A Study of TAK-951 in Healthy Adults

A Randomized, Double-Blind, Sponsor-Open, Placebo-Controlled, 3-Part Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-951 in Healthy Subjects

Feeling sick in the stomach (nausea) or throwing up (vomiting) are among the most common symptoms during treatment with medicines. It is hoped that a medicine called TAK-951 may help people to not feel sick in the stomach or throw up. The main aim of this study is to learn about side effects of TAK-951 when given as a single or multiple doses to healthy adults. Side effects are medical problems thought to be caused by the study treatment. Another aim is to learn how a healthy adult's body processes TAK-951 (this is called pharmacokinetics or PK). In this study, participants will receive either TAK-951 or placebo. The placebo looks like TAK-951 but does not have any medicine in it. Both TAK-951 and placebo will be given as an injection directly under the skin. This is called subcutaneous or subcutaneous (SC).

The study will be conducted in 3 parts:

• In Part 1, participants will be given one SC injection of either TAK-951 or placebo.
• In Part 2, participants will receive up to three daily SC injections of either TAK-951 or placebo of the same dose
• In Part 3, participants will receive one SC injection of either TAK-951 or placebo and another SC injection up to 1 week later.

Participants will be checked for their health either 28 days after the last injection (Parts 1 and 2) or 14 days after the last injection (Part 3).

Study Overview

• Status: Terminated
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: TAK-951; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Lenexa, Kansas, United States, 66219
      • ICON
  • Utah
    • Salt Lake City, Utah, United States, 84124
      • ICON

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria

To be eligible for participation in this study, the participant must:

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.
3. Be a healthy man or woman aged 18 to 55 years, inclusive, at the screening visit.
4. Be a continuous nonsmoker who has not used nicotine and tobacco-containing products for at least 3 months prior to dosing and throughout the study.
5. Have a body mass index (BMI) greater than equal to (≥)18 and less than equal to (≤)32 kilograms per meter square (kg/m^2) at the screening visit.
6. Be judged to be in good health (e.g., no evidence of psychiatric, hepatic, renal, pulmonary, or cardiovascular (CV) disease) by the investigator, based on clinical evaluations including laboratory safety tests, medical history, physical examination, ECG, and vital sign measurements performed at the screening visit and before administration of the initial dose of study drug or invasive procedure.

7. Meet the following birth control requirements:

   • Is a male participant who is sterile or agrees to use an appropriate method of contraception, including a condom with or without spermicidal cream or jelly, from the first dose of study drug until 30 days after the last dose of study drug. No restrictions are required for a vasectomized male participant provided the participant is at least 1 year after bilateral vasectomy procedure before the first dose of study drug. A male participant whose vasectomy procedure was performed less than 1 year before the first dose of study drug must follow the same restrictions as a non-vasectomized man. Appropriate documentation of surgical procedure should be provided.
   • Is a male participant who agrees not to donate sperm from the first dose of study drug until 30 days after the last dose of study drug.
   • Women of childbearing potential are eligible for the study provided they have a negative pregnancy test, are not lactating or breastfeeding, and are willing and agreeable to use highly effective contraception during the study and up to 30 days after the last dose of study drug.

   • Is a female participant of nonchildbearing potential, defined by at least 1 of the following criteria:

     1. Postmenopausal (defined as 12 months of spontaneous amenorrhea in females aged greater than (>)45 years or 6 months of spontaneous amenorrhea in females aged >45 years with serum follicle-stimulating hormone (FSH) levels >40 milli-international units per milliliter [mIU/mL]). Appropriate documentation of FSH levels is required.
     2. Surgically sterile by hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy with appropriate documentation of surgical procedure.
     3. Had a bilateral tubal ligation with appropriate documentation of surgical procedure.
     4. Has a congenital condition resulting in no uterus. Exclusion Criteria

Any participant who meets any of the following criteria will not qualify for entry into the study:

1. The participant has participated in another investigational study within 4 weeks (or based on local regulations) or within 5 half-lives, whichever is longest, 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 AE related to the study procedure in the previous study to the screening visit of the current study.
2. The participant is an employee of the sponsor or study site or immediate family member (e.g., spouse, parent, child, sibling) of the sponsor or study site.
3. The participant has a history of significant multiple and/or severe allergies (e.g., food, drug, latex allergy) or has had an anaphylactic reaction or significant intolerance to prescription or nonprescription drugs or food, as determined by the investigator.
4. The participant has a known hypersensitivity or contraindication to any component of TAK-951.
5. The participant has a positive pregnancy test or is lactating or breastfeeding.
6. The participant has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency antibody/antigen, at the screening visit.
7. The participant had major surgery or donated or lost 1 unit of blood (approximately 500 milliliters [mL]) within 4 weeks before the screening visit.
8. The participant is unable to refrain from or anticipates using any medications including herbal medicines beginning approximately 7 days before administration of the first dose of study drug, throughout the study until 2 days after discharge.
9. The participant is unable to refrain from or anticipates using marijuana or cannabis-containing products beginning approximately 7 days before administration of the first dose of study drug, throughout the study until after the last pharmacokinetic (PK) dose.
10. The participant has a history or presence of alcoholism or drug abuse within the past 2 years prior to dosing, or frequent or heavy use (i.e., near-daily) of medical or recreational cannabis in the past 3 months before screening, as determined by the investigator.
11. The participant drinks alcohol in excess of 7 drinks/week for women or 14 drinks/week for men (where 1 drink=5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor [45% alcohol]) within 3 months before screening.
12. The participant has a positive alcohol test or urine drug screen results at screening or check-in.
13. The participant has had a previous major psychiatric disorder.

14. The participant has a history or presence of:

    • 3 or more incidences of vasovagal syncope within the last 5 years prior to screening; or
    • A family history of unexplained sudden death or channelopathy; or
    • Brugada syndrome (i.e., right bundle branch block [RBBB] pattern with ST-elevation in leads V1-V3); or
    • Cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction, stroke, sick sinus syndrome, pulmonary congestion, symptomatic or significant cardiac arrhythmia, 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; or
    • Risk factors for Torsade de Pointes (e.g., heart failure, cardiomyopathy, or family history of Long QT Syndrome); or
    • Any clinically significant ECG findings or medical history including: long or short QTcF (over 450 milliseconds (msec) or less than 360 msec), bifascicular block or QRS ≥120 msec or PR interval >210 msec at screening or Day 1 pre-Hour 0; or
    • The participant has a documented history of sinus bradycardia (<45 beats per minute [bpm]), sinoatrial block or sinus pause ≥3 seconds.
15. The participant has an average semirecumbent blood pressure (BP) less than (<)90/60 millimeters of mercury (mm Hg) or >140/90 mm Hg from screening to predose, inclusive. Any assessments on Day -1 that do not meet this criterion must be discussed with the medical monitor for approval.
16. The participant has an average semirecumbent heart rate (HR) (pulse) <55 or >100 bpm at any time point from screening to predose, inclusive. Participants with an average HR (pulse) <55 bpm can be enrolled only with medical monitor approval. Any assessments after admission with an average HR (pulse) <55 bpm at any time point, from Day -2 to predose (inclusive), will be left to the judgment of the investigator, unless HR (pulse) is <50 bpm, which must be discussed with the medical monitor for approval.
17. The participant has orthostatic hypotension defined as a decrease in systolic blood pressure (SBP) ≥20 mm Hg or a decrease in diastolic blood pressure (DBP) ≥10 mm Hg at approximately 3 minutes of standing when compared with BP from the semirecumbent position at screening to predose assessments, inclusive. In asymptomatic participants, any assessments after screening that do not meet this criterion may be repeated after the participant has remained in the semirecumbent or supine position for 15 minutes. If the repeat assessment is exclusionary based on the above criterion, the participant will not be eligible. If the repeat assessment is not exclusionary, the participant will be eligible.
18. The participant has postural orthostatic tachycardia, defined as an increase of >30 bpm or pulse >120 bpm at approximately 3 minutes of standing, at screening to predose assessments, inclusive. Any assessments after screening that do not meet this criterion may be repeated with the participant remaining standing for up to a total of 5 minutes, provided that the participant remains asymptomatic. If the repeat assessment occurring within 5 minutes is exclusionary based on the above criterion, the participant will not be eligible. A confirmed orthostatic increase of >30 bpm, but <40 bpm, on 1 or more Day -1 assessments may not be considered exclusionary if not considered clinically significant by the investigator and the medical monitor. Such assessments must be discussed with the medical monitor before determination that the participant is eligible to proceed.
19. The participant has a known or suspected current coronavirus disease 2019 (COVID-19) infection or is at risk of COVID-19 infection as assessed by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Part 1: Pooled Placebo; Participants will receive a single SC dose of TAK-951 matching placebo on Day 1.	Drug: Placebo; TAK-951 matching placebo SC injection
Experimental: Part 1, Cohort 1: TAK-951 Dose 1; Participants will receive a single SC dose of TAK-951 Dose 1 on Day 1.	Drug: TAK-951; TAK-951 SC injection
Experimental: Part 1, Cohort 2: TAK-951 Dose 2; Participants will receive a single SC dose of TAK-951 Dose 2 on Day 1.	Drug: TAK-951; TAK-951 SC injection
Experimental: Part 1, Cohort 3: TAK-951 Dose 3; Participants will receive a single SC dose of TAK-951 Dose 3 on Day 1.	Drug: TAK-951; TAK-951 SC injection
Experimental: Part 1, Cohort 4: TAK-951 Dose 4; Participants will receive a single SC dose of TAK-951 Dose 4 on Day 1.	Drug: TAK-951; TAK-951 SC injection
Experimental: Part 1, Cohort 5: TAK-951 Dose 5; Participants will receive a single SC dose of TAK-951 Dose 5 on Day 1.	Drug: TAK-951; TAK-951 SC injection
Experimental: Part 1, Cohort 6: TAK-951 Dose 6; Participants will receive a single SC dose of TAK-951 Dose 6 on Day 1.	Drug: TAK-951; TAK-951 SC injection
Experimental: Part 2: TAK-951 Multiple Rising Doses; Participants will receive multiple rising SC doses of TAK-951 twice daily (BID) or 3 times a day (TID) in Part 2.	Drug: TAK-951; TAK-951 SC injection
Experimental: Part 3: TAK-951 Multiple Dose Titration; Participants will receive multiple rising SC doses of TAK-951 once daily (QD), BID, or TID from Days 1 to 5 followed by a washout period of 2 to 7 days and a single redose on any day from Days 8 to 13 in Part 3.	Drug: TAK-951; TAK-951 SC injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug. An AE can be any unfavorable and unintended sign (including physical examinations, vital signs, electrocardiogram (ECG), laboratory assessment findings), symptom, or disease temporally associated with the use of a drug whether or not it is considered related to the drug. A TEAE was defined as an AE that started or worsened after first study drug administration and within 30 days of last dose of study drug.	From the first dose of study drug up to Day 29 in Part 1
Part 2: Number of Participants With TEAEs	An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug. An AE can be any unfavorable and unintended sign (including physical examinations, vital signs, ECG, laboratory assessment findings), symptom, or disease temporally associated with the use of a drug whether or not it is considered related to the drug. A TEAE was defined as an AE that started or worsened after first study drug administration and within 30 days of last dose of study drug.	From the first dose of study drug up to Day 33 in Part 2
Part 3: Number of Participants With TEAEs	An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug. An AE can be any unfavorable and unintended sign (including physical examinations, vital signs, ECG, laboratory assessment findings), symptom, or disease temporally associated with the use of a drug whether or not it is considered related to the drug. A TEAE was defined as an AE that started or worsened after first study drug administration and within 30 days of last dose of study drug.	From the first dose of study drug up to Day 27 in Part 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 2: Maximum Observed Plasma Concentration (Cmax) for TAK-951 on Day 1 of Drug Dosing		Predose and at multiple time points post-dose up to 24 hours on Day 1 in Part 2
Part 2: Time of First Occurrence of Cmax (Tmax) for TAK-951 on Day 1 of Drug Dosing		Predose and at multiple time points post-dose up to 24 hours on Day 1 in Part 2
Part 2: AUCτ: Area Under the Plasma Concentration-time Curve During a Dosing Interval for TAK-951 on Day 1	Tau (τ) indicates the length of the dosing interval.	Predose and at multiple time points post-dose up to 24 hours on Day 1 in Part 2
Part 2: Cmax,ss: Maximum Observed Concentration at Steady State for TAK-951		Predose on Day 1 and at multiple time points post-dose up to Day 7 in Part 2
Part 2: Tmax for TAK-951 at Steady State		Predose on Day 1 and at multiple time points post-dose up to Day 7 in Part 2
Part 2: Terminal Disposition Phase Half-life (t1/2z) for TAK-951 at Steady State		Predose on Day 1 and at multiple time points post-dose up to Day 7 in Part 2
Part 2: Ctrough: Observed Plasma Concentration at the End of a Dosing Interval for TAK-951 at Steady State		Predose on Day 1 and at multiple time points post-dose up to Day 7 in Part 2
Part 2: Number of Participants With ADA		Predose on Day 1 and post-dose on Days 14 and 29 in Part 2
Part 2: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24) for TAK-951 on Day 1 of Drug Dosing		Predose and at multiple time points post-dose up to 24 hours on Day 1 in Part 2
Part 2: AUCτ for TAK-951 at Steady State	τ indicates the length of the dosing interval.	Predose and at multiple time points post-dose up to 24 hours on Day 1 in Part 2
Part 2: AUC24 for TAK-951 at Steady State		Predose on Day 1 and at multiple time points post-dose up to 24 hours on Day 1 in Part 2
Part 2: Apparent Clearance After Extravascular Administration (CL/F) for TAK-951 at Steady State	Apparent clearance after extravascular administration was to be calculated as Dose/AUCτ after multiple dosing.	Predose on Day 1 and at multiple time points post-dose up to Day 7 in Part 2
Part 2: Apparent Volume of Distribution During the Terminal Disposition Phase After Extravascular Administration (Vz/F) for TAK-951 at Steady State	Apparent volume of distribution during the terminal disposition phase after extravascular administration was to be calculated as (CL/F)/λz at steady state, with λz as the terminal elimination rate constant.	Predose on Day 1 and at multiple time points post-dose up to Day 7 in Part 2
Part 2: Rac[AUC]: Accumulation Ratio Based on AUCτ for TAK-951 at Steady State	Rac[AUC] was to be calculated as the ratio of AUCτ at steady state/AUCτ after a single dose.	Predose on Day 1 and at multiple time points post-dose up to Day 7 in Part 2
Part 2: Rac[Cmax]: Accumulation Ratio Based on Cmax for TAK-951 at Steady State	Rac[Cmax] was to be calculated as the ratio of Cmax at steady state/Cmax after a single dose.	Predose on Day 1 and at multiple time points post-dose up to Day 7 in Part 2
Part 3: Number of Participants With AEs	An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug. An AE can be any unfavorable and unintended sign (including physical examinations, vital signs, ECG, laboratory assessment findings), symptom, or disease temporally associated with the use of a drug whether or not it is considered related to the drug.	From the re-treatment dose of study drug (any day from Days 8 to 13) up to Day 27 in Part 3
Part 1: Number of Participants Based on Antidrug Antibodies (ADA) Status in Serum	A 3-tiered ADA testing strategy was used in this study. A sample was initially screened for ADA by the ADA screening assay. Any positive sample in the screening assay was considered a potential positive, which was confirmed for true positivity by the confirmatory assay. If a sample was confirmed as an ADA true positive, ADA titer was assessed. ADA-positive was defined as participants who have confirmed positive ADA status in at least 1 postbaseline assessments. ADA-negative was defined as participants who did not have a confirmed positive ADA status in any postbaseline assessment. For ADA-positive only, high ADA titer was defined as participant who had at least 1 postbaseline ADA titer >16; low ADA titer was defined as participant whose postbaseline ADA titers were all ≤16 and data is presented accordingly for each of these categories.	Predose on Day 1 and post-dose on Days 14 and 29 in Part 1
Part 3: Number of Participants With ADA		Predose on Day 1 and post-dose on Days 14 and 29 in Part 3

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Cmax: Maximum Observed Plasma Concentration of TAK-951	Due to confidentiality reasons and chances of exposing the doses for TAK-951, the data for this pharmacokinetic outcome measure was not reported.	Predose on Day 1 and at multiple time points post-dose up to Day 3 in Part 1
Part 1: AUC24: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours for TAK-951	Due to confidentiality reasons and chances of exposing the doses for TAK-951, the data for this pharmacokinetic outcome measure was not reported.	Predose and at multiple time points post-dose up to 24 hours on Day 1 in Part 1
Part 1: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-951	Due to confidentiality reasons and chances of exposing the doses for TAK-951, the data for this pharmacokinetic outcome measure was not reported.	Predose on Day 1 and at multiple time points post-dose up to Day 3 in Part 1
Part 1: AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Concentration for TAK-951	Due to confidentiality reasons and chances of exposing the doses for TAK-951, the data for this pharmacokinetic outcome measure was not reported.	Predose on Day 1 and at multiple time points post-dose up to Day 3 in Part 1
Part 1: Tmax: Time of First Occurrence of Cmax for TAK-951	Due to confidentiality reasons and chances of exposing the doses for TAK-951, the data for this pharmacokinetic outcome measure was not reported.	Predose on Day 1 and at multiple time points post-dose up to Day 3 in Part 1
Part 1: t1/2z: Terminal Disposition Phase Half-life for TAK-951	Due to confidentiality reasons and chances of exposing the doses for TAK-951, the data for this pharmacokinetic outcome measure was not reported.	Predose on Day 1 and at multiple time points post-dose up to Day 3 in Part 1
Part 1: CL/F: Apparent Clearance After Extravascular Administration of TAK-951	Apparent clearance after extravascular administration was calculated as Dose/AUC∞. Due to confidentiality reasons and chances of exposing the doses for TAK-951, the data for this pharmacokinetic outcome measure was not reported.	Predose on Day 1 and at multiple time points post-dose up to Day 3 in Part 1
Part 1: Vz/F: Apparent Volume of Distribution During the Terminal Disposition Phase After Extravascular Administration	Apparent volume of distribution during the terminal disposition phase after extravascular administration was calculated as (CL/F)/λz, where λz is the terminal elimination rate constant. Due to confidentiality reasons and chances of exposing the doses for TAK-951, the data for this pharmacokinetic outcome measure was not reported.	Predose on Day 1 and at multiple time points post-dose up to Day 3 in Part 1

Collaborators and Investigators

• Sponsor: Takeda

Study record dates

Study Major Dates

• Study Start (Actual): January 7, 2022
• Primary Completion (Actual): September 21, 2023
• Study Completion (Actual): September 21, 2023

Study Registration Dates

• First Submitted: September 21, 2024
• First Submitted That Met QC Criteria: September 21, 2024
• First Posted (Actual): September 24, 2024

Study Record Updates

• Last Update Posted (Estimated): November 22, 2024
• Last Update Submitted That Met QC Criteria: September 28, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: TAK-951
• Other Study ID Numbers: TAK-951-1008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/ For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No