First in Man Clinical Trial of Emodepside (BAY 44-4400)

Phase 1

Completed

Conditions: Healthy Volunteers

Interventions: Drug: emodepside (BAY 44-4400)
Drug: placebo

Registration Number: NCT02661178

Lead Sponsor: Drugs for Neglected Diseases

Brief Summary: This study will investigate the safety, tolerability, and pharmacokinetics of single ascending doses of emodepside (BAY 44-4400) in healthy male volunteers. This study will also conduct an exploratory investigation of the relative bioavailability of emodepside administered as tablets and determine the effect of food on the pharmacokinetics.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 79

Inclusion Criteria

Male, Caucasian volunteers, deemed healthy on the basis of a clinical history, physical examination, ECG, vital signs, and laboratory tests of blood and urine. Optionally, after further evaluation during the study, at the sponsor's discretion other ethnic groups may be recruited.
Aged 18 to 55 years.
With a body mass index (BMI; Quetelet index) in the range of 18 to 30.1 kg/m2 at screening.
Sufficient intelligence to understand the nature of the trial and any hazards of participating in it. Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of, the entire trial.
Willingness to give written consent to participate, after reading the information and consent form, and after having the opportunity to discuss the trial with the investigator or his delegate

Exclusion Criteria

Participation in another clinical trial within 3 months prior and during the study, or 5-times the half-life of the drug tested in the previous clinical trial, whichever is longer (time calculated relative to the last dose in the previous clinical trial)
Clinically relevant abnormal medical history, concurrent medical condition, acute or chronic illness or history of chronic illness sufficient to invalidate the subject's participation in the trial or make it unnecessarily hazardous.
Surgery (eg stomach bypass) or medical condition that might affect absorption of study drug taken orally.
Presence of abnormal physical findings, ECG, or laboratory values at the pre-trial screening assessment that could interfere with the objectives of the trial or the safety of the subject.
Positive tests for hepatitis B & C, HIV
Presence or history of drug or alcohol abuse during the last 10 years, or intake of more than 21 units of alcohol weekly.
Regular daily consumption of more than one liter of xanthine-containing beverages
Regular daily consumption of more than 5 cigarettes daily, or use more than 3 grams (1/8 ounce) of tobacco
Use of a prescription medicine during the 28 days before the first dose of trial medication or use of an over-the-counter medicine, with the exception of acetaminophen (paracetamol), during the 7 days before the first dose of trial medication
Use of dietary supplements or herbal remedies (such as St John's Wort) known to interfere with the CYP3A4 and/or P-gp metabolic pathways during the 28 days before the first dose of trial medication (see list in Study Procedures Manual)

Additional exclusion criteria for cohort with ophthalmological assessments:

No contact lenses wear within 1 month prior to first dose of IMP. Contact lenses wear is not permitted during the study
Any ocular disorder for which topical ocular therapy is currently or chronically prescribed, including inflammatory eye disease (dry eye allergic conjunctivitis [seasonal allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis], uveitis and glaucoma)
Past history of ocular disease requiring ongoing treatment
Past ocular surgery including laser or other refractive corneal surgery
Evidence of eye irritation, visual difficulties, corneal opacity, ocular surface (corneal or conjunctival damage, with or without ocular symptoms)
Evidence of narrow anterior chamber angles causing increased risk of acute glaucoma
Evidence of ocular media opacity including lens opacity/vitreous opacities
Evidence of retinal or optic nerve pathology
Evidence of pronounced colour blindness, as indicated by an Ishihara score of 9/13 or below

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
emodepside (BAY 44-4400)	emodepside (BAY 44-4400)	Up to 10 cohorts with single ascending dose
placebo of emodepside (BAY 44-4400)	placebo	Up to 10 cohorts with single ascending dose

Primary Outcome Measures

Name	Time	Method
Safety and Tolerability as Measured by 12-lead ECG	Up to 14 days post dose (may be extended to 21 days)	The following variables were recorded in 12-lead ECGs and extracted from continuous 12-lead ECG recordings: ventricular rate, PR interval, QRS interval, QTcB and QTcF interval.
Safety and Tolerability as Measured by Clinical Laboratory Parameters	Up to 14 days post dose (may be extended to 21 days)	Clinical laboratory parameters included hematology, biochemistry, serology and coagulation in blood samples and urinalysis in urine samples
Safety and Tolerability as Measured by Physical and Neurological Examination Findings	Up to 14 days post dose (may be extended to 21 days)	Abnormal or clinically significant neurological examination findings during the study or reported as an AE
Safety and Tolerability as Measured by Ophthalmological Examination Findings in One Study Arm Only	Up to 14 days post dose (may be extended to 21 days)	Subjects attended a specialist eye hospital for ophthalmology assessments by a Consultant Ophthalmologist. Opthalmology assessments included:ocular symptoms, past ocular history, auto-refraction, best corrected distance visual acuity, color vision assessment, amsler grid assessment, ocular alignment and ocular motility assessment, confrontation visual field assessment, slit lamp examination (anterior segment), intraocular pressure (Goldmann Tonometry), optical coherence scanning of tomography, post mydriatic ocular media (at Screening visit 2 only) and retinal examination with slit lamp and lens.
Safety and Tolerability as Measured by Adverse Events	Up to 14 days post dose (may be extended to 21 days)	Deaths, serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs)
Safety and Tolerability as Measured by Vital Signs	Up to 14 days post dose (may be extended to 21 days)	Vital signs included heart rate, systolic and diastolic blood pressure,

Secondary Outcome Measures

Name	Time	Method
The t½ of Emodepside in Plasma	From pre-dose until 336h post-dose (may be extended to 504h post-dose)	Terminal half-life (t½), calculated according to the equation t½ = ln2/λz, where λz is the apparent terminal elimination rate constant, estimated by linear regression of log-transformed concentration versus time data
The MRT of Emodepside in Plasma	From pre-dose until 336h post-dose (may be extended to 504h post-dose)	The mean residence time (MRT) was calculated as MRT = AUMC/AUC∞, where AUMC is the area under the first moment of the concentration-time curve from zero time (pre-dose) extrapolated to infinite time
The AUC 0-24 of Emodepside in Plasma	From pre-dose until 336h post-dose (may be extended to 504h post-dose)	Area under the plasma concentration-time curve from time zero (pre-dose) to 24 h was calculated using the trapezoidal method
Frel of the IR (Immediate Release) Tablet of Emodepside	From pre-dose until 336h post-dose (may be extended to 504h post-dose)	The average relative bioavailability (Frel) of the IR tablet was calculated
The Cmax/D of Emodepside in Plasma	From pre-dose until 336h post-dose (may be extended to 504h post-dose)	Dose-normalized observed maximum plasma concentration (Cmax/D) was calculated as Cmax/Dose administered
The Tmax of Emodepside in Plasma	From pre-dose until 336h post-dose (may be extended to 504h post-dose)	Time to reach maximum plasma concentration (Tmax) was obtained directly from the concentration-time data
The AUC∞ of Emodepside in Plasma	From pre-dose until 336h post-dose (may be extended to 504h post-dose)	The area under the plasma drug concentration versus time curve from time zero to infinity (AUC∞)
The AUC∞/D of Emodepside in Plasma	From pre-dose until 336h post-dose (may be extended to 504h post-dose)	Dose-normalized area under the plasma drug concentration versus time curve from time zero to infinity (AUC∞/D), calculated as AUC∞/Dose administered.
The Cmax of Emodepside in Plasma	From pre-dose until 336h post-dose (may be extended to 504h post-dose)	Maximum observed plasma concentration (Cmax) was obtained directly from the concentration-time data
The Cmax, Norm of Emodepside in Plasma	From pre-dose until 336h post-dose (may be extended to 504h post-dose)	The observed maximum plasma concentration (Cmax) normalized by dose and body weight was calculated as Cmax/(Dose administered\*body weight)
The CL/F of Emodepside in Plasma	From pre-dose until 336h post-dose (may be extended to 504h post-dose)	Apparent total clearance from plasma (CL/F) was calculated as CL/F = Dose/AUC∞
The AUC 0-24/D of Emodepside in Plasma	From pre-dose until 336h post-dose (may be extended to 504h post-dose)	Dose-normalized area under the concentration-time curve (AUC) from time zero (pre-dose) to 24 h was calculated as AUC0-24/Dose administered
The AUC 24, Norm of Emodepside in Plasma	From pre-dose until 336h post-dose (may be extended to 504h post-dose)	Area under the concentration-time curve from time zero (pre-dose) to 24 h, normalized by dose and body weight (AUC 24, norm) was calculated as AUC0-24/(Dose administered\*body weight)
The AUC Last of Emodepside in Plasma	From pre-dose until 336h post-dose (may be extended to 504h post-dose)	The area under the concentration-time curve from time zero (pre-dose) to the time of last quantifiable concentration (t), calculated using the linear trapezoidal method for increasing concentrations and the log trapezoidal method for decreasing concentrations
The AUC Last, Norm of Emodepside in Plasma	From pre-dose until 336h post-dose (may be extended to 504h post-dose)	The area under the concentration-time curve from time zero (pre-dose) to the time of last quantifiable concentration normalized by dose and body weight (AUClast/(Dose administered\*body weight))
Effect of Food on the Bioavailability (Cmax) of Emodepside (BAY 44-4400) After Single Oral Dose Administered as Solution or IR Tablets in One Arm Only	From pre-dose until 336h post-dose (may be extended to 504h post-dose)	Results of the statistical analysis of the effect of food on Emodepside exposure, after a single dose of 10 mg Emodepside LSF solution.
The Vz/F of Emodepside in Plasma	From pre-dose until 336h post-dose (may be extended to 504h post-dose)	Apparent volume of distribution (Vz/F) was calculated as Vz/F = Dose/(λz × AUC∞), where λz is the apparent terminal elimination rate constant, estimated by linear regression of log-transformed concentration versus time data
Effect of Food on the Bioavailability (AUC24) of Emodepside (BAY 44-4400) After Single Oral Dose Administered as Solution or IR Tablets in One Arm Only	From pre-dose until 336h post-dose (may be extended to 504h post-dose)	Results of the statistical analysis of the effect of food on Emodepside exposure, after a single dose of 10 mg Emodepside LSF solution.