Safety, Tolerability, and Pharmacokinetics of Multiple-Dose TAK-058 in Healthy Participants

Phase 1

Completed

• Conditions: Healthy Volunteers
• Interventions: Drug: TAK-058; Drug: TAK-058 Placebo

• Registration Number: NCT02389881
• Lead Sponsor: Takeda

Brief Summary

The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of multiple doses of TAK-058 in healthy non-elderly and elderly participants.

Detailed Description

The drug being tested in this study is TAK-058, which is under evaluation for the treatment of schizophrenia.

This study will enroll approximately 32 healthy non-elderly and 8 healthy elderly participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the five treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

* Cohort 1 Non-elderly Healthy: TAK-058 25 mg

* Cohort 2 Non-elderly Healthy: TAK-058 75 mg

* Cohort 3 Non-elderly Healthy: TAK-058 150 mg

* Cohort 4 Elderly Healthy: TAK-058 25 mg

* Cohort 5 Non-elderly Healthy: TAK-058 300 mg

* Cohort 1-4 Non Elderly Placebo (dummy inactive solution) - this is an oral solution that looks like the study drug but has no active ingredient.

* Cohort 5 Elderly Placebo This single-center trial will be conducted in the United States. The overall time to participate in this study is 40 days if assigned to Cohort 1 to 4. Participants will be confined to the clinic for 12 days, and will be contacted by telephone 11 and 30 days after last dose of study drug for a follow-up assessment (Days 21 and 40).

The overall time to participate in this study is 14 days if assigned to Cohort 5. Participants will be confined to the clinic for 4 days, and will be contacted by telephone 14 days after last dose of study drug for a follow-up assessment (Day 14).

Study Timeline

• Study Start: 2015-02
• Study First Submitted: 2015-03-10
• Study First Submitted QC: 2015-03-10
• Study First Posted: 2015-03-17
• Primary Completion: 2015-12
• Study Completion: 2015-12
• Results First Submitted: 2016-10-07
• Status Verified: 2017-01
• Results First Submitted QC: 2017-01-03
• Last Update Submitted: 2017-01-03
• Results First Posted: 2017-02-23
• Last Update Posted: 2017-02-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

• Ages for this study are 18 to 60 years for non-elderly and 18 to 65 years for elderly.
• 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.
• A female participant with no childbearing potential, which is defined as the subject has been surgically sterilized (hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (defined as continuous amenorrhea of at least 2 years and follicle-stimulating hormone [FSH]>40 IU/L).
• Weighs at least 45 kg (99 lbs) and has a body mass index (BMI) between 18.0 and 30.0 kg/m^2, inclusive at Screening.

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Exclusion Criteria

• Has received any investigational compound within 30 days prior to the first dose of study medication.
• Has received TAK-058 in a previous clinical study.
• 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 (eg, spouse, parent, child, sibling) or may consent under duress.
• Has a known hypersensitivity to any component of the formulation of TAK-058.
• Has a positive urine drug result for drugs of abuse at Screening or Check-in (Day -1).
• Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 6 months prior to the Screening Visit or is unwilling to agree to abstain from alcohol and drugs throughout the study.
• Female participants of childbearing potential (premenopausal, non-sterilized), or has a positive pregnancy test.
• Male participants that intend to donate sperm during the course of this study or for 12 weeks thereafter.
• Has evidence of current cardiovascular, central nervous system, 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 subject's medical history, physical examination, or safety laboratory tests giving reasonable suspicion of a disease that would contraindicate taking TAK-058, 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.
• Has previously had a seizure or convulsion (lifetime), including absence seizure and febrile convulsion.
• Has current or recent (within 6 months) gastrointestinal disease that would be expected to influence the absorption of drugs (ie, a history of malabsorption, any surgical intervention known to impact absorption [eg, 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 or other malignancy, 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 surface antigen (HBsAg), antibody to hepatitis C virus (anti-HCV) or a known history of human immunodeficiency virus infection at Screening.
• Has poor peripheral venous access.
• 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 45 days prior to Day 1.
• Has a Screening or Check-in (Day -1) abnormal (clinically significant [CS]) electrocardiogram (ECG).
• Has a supine blood pressure outside the ranges of 90 to 140 mm Hg for systolic and 60 to 90 mm Hg for diastolic, confirmed with one repeat testing within a maximum of 5 minutes, at the Screening Visit or Check-in (Day -1) Visit.
• Has a resting heart rate outside the range 50 to 100 bpm, confirmed with repeat testing within a maximum of 5 minutes, at the Screening Visit or Check-in (Day -1) Visit.
• Has a QT interval with Fridericia's correction method (QTcF) >450 ms (males) or >470 ms (females) or PR outside the range of 120 to 220 ms, confirmed with one repeat testing within a maximum of 5 minutes, at the Screening Visit or Check-in (Day -1) Visit.
• Has abnormal Screening or Check-in (Day -1) laboratory values that suggest a CS underlying disease or subject with the following lab abnormalities: ALT and/or AST >1.5 the upper limits of normal.
• Has a risk of suicide according to the investigator's clinical judgment (eg, per Columbia-Suicide Severity Rating Scale [C-SSRS]) or has made a suicide attempt in the previous 6 months.
• Has uncontrolled, CS neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, endocrine disease, or psychiatric disorder, or other abnormality, which may impact the ability of the subject to participate or potentially confound the study results.
• Has used nicotine-containing products (including but not limited to cigarettes, electronic cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days prior to Check-in (Day -1). Cotinine test is positive at Screening or Check-in (Day -1).

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 4 Elderly Healthy: TAK-058 25 mg	TAK-058	TAK-058 25 mg solution, orally, once daily on Day 1 and Days 4 through 10, in elderly healthy participants.
Cohort 5 Non-elderly Healthy: TAK-058 300 mg	TAK-058	TAK-058 300 mg solution, orally, once daily on Day 1, in non-elderly healthy participants.
Cohort 3 Non-elderly Healthy: TAK-058 150 mg	TAK-058	TAK-058 150 mg solution, orally, once daily on Day 1 and Days 4 through 10, in non-elderly healthy participants.
Cohort 4 Elderly Healthy: Placebo	TAK-058 Placebo	TAK-058 placebo-matching solution, orally, once daily on Day 1 and Days 4 through 10, in non-elderly healthy participants.
Cohorts 1, 2, 3 and 5 Non-elderly Healthy: Placebo	TAK-058 Placebo	TAK-058 placebo-matching solution, orally, once daily on Day 1 and Days 4 through 10 (Cohorts 1, 2 and 3), or TAK-058 placebo-matching solution, orally, once on Day 1 (Cohort 5), in non-elderly healthy participants.
Cohort 2 Non-elderly Healthy: TAK-058 75 mg	TAK-058	TAK-058 75 mg solution, orally, once daily on Day 1 and Days 4 through 10, in non-elderly healthy participants.
Cohort 1 Non-elderly Healthy: TAK-058 25 mg	TAK-058	TAK-058 25 mg solution, orally, once daily on Day 1 and Days 4 through 10, in non-elderly healthy participants.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Signs at Least Once Post-Dose	Cohorts 1-4 Day 1 to Day 40; Cohort 5 Day 1 to Day 14	The percentage of participants with any markedly abnormal standard vital sign values collected throughout study. Vital signs included blood pressure (after 5 minutes supine and at 1 and 3 minutes after standing), pulse and oral temperature.
Percentage of Participants Who Experienced at Least 1 Treatment-Emergent Adverse Event	Cohorts 1-4 Day 1 to Day 40; Cohort 5 Day 1 to Day 14	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post-Dose	Cohorts 1-4 Day 1 to Day 40; Cohort 5 Day 1 to Day 14	The percentage of participants with any markedly abnormal standard safety laboratory values (chemistry and hematology) collected throughout study.

Secondary Outcome Measures

Name	Time	Method
Mean Cmax: Maximum Observed Plasma Concentration for TAK-058	Day 1 predose and at multiple time points (up to 72 hours) postdose, and Day 10 predose and at multiple time points (up to 24 hours) postdose	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Mean AUC24: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Postdose for TAK-058	Day 1 predose and at multiple time points (up to 24 hours) postdose	AUC24 is measure of area under the curve from time 0 to 24 hours postdose.
Mean AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-058	Day 1 predose and at multiple time points (up to 72 hours) postdose	AUClast is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration.
Mean AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for TAK-058	Day 10 predose and at multiple time points (up to 24 hours) postdose	Area under the plasma concentration-time curve during a dosing interval, where tau (τ) is the length of the dosing interval.