Study to Assess Absolute Bioavailability of TAK-935 (OV935) and to Characterize Mass Balance, Pharmacokinetics, Metabolism, and Excretion of [14C]TAK-935 (OV935) in Healthy Male Participants

A Phase 1 Study to Assess Absolute Bioavailability of TAK-935 (OV935) and to Characterize Mass Balance, Pharmacokinetics, Metabolism, and Excretion of [14C]TAK-935 (OV935) in Healthy Adult Male Participants

The purpose of this study is to determine absolute bioavailability (ABA) of TAK-935 (F) following a single microdose intravenous (IV) administration of 50 microgram (μg) (approximately 1 microcurie [μCi]) [14C]TAK-935 and a single oral administration of 3×100 mg milligram (mg) TAK-935 tablets in Treatment Period 1, and to assess the mass balance, characterize the pharmacokinetics (PK) of TAK-935 and metabolite [M-I (N-oxide)] in plasma and urine, and total radioactivity concentration equivalents in plasma and whole blood following a single oral administration of 300 mg (approximately 100 μCi) [14C]TAK-935 in Treatment Period 2.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: TAK-935 Oral Tablet; Drug: [14C]TAK-935 IV Infusion; Drug: [14C]TAK-935 Oral Solution

Detailed Description

The drug being tested in this study is called TAK-935 (also known as soticlestat/OV935). The study determines ABA in Treatment Period 1, and the absorption, metabolism, excretion, and mass balance of TAK-935 after single oral administration in Treatment Period 2 in healthy adult male participants, by collecting plasma, urine, and feces samples for drug concentration analysis, and plasma, whole blood, urine, and fecal samples for total radioactivity analysis and metabolic profiling.

The study will enroll approximately 6 healthy adult male participants. The study is designed to consist of 2 periods: Treatment Period 1 (ABA Study Period) and Treatment Period 2 (Absorption, Distribution, Metabolism, and Elimination [ADME] Study Period). In Treatment Period 1, all participants will receive a single unlabelled oral dose of TAK-935 as 3×100 mg tablets and a microdose IV infusion of 50 μg (approximately 1 μCi) [14C]TAK-935, followed by a Washout Period of 7 days before the dose in Treatment Period 2. In Treatment Period 2, all participants will receive a single dose of 300 mg (approximately 100 μCi) [14C]TAK-935 as an oral solution.

This single center trial will be conducted in the United States. The overall time to participate in this study is approximately 65 days including Screening Period. Participants will be contacted approximately 30 days after the last dose of study drug for a follow-up assessment. This compound was transferred to Takeda and acquired on 29 March 2021. This registration is retrospective due to the transfer of ownership.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Nebraska
    • Lincoln, Nebraska, United States, 68502
      • Celerion

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Weighs at least 50 kg and body mass index (BMI) ≥18.0 and ˂32.0 kg/m^2 at Screening Visit.
2. Continuous nonsmoker who has not used nicotine-containing products (including vaping) for at least 3 months prior to the first dosing and throughout the study, based on participant self-reporting.
3. Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs or ECGs, as deemed by the Investigator or designee.

Exclusion Criteria:

1. History or presence of cataracts or other clinically significant vision disturbances.

2. Abnormal and clinically significant ECG abnormality at Screening visit:

   • QT interval with Fridericia's correction method (QTcF) >450 milliseconds (ms) confirmed with one repeat testing.
3. History or presence of gastritis, gastrointestinal tract, gastric bypass surgery, or hepatic disorder or other clinical condition which, in the opinion of the Investigator or designee, may affect the absorption, distribution, metabolism, or elimination of study drug.
4. Has a risk of suicide according to the Investigator's clinical judgment [e.g., per Columbia-Suicide Severity Rating Scale (C-SSRS)] or has made a suicide attempt in the previous year prior to Screening Visit.
5. Positive urine drug or alcohol results at screening or first check-in.
6. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) or novel coronavirus 2019 (COVID-19).
7. Seated blood pressure is less than 90/40 millimeter of mercury (mmHg) or greater than 140/90 mmHg at Screening.
8. Seated HR is lower than 40 beats per minute (bpm) or higher than 99 bpm at Screening Visit.
9. Estimated creatinine clearance <80 mL/min at Screening Visit.
10. Has tattoo(s) or scarring at or near the site of IV infusion or any other condition which may interfere with infusion site examination, in the opinion of the Investigator.
11. Has infrequent bowel movements (less than approximately once per day) within 30 days prior to first dosing.
12. Recent history of abnormal bowel movements, such as diarrhea, loose stools, or constipation, within 2 weeks prior to first dosing.
13. Has received radiolabeled substances or has been exposed to radiation sources within 12 months of first dosing or is likely to receive radiation exposure or radioisotopes within 12 months of first dosing such that participation in this study would increase their total exposure beyond the recommended levels considered safe [i.e., weighted annual limit recommended by the International Commission on Radiological Protection (ICRP) of 3000 milli roentgen equivalent man (mrem)].

14. Unable to refrain from or anticipates the use of:

    1. Any drug, including prescription and nonprescription medications, herbal remedies, or vitamin supplements within 14 days prior to the first dosing and throughout the study, including the Follow-up Period. Thyroid hormone replacement medication may be permitted if the participant has been on the same stable dose for the immediate 3 months prior to first study drug administration. After the first dose of study drug, ibuprofen (up to 1.2 g per 24 hours) may be administered at the discretion of the Investigator or designee. Milk of Magnesia (i.e., magnesium hydroxide) (≤60 mL per day) may be administered to ensure defecation, at discretion of the Investigator or designee.
    2. Any drugs known to be significant inducers of cytochrome P450 (CYP)3A4, CYP2C19 or uridine diphosphate glucuronosyltransferase (UGT), including St. John's Wort, within 28 days prior to the first dosing and throughout the study, including the Follow-up Period. Appropriate sources (e.g., Flockhart Table^TM) will be consulted to confirm lack of PK/pharmacodynamic interaction with study drug(s).
    3. Alcohol
15. Has been on a diet incompatible with the on-study diet, in the opinion of the Investigator or designee, within the 30 days prior to the first dosing and throughout the study.
16. Donation of blood or significant blood loss within 56 days prior to the first dosing.
17. Plasma donation within 7 days prior to the first dosing.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TAK-935 300 mg + [14C]TAK-935 50 μg + [14C]TAK-935 300 mg; TAK-935 3×100 mg, tablets, orally, once on Day 1, followed by [14C]TAK-935 50 micrograms (μg) [approximately 1 μCi], IV infusion, once on Day 1 of Treatment Period 1, followed by a Washout Period of 7 days, further followed by [14C]TAK-935 300 mg (approximately 100 μCi) solution, orally, once on Day 1 of Treatment Period 2.	Drug: TAK-935 Oral Tablet; TAK-935 tablet; Other Names: OV935; Soticlestat; Drug: [14C]TAK-935 IV Infusion; [14C]TAK-935 IV infusion; Other Names: OV935; Drug: [14C]TAK-935 Oral Solution; [14C]TAK-935 oral solution; Other Names: OV935

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Period 1: Percent Absolute Bioavailability (%F) for TAK-935	Bioavailability is defined as the proportion of a drug which enters the circulation when introduced into the body and so is able to have an active effect. Percent absolute bioavailability, calculated for plasma TAK-935 as [Actual Dose (IV) x Area Under the Concentration-time Curve from Time 0 to Infinity {AUCinf} (oral)] / [Actual Dose (oral) x AUCinf (IV)] x 100.	Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Treatment Period 1
Period 2: Total Radioactivity Expressed as Cumulative Percentage of Dose of [14C]TAK-935 Excreted in Urine and Feces Combined [Combined Cum%Dose]		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: Total Radioactivity Expressed as Amount of [14C]TAK-935 Excreted in Urine (CumAe[u])		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: Total Radioactivity Expressed as Amount of [14C]TAK-935 Excreted in Feces (CumAe[f])		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: Total Radioactivity Expressed as Amount of [14C]TAK-935 Excreted in Urine and Feces Combined (Combined CumAe)		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: Percentage of Administered Radioactive Dose of [14C]TAK-935 Excreted in Urine (Cum%Dose[u])		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: Percentage of Administered Radioactive Dose of [14C]TAK-935 Excreted in Feces (Cum%Dose[f])		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: Cmax: Maximum Observed Plasma Concentration of TAK-935		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of TAK-935		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: t(1/2)z: Terminal Disposition Phase Half-life of TAK-935 in Plasma		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: AUC0-inf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity of TAK-935		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t for TAK-935		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: AUC0-last: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration of TAK-935		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: Cmax: Maximum Observed Plasma Radioactivity Concentration		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: Tmax: Time to Reach the Maximum Plasma Radioactivity Concentration (Cmax)		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: t(1/2)z: Terminal Disposition Phase Half-life of Plasma Radioactivity Concentration		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: AUC0-inf: Area Under the Plasma Radioactivity Concentration-time Curve From Time 0 to Infinity		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: AUC0-t: Area Under the Plasma Radioactivity Concentration-time Curve From Time 0 to Time t		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: AUC0-last: Area Under the Plasma Radioactivity Concentration-time Curve From Time 0 to Last Quantifiable Concentration		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: Cmax: Maximum Observed Whole Blood Radioactivity Concentration		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: Tmax: Time to Reach the Maximum Whole Blood Radioactivity Concentration (Cmax)		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: t(1/2)z: Terminal Disposition Phase Half-life of Whole Blood Radioactivity Concentration		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: AUC0-inf: Area Under the Whole Blood Radioactivity Concentration-time Curve From Time 0 to Infinity		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: AUC0-t: Area Under the Whole Blood Radioactivity Concentration-time Curve From Time 0 to t		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: AUC0-last: Area Under the Whole Blood Radioactivity Concentration-time Curve From Time 0 to Last Quantifiable Concentration		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: CLR: Renal Clearance for TAK-935 in Urine	Renal clearance (CLr) is the volume of plasma entering the kidney that is completely cleared of drug per unit of time.	Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: Aet1-t2: Amount of TAK-935 Excreted in the Urine in Each Collection Interval		0-12, 12-24, 24-48, 48-72, 72-96, 96-120 hours post-dose in Treatment Period 2
Period 2: Whole Blood to Plasma Partitioning Ratio: Change From Baseline in Percentage of [14C]TAK-935 Radioactivity in Whole Blood Relative to Plasma		0.17, 0.42, 0.75, 1.5, 2.5, 4.5, 8, 12, and 24 hours post-dose in Treatment Period 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Period 1: Ceoi: Plasma Concentration at the End of Infusion for [14C]TAK-935		Day 1: At the end of infusion (at 15 minutes post dose) in Treatment Period 1
Period 1: Cmax: Maximum Observed Plasma Concentration for TAK-935 After Oral Administration		Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Treatment Period 1
Period 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-935 After Oral Administration		Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Treatment Period 1
Period 1: AUC0-inf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-935 After Oral Administration		Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Treatment Period 1
Period 1: AUC0-inf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for [14C]TAK-935 After IV Administration		Day 1 pre-dose and at multiple time points (up to 47.5 hours) post-dose in Treatment Period 1
Period 1: AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to t After Oral Administration		Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Treatment Period 1
Period 1: AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t for TAK-935 After IV Administration		Day 1 pre-dose and at multiple time points (up to 47.5 hours) post-dose in Treatment Period 1
Period 1: AUC0-last: Area Under the Plasma Concentration-time Curve From Time 0 to Last Quantifiable Concentration for TAK-935 After Oral Administration		Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Treatment Period 1
Period 1: AUC0-last: Area Under the Plasma Concentration-time Curve From Time 0 to Last Quantifiable Concentration for [14C]TAK-935 After IV Administration		Day 1 pre-dose and at multiple time points (up to 47.5 hours) post-dose in Treatment Period 1
Period 1: t(1/2)z: Terminal Disposition Half-life for TAK-935 After Oral Administration in Plasma		Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose
Period 1: t(1/2)z: Terminal Disposition Half-life for [14C]TAK-935 After IV Administration in Plasma		Day 1 pre-dose and at multiple time points (up to 47.5 hours) post-dose
Period 1: Total Radioactivity Expressed as Amount of [14C]TAK-935 Excreted in Urine (CumAe[u]) After IV Administration		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 1
Period 1: Total Radioactivity Expressed as Amount of [14C]TAK-935 Excreted in Feces (CumAe[f]) After IV Administration		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 1
Period 1: Total Radioactivity Expressed as Amount of [14C]TAK-935 Excreted in Urine and Feces Combined (Combined CumAe) After IV Administration		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 1
Period 1: Percentage of Administered Radioactive Dose of [14C]TAK-935 Excreted in Urine (Cum%Dose[u]) After IV Administration		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 1
Period 1: Percentage of Administered Radioactive Dose of [14C]TAK-935 Excreted in Feces (%Dose[f]) After IV Administration		Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 1
Period 2: Metabolic Profile of TAK-935 in Plasma After Oral Administration of [14C]TAK-935	The metabolic profile of TAK-935 after oral administration of [14C]TAK-935 was done to assess the presence of TAK-935 and various metabolites (M1 to M9) in plasma in at least one sample using radiometric detection and/or liquid chromatography mass spectroscopy (LCMS). The presence of any metabolite is indicated as '1' and absence is indicated as '0'. Only categories with value '1' are reported.	Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Period 2: Metabolic Profile of TAK-935 in Urine and Feces After Oral Administration of [14C]TAK-935	The metabolic profile of TAK-935 after oral administration of [14C]TAK-935 was done to assess the presence of TAK-935 and various metabolites (M1 to M9) in urine and feces in at least one sample using radiometric detection and/or LCMS. The presence of any metabolite is indicated as '1' and absence is indicated as '0'. Data is reported separately for urine and feces.	Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose in Treatment Period 2
Percentage of Participants Reporting One or More Treatment Emergent Adverse Events (TEAEs)	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 (example, 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 TEAE is defined as an AE that is starting or worsening at the time of or after study drug administration.	From first dose up to 30 days after last dose of study drug (up to approximately 40 days)
Percentage of Participants With Treatment Emergent Clinically Relevant Changes in Electrocardiogram (ECG) Parameters		From first dose up to 30 days after last dose of study drug (up to approximately 40 days)
Percentage of Participants With Treatment Emergent Clinically Relevant Changes in Vital Sign Parameters	Vital Signs included blood pressure (systolic and diastolic), heart rate (HR), respiratory rate, and temperature.	From first dose up to 30 days after last dose of study drug (up to approximately 40 days)
Percentage of Participants With Treatment Emergent Clinically Relevant Changes in Laboratory Parameters	The laboratory parameters included tests for serum chemistry, hematology, coagulation, and urinalysis.	From first dose up to 30 days after last dose of study drug (up to approximately 40 days)

Collaborators and Investigators

• Sponsor: Takeda

Study record dates

Study Major Dates

• Study Start (Actual): July 9, 2020
• Primary Completion (Actual): August 18, 2020
• Study Completion (Actual): August 18, 2020

Study Registration Dates

• First Submitted: August 3, 2021
• First Submitted That Met QC Criteria: August 3, 2021
• First Posted (Actual): August 5, 2021

Study Record Updates

• Last Update Posted (Actual): October 4, 2021
• Last Update Submitted That Met QC Criteria: October 1, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Drug Therapy
• Other Study ID Numbers: TAK-935-1008

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