Clinical trial NCT04019652: The Effect of CS-3150 Exposure on Corrected QT (QTc) Interval Duration in Healthy Volunteers
Official title: A Randomized, Double-Blind, Single-Dose, Placebo- and Positive-Controlled Crossover Study to Evaluate the Effect of Therapeutic and Supratherapeutic Exposure to CS-3150 on QTc Interval Duration in Healthy Male and Female Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hypertension
Mineralocorticoid Receptor Antagonist
Keywords: Hypertension
Mineralocorticoid receptor antagonist
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
First posted: 2019-07-15
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This is a phase 1, single center, randomized, single-dose, double-blind, double-dummy, placebo- and positive-controlled, 4-period crossover study. Participants will be randomized to one of the following 4 treatment sequences:

1. CS-3150 (10-mg dose)/CS-3150 (40-mg dose)/moxifloxacin/placebo
2. CS-3150 (40-mg dose)/placebo/CS-3150 (10-mg dose)/moxifloxacin
3. Moxifloxacin/CS-3150 (10-mg dose)/placebo/CS-3150 (40-mg dose)
4. Placebo/moxifloxacin/CS-3150 (40-mg dose)/CS-3150 (10-mg dose)
Primary purpose: PREVENTION

Brief summary: This study will test if a study drug (CS-3150) will affect the heart rate in healthy males and females. Two doses of the study drug will be tested. Heart rate is not expected to be different between the study groups.

Detailed description: This study will assess the effect of therapeutic and supratherapeutic plasma exposures of CS-3150 on the corrected QT (QTc) interval duration after administration of single oral 10-mg and 40-mg doses of CS-3150 in healthy male and female participants. This study will also determine the safety and tolerability of CS-3150 administration, assess the effect on electrocardiogram (ECG) parameters, detect QT interval (QT)/QTc prolongation with a positive control (moxifloxacin), characterize pharmacokinetics (PK) of CS-3150, and assess exposure-response relationship of CS-3150 on QTc.

Eligibility criteria: Inclusion Criteria:

* Healthy males and/or females 18 years to 45 years of age with a body mass index of 19 kg/m2 to 32 kg/m2 (inclusive)
* Laboratory results (serum chemistry, hematology, and urinalysis \[UA\]), liver function, and serum K+ levels within normal range
* Written informed consent
* Female participants: Negative pregnancy test and must either be surgically sterile, postmenopausal, or agree to use acceptable nonhormonal contraception.

Exclusion Criteria:

* All prescription or over-the-counter (OTC) medication (systemic and topical) and herbal supplements will not be permitted for 14 days before the first dose and for the duration of the study.
* Oral, injected, or implanted hormonal contraception methods, or hormonal replacement therapy, should not have been received in the 3 months prior to the first dose, and for the duration of the study.
* Female participants: positive pregnancy test or are breast feeding.
* Supine systolic/diastolic blood pressure at screening, after resting for 10 min, higher than 140/90 mmHg or lower than 90/50 mmHg, confirmed after repeated testing at least approximately 1 h apart.
* Supine pulse at screening, after resting for 10 min, outside the range of 40 to 100 beats per minute (bpm).
* QTcF interval duration \> 450 ms for male and female obtained as an average from the triplicate screening ECGs after at least 10 min in a fully supine quiet rest.
* Abnormal waveform morphology on any of the screening ECGs that would preclude accurate measurement of the QT interval duration.
* Family history of congenital Long QT syndrome (LQTS), a history of surviving an unexplained drowning episode, a history of any form of syncope or loss of consciousness, or known symptomatic cardiac arrhythmias.
* Known allergy to moxifloxacin.
* An estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) equation lower than 90 mL/min.
* Previous participation in a CS-3150 study within 6 months prior to the single dose of CS-3150.
* History or current evidence of clinically significant cardiac, hepatic, renal, pulmonary, endocrine, neurologic, infectious, gastrointestinal, hematologic, or oncologic disease as determined by the PI after reviewing screening history, physical examination, laboratory test results, and 12-lead ECG
* Clinically significant illness (at the discretion of principal investigator) within 4 weeks of first dose, are carriers of Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV), or human immunodeficiency virus (HIV) antibody, and any other reason not deemed suitable for the study (at the discretion of the principal investigator).

Primary outcomes:
measure: Change in corrected QT (QTc) interval from baseline following oral administration of 1 of 4 treatment sequences with CS-3150
timeFrame: Day -1 of Period 1 through Day 8 of Period 4 (~36 days)
Secondary outcomes:
measure: Percentage of participants reporting treatment-emergent adverse events (TEAEs) following oral administration of 1 of 4 treatment sequences with CS-3150
timeFrame: Day -1 of Period 1 through Day 8 of Period 4 (~36 days)
measure: Change in corrected QT (QTc) interval from baseline following oral administration of 1 of 4 treatment sequences with moxifloxacin
timeFrame: Day -1 of Period 1 through Day 8 of Period 4 (~36 days)
measure: Change in the interval between the P and R waves (PR) from baseline following oral administration of 1 of 4 treatment sequences with CS-3150
timeFrame: Day -1 of Period 1 through Day 8 of Period 4 (~36 days)
measure: Change in QRS wave complex (QRS) from baseline following oral administration of 1 of 4 treatment sequences with CS-3150
timeFrame: Day -1 of Period 1 through Day 8 of Period 4 (~36 days)
measure: Change in QT interval (QT) from baseline following oral administration of 1 of 4 treatment sequences with CS-3150
timeFrame: Day -1 of Period 1 through Day 8 of Period 4 (~36 days)
measure: Change in QTc corrected by Bazett's formula (QTcB) from baseline following oral administration of 1 of 4 treatment sequences with CS-3150
timeFrame: Day -1 of Period 1 through Day 8 of Period 4 (~36 days)
measure: Change in QTc corrected by Fridericia's formula (QTcF) from baseline following oral administration of 1 of 4 treatment sequences with CS-3150
timeFrame: Day -1 of Period 1 through Day 8 of Period 4 (~36 days)
measure: Change in heart rate (HR) from baseline following oral administration of 1 of 4 treatment sequences with CS-3150
timeFrame: Day -1 of Period 1 through Day 8 of Period 4 (~36 days)
Other outcomes:
Locations:
city: San Antonio
country: United States
facility: Worldwide Clinical Trials
state: Texas
Study officials:
affiliation: Daiichi Sankyo
name: Clinical Study Leader
role: STUDY_DIRECTOR
References:
citation: Mendell J, Kobayashi F, Shimizu T. Randomized, Double-Blind, Single-Dose, Placebo-Controlled Crossover Study to Evaluate the Effects of Esaxerenone on QTc Interval in Healthy Subjects. Clin Pharmacol Drug Dev. 2020 Aug;9(6):709-718. doi: 10.1002/cpdd.794. Epub 2020 Apr 7.