A Study of TAK-105 in Healthy Adults

Study Overview
=================
Brief Summary
-----------------
It is hoped that in the future, TAK-105 will be used to help treat people with nausea and vomiting. The main aims of this study are as follows: To check for side effects from TAK-105 in healthy adults. To learn how much TAK-105 they can receive without getting side effects from it. Participants will receive either TAK-105 as TAK-105-a or TAK-105-b (depending upon the part they are enrolled in) or a placebo as an injection under the skin (sub-cutaneous injection). A placebo looks like TAK-105-a or TAK-105-b but will not have any medicine in it. Three times as many participants will receive TAK-105-a or TAK-105-b than placebo. The study will have 6 parts. Each part will have several small groups of participants, called cohorts. Participants will only be in 1 cohort in 1 part of the study. Part 1: Participants will check into the study clinic to receive a single dose of TAK-105-a or placebo and will stay in the clinic for about 10 days. Then, participants return to the clinic for follow-up visits up to about 60 days after the dose. Part 2: Participants will check into the study clinic to receive TAK-105-a or placebo once a week for 4 weeks, and will stay in the clinic for about 26 days. Then, participants return to the clinic for follow-up visits up to about 60 days after last dose. Part 3: Participants will check into the study clinic to receive 2, 3 or 4 weekly doses of TAK-105-a or placebo. Their clinic stay will be for 10 to 24 days depending which cohort they are in. Then, participants return to the clinic for follow-up visits up to about 28 days after last dose. Part 4: Participants will check into the study clinic to receive 2 doses (once a week for 2 weeks) of TAK-105-a or placebo and will stay in the study clinic for about 12 days. They will return to the clinic later (in about 1-3 weeks) for another (third) dose and will stay for 2 days after the third dose. Then, participants return to the clinic for follow-up visits up to about 3 months after first dose. Part 5a: Participants will check into the study clinic to receive a single dose of TAK-105-a or placebo and will stay in the clinic for about 10 days. Then, participants return to the clinic for follow-up visits up to about 60 days after the dose. Part 5b: Participants will check into the study clinic to receive TAK-105-a or placebo once a week for 4 weeks, and will stay in the clinic for about 26 days. Then, participants return to the clinic for follow-up visits up to about 60 days after last dose. Part 5b will be optional, depending on the pharmacokinetic (PK) and safety data observed in Part 2. Part 6: Participants will check into the study clinic to receive a single dose of TAK-105-b or placebo and will stay in the clinic for about 10 days. Then, participants return to the clinic for follow-up visits up to about 60 days after the dose.

Detailed Description
-----------------
The drug being tested in this study is called TAK-105. The study will look at the safety, tolerability, and PK of TAK-105-a and TAK-105-b in healthy participants. Participants in each cohort will be randomized to receive treatment with TAK-105-a or TAK-105-b or matching placebo which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need). The study consists of 6 parts and up to 34 cohorts as mentioned below: Part 1 (SRD) will enroll healthy participants in up to 12 cohorts. Part 2 (MRD) will enroll healthy participants in up to 5 ascending cohorts. Part 3 (Dose titration) will enroll healthy participants in up to 6 multiple-dose cohorts. Part 4 (Redosing) will enroll healthy participants in up to 4 redosing cohorts. Part 5a (SRD) will enroll healthy Japanese participants in up to 3 cohorts. Part 5b (MRD) (optional) will enroll healthy Japanese participants in up to 2 cohorts. The MRD cohorts in Part 5b will be optional, depending on the PK and safety data observed in Part 2 (MRD). Part 6 (SRD) will enroll healthy participants in up to 2 cohorts. Each cohort in all the parts will have 8 randomized participants with 6 participants receiving a single dose of TAK-105-a in Parts 1 to 5 or TAK-105-b in Part 6, and 2 receiving TAK-105-a matching placebo (Parts 1 to 5) or TAK-105-b matching placebo (Part 6) in a 3:1 ratio. This multi-center trial will be conducted in the United States. The overall duration of the study is approximately 18 months.

Official Title
-----------------
A Randomized, Double-Blind, Sponsor-Open, Placebo-Controlled, Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-105 in Healthy Subjects

Conditions
-----------------
Healthy Volunteers

Intervention / Treatment
-----------------
* Drug: TAK-105-a
* Drug: TAK-105-a Placebo
* Drug: TAK-105-b
* Drug: TAK-105-b Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: For All Cohorts Must have a body mass index (BMI) greater than or equal to (>=) 18.0 and less than or equal to (<=) 30.0 kilogram per square meter (kg/m^2). Continuous nonsmoker who has not used nicotine and tobacco-containing products for at least 3 months prior to screening and through discharge. Be judged to be in good health (example, no evidence of psychiatric, hepatic, renal, pulmonary, or cardiovascular disease) by the investigator, based on clinical evaluations including laboratory safety tests, medical history, physical examination, electrocardiogram (ECG), and vital sign measurements performed at the screening visit and before administration of the initial dose of study drug or invasive procedure. For Japanese participants in Part 5 (Cohorts 28 to 32 only): Has 2 Japanese parents and 4 Japanese grandparents, as confirmed by interview. Exclusion Criteria: Participated in another investigational study within 4 weeks (or based on local regulations) or within 5 half-lives of the investigational product before the screening visit. The 4-week or 5 half-lives window will be derived from the date of the last dose and/or adverse event (AE) related to the study procedure in the previous study to the screening visit of the current study. Has a history of significant multiple and/or severe allergies (example, food, drug, latex allergy) or has had an anaphylactic reaction or significant intolerance to prescription or nonprescription drugs or food. Has a known hypersensitivity or contraindication to any component of TAK 105. Has positive pregnancy test or is lactating or breastfeeding. Has known or suspected current coronavirus disease 2019 (COVID-19) infection or is at risk of COVID-19 infection as assessed by the investigator. Unable to refrain from or anticipates using all medications including herbal medicines beginning approximately 7 days before administration of the first dose of study drug, throughout the study until the last follow-up visit. With history or presence of: 3 or more incidences of syncope (example, vasovagal) within the last 5 years prior to screening; A family history of unexplained sudden death or channelopathy; Brugada syndrome (RBBB [right bundle branch block] pattern with ST-elevation in leads V1 V3); CV or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction, stroke, sick sinus syndrome, pulmonary congestion, symptomatic or significant cardiac arrhythmia, supraventricular or ventricular tachycardia, second-degree atrioventricular (AV) block type 2, third degree AV block, prolonged QT interval with Fridericia correction method (QTcF) interval, hypokalemia, hypomagnesemia, or conduction abnormalities; Risk factors for Torsade de Pointes (example, heart failure, cardiomyopathy, or family history of Long QT Syndrome); Any clinically significant ECG findings or medical history including: long or short QTcF (over 450 milli second [msec] or less than 360 msec), bifascicular block or QRS greater than equal to (>=)120 msec or PR interval > 200 msec at screening or Day 1 pre-Hour 0; Has a documented history of sinus bradycardia less than (<) 45 beats per minute [bpm]) based upon vital signs assessments, sinoatrial block as evidenced on ECG or sinus pause >=3 seconds on ECG or predose telemetry. Has an average semi recumbent blood pressure (BP) less than 90 (systolic) and 60 (diastolic) millimeter of mercury (mmHg) or greater than 140/90 mmHg from screening to predose, inclusive. From screening to Day -2, participants with an average semirecumbent heart rate (HR) <55 or >100 beats per minute (bpm) should be excluded. From Day -2 to predose, enrollment of participants with an average HR <55 or >100 bpm will be left to the judgment of the investigator, unless HR is <50 bpm, which must be discussed with the medical monitor for approval. Has orthostatic hypotension defined as a decrease in systolic BP (SBP) >=20 mmHg or a decrease in diastolic BP (DPB) >=10 mmHg at approximately 2 minutes of standing when compared with BP from the semirecumbent position at screening to predose assessments, inclusive. Has postural orthostatic tachycardia, defined as an increase of >30 bpm or HR >120 bpm at approximately 2 minutes of standing, at screening to predose assessments, inclusive.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: TAK-105-a<br>TAK-105-a at starting dose of 30 microgram (mcg) or placebo-matching solution, subcutaneously, once on Day 1. Staggered dosing will be done in the first cohort of Part 1 (Cohort 1). Staggered dosing in subsequent Cohorts (Cohorts 2-12) may be used. After the pre-specified first dose, subsequent doses will be determined in the dose escalation meeting based on emerging safety, tolerability, and PK data from the study. | Drug: TAK-105-a<br>* TAK-105-a subcutaneous solution.<br>Drug: TAK-105-a Placebo<br>* TAK-105-a placebo-matching solution.<br>|
| Experimental: Part 2: TAK-105-a<br>TAK-105-a dose to be decided (TBD) or TAK-105-a matching-placebo, subcutaneously, once weekly for 4 weeks. Dose of multiple rising dose (MRD) Cohorts (Cohorts 13-17) of Part 2 will be determined based on emerging safety, immunogenicity, tolerability, and PK data from Part 1 (SRD) determined in the dose escalation meeting. | Drug: TAK-105-a<br>* TAK-105-a subcutaneous solution.<br>Drug: TAK-105-a Placebo<br>* TAK-105-a placebo-matching solution.<br>|
| Experimental: Part 3: TAK-105-a<br>TAK-105-a dose TBD or placebo-matching solution, subcutaneously, once weekly for 2-4 weeks. Dose for the first 2 Cohorts (Cohorts 18-19) of Part 3 will be based on emerging safety, tolerability, and available PK data from Part 1 single rising dose (SRD) and Part 2 (MRD) as determined in the dose escalation meeting. The data from Cohorts 18-19 will further determine additional enrollment of Cohorts 20, 21, 22 and 23. Part 3 will evaluate whether dose titration result in different tolerability in relation with CV observations. | Drug: TAK-105-a<br>* TAK-105-a subcutaneous solution.<br>Drug: TAK-105-a Placebo<br>* TAK-105-a placebo-matching solution.<br>|
| Experimental: Part 4: TAK-105-a<br>TAK-105-a dose TBD or placebo-matching solution, subcutaneously, once a week for 2 weeks, followed by a period of withholding drug and then redosing with a third dose. Part 4 (Cohorts 24 to 27) will provide an exploratory evaluation to assess the safety and CV tolerability profile of redosing with TAK 105. | Drug: TAK-105-a<br>* TAK-105-a subcutaneous solution.<br>Drug: TAK-105-a Placebo<br>* TAK-105-a placebo-matching solution.<br>|
| Experimental: Parts 5a and 5b: TAK-105-a<br>TAK-105-a dose TBD or TAK-105-a placebo-matching solution, subcutaneously, once on Day 1 for the SRD Cohorts (Cohorts 28 to 30), during Part 5a of the study and TAK-105-a dose TBD or TAK-105-a matching-placebo, subcutaneously, once weekly for 4 weeks for the optional MRD Cohorts (Cohorts 31 and 32), during Part 5b of the study. Dose of the SRD and optional MRD Cohorts (28 to 32) will be determined during the dose escalation meeting based on emerging safety, tolerability, and available PK data during the study. The MRD Cohorts in Part 5b will be optional, depending on the PK, safety data observed in Part 2 MRD. | Drug: TAK-105-a<br>* TAK-105-a subcutaneous solution.<br>Drug: TAK-105-a Placebo<br>* TAK-105-a placebo-matching solution.<br>|
| Experimental: Part 6: TAK-105-b<br>TAK-105-b dose TBD or TAK-105-b placebo-matching solution, subcutaneously, once on Day 1. Dose of the SRD Cohorts (33 and 34) will be determined during the dose escalation meeting based on emerging safety, tolerability, and available PK data from Part 1 (SRD). | Drug: TAK-105-b<br>* TAK-105-b subcutaneous solution.<br>Drug: TAK-105-b Placebo<br>* TAK-105-b placebo-matching solution.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With At Least one Adverse Event |  | Baseline up to Month 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts 1, 2, 5a, 5b, and 6, Cmax: Maximum Observed Plasma Concentration for TAK-105 |  | Day 1(Parts 1, 5a, and 6): pre-dose and at multiple time points(up to Day 60)post-dose; Day 1(Parts 2 and 5b): pre-dose and at multiple time-points(up to Day 6)post-dose; Day 22(Parts 2 and 5b): pre-dose and multiple time points(up to Day 82)post-dose | 
| Parts 1, 5a, and 6, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-105 |  | Day 1 (Parts 1, 5a, and 6): pre-dose and at multiple time points (up to Day 60) post-dose | 
| Parts 1, 5a, and 6, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-105 |  | Day 1 (Parts 1, 5a, and 6): pre-dose and at multiple time points (up to Day 60) post-dose | 
| Parts 1, 2, 5a, 5b, and 6, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-105 |  | Day 1(Parts 1, 5a, and 6): pre-dose and at multiple time points(up to Day 60)post-dose; Day 1(Parts 2, and 5b): pre-dose and at multiple time-points(up to Day 6)post-dose; Day 22(Parts 2 and 5b): pre-dose and multiple time points(up to Day 82)post-dose | 
| Parts 1, 2, 5a, 5b, and 6, T1/2z: Terminal Disposition Phase Half-life for TAK-105 |  | Day 1 (Parts 1, 5a, and 6): pre-dose and at multiple time points (up to 60 days) post-dose; Day 22 (Parts 2 and 5b): pre-dose and multiple time points (up to Day 82) post-dose | 
| Parts 1, 2, 5a, 5b, and 6, CL/F: Apparent Clearance After Extravascular Administration for TAK-105 |  | Day 1 (Parts 1, 5a, and 6): pre-dose and at multiple time points (up to 60 days) post-dose; Day 22 (Parts 2 and 5b): pre-dose and multiple time points (up to Day 82) post-dose | 
| Parts 1, 2, 5a, 5b, and 6, Vz/F: Apparent Volume of Distribution During the Terminal Disposition Phase After Extravascular Administration for TAK-105 |  | Day 1 (Parts 1, 5a, and 6): pre-dose and at multiple time points (up to 60 days) post-dose; Day 22 (Parts 2 and 5b): pre-dose and multiple time points (up to Day 82) post-dose | 
| Parts 2 and 5b, AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to tau Over Dosing Interval for TAK-105 |  | Day 1 (Parts 2 and 5b): pre-dose and at multiple time points (up to Day 6) post-dose; Day 22 (Parts 2 and 5b): pre-dose and multiple time points (up to Day 82) post-dose | 
| Parts 2 and 5b, Ctrough: Observed Plasma Concentration at the end of a Dosing Interval at Steady State for TAK-105 |  | Day 22 (Parts 2 and 5b): pre-dose and multiple time points (up to Day 82) post-dose | 
| Parts 1, 2, 5a, and 5b, Aet: Amount of Drug Excreted in Urine From Time 0 to Time t for TAK-105 |  | Day 1(Parts 1 and 5a): pre-dose and at multiple time points(up to Day 8)post-dose; Day 1(Parts 2 and 5b): pre-dose and at multiple time points(up to Day 7)post-dose; Day 22(Parts 2 and 5b): pre-dose and at multiple time points(up to 48 hours)post-dose | 
| Parts 1, 2, 5a, and 5b, Aet1-t2: Amount of Drug Excreted in Urine From Time 1 to Time 2 for TAK-105 |  | Day 1(Parts 1 and 5a): pre-dose and at multiple time points(up to Day 8)post-dose; Day 1(Parts 2 and 5b): pre-dose and at multiple time points (up to Day 7)post-dose; Day 22(Parts 2 and 5b): pre-dose and at multiple time points(up to 48 hours)post-dose | 
| Parts 1, 2, 5a, and 5b, Aeτ: Amount of Drug Excreted in Urine During a Dosing Interval (τ) at Steady State for TAK-105 |  | Day 1(Parts 1 and 5a): pre-dose and at multiple time points(up to Day 8)post-dose; Day 1(Parts 2 and 5b): pre-dose and at multiple time points(up to Day 7)post-dose; Day 22(Parts 2 and 5b): pre-dose and at multiple time points(up to 48 hours)post-dose | 
| Parts 1, 2, 5a, and 5b, fe,t: Fraction of Administered Dose of Drug Excreted From Urine From Time 0 to Time t for TAK-105 |  | Day 1(Parts 1 and 5a): pre-dose and at multiple time points(up to Day 8)post-dose; Day 1 (Parts 2 and 5b): pre-dose and at multiple time points(up to Day 7)post-dose; Day 22(Parts 2 and 5b): pre-dose and at multiple time points(up to 48 hours)post-dose | 
| Parts 1, 2, 5a, and 5b, CLR: Renal clearance for TAK-105 |  | Day 1(Parts 1 and 5a): pre-dose and at multiple time points(up to Day 8)post-dose; Day 1(Parts 2 and 5b): pre-dose and at multiple time points(up to Day 7)post-dose; Day 22(Parts 2 and 5b): pre-dose and at multiple time points(up to 48 hours)post-dose | 
| Number of Participants Based on Antidrug Antibody (ADA) Levels in Serum | The number participants in each category of the immunogenicity status (ADA-negative or ADA-positive) will be determined in this study. A 3-tiered ADA testing strategy will be used in this study. A Sample will initially be screened for ADA by the ADA screening assay. Any positive sample in the screening assay is considered a potential positive, which will be confirmed for true positivity by the confirmatory assay. If a sample is confirmed as an ADA true positive, ADA titer will be assessed. | Baseline up to Month 18 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Drug Therapy