Phase 1 TAK-041 First-in-Human Safety, Tolerability, and Pharmacokinetics Study
Condition: Healthy Volunteers; Schizophrenia
MeSH terms: Schizophrenia
Intervention: TAK-041; TAK-041 Placebo
Intervention description: TAK-041 tablets or oral suspension.; TAK-041 placebo-matching suspension or tablet.
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 114.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Drug Therapy

Summary:

      The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics (PK)
      of TAK-041:

        1. Following oral single and multiple doses in healthy participants.

        2. As add-on therapy to antipsychotics in stable schizophrenia participants.

        3. To determine the oral bioavailability of the TAK-041 tablet formulation compared to the
           oral suspension formulation in the fasted state.

        4. To assess the effect of food on the PK of TAK-041 in healthy participants.
    

Eligibility criteria:

        Inclusion Criteria:

        Healthy Participants and Participants with Schizophrenia:

          1. In the opinion of the investigator, the participant is capable of understanding and
             complying with protocol requirements.

          2. The participant signs and dates a written, informed consent form and any required
             privacy authorization prior to the initiation of any participant procedures including
             requesting that a participant fast for any laboratory evaluations.

          3. The participant is willing to comply with study restrictions described in the
             protocol.

          4. The participant is a healthy adult man or woman (of non-childbearing potential as
             described in the protocol)

          5. The participant is aged 18 to 55 years, inclusive, at the time of informed consent.

          6. The participant weighs at least 45 kilogram (kg) (99 pound [lb]) with a body mass
             index from 18 to 32 kilogram per square meter (kg/m^2) for healthy participants and up
             to 40.5 kg/m^2 for participants with schizophrenia, 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 (as defined in the
             protocol)from signing of informed consent throughout the duration of the study and for
             145 days have elapsed since the last dose of study drug.

        Participants with schizophrenia only-:

          1. Is on a stable dose of an antipsychotic medication for at least 2 months as documented
             by medical history and assessed by site staff.

          2. Meets schizophrenia criteria as defined by the Diagnostic and Statistical Manual of
             Mental Disorders, Fifth Edition (DSM-5) by the Mini International Neuropsychiatric
             Interview (MINI).

          3. Has Positive and Negative Syndrome Scale (PANSS) total score less than or equal to
             (<=) 90 and PANSS Negative Symptom Factor Score (NSFS; Sum of PANSS N1, N2, N3, N4,
             N6, G7, and G16) greater than or equal to (>=) 15 at screening and baseline (Day-1).

          4. Has stable screening and baseline (Day -1) PANSS and NSFS total scores (less than [<]
             20 percent (%) change).

        Exclusion Criteria:

        Healthy Participants:

          1. The participant has received any investigational compound within 30 days prior to the
             first dose of study drug, or due to the half-life of the investigational drug is
             likely to still have detectable plasma levels of that compound.

          2. The participant 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

          3. The participant has a known hypersensitivity to any component of the formulation of
             TAK-041.

          4. The participant has a positive urine/blood drug result for drugs of abuse (defined as
             any illicit drug use) at Screening or Check-in (Day -1).

          5. The participant taken any excluded medication, supplements, or food products during
             the time periods listed in the protocol.

          6. The participant is lactose intolerant (Part3 only).

          7. If female, the participant is of childbearing potential (example, premenopausal, not
             sterilized).

          8. If male, the participant intends to donate sperm during the course of this study or
             for 145 days have elapsed since the last dose of study drug.

          9. The participant has evidence of current active cardiovascular, central nervous system,
             hepatobiliary disease including history of biliary tree disorders, gallstones,
             endoscopic retrograde cholangio pancreatography (ERCP), and/or cholecystectomy,
             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 test results (including elevated alkaline phosphatase (ALP), elevated
             bilirubin, elevated GGT, or elevated 5'-nucleotidase) that in the judgment of the
             principal investigator represents a reasonable suspicion of a disease that would
             contraindicate taking TAK-041, or that might interfere with the conduct of the study.
             This includes, but is not limited to, peptic ulcer disease, cholestasis, seizure
             disorders, and cardiac arrhythmias.

         10. The participant has current or recent (within 6 months) gastrointestinal disease that
             would be expected to influence the absorption of drugs (that is, a history of
             malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis, frequent
             [more than once per week] occurrence of heartburn, or any surgical intervention).

         11. Had major surgery, or donated or lost 1 unit of blood (approximately 500 mL) within 4
             weeks prior to Screening.

         12. The participant has a history of cancer, except basal cell carcinoma that has been in
             remission for at least 5 years prior to Day 1. Participant has a positive test result
             for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody at Screening
             or a known history of human immunodeficiency virus (HIV) infection.

         13. The participant has used nicotine-containing products (including but not limited to
             cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 21
             days prior to Check-in on Day -1. Cotinine test is positive at Screening or Day -1.

         14. The participant has poor peripheral venous access.

         15. Had a transfusion of any blood product within 30 days prior to Day 1.

         16. Participant has a Screening or Check-in abnormal (clinically significant)
             electrocardiogram (ECG). Entry of any participant with an abnormal (not clinically
             significant) ECG must be approved, and documented by signature of the principal
             investigator or a medically qualified sub-investigator.

         17. The participant has a sustained resting heart rate outside the range 40 to 100 beats
             per minute (bpm), confirmed on repeat testing within a maximum of 30 minutes, at
             Screening or Check-in.

         18. The participant has a QT interval with Fridericia correction method (QTcF) >450
             millisecond (ms) or PR outside the range 120 to 220 ms, confirmed on repeat testing
             within a maximum of 30 minutes, at the Screening Visit or Check-in.

         19. The participant has abnormal Screening or Check-in laboratory values (> upper limit of
             normal [ULN] for the respective serum chemistries) of alanine transaminase (ALT),
             aspartate aminotransferase (AST), total bilirubin (TBILI), ALP, gamma-glutamyl
             transpeptidase (GGT), 5'nucleotidase (Screening only) and/or abnormal urine
             osmolality, confirmed upon repeat testing.

         20. The participant has a clinically significant history of head injury or trauma
             associated with loss of consciousness for >15 minutes.

         21. Is considered by the investigator to be at an imminent risk of suicide injury to self,
             other, property, or participants who within the past year prior to Screening have
             attempted suicide. Participants having positive answer on item 4 or 5 on Columbia
             Suicide Severity Rating Scale (C-SSRS) (based on the past year) prior to randomization
             are excluded.

         22. The participant has a history of significant skin reactions (hypersensitivity) to
             adhesives, metals or plastic; this criterion applies only to participants
             participating in the study of the two wearable digital devices.

        Participants with schizophrenia only:

          1. Has an undetectable level of baseline antipsychotic medication at Screening.

          2. Has a lifetime diagnosis of schizoaffective disorder; a lifetime diagnosis of bipolar
             disorder; or a lifetime diagnosis of obsessive compulsive disorder based on the Mini
             International Neuropsychiatric Interview (MINI) combined with the general psychiatric
             evaluation. As an exception, participants with a historical prior lifetime diagnosis
             of schizoaffective disorder may be enrolled in the study with sponsor or designee
             approval provided that the principal investigator can attest that the participant's
             overall history and current clinical presentation and history is most consistent with
             schizophrenia, not schizoaffective disorder.

          3. Has a recent (within the last 6 months) diagnosis of panic disorder, depressive
             episode, or other comorbid psychiatric conditions requiring clinical attention based
             on the MINI for DSM-5 and the general psychiatric evaluation.

          4. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol
             abuse (defined as 4 or more alcoholic beverages per day) within 1 year prior to the
             Screening Visit or is unwilling to agree to abstain from alcohol and drugs throughout
             the study.

          5. Has a diagnosis of substance use disorder (with the exception of nicotine dependence)
             within the preceding 6 months based on the MINI for DSM-5 and the general psychiatric
             evaluation.

          6. Has evidence or history of current clinically significant cardiovascular disease,
             including uncontrolled hypertension (standing or supine diastolic blood pressure >90
             millimeter of mercury (mm Hg) and/or standing or supine systolic blood pressure >145
             mm Hg, with or without treatment), symptomatic ischemic heart disease, uncompensated
             heart failure or recent (past 12 months) acute myocardial infarction or bypass
             surgery. Controlled essential hypertension, non-clinically significant sinus
             bradycardia and sinus tachycardia will not be considered significant medical illnesses
             and would not exclude a participant from the study. Other well-controlled medical
             illnesses may be permitted that do not increase hepatic risks or other safety risks to
             the participant's participation in the judgement of the investigator in consultation
             with the sponsor or designee.

          7. Has evidence of clinically significant extrapyramidal symptoms as measured by a
             Simson-Angus Scale (SAS) score >6.

          8. The participant has evidence of depression as measured by a Calgary Depression Score
             (CDSS) score >9.

          9. Has received TAK-041 in a previous clinical study; or has previously or is currently
             participating in this study; has received treatment with other experimental therapies
             within the preceding 60 days or <5 half-lives prior to randomization, whichever is
             longer; has participated in 2 or more clinical studies within 12 months prior to
             Screening; or has participated in a clinical study for a psychiatric condition that is
             exclusionary per this protocol.