| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039626 |
| E.1.2 | Term | Schizophrenia |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine whether TAK-831 is superior to placebo in improving the
average % of conditioned responses during the eyeblink conditioning
(EBC) test. |
|
| E.2.2 | Secondary objectives of the trial |
To determine whether add-on TAK-831 can be discriminated from
placebo during the Task Set Switching (TSS) paradigm as measured by
the pattern of functional magnetic resonance imaging (fMRI) blood
oxygen level-dependent activation. To determine whether add-on TAK-
831 compared to placebo increases ventral striatum activation as
measured by fMRI BOLD during the monetary incentive delay task
(MID). To determine whether add-on TAK-831 compared to placebo
improves sensory processing as measured by event-related potentials
(ERPs) mismatch negativity (MMN) and p300. To determine whether
add-on TAK-831 compared to placebo improves the auditory steadystate
response (ASSR) to 40 Hz stimulation. To determine whether addon
TAK-831 compared to placebo increases cerebellar blood flow as
measured by arterial spin labeling (ASL). To determine whether add-on
TAK-831 compared to placebo improves the composite score of a
neurocognitive test battery. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Understand the study procedures and agree to participate by providing written informed consent.
2. Be willing and able to comply with all study procedures and restrictions (see Sections 7.3 and 7.4 for a summary of restrictions).
3. Be male or a female aged 18 to 50 years, inclusive, at the Screening Visit.
4. Have a body mass index (BMI) ≥18.5 and ≤33.0 (kg/m2) at the Screening Visit.
5. Had a structural brain MRI within the preceding year or during screening indicating no concerning structural brain abnormalities or that would interfere with interpretation of functional brain imaging results.
6. Be judged to be in good health by the investigator, based on clinical evaluations including laboratory safety tests, medical history, physical examination, 12-lead ECG, and vital sign measurements performed at the Screening Visit and prior to administration of the initial dose
of study drug/invasive procedure.
7. Meet the following birth control requirements:
– Is a male subject who is sterile or agrees to use an appropriate method of contraception, including a condom with spermicide, from study drug administration on the first day of the first dose until 5 half lives plus 90 days after the last dose of study drug administration. No
restrictions are required for a vasectomized male subject provided the subject is at least 1 year post–bilateral vasectomy procedure prior to study drug administration on first day of the first dose. A male subject whose vasectomy procedure was performed less than 4 months prior to study drug administration on the first day of the first dose must follow the same restrictions as a nonvasectomized male. Appropriate documentation of surgical procedure should be provided.
– Is a male subject who agrees to not donate sperm from study drug administration on the first day of the first dose until 5 half lives plus 90 days after the last dose of study drug administration.
– Is a female subject with no childbearing potential, defined by at least 1 of the following criteria:
a) Postmenopausal (defined as 12 months of spontaneous amenorrhea in females aged >45 years, 6 months of spontaneous amenorrhea in females aged >45 years with serum follicle-stimulating hormone [FSH] levels >40 mIU/mL). Appropriate documentation of FSH levels is required.
b) Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate
documentation of surgical procedure.
c) Had a tubal ligation with appropriate documentation of surgical procedure.
d) Has a congenital condition resulting in no uterus.
– Is a female subject with child-bearing potential must have the following criteria:
a) A negative pregnancy test at Screening and Baseline.
b) Agrees to use 2 forms of contraception methods.
c) Is not breastfeeding.
8. With a current DSM-5 diagnosis of schizophrenia who are receiving stable antipsychotic therapy (no increase, no decrease >20% in dose in the preceding 2 months).
9. With stable screening and baseline PANSS total and NSFS scores (<20% change); PANSS total ≤90; NSFS ≥15.
10. Receiving stable antipsychotic medication at doses not to exceed risperidone 10 mg or its equivalent.
11. Able to swallow study drug in tablet form.
12. Should a patient require a caregiver to accompany him/her during the study, the caregiver should be available for the full duration of the study. |
|
| E.4 | Principal exclusion criteria |
1. Has participated in another investigational study within 30 days prior to the prestudy (screening) visit or <5 half-lives prior to the first dose. The 30 days window will be derived from the date of the last study procedure and/or adverse event (AE) related to the study procedure in the previous study to the prestudy/Screening Visit of the current study.
2. Is an employee or immediate family member (eg, spouse, parent, child, sibling) of the study site personnel or of the Sponsor.
3. Has a history of cancer (malignancy) excluding treated basal cell carcinoma or treated stage 0 (in situ) cervical carcinoma.
4. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy) or has had an anaphylactic reaction or significant intolerability to prescription or nonprescription drugs or food.
5. Subject has a QT interval with Fridericia’s correction method (QTcF) >450 ms (males) or >470 ms (females) confirmed with one repeat testing, at the Screening Visit or Check-in.
6. Has a positive alcohol or drug screen.
7. Has a positive pregnancy test or plan to become pregnant during the study (female subjects only).
8. Is positive for hepatitis B surface antigen (HBsAg), hepatitis C antibodies, or human immunodeficiency virus (HIV) (confirmatory testing is allowed; most sensitive test should take precedence).
9. Had major surgery, donated or lost 250 mL of blood within 4 weeks prior to the prestudy (screening) visit.
10. Use of disallowed concomitant medications.
11. Is unable to refrain from or anticipates the use of any medication (except those prescribed), including prescription and nonprescription drugs or herbal remedies beginning approximately 7 days prior to administration of the initial dose of study drug, throughout the study (including washout intervals between treatment periods), until the poststudy visit. There may be certain medications that are permitted, see Section 7.3.
12. Consumes >15 cigarettes/day or is unable to refrain from nicotine consumption for >5 hours
13. Unwilling or unable to comply with the requirements of the protocol, including inability to participate in magnetic resonance imaging (MRI) scanning.
14. Subject has a known hypersensitivity to any component of the formulation of TAK-831
15. If male, the subject intends to donate sperm during the course of this study or for 184 days (ie, 90 days after 5 half-lives) have elapsed since the last dose of study drug.
16. Subject has a history of significant skin reactions (hypersensitivity) to adhesives, metals or plastic.
17. The subject is considered by the investigator to be at imminent risk of suicide or injury to self, others, or property, or subjects who within the past year prior to Screening have attempted suicide. Subjects who have positive answers on item 4 or 5 on the C-SSRS (based on the past year) prior to randomization are excluded.
18. Ongoing disability, medical or neurological history, cognitive impairment or conditions that, in the opinion of the investigator, may interfere with study conduct or clinical assessments, including but not limited to:
a) Panic attacks, depressive episode or other major psychiatric comorbid conditions within the preceding 6 months.
b) Substance abuse or dependence (with the exception of nicotine dependence) within the preceding 12 months.
c) Positive drug screen for disallowed substances.
d) Evidence of extrapyramidal AEs as measured by a SAS score >6
e) Evidence of depression as measured by a CDSS score >9.
f) Presence of certain implanted medical devices, ferromagnetic metallic foreign bodies or claustrophobia preventing participation in MRI scanning.
g) Hearing deficits preventing participation in event related potential testing.
h) History of brain trauma associated with loss of consciousness for >15 minutes. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Average % of conditioned responses during the EBC test. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1.Computed probability that the pattern of fMRI BOLD activation
during the TSS paradigm came from a subject receiving add-on TAK-
831 treatment at that time.
2.fMRI BOLD signal in the ventral striatum during the anticipation
period of reward trials vs the anticipation period of the neutral trials of
the MID.
3.MMN amplitude at Fz (electroencephalogram [EEG]).
4.P300 amplitude at midline parietal electrode (Pz) (EEG).
5.ASSR at midline central electrode (Cz) (EEG).
6.Cerebellar blood flow (CBF) using ASL in cerebellar grey matter.
7.Cognitive battery composite score.
8.Plasma D-serine and L-serine levels, and plasma D-serine:total
serine ratio.
9.TAK-831 plasma concentrations. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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