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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1, Blinded, Randomized, Placebo Controlled, Parallel-Group, Single-Dose, Dose-Escalation Study to Investigate Safety, Tolerability, and Pharmacokinetics of Emodepside (BAY 44-4400) After Oral Dosing in Healthy Male Subjects

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: emodepside (BAY 44-4400)
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: emodepside (BAY 44-4400)<br>Up to 10 cohorts with single ascending dose | Drug: emodepside (BAY 44-4400)<br> <br> |
| Placebo Comparator: placebo of emodepside (BAY 44-4400)<br>Up to 10 cohorts with single ascending dose | Drug: placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability as Measured by Adverse Events | Deaths, serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs) | Up to 14 days post dose (may be extended to 21 days) | 
| Safety and Tolerability as Measured by Physical and Neurological Examination Findings | Abnormal or clinically significant neurological examination findings during the study or reported as an AE | Up to 14 days post dose (may be extended to 21 days) | 
| Safety and Tolerability as Measured by Vital Signs | Vital signs included heart rate, systolic and diastolic blood pressure, | Up to 14 days post dose (may be extended to 21 days) | 
| Safety and Tolerability as Measured by 12-lead ECG | 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. | Up to 14 days post dose (may be extended to 21 days) | 
| Safety and Tolerability as Measured by Clinical Laboratory Parameters | Clinical laboratory parameters included hematology, biochemistry, serology and coagulation in blood samples and urinalysis in urine samples | Up to 14 days post dose (may be extended to 21 days) | 
| Safety and Tolerability as Measured by Ophthalmological Examination Findings in One Study Arm Only | 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. | Up to 14 days post dose (may be extended to 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The AUC∞ of Emodepside in Plasma | The area under the plasma drug concentration versus time curve from time zero to infinity (AUC∞) | From pre-dose until 336h post-dose (may be extended to 504h post-dose) | 
| The AUC∞/D of Emodepside in Plasma | Dose-normalized area under the plasma drug concentration versus time curve from time zero to infinity (AUC∞/D), calculated as AUC∞/Dose administered. | From pre-dose until 336h post-dose (may be extended to 504h post-dose) | 
| The Cmax of Emodepside in Plasma | Maximum observed plasma concentration (Cmax) was obtained directly from the concentration-time data | From pre-dose until 336h post-dose (may be extended to 504h post-dose) | 
| The Cmax/D of Emodepside in Plasma | Dose-normalized observed maximum plasma concentration (Cmax/D) was calculated as Cmax/Dose administered | From pre-dose until 336h post-dose (may be extended to 504h post-dose) | 
| The Cmax, Norm of Emodepside in Plasma | The observed maximum plasma concentration (Cmax) normalized by dose and body weight was calculated as Cmax/(Dose administered*body weight) | From pre-dose until 336h post-dose (may be extended to 504h post-dose) | 
| The Tmax of Emodepside in Plasma | Time to reach maximum plasma concentration (Tmax) was obtained directly from the concentration-time data | From pre-dose until 336h post-dose (may be extended to 504h post-dose) | 
| The t½ of Emodepside in Plasma | 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 | From pre-dose until 336h post-dose (may be extended to 504h post-dose) | 
| The MRT of Emodepside in Plasma | 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 | From pre-dose until 336h post-dose (may be extended to 504h post-dose) | 
| The CL/F of Emodepside in Plasma | Apparent total clearance from plasma (CL/F) was calculated as CL/F = Dose/AUC∞ | From pre-dose until 336h post-dose (may be extended to 504h post-dose) | 
| The AUC 0-24 of Emodepside in Plasma | Area under the plasma concentration-time curve from time zero (pre-dose) to 24 h was calculated using the trapezoidal method | From pre-dose until 336h post-dose (may be extended to 504h post-dose) | 
| The AUC 0-24/D of Emodepside in Plasma | Dose-normalized area under the concentration-time curve (AUC) from time zero (pre-dose) to 24 h was calculated as AUC0-24/Dose administered | From pre-dose until 336h post-dose (may be extended to 504h post-dose) | 
| The AUC 24, Norm of Emodepside in Plasma | 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) | From pre-dose until 336h post-dose (may be extended to 504h post-dose) | 
| The Vz/F of Emodepside in Plasma | 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 | From pre-dose until 336h post-dose (may be extended to 504h post-dose) | 
| The AUC Last of Emodepside in Plasma | 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 | From pre-dose until 336h post-dose (may be extended to 504h post-dose) | 
| Frel of the IR (Immediate Release) Tablet of Emodepside | The average relative bioavailability (Frel) of the IR tablet was calculated | From pre-dose until 336h post-dose (may be extended to 504h post-dose) | 
| The AUC Last, Norm of Emodepside in Plasma | 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)) | From pre-dose until 336h post-dose (may be extended to 504h post-dose) | 
| 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 | Results of the statistical analysis of the effect of food on Emodepside exposure, after a single dose of 10 mg Emodepside LSF solution. | From pre-dose until 336h post-dose (may be extended to 504h post-dose) | 
| 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 | Results of the statistical analysis of the effect of food on Emodepside exposure, after a single dose of 10 mg Emodepside LSF solution. | From pre-dose until 336h post-dose (may be extended to 504h post-dose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parasitic Diseases, Helminthiasis, Nematode Infections, Secernentea Infections, Spirurida Infections, Filariasis, Skin Diseases, Parasitic, Skin and Connective Tissue Diseases, Skin Diseases, Skin Diseases, Infectious, Depsipeptides, Emodepside, Neglected disease, Africa, New drug, Oral drug, Parasite, Anthelmintic drug, Cyclooctadepsipeptide, Single ascending dose, Volunteers, Phase 1, Safety, Tolerability, Pharmacokinetics, Relative bioavailability, Onchocerciasis