post-TAK-831 Dose for Dextro-serine (D-serine) and Levo-serine (L-serine) |
|---|---|
| Description | |
| Time Frame | Set A: Baseline, 24 hours post-TAK-831 dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| The pharmacodynamic (PD) set for D- and L-serine included all participants in Set A who received study drug (TAK-831) and had at least 1 measurable D- and L-serine plasma measurement both at pre-dose and following TAK-831 dosing. |
| Arm/Group Title | Set A: TAK-831 100 mg | Set A: TAK-831 200 mg | Set A: TAK-831 250 mg | Set A: TAK-831 500 mg |
|---|---|---|---|---|
| Arm/Group Description | TAK-831 100 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 200 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 250 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 500 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. |
| Measure Participants | 4 | 2 | 5 | 2 |
| D-serine |
8.65
(7.209)
|
21.90
(NA)
|
18.08
(8.309)
|
8.70
(NA)
|
| L-serine |
10.88
(5.905)
|
2.00
(NA)
|
-2.46
(10.301)
|
5.10
(NA)
|
| Title | Set A: Percent Change From Baseline to Post-TAK-831 Dose in AUEC(0-24)Serine: Area Under the Effect-time Curve From Time 0 to 24 Hours Post-TAK-831 Dose for Ratio of D-serine to Total Serine |
|---|---|
| Description | |
| Time Frame | Set A: Baseline, 24 hours post-TAK-831 dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PD set for D- and L-serine included all participants in Set A who received study drug (TAK-831) and had at least 1 measurable D- and L-serine plasma measurement both at pre-dose and following TAK-831 dosing. |
| Arm/Group Title | Set A: TAK-831 100 mg | Set A: TAK-831 200 mg | Set A: TAK-831 250 mg | Set A: TAK-831 500 mg |
|---|---|---|---|---|
| Arm/Group Description | TAK-831 100 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 200 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 250 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 500 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. |
| Measure Participants | 4 | 2 | 5 | 2 |
| Mean (Standard Deviation) [percent change] |
-1.18
(4.748)
|
19.75
(NA)
|
21.30
(6.958)
|
6.25
(NA)
|
| Title | Set A: Percent Change in Maximum Drug-induced Effect (Emax,Serine) on Change in Plasma Concentrations of D-serine and L-serine |
|---|---|
| Description | |
| Time Frame | Set A: Baseline, 24 hours post-TAK-831 dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PD set for D- and L-serine included all participants in Set A who received study drug (TAK-831) and had at least 1 measurable D- and L-serine plasma measurement both at pre-dose and following TAK-831 dosing. |
| Arm/Group Title | Set A: TAK-831 100 mg | Set A: TAK-831 200 mg | Set A: TAK-831 250 mg | Set A: TAK-831 500 mg |
|---|---|---|---|---|
| Arm/Group Description | TAK-831 100 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 200 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 250 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 500 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. |
| Measure Participants | 4 | 2 | 5 | 2 |
| D-serine |
9.58
(9.769)
|
27.05
(NA)
|
17.46
(9.122)
|
40.30
(NA)
|
| L-serine |
17.40
(7.318)
|
11.50
(NA)
|
-2.02
(12.917)
|
16.10
(NA)
|
| Title | Set A: Percent Change in Maximum Drug-induced Effect (Emax, D: Total Serine Ratio) on the Ratio of D-serine to Total Serine |
|---|---|
| Description | |
| Time Frame | Set A: Baseline, 24 hours post-TAK-831 dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PD set for D- and L-serine included all participants in Set A who received study drug (TAK-831) and had at least 1 measurable D- and L-serine plasma measurement both at pre-dose and following TAK-831 dosing. |
| Arm/Group Title | Set A: TAK-831 100 mg | Set A: TAK-831 200 mg | Set A: TAK-831 250 mg | Set A: TAK-831 500 mg |
|---|---|---|---|---|
| Arm/Group Description | TAK-831 100 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 200 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 250 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 500 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. |
| Measure Participants | 4 | 2 | 5 | 2 |
| Mean (Standard Deviation) [percent change] |
-1.40
(9.515)
|
20.95
(NA)
|
25.38
(12.604)
|
20.45
(NA)
|
| Title | Set A: Time to Reach the Maximum PD Effect (Time to Emax,Serine) for D-serine and L-serine |
|---|---|
| Description | |
| Time Frame | Set A: Day -1 At 1, 4 and 12 hours post check-in and Day 1 pre-dose and at multiple time points (up to 24 hours) post-TAK-831 dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PD set for D- and L-serine included all participants in Set A who received study drug (TAK-831) and had at least 1 measurable D- and L-serine plasma measurement both at pre-dose and following TAK-831 dosing. PD set where data at specified time points were available. |
| Arm/Group Title | Set A: TAK-831 100 mg | Set A: TAK-831 200 mg | Set A: TAK-831 250 mg | Set A: TAK-831 500 mg |
|---|---|---|---|---|
| Arm/Group Description | TAK-831 100 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 200 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 250 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 500 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. |
| Measure Participants | 4 | 2 | 5 | 2 |
| D-serine: Day -1 |
4.955
|
1.000
|
3.320
|
11.900
|
| D-serine: Day 1 |
18.000
|
18.000
|
15.206
|
25.100
|
| L-serine: Day -1 |
4.267
|
5.750
|
6.086
|
2.350
|
| L-serine: Day 1 |
13.993
|
24.000
|
12.026
|
30.200
|
| Title | Set A: Time to Reach the Maximum PD Effect (Time to Emax,Serine) for Ratio of D-serine to Total Serine |
|---|---|
| Description | |
| Time Frame | Set A: Day -1 At 1, 4 and 12 hours post check-in and Day 1 pre-dose and at multiple time points (up to 24 hours) post-TAK-831 dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PD set for D- and L-serine included all participants in Set A who received study drug (TAK-831) and had at least 1 measurable D- and L-serine plasma measurement both at pre-dose and following TAK-831 dosing. PD set where data at specified time points were available. |
| Arm/Group Title | Set A: TAK-831 100 mg | Set A: TAK-831 200 mg | Set A: TAK-831 250 mg | Set A: TAK-831 500 mg |
|---|---|---|---|---|
| Arm/Group Description | TAK-831 100 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 200 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 250 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. | TAK-831 500 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 26 hours post-TAK-831 dose. |
| Measure Participants | 4 | 2 | 5 | 2 |
| Day -1 |
6.875
|
1.000
|
1.875
|
11.100
|
| Day 1 |
26.725
|
25.000
|
23.750
|
30.100
|
Adverse Events
| Time Frame | Treatment-emergent adverse events are adverse events that started after the first dose of study drug up to Day 15 in set A and up to Day 12 in set B. | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | At each visit, investigator had to document any occurrence of adverse events and abnormal laboratory findings.Any event spontaneously reported by participant/observed by investigator was recorded,irrespective of relation to study treatment. | |||||||||||||||||||||||||||
| Arm/Group Title | Set A: [18F]PGM299 Dose 1 to Prior TAK-831 100 mg Dose | Set A: [18F]PGM299 Dose 1 to Prior TAK-831 200 mg Dose | Set A: [18F]PGM299 Dose 1 to Prior TAK-831 250 mg Dose | Set A: [18F]PGM299 Dose 1 to Prior TAK-831 500 mg Dose | Set A: TAK-831 100 mg Dose to Prior [18F]PGM299 Dose 2 | Set A: TAK-831 200 mg Dose to Prior [18F]PGM299 Dose 2 | Set A: TAK-831 250 mg Dose to Prior [18F]PGM299 Dose 2 | Set A: TAK-831 500 mg Dose to Prior [18F]PGM299 Dose 2 | SetA:TAK-831 100mg:[18F]PGM299 Dose 3 up to Follow-up (Day 15) | SetA:TAK-831 200mg:[18F]PGM299 Dose 3 up to Follow-up (Day 15) | SetA:TAK-831 250mg:[18F]PGM299 Dose 3 up to Follow-up (Day 15) | SetA:TAK-831 500mg:[18F]PGM299 Dose 3 up to Follow-up (Day 15) | Set B: [18F]PGM299 | Set A: [18F]PGM299 Baseline | ||||||||||||||
| Arm/Group Description | [18F]PGM299 up to 100 MBq with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline; and prior to TAK-831 100 mg, suspension, orally, once on Day 1. | [18F]PGM299 up to 100 MBq with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline; and prior to TAK-831 200 mg, suspension, orally, once on Day 1. | [18F]PGM299 up to 100 MBq with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline; and prior to TAK-831 250 mg, suspension, orally, once on Day 1. | [18F]PGM299 up to 100 MBq with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline; and prior to TAK-831 500 mg, suspension, orally, once on Day 1. | TAK-831 100 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at [18F]PGM299 Dose 2 (2 hours post-TAK-831 dose). | TAK-831 200 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at 18F]PGM299 Dose 2 (2 hours post-TAK-831 dose). | TAK-831 250 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at 18F]PGM299 Dose 2 (2 hours post-TAK-831 dose). | TAK-831 500 mg, suspension, orally, once on Day 1 and up to 100 MBq of [18F]PGM299 with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at 18F]PGM299 Dose 2 (2 hours post-TAK-831 dose). | [18F]PGM299 up to 100 MBq with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at 26 hours post-TAK-831 100 mg dose up to follow up on Day 15. | [18F]PGM299 up to 100 MBq with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at 26 hours post-TAK-831 200 mg dose up to follow up on Day 15. | [18F]PGM299 up to 100 MBq with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at 26 hours post-TAK-831 250 mg dose up to follow up on Day 15. | [18F]PGM299 up to 100 MBq with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at 26 hours post-TAK-831 500 mg dose up to follow up on Day 15. | [18F]PGM299 up to 100 MBq (with a maximal mass up to 12.5 mcg), injection, intravenously, prior to PET imaging on Days 1 and 10. | [18F]PGM299 up to 100 MBq with a maximal mass up to 12.5 mcg, injection, intravenously, prior to PET imaging at Baseline only. Participant in this reporting group discontinued from the study and did not receive any TAK-831 dose. | ||||||||||||||
All Cause Mortality |
||||||||||||||||||||||||||||
| Set A: [18F]PGM299 Dose 1 to Prior TAK-831 100 mg Dose | Set A: [18F]PGM299 Dose 1 to Prior TAK-831 200 mg Dose | Set A: [18F]PGM299 Dose 1 to Prior TAK-831 250 mg Dose | Set A: [18F]PGM299 Dose 1 to Prior TAK-831 500 mg Dose | Set A: TAK-831 100 mg Dose to Prior [18F]PGM299 Dose 2 | Set A: TAK-831 200 mg Dose to Prior [18F]PGM299 Dose 2 | Set A: TAK-831 250 mg Dose to Prior [18F]PGM299 Dose 2 | Set A: TAK-831 500 mg Dose to Prior [18F]PGM299 Dose 2 | SetA:TAK-831 100mg:[18F]PGM299 Dose 3 up to Follow-up (Day 15) | SetA:TAK-831 200mg:[18F]PGM299 Dose 3 up to Follow-up (Day 15) | SetA:TAK-831 250mg:[18F]PGM299 Dose 3 up to Follow-up (Day 15) | SetA:TAK-831 500mg:[18F]PGM299 Dose 3 up to Follow-up (Day 15) | Set B: [18F]PGM299 | Set A: [18F]PGM299 Baseline | |||||||||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | ||||||||||||||
Serious Adverse Events |
||||||||||||||||||||||||||||
| Set A: [18F]PGM299 Dose 1 to Prior TAK-831 100 mg Dose | Set A: [18F]PGM299 Dose 1 to Prior TAK-831 200 mg Dose | Set A: [18F]PGM299 Dose 1 to Prior TAK-831 250 mg Dose | Set A: [18F]PGM299 Dose 1 to Prior TAK-831 500 mg Dose | Set A: TAK-831 100 mg Dose to Prior [18F]PGM299 Dose 2 | Set A: TAK-831 200 mg Dose to Prior [18F]PGM299 Dose 2 | Set A: TAK-831 250 mg Dose to Prior [18F]PGM299 Dose 2 | Set A: TAK-831 500 mg Dose to Prior [18F]PGM299 Dose 2 | SetA:TAK-831 100mg:[18F]PGM299 Dose 3 up to Follow-up (Day 15) | SetA:TAK-831 200mg:[18F]PGM299 Dose 3 up to Follow-up (Day 15) | SetA:TAK-831 250mg:[18F]PGM299 Dose 3 up to Follow-up (Day 15) | SetA:TAK-831 500mg:[18F]PGM299 Dose 3 up to Follow-up (Day 15) | Set B: [18F]PGM299 | Set A: [18F]PGM299 Baseline | |||||||||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/4 (0%) | 0/2 (0%) | 0/5 (0%) | 0/2 (0%) | 0/4 (0%) | 0/2 (0%) | 0/5 (0%) | 0/2 (0%) | 0/4 (0%) | 0/2 (0%) | 0/5 (0%) | 0/2 (0%) | 0/6 (0%) | 0/1 (0%) | ||||||||||||||
Other (Not Including Serious) Adverse Events |
||||||||||||||||||||||||||||
| Set A: [18F]PGM299 Dose 1 to Prior TAK-831 100 mg Dose | Set A: [18F]PGM299 Dose 1 to Prior TAK-831 200 mg Dose | Set A: [18F]PGM299 Dose 1 to Prior TAK-831 250 mg Dose | Set A: [18F]PGM299 Dose 1 to Prior TAK-831 500 mg Dose | Set A: TAK-831 100 mg Dose to Prior [18F]PGM299 Dose 2 | Set A: TAK-831 200 mg Dose to Prior [18F]PGM299 Dose 2 | Set A: TAK-831 250 mg Dose to Prior [18F]PGM299 Dose 2 | Set A: TAK-831 500 mg Dose to Prior [18F]PGM299 Dose 2 | SetA:TAK-831 100mg:[18F]PGM299 Dose 3 up to Follow-up (Day 15) | SetA:TAK-831 200mg:[18F]PGM299 Dose 3 up to Follow-up (Day 15) | SetA:TAK-831 250mg:[18F]PGM299 Dose 3 up to Follow-up (Day 15) | SetA:TAK-831 500mg:[18F]PGM299 Dose 3 up to Follow-up (Day 15) | Set B: [18F]PGM299 | Set A: [18F]PGM299 Baseline | |||||||||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 2/4 (50%) | 0/2 (0%) | 1/5 (20%) | 0/2 (0%) | 0/4 (0%) | 0/2 (0%) | 2/5 (40%) | 1/2 (50%) | 2/4 (50%) | 0/2 (0%) | 0/5 (0%) | 1/2 (50%) | 0/6 (0%) | 0/1 (0%) | ||||||||||||||
| Gastrointestinal disorders | ||||||||||||||||||||||||||||
| Nausea | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 1/5 (20%) | 1 | 1/2 (50%) | 1 | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/6 (0%) | 0 | 0/1 (0%) | 0 |
| General disorders | ||||||||||||||||||||||||||||
| Catheter site pain | 1/4 (25%) | 1 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 2/5 (40%) | 2 | 0/2 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/6 (0%) | 0 | 0/1 (0%) | 0 |
| Catheter site bruise | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 1/2 (50%) | 1 | 0/6 (0%) | 0 | 0/1 (0%) | 0 |
| Catheter site haematoma | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/6 (0%) | 0 | 0/1 (0%) | 0 |
| Nervous system disorders | ||||||||||||||||||||||||||||
| Headache | 1/4 (25%) | 1 | 0/2 (0%) | 0 | 1/5 (20%) | 1 | 0/2 (0%) | 0 | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/6 (0%) | 0 | 0/1 (0%) | 0 |
| Dizziness | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 1/5 (20%) | 1 | 0/2 (0%) | 0 | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/6 (0%) | 0 | 0/1 (0%) | 0 |
| Paraesthesia | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/6 (0%) | 0 | 0/1 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||||||||||||||||
| Throat irritation | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 2/5 (40%) | 2 | 0/2 (0%) | 0 | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/6 (0%) | 0 | 0/1 (0%) | 0 |
| Vascular disorders | ||||||||||||||||||||||||||||
| Peripheral coldness | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 1/4 (25%) | 1 | 0/2 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/6 (0%) | 0 | 0/1 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Generally, the PI may publish results of the study following the publication of results by the Sponsor.
Results Point of Contact
| Name/Title | Neurocrine Medical Information |
|---|---|
| Organization | Neurocrine Biosciences |
| Phone | 877-641-3461 |
| medinfo@neurocrine.com |
- TAK-831-1003
- 2015-004509-17
- U1111-1176-7493
- 15/LO/1916