A Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) of Single and Multiple Oral Dose of TAK-418 in Healthy Female Participants

A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Oral Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-418 in Healthy Female Subjects

The purpose of this study is to characterize safety and tolerability of TAK-418 in non-Japanese and Japanese healthy female participants when administered at single or multiple (once daily [QD]) oral doses.

Study Overview

• Status: Terminated
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: TAK-418; Drug: TAK-418 Matching Placebo

Detailed Description

The drug being tested in this study is called TAK-418. This study will assess the safety, tolerability, PK and PD of single and multiple rising doses of TAK-418 in healthy Japanese or non-Japanese females.

The study will enroll approximately 48 participants in 6 cohorts and each cohort will have 8 participants. The study will include 2 parts: single rising dose (SRD) in Cohort 1 and multiple rising dose (MRD) in Cohorts 2 to 6. Cohort 3 will include cerebrospinal fluid (CSF) collection. Participants will be randomly assigned (by chance, like flipping a coin) to one of the 6 cohorts.

This two-center trial will be conducted in the United States. The overall time to participate in Cohort 1 of this study is approximately 105 days and 98 days in Cohort 2. Participants will be contacted by telephone 14 days after last dose of study drug for a follow-up assessment.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Glendale, California, United States, 91206
      • PAREXEL International
  • Utah
    • Salt Lake City, Utah, United States, 84124
      • PRA Health Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Has a body mass index (BMI) greater than or equal to (>=) 18.5 and less than or equal to (<=) 30.0 kilogram per square meter (kg/m^2) at the Screening Visit. (Cohorts 1 to 4 only).
2. Is a nonsmoker who has not used tobacco- or nicotine-containing products (example, nicotine patch) for at least 6 months before administration of the first dose of trial drug or invasive procedure.
3. The participant either is of nonchildbearing potential, OR, if of childbearing potential, is using a highly effective method of contraception with low user dependency during the entire duration of the study.

For Cohorts 5 and 6 (Japanese participants) only:

1. Has a BMI >=18.0 and <= 26.0 kg/m^2, at the Screening Visit.

Exclusion Criteria:

1. Has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV), or human immunodeficiency virus (HIV) antibody/antigen, at Screening.
2. Had major surgery, donated or lost 1 unit of blood (approximately 500 milliliter [mL]) within 4 weeks before the Screening Visit.
3. Has a history of alcohol consumption exceeding 2 standard drinks per day on average (1 glass is approximately equivalent to beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce] per day).
4. Consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per day.
5. Has a substance abuse disorder.
6. Has risk of suicide according to the investigator's clinical judgment per Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening or has made a suicide attempt in the 6 months before Screening.
7. Has luteinizing hormone (LH), follicle-stimulating hormone (FSH), or estradiol levels that are clinically abnormal.
8. Has a resting heart rate outside of the range of 50 to 100 beats per minute, confirmed on repeat testing within a maximum of 30 minutes, at the Screening Visit or Check-in (Day -1).

For Cohort 3 only (includes CSF sample collection):

1. Has had CSF collection performed within 30 days before Check-in (Day -1).
2. Has significant vertebral deformities (scoliosis or kyphosis) that, in the opinion of the investigator, may interfere with the lumbar puncture procedure.
3. Has a local infection at the puncture site.
4. Has thrombocytopenia or other suspected bleeding tendencies noted before the procedure.
5. Has developed signs and symptoms of spinal radiculopathy, including lower extremity pain and paresthesia.
6. Has any focal neurological deficit that might suggest an increase in intracranial pressure.
7. Has any abnormal finding on ophthalmological assessment/fundoscopy indicative of raised intracranial pressure (that is, optic disc swelling/edema; or [uncontrolled] hypertensive retinopathy).
8. Regularly has moderate-to-severe headaches requiring analgesics.
9. Has any bleeding abnormality or history of bleeding abnormalities.
10. Has abnormal coagulation tests (prothrombin time [PT]/international normalized ratio [INR], partial thromboplastin time [PTT]) at Screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Non-Japanese Cohort 1: TAK-418 120 mg and TAK-418 160 mg; TAK-418 120 milligram (mg) or TAK-418 matching placebo, capsule, orally, once on Day 1 of Period A followed by a minimum of 14 days of washout period, followed by TAK-418 160 mg or TAK-418 matching placebo, capsule, orally, once on Day 1 of Period B. The actual TAK-418 dose for Period B will be determined based on safety, tolerability, and PK data available from the previous dose in Period A.	Drug: TAK-418; TAK-418 capsules.; Drug: TAK-418 Matching Placebo; TAK-418 matching placebo capsules.
Experimental: Non-Japanese Cohort 2: TAK-418 20 mg; TAK-418 20 mg or TAK-418 matching placebo, capsule, orally, once daily for 10 days.	Drug: TAK-418; TAK-418 capsules.; Drug: TAK-418 Matching Placebo; TAK-418 matching placebo capsules.
Experimental: Non-Japanese Cohort 3: TAK-418 40 mg; TAK-418 40 mg or TAK-418 matching placebo, capsule, orally, once daily for 10 days. The actual TAK-418 dose for Cohort 3 will be determined based on safety, tolerability, and PK data available from the previous doses.	Drug: TAK-418; TAK-418 capsules.; Drug: TAK-418 Matching Placebo; TAK-418 matching placebo capsules.
Experimental: Non-Japanese Cohort 4: TAK-418 60 mg; TAK-418 60 mg or TAK-418 matching placebo, capsule, orally, once daily for 10 days. The actual TAK-418 dose for Cohort 4 will be determined based on safety, tolerability, and PK data available from the previous doses.	Drug: TAK-418; TAK-418 capsules.; Drug: TAK-418 Matching Placebo; TAK-418 matching placebo capsules.
Experimental: Japanese Cohort 5: TAK-418 20 mg; TAK-418 20 mg or TAK-418 matching placebo, capsule, orally, once daily for 10 days. The actual TAK-418 dose for Cohort 5 will be determined based on safety, tolerability, and PK data available from the previous doses.	Drug: TAK-418; TAK-418 capsules.; Drug: TAK-418 Matching Placebo; TAK-418 matching placebo capsules.
Experimental: Japanese Cohort 6: TAK-418 40 mg; TAK-418 40 mg or TAK-418 matching placebo, capsule, orally, once daily for 10 days. The actual TAK-418 dose for Cohort 6 will be determined based on safety, tolerability, and PK data available from the previous doses.	Drug: TAK-418; TAK-418 capsules.; Drug: TAK-418 Matching Placebo; TAK-418 matching placebo capsules.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Cohort 1: Number of Participants Who Experienced at Least One Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Event (SAE)	Baseline up to Day 60
Cohorts 2 to 5: Number of Participants Who Experienced at Least One TEAEs and SAE	Baseline up to Day 70
Cohort 1: Number of Participants With Markedly Abnormal Criteria for Clinical Laboratory Values at Least Once Postdose	Baseline up to Day 60
Cohorts 2 to 5: Number of Participants With Markedly Abnormal Criteria for Clinical Laboratory Values at Least Once Postdose	Baseline up to Day 70
Cohort 1: Number of Participants With Markedly Abnormal Criteria for Vital Signs at Least Once Postdose	Baseline up to Day 60
Cohorts 2 to 5: Number of Participants With Markedly Abnormal Criteria for Vital Signs at Least Once Postdose	Baseline up to Day 70
Cohort 1: Number of Participants Who Meet the Markedly Abnormal Values of 12-lead Electrocardiogram (ECG) Parameters at Least Once Post Dose	Baseline up to Day 60
Cohorts 2 to 5: Number of Participants Who Meet the Markedly Abnormal Values of 12-lead ECG Parameters at Least Once Post Dose	Baseline up to Day 70

Secondary Outcome Measures

Outcome Measure	Time Frame
Cohort 1; AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-418 on Day 1	Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose
Cohort 2 to 5: AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Over the Dosing Interval for TAK-418 on Days 1 and 10	Days 1 and 10 pre-dose and at multiple time points (up to 24 hours) post-dose
Cmax: Maximum Observed Plasma Concentration for TAK-418	Cohort 1: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Cohorts 2 to 5: Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose
Tmax: Time to Reach the Cmax for TAK-418	Cohort 1: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Cohorts 2 to 5: Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose

Collaborators and Investigators

• Sponsor: Millennium Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Yin W, Arkilo D, Khudyakov P, Hazel J, Gupta S, Quinton MS, Lin J, Hartman DS, Bednar MM, Rosen L, Wendland JR. Safety, pharmacokinetics and pharmacodynamics of TAK-418, a novel inhibitor of the epigenetic modulator lysine-specific demethylase 1A. Br J Clin Pharmacol. 2021 Dec;87(12):4756-4768. doi: 10.1111/bcp.14912. Epub 2021 Jun 10.

Study record dates

Study Major Dates

• Study Start (Actual): May 30, 2018
• Primary Completion (Actual): December 26, 2018
• Study Completion (Actual): December 26, 2018

Study Registration Dates

• First Submitted: April 10, 2018
• First Submitted That Met QC Criteria: April 10, 2018
• First Posted (Actual): April 18, 2018

Study Record Updates

• Last Update Posted (Actual): June 16, 2020
• Last Update Submitted That Met QC Criteria: June 3, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Drug Therapy
• Other Study ID Numbers: TAK-418-1003; U1111-1209-4647 (Other Identifier: WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

Drug and device information, study documents

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