Relative Bioavailability Study of Emodepside IR-tablets and Solution

Study Overview
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Brief Summary
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This study evaluates 2 new immediate release (IR)-tablet formulations of emodepside and they will be compared to the oral liquid service formulation (LSF) used in the FIH Single Ascending Dose study (DNDi-EMO-001 study) (CT.gov identifier: NCT02661178)

Detailed Description
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There is an urgent need for a macrofilaricidal drug, killing or sterilizing permanently O. volvulus adult worms, which could be used in individual case management and, after appropriate testing, as an alternative drug to ivermectin in MDA programs. Emodepside is a promising candidate to kill the adult and sexually mature O. volvulus. Emodepside was shown to be macrofilaricidal against a variety of filarial nematodes and is a registered drug for animal health, commercialized by Bayer AG under the name of Profender® (in combination with praziquantel) or Procox® (in combination with toltrazuril). A first-in-human (FIH) double-blind, placebo-controlled study of single ascending doses of emodepside in healthy Caucasian men has been conducted and the preliminary results are favourable, and support continuing the Phase I development program. For this reason, new tablet formulations have been developped and the present study will evaluate bioavailability, PK safety and tolerability, and as well food effect of single doses of 2 new immediate release (IR)-tablet formulations of emodepside compared to the oral liquid service formulation (LSF) used in the FIH study.

Official Title
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Phase1,Randomized,Open-Label,Parallel-Group,Relative Bioavailability Study to Investigate PK,Including Food Effect,Safety and Tolerability of Single Doses of New Immediate Release Tablet Formulations of Emodepside (BAY 44-4400),Compared to Oral Solution,in Healthy Male Subjects

Conditions
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Filariasis

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male, Caucasian volunteers, deemed healthy based on a clinical history, physical examination, ECG, vital signs, and laboratory tests of blood and urine. 18 to 45 years of age Normal body weight (Body Mass Index (BMI); Quetelet index) in the range 18.0 to 30.1 kg/m2 at screening Mean blood pressure and heart rate (from the triplicate readings) in the supine position at the screening assessment outside one (or more) of the ranges: 90-140 mm Hg systolic BP 60-90 mm Hg diastolic BP 45-100 beats/min HR 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 Willingness to give written consent to have data entered into The Overvolunteering Prevention System (TOPS) Willingness to follow contraception requirements of the study, from the first dose of the IMP until 90 days after dosing and inform HMR as soon as possible if their partner becomes pregnant in the 90 days after dosing Exclusion Criteria: Administration of a licensed or unlicensed medicinal product as part of another clinical trial in the 3 months before the first dose of study medication, or within 5 half-lives of administration of a medicinal product given in the previous study (whichever is longer), or otherwise in the follow-up period for any clinical trial Clinically relevant abnormal medical history, concurrent medical condition, acute or chronic illness, or history of chronic illness (such as diabetes mellitus or other abnormalities of glucose homeostasis) sufficient to invalidate the subject's participation in the trial or make it unnecessarily hazardous Past surgery (e.g. stomach bypass) or medical condition that might affect absorption of the study drug when taken orally Presence of abnormal physical findings, ECG, or laboratory values at the screening assessment that could interfere with the objectives of the trial or the safety of the subject Loss of more than 400 mL of blood within the 3 months before admission Clinically relevant history of vital organ disease, or other organ or central nervous system disease (e.g. diabetes mellitus, liver disease, seizures, etc.) Current or previous medical or psychiatric disorder that, in the opinion of the Investigator or the Sponsor, would increase the risk and ability to participate in and/or complete the study Positive test for hepatitis B, hepatitis C or HIV Febrile illness (e.g. fever) within 1 week before the first dose of study medication History of a severe allergy, non-allergic drug reaction, severe adverse reaction to any drug, or multiple drug allergies Hypersensitivity to any ingredient of the study medication, including the active ingredient (emodepside) Presence or history of drug or alcohol abuse in the last year, or intake of more than 21 units (1 unit = 1/2 pint of beer, 1 small glass of wine or 1 measure of spirits) of alcohol weekly Regular daily consumption of more than one litre of beverages containing xanthine Daily consumption of more than 10 cigarettes or more than 6 grams (1/4 ounce) of tobacco Use of a prescription medicine during the 28 days before the dose of study medication, or use of an over-the-counter medicine (with exception of acetaminophen (paracetamol)), during the 7 days before the dose of study medication Use, within 14 days before the dose of study medication, of dietary supplements or herbal remedies (such as St John's Wort) that are known to be inducers or inhibitors of CYP3A4, or other co-medications known to be relevant substrates of CYP3A4 (see list in the Study Procedures Manual) Use, within 14 days before the dose of study medication, of dietary supplements or herbal remedies that are known to be strong inhibitors of P-gp, or other co-medications known to be relevant substrates of P-gp (see list in the Study Procedures Manual) Relevant pathological abnormalities in the ECG at screening, such as: second or third-degree atrioventricular (AV) block prolongation of the QRS complex > 120 msec, QTc-interval (QTcB or QTcF) > 450 msec. The mean of the triplicate ECG readings will be used to assess eligibility. Evidence of drug abuse (via urine testing) at the screening assessment or admission to the ward Use of excluded therapies that may impact on the interpretation of study results in the opinion of the Investigator or Sponsor Objection by General Practitioner (GP) to subject entering trial History of residing for 6 or more continuous months during the last 3 years in regions with endemic parasitic infections, as determined by the Investigator Possibility that subject will not cooperate with the requirements of the protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a single-centre, open-label, randomized, parallel-group relative bioavailability study in healthy men. The study will be done in 2 parts, as follows: Part 1 - single oral doses of 5 mg emodepside will be tested: Part 1a - the LSF (reference formulation) and 2 new IR-tablet formulations (test formulations) will be administered in the fasted state. Part 1b - the 2 new IR-tablet formulations will be administered in the fed state (high-fat, high-calorie meal). Part 2 - single oral doses of 10 mg emodepside will be tested: depending on the results from Part 1, one or both IR-tablet formulations will be administered in the fasted state.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1a - treatment A<br>5 mg emodepside LSF, fasted | Drug: Emodepside (BAY 44-4400)<br>* 2 tablets compared to the liquid formulation<br>* Other names: Procox® (in combination with toltrazuril) FOR VETERINARY USE;|
| Experimental: Part 1a - treatment B<br>5 mg emodepside IR-tablet #406, fasted | Drug: Emodepside (BAY 44-4400)<br>* 2 tablets compared to the liquid formulation<br>* Other names: Procox® (in combination with toltrazuril) FOR VETERINARY USE;|
| Experimental: Part 1a - treatment C<br>5 mg emodepside IR-tablet #416, fasted | Drug: Emodepside (BAY 44-4400)<br>* 2 tablets compared to the liquid formulation<br>* Other names: Procox® (in combination with toltrazuril) FOR VETERINARY USE;|
| Experimental: Part 1b - treatment D<br>5 mg emodepside IR-tablet #406, fed | Drug: Emodepside (BAY 44-4400)<br>* 2 tablets compared to the liquid formulation<br>* Other names: Procox® (in combination with toltrazuril) FOR VETERINARY USE;|
| Experimental: Part 1b - treatment E<br>5 mg emodepside IR-tablet #416, fed | Drug: Emodepside (BAY 44-4400)<br>* 2 tablets compared to the liquid formulation<br>* Other names: Procox® (in combination with toltrazuril) FOR VETERINARY USE;|
| Experimental: Part 2 - treatment F<br>2 x 5 mg emodepside IR-tablet #406, fasted (may be tested or not, depending on the results of the part 1) | Drug: Emodepside (BAY 44-4400)<br>* 2 tablets compared to the liquid formulation<br>* Other names: Procox® (in combination with toltrazuril) FOR VETERINARY USE;|
| Experimental: Part 2 - treatment G<br>2 x 5 mg emodepside IR-tablet #416, fasted (may be tested or not, depending on the results of the part 1) | Drug: Emodepside (BAY 44-4400)<br>* 2 tablets compared to the liquid formulation<br>* Other names: Procox® (in combination with toltrazuril) FOR VETERINARY USE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK (AUC0-7d) of Two New Tablet Formulations of Emodepside in Comparison to the Liquid Formulation (LSF) Oral Solution. | Means AUC from zero to 7 days (AUC0-7d) = means area under the plasma concentration-time curve from time zero (pre-dose) to 7 days. To create the curve, the following PK Timepoints have been collected: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3,4,6,8,12,36,48,72,120 and 168h post dose | means from zero to 7 days | 
| PK (Cmax) of Two New Tablet Formulations of Emodepside in Comparison to the Liquid Formulation (LSF) Oral Solution. | Cmax means maximum observed plasma concentration. To create the PK curve, the following PK timepoints have been collected: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3,4,6,8,12,36,48,72,120 and 168h post dose | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability as Measured by Number of Participants With Treatment-related Adverse Events | number of participants with treatment-related adverse events | 7 days | 
| Safety and Tolerability as Measured by Number of Participants With Physical Examination Findings | number of participants with abnormal physical examination (PE) findings. Standard examination done on head, ears, eyes, nose, thyroid, lymph node, back, neck, lungs, skin, abdomen, chest. The details are listed in protocol section 8.11.3 | 7 days | 
| Safety and Tolerability as Measured by Number of Participants With Neurological Examination Findings | Number of participants with abnormal neurological examination (NE) findings | 7 days | 
| Safety and Tolerability as Measured by Number of Participants With Vital Signs Findings | number of participants with vital signs (VS) findings. The vital signs ranges are the following Supine Systolic BP : 85-160mm HG, Supine Diastolic BP: 40-90mm HG, Supine HR: 35-100 beats/min. Details are described in the protocol section 8.11.2 | 7 days | 
| Safety and Tolerability as Measured by Number of Participants With 12-lead ECG Findings | number of participants with 12-lead ECG findings. The ECG reference ranges used are the following: ventricular rate: 45-100beats/min, PR interval:120-220msec, QRS:<120msec, QTc:<430msec | 7 days | 
| Safety and Tolerability as Measured by Number of Participants With Clinical Laboratory Tests Findings | number of participants with relevant abnormal laboratory tests results | 7 days |