Phase 1, TAK-648, Single-Rising Dose Study

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety, tolerability and pharmacokinetics of TAK-648 when administered as a single oral dose of TAK-648 solution at escalating dose levels in healthy participants.

Detailed Description
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This was a phase 1, randomized, double-blind, placebo-controlled, single-center, single-dose study in healthy participants. The study is the first TAK-648 study in humans and is designed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a single dose of TAK-648 to healthy participants. The compound being tested in this study is TAK-648. TAK-648 is being tested to find a safe and well-tolerated single dose. This study measured how much of the study drug got into the blood stream and how long it took the body to get rid of it. Information about any side effects that may have occurred was also collected. This study was a randomized dose-rising study which means that the first group of research participants was assigned by chance to receive either the study drug or placebo. Placebo is a solution that looks like the study drug but has no active ingredient. The lowest dose of the study drug or placebo was given to the 1st group of participants (1st cohort) and a higher dose was given to the next group until all the doses of the study drug were tested. TAK-648 was dosed in 5 sequential cohorts with escalating doses from the lowest dose given in Cohort 1 to higher doses given in the subsequent cohort. Doses could be adjusted based on available safety, tolerability, and pharmacokinetic (PK) data. Approximately 40 healthy male and female participants were planned for enrollment with 8 subjects planned (6 randomized to TAK-648 and 2 randomized to placebo) for each cohort. The study included 5 cohorts. This single-center trial was conducted in the United States. The overall time to participate in this study was up to 45 days. Participants made multiple visits to the clinic, including one 5-day period of confinement to the clinic. All participants were contacted by telephone 14 days after the last dose of study drug and on Day 84 (+/-2 days) for a follow-up assessment.

Official Title
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A Phase 1, Randomized, Double-Blind, Placebo- Controlled, Safety, Tolerability, and Pharmacokinetic Study of Escalating Single Oral TAK-648 Doses in Healthy Subjects

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: TAK-648
* Drug: TAK-648 Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is a healthy adult male or non-pregnant, non-lactating female. Is aged 18 to 55 years, inclusive. Weighs at least 55 kg (121 lbs) and has a body mass index (BMI) between 18.0 and 30.0 kg/m^2, inclusive. Has a systolic blood pressure >90 and ≤150 mm Hg and a diastolic blood pressure of >60 and ≤90 mm Hg at Screening and at Check-in (Day -2). Has a calculated creatinine clearance >60 mL/min at Screening and Check-in (Day -2). Exclusion Criteria: Has a known hypersensitivity to any component of the formulation of TAK-648, phosphodiesterase inhibitors or Listerine strips. Has significant medical histories or currently uncontrolled clinical conditions, which may not be safe for participant to participate in the study, may impact the participant's ability to participate in the study; may influence absorption of the study drug, or may potentially confound the study results. Has a history of persistent, chronic or intermittent nausea, vomiting, or diarrhea or had a current or recent (within 6 months) gastrointestinal disease that would influence the absorption of drugs Has a diagnosis of major depression, bipolar disorder, or anxiety disorders or received any medication to treat any psychological disorders within 1 year prior to Screening. Has abnormal laboratory values that suggest a clinically significant underlying disease or has the following laboratory abnormalities: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >2.5 times the upper limits of normal. Use of any excluded medications, supplement, or food product outlined in the protocol. Use of new medications during the course of the study including through the Follow-up period.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: TAK-648 0.05 mg<br>TAK-648 0.05 mg, solution, orally, once on Day 1. | Drug: TAK-648<br>* TAK-648 Solution<br>|
| Experimental: Cohort 2: TAK-648 0.15 mg<br>TAK-648 0.15 mg, solution, orally, once on Day 1. | Drug: TAK-648<br>* TAK-648 Solution<br>|
| Experimental: Cohort 3: TAK-648 0.35 mg<br>TAK-648 0.35 mg, solution, orally, once on Day 1. | Drug: TAK-648<br>* TAK-648 Solution<br>|
| Experimental: Cohort 4: TAK-648 0.7 mg<br>TAK-648 0.7 mg, solution, orally, once on Day 1. | Drug: TAK-648<br>* TAK-648 Solution<br>|
| Experimental: Cohort 5: TAK-648 0.85 mg<br>TAK-648 0.85 mg, solution, orally, once on Day 1. | Drug: TAK-648<br>* TAK-648 Solution<br>|
| Placebo Comparator: Cohort 1-5: Placebo<br>TAK-648 placebo-matching solution, orally, once on Day 1. | Drug: TAK-648 Placebo<br>* TAK-648 placebo-matching solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Have at Least One Treatment-Emergent Adverse Event (TEAE) | 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. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. | Day 1 to Day 14 | 
| Percentage of Participants Who Meet the Markedly Abnormal Criteria, for Safety Laboratory Tests at Least Once Post-dose | The percentage of participants with any markedly abnormal standard safety laboratory values (chemistry, hematology and urinalysis) collected throughout study. | Day 1 to Day 4 | 
| Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Signs Measurements at Least Once Post-dose | Vital signs will include body temperature (oral), sitting blood pressure (after the participant has rested for at least 5 minutes), respiration rate and pulse (bpm). | Day 1 to Day 4 | 
| Percentage of Participants With at Least One Occurrence of Severe Hypoglycemia Post-dose | Severe hypoglycemia is defined as an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. | Day 1 to Day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax: Maximum Observed Plasma Concentration for TAK-648 |  | Multiple time-points (up to 72 hours) post-dose | 
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-648 |  | Multiple time-points (up to 72 hours) post-dose | 
| AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-648 |  | Multiple time-points (up to 72 hours) post-dose | 
| AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-648 |  | Multiple time-points (up to 72 hours) post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy