A Study of Soticlestat in Healthy Adults To Evaluate the Effect on QTc Interval

A Phase 1, Double-Blinded, Placebo- and Active-Controlled, Randomized Study to Investigate the Potential of Soticlestat to Prolong the QTc Interval in Healthy Adult Participants

The main aim is to see if soticlestat has any effect in the heart rate.

Participants will receive 4 doses of soticlestat in tablets and will complete some assessment which include to record activity of the heart and collection of blood samples.

Then, the clinic will contact the participants 14 days after their final dose of soticlestat to check if they have any health problems.

Study Overview

• Status: Withdrawn
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Soticlestat; Drug: Placebo; Drug: Moxifloxacin; Drug: Placebo

Detailed Description

The drug being tested in this study is called soticlestat. Soticlestat is being tested in healthy participants for the purpose of this study. This study will assess the effect of single-dose of soticlestat on the heart rate (QTc prolongation). The study will enroll approximately 60 participants.

Participants will be randomly assigned (by chance, like flipping a coin) to 1 of the 4 treatments sequences.

• Sequence 1: (Regimen A+ Regimen B + Regimen C + Regimen D)
• Sequence 2: (Regimen B+ Regimen D + Regimen A + Regimen C)
• Sequence 3: (Regimen C+ Regimen A + Regimen D + Regimen B)
• Sequence 4: (Regimen D+ Regimen C + Regimen B + Regimen A)

All participants will receive all 4 treatment regimens. Treatment order will remain undisclosed to the participants and study doctor (unless there is an urgent medical need). This is a single-center trial. Participants will be followed up for up to 14 days after the last dose of study drug for a follow-up assessment. The overall time to participate in this study is approximately 63 days including screening period and follow-up period.

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Male participants agree to comply with any applicable contraceptive requirements of the protocol.
2. Body mass index (BMI) greater than or equal to (>=)18.0 and <=32.0 kilogram per square meter (kg/m^2) at screening.
3. Continuous non-smoker who has not used nicotine-containing products for at least 90 days prior to the first dosing, based on participant self-reporting.

4. No clinically significant history or presence of ECG findings as judged by the Investigator or designee, including each criterion as listed below:

   • Normal sinus rhythm (HR between 45 bpm and 100 bpm inclusive) at screening and check-in;
   • QTcF is <=450 ms (males) or <=470 ms (females) at screening and check-in;
   • QRS interval <=110 ms; if >110 ms, result will be confirmed by a manual over read at screening and check-in;
   • PR interval <=220 ms at screening and check-in.

Exclusion Criteria:

1. Mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study.

2. History or presence of any of the following, deemed clinically significant by the Investigator or designee:

   • epilepsy, seizure, or convulsion, tremor or related symptoms;
   • risk factors for Torsade de Pointes (TdP) (example, heart failure, unexplained syncope, cardiomyopathy, or family history of Long QT Syndrome);
   • family history of sudden death;
   • sick sinus syndrome, second or third degree atrioventricular block, myocardial infarction, pulmonary congestion, symptomatic or significant cardiac arrhythmia, prolonged QTcF interval, or conduction abnormalities;
   • ischemic heart disease, poorly controlled hypertension, or other cardiovascular disorder;
   • T wave flattening or other abnormalities which in the opinion of the investigator or designee may interfere with the analysis of QT intervals;
   • clinically significant hyper- or hypokalemia.
3. Any positive responses on the Columbia-Suicide Severity Rating Scale (C-SSRS) that in the clinical judgement of the Investigator has a risk of suicide or has made a suicide attempt in the previous 12 months prior to the first dosing.
4. Positive urine drug or alcohol results at screening or at check-in.
5. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or antibody test for hepatitis C virus (HCV).

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

   • Any vaccines, drugs, including prescription and non-prescription medications, herbal remedies, or vitamin supplements within 14 days prior to the first dosing. 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 dosing.
   • Any drugs known to be significant inducers of cytochrome P450 (CYP)3A, CYP2C19, uridine 5' diphospho-glucuronosyltransferase (UGT)1A9 or (UGT)2B4 enzymes and/or P-glycoprotein (P-gp), including St. John's Wort, within 28 days prior to the first dosing. Appropriate sources (example, Flockhart TableTM) will be consulted to confirm lack of Pharmacokinetics (PK)/pharmacodynamics interaction with study drug.
7. Consumes excessive amounts, defined as greater than 4 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks or other caffeinated beverages per day.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Sequence 1: (Regimen A + Regimen B + Regimen C + Regimen D); Regimen A (soticlestat 300 milligram [mg] tablets + soticlestat placebo-matching tablets + moxifloxacin placebo-matching capsule), orally, in fasting condition once on Day 1 of Treatment Period 1, followed by at least 7 days washout period, followed by Regimen B (soticlestat 900 mg tablets + moxifloxacin placebo-matching capsule), orally, in fasting condition once on Day 1 of Treatment Period 2, followed by at least 7 days washout period, followed by Regimen C (soticlestat placebo-matching tablets + moxifloxacin 400 mg over-encapsulated tablet), orally, in fasting condition, once on Day 1 of Treatment Period 3, followed by at least 7 days washout period, followed by Regimen D (soticlestat placebo-matching tablets + moxifloxacin placebo-matching capsule), orally, in fasting condition once on Day 1 of Treatment Period 4.	Drug: Soticlestat; Soticlestat tablet.; Other Names: TAK-935; Drug: Placebo; Soticlestat placebo-matching tablet.; Drug: Moxifloxacin; Moxifloxacin over-encapsulated tablet.; Drug: Placebo; Moxifloxacin placebo-matching capsule.
EXPERIMENTAL: Sequence 2: (Regimen B + Regimen D + Regimen A + Regimen C); Regimen B (soticlestat 900 mg tablets + moxifloxacin placebo-matching capsule), orally, in fasting condition once on Day 1 of Treatment Period 1, followed by at least 7 days washout period, followed by Regimen D (soticlestat placebo-matching tablets + moxifloxacin placebo-matching capsule), orally, in fasting condition once on Day 1 of Treatment Period 2, followed by at least 7 days washout period, followed by Regimen A (soticlestat 300 mg tablets + soticlestat placebo-matching tablets + moxifloxacin placebo-matching capsule), orally, in fasting condition, once on Day 1 of Treatment Period 3, followed by at least 7 days washout period, followed by Regimen C (soticlestat -matching tablets + moxifloxacin 400 mg over-encapsulated tablet), orally, in fasting condition once on Day 1 of Treatment Period 4.	Drug: Soticlestat; Soticlestat tablet.; Other Names: TAK-935; Drug: Placebo; Soticlestat placebo-matching tablet.; Drug: Moxifloxacin; Moxifloxacin over-encapsulated tablet.; Drug: Placebo; Moxifloxacin placebo-matching capsule.
EXPERIMENTAL: Sequence 3: (Regimen C + Regimen A + Regimen D + Regimen B); Regimen C (soticlestat placebo-matching tablets + moxifloxacin 400 mg over-encapsulated tablet), orally, in fasting condition once on Day 1 of Treatment Period 1, followed by at least 7 days washout period, followed by Regimen A (soticlestat 300 mg tablets + soticlestat placebo-matching tablets + moxifloxacin placebo-matching capsule), orally, in fasting condition once on Day 1 of Treatment Period 2, followed by at least 7 days washout period, followed by Regimen D (soticlestat placebo-matching tablets + moxifloxacin placebo-matching capsule), orally, in fasting condition, once on Day 1 of Treatment Period 3, followed by at least 7 days washout period, followed by Regimen B (soticlestat 900 mg tablets + moxifloxacin placebo-matching capsule), orally, in fasting condition once on Day 1 of Treatment Period 4.	Drug: Soticlestat; Soticlestat tablet.; Other Names: TAK-935; Drug: Placebo; Soticlestat placebo-matching tablet.; Drug: Moxifloxacin; Moxifloxacin over-encapsulated tablet.; Drug: Placebo; Moxifloxacin placebo-matching capsule.
EXPERIMENTAL: Sequence 4: (Regimen D + Regimen C + Regimen B + Regimen A); Regimen D (soticlestat placebo-matching tablets + moxifloxacin placebo-matching capsule), orally, in fasting condition once on Day 1 of Treatment Period 1, followed by at least 7 days washout period, followed by Regimen C (soticlestat placebo-matching tablets + moxifloxacin 400 mg over-encapsulated tablet), orally, in fasting condition once on Day 1 of Treatment Period 2, followed by at least 7 days washout period, followed by Regimen B (soticlestat 900 mg tablets + moxifloxacin placebo-matching capsule), orally, in fasting condition, once on Day 1 of Treatment Period 3, followed by at least 7 days washout period, followed by Regimen A (soticlestat 300 mg tablets + soticlestat placebo-matching tablets + moxifloxacin placebo-matching capsule), orally, in fasting condition once on Day 1 of Treatment Period 4.	Drug: Soticlestat; Soticlestat tablet.; Other Names: TAK-935; Drug: Placebo; Soticlestat placebo-matching tablet.; Drug: Moxifloxacin; Moxifloxacin over-encapsulated tablet.; Drug: Placebo; Moxifloxacin placebo-matching capsule.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Placebo-corrected Change From Baseline in Corrected QT Interval (QTc)	The QTc interval will be measured by continuous electrocardiogram (ECG) recordings. The primary QT correction method will be Fridericia's correction. In case a substantial HR effect is observed on-treatment with soticlestat, drug-free QT/RR data will be collected over a range of Heart Rate (HR) seen off-treatment to allow the generation of individualized QT correction methods. QTc will be calculated from Day -1 of the first treatment period both during the periods of supine rest (QTcS) and from all evaluable QT/RR pairs in the 24-hour recording (QTcI). The method that removes the HR dependence of the QT interval most efficiently will be chosen as primary correction method. The analysis for QTc will be based on a linear mixed-effects model with ΔQTc as the dependent variable, period, sequence, time (that is, nominal post-dose time point), treatment, and time-by-treatment interaction as fixed effects, and baseline QTc as a covariate.	Day -1 up to 24 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in HR	HR will be measured by continuous ECG recordings.	Day 1: Pre-dose up to 24 hours post-dose
Change From Baseline in QTc With the Methods Not Selected as Primary	The QTc interval will be measured by continuous ECG recordings. Pre-dose will be the average of the derived ECG intervals from the 3 ECG time-points (-0.75, -0.5, and -0.25 hours) prior to treatment administration on Day 1 within each respective period.	Day 1: Pre-dose up to 24 hours post-dose
Change From Baseline in Individualized HR-corrected QT interval (QTcS)	The QTcS interval will be measured by continuous ECG recordings and QT/RR interval of ECG (RR) data obtained at supine resting time points. The analysis for QTcS will be based on a linear mixed-effects model.	Day 1: Pre-dose up to 24 hours post-dose
Change From Baseline in Optimized QT Interval (QTcI)	The QTcI interval will be measured by continuous ECG recordings and QT/RR data obtained at supine resting time points. The analysis for QTcI will be based on a linear regression model.	Day 1: Pre-dose up to 24 hours post-dose
Change From Baseline in PR Interval of the ECG (PR)	PR will be measured by continuous ECG recordings.	Day 1: Pre-dose up to 24 hours post-dose
Change From Baseline in QRS Interval of the ECG (QRS)	QRS will be measured by continuous ECG recordings.	Day 1: Pre-dose up to 24 hours post-dose
Placebo-corrected Change From Baseline in HR	Placebo-corrected HR will be measured by continuous ECG recordings.	Day 1: Pre-dose up to 24 hours post-dose
Placebo-corrected Change From Baseline in QTc With the Methods Not Selected as Primary	Placebo-corrected QTc interval will be measured by continuous ECG recordings. Pre-dose will be the average of the derived ECG intervals from the 3 ECG time-points (-0.75, -0.5, and -0.25 hours) prior to treatment administration on Day 1 within each respective period.	Day 1: Pre-dose up to 24 hours post-dose
Placebo-corrected Change From Baseline in PR Interval of ECG	Placebo-corrected PR interval will be measured by continuous ECG recordings.	Day 1: Pre-dose up to 24 hours post-dose
Placebo-corrected Change From Baseline in QRS Interval of ECG	Placebo-corrected QRS interval will be measured by continuous ECG recordings.	Day 1: Pre-dose up to 24 hours post-dose
Number of Participants with Categorical Outlier Values for HR	Number of participants with categorical outlier values for HR will be determined. A participant will be determined as an outlier if the following criteria were met for the ECG intervals at any time point: Decrease of HR from baseline greater than (>) 25 percent (%) resulting in HR less than (<) 50 beats per minute (bpm) and increase in HR from baseline resulting in HR >100 bpm.	Day 1: Pre-dose up to 24 hours post-dose
Number of Participants with Categorical Outliers Values for PR	Number of participants with categorical outlier values for PR will be determined. A participant will be determined as an outlier if the following criteria were met for the ECG interval at any time point: Increase of PR from Baseline >25% resulting in PR >200 millisecond (ms).	Day 1: Pre-dose up to 24 hours post-dose
Number of Participants with Categorical Outliers Values for QRS	Number of participants with categorical outliers values for QRS will be determined. A participant will be determined as an outlier if the following criteria were met for the ECG interval at any time point: Increase of QRS from Baseline >25% resulting in QRS >120 ms.	Day 1: Pre-dose up to 24 hours post-dose
Number of Participants with Categorical Outliers Values for QTc	Number of participants with categorical outliers values for QTc will be determined. A participant will be determined as an outlier if the following criteria were met for the ECG interval at any time point: Increase in treatment-emergent value >450 and less than or equal to (<=) 480 ms; >480 and <=500; change from Baseline of >30 and <=60 ms or >60 ms.	Day 1: Pre-dose up to 24 hours post-dose
Percentage of Participants with Change From Baseline in ECG Morphology	ECG morphological analyses will be performed using the ECG waveform interpretation as defined by the central ECG laboratory's cardiologist.	Day 1: Pre-dose up to 24 hours post-dose
Number 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 who has signed informed consent to participate in a study; it does not necessarily have to have a causal relationship with the treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.	Baseline (Day 1) up to 14 days after the last dose of study drug in Period 4 (Day 39)
Cmax: Maximum Observed Plasma Concentration for Soticlestat		Day 1: Pre-dose and at multiple timepoints (up to 24 hours) post-dose
AUC∞: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for Soticlestat		Day 1: Pre-dose and at multiple timepoints (up to 24 hours) post-dose
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Soticlestat		Day 1: Pre-dose and at multiple timepoints (up to 24 hours) post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Soticlestat		Day 1: Pre-dose and at multiple timepoints (up to 24 hours) post-dose
T1/2z: Terminal Phase Elimination Half-life for Soticlestat		Day 1: Pre-dose and at multiple timepoints (up to 24 hours) post-dose

Collaborators and Investigators

• Sponsor: Takeda

Publications and helpful links

Helpful Links

• To obtain more information on the study, click here/on this link

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): October 11, 2022
• Primary Completion (ANTICIPATED): December 6, 2022
• Study Completion (ANTICIPATED): December 6, 2022

Study Registration Dates

• First Submitted: March 30, 2022
• First Submitted That Met QC Criteria: March 30, 2022
• First Posted (ACTUAL): April 4, 2022

Study Record Updates

• Last Update Posted (ACTUAL): November 14, 2022
• Last Update Submitted That Met QC Criteria: November 9, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Drug Therapy
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Moxifloxacin
• Other Study ID Numbers: TAK-935-1001

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
• product manufactured in and exported from the U.S.: No