Safety, Tolerability and PK of Multiple-ascending Doses of Emodepside

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

The study evaluates safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of emodepside, after administration as a Liquid Service Formulation (LSF), over 10 days, in healthy male caucasian subjects.

Study Overview

• Status: Completed
• Conditions: Filariasis
• Intervention / Treatment: Drug: LSF emodepside (BAY 44-4400) or matching placebo

Detailed Description

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 Mass Drug Administration (MDA) programs. Emodepside is a promising candidate to kill the adult and sexually mature O. volvulus as explained below. 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, supporting continuation of the Phase I development program. In the present repeat dose study, PK as well as safety and tolerability of the liquid service formulation of emodepside, given over 10 days, will be tested.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, NW10 7EW
    • Hammersmith Medicines Research Limited

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 41 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Male, Caucasian volunteers, deemed healthy based on a clinical history, physical examination, ECG, vital signs, and laboratory tests of blood and urine.
2. 18 to 45 years of age.
3. Normal body weight (BMI; Quetelet index) in the range 18 to 30.1 kg/m2 at screening.
4. Blood pressure and heart rate in the supine position prior to randomisation must be within the ranges 90-140 mm Hg systolic, 60-90 mm Hg diastolic; heart rate 45-100 beats/min.
5. 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.
6. 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.
7. Willingness to give written consent to have data entered into the Overvolunteering Prevention System.
8. Willingness to agree to the contraceptive requirements of the study from the first dose until 120 days after the last dose of study medication.

Exclusion Criteria:

1. Administration of a licensed or unlicensed medicinal product as part of another clinical trial within the 3 months before, or within 5 half-lives of, their first dose of study medication, whichever is longer, or is currently in the follow-up period for any clinical trial.
2. 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.
3. Past surgery (e.g., stomach bypass) or medical condition that might affect absorption of study drug taken orally.
4. 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.
5. Loss of more than 400 mL of blood within 3 months before admission.
6. Clinically relevant history of vital organ disease or other disease of an organ or the central nervous system.
7. Current or previous medical or psychiatric disorder, condition or history of such (e.g., seizures) that, in the opinion of the Investigator or the Sponsor, would increase the risk associated with study participation, or impair the subject's ability to participate or complete this study.
8. Positive test for hepatitis B, hepatitis C or HIV.
9. Febrile illness within 1 week before the first dose of study medication.
10. History of severe allergy, non-allergic drug reactions, severe adverse reaction to any drug, or multiple drug allergies.
11. Subjects with hypersensitivity to any ingredient of the study medication, including the active ingredient, emodepside.
12. Presence or history of drug or alcohol abuse in the last 10 years, or intake of more than 21 units of alcohol weekly.
13. Regular daily consumption of more than one liter of xanthine-containing beverages.
14. Regular daily consumption of more than 5 cigarettes daily, or use more than 3 grams (1/8 ounce) of tobacco.
15. Use of a prescription medicine during the 28 days before the first dose of study medication or use of an over-the-counter medicine (with exception of acetaminophen [paracetamol]), during the 7 days before the first dose of study medication.
16. Use 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, during the 28 days before the first dose of study medication (see list in the Study Procedures Manual).
17. Use of dietary supplements or herbal remedies (such as St John's Wort) that are known to be strong inhibitors of P-gp, or other co-medications known to be relevant substrates of P-gp, during the 28 days before the first dose of study medication (see list in the Study Procedures Manual).
18. Relevant pathological abnormalities in the ECG at screening, such as a second or third-degree atrioventricular (AV) block or prolongation of the QRS complex over 120 msec or QTc-interval over 450 msec (corrected using Bazett's [QTcB] or Fridericia's [QTcF] formulae).
19. Evidence of drug abuse (via urine testing) at the screening assessment or admission to the ward.
20. Use of excluded therapies that may impact on the interpretation of study results in the opinion of the Investigator or Sponsor.
21. Objection by General Practitioner (GP) to subject entering trial.
22. History of residing for 6 or more continuous months, within the last 3 years, in regions with endemic parasitic infections as determined by the Investigator.
23. Possibility that subject will not cooperate with the requirements of the protocol.
24. No contact lenses wear within 1 month before dosing. Wearing contact lenses is not permitted during the study.
25. 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).
26. Past history of ocular disease requiring ongoing treatment.
27. Past ocular surgery including laser or other refractive corneal surgery.
28. Evidence of eye irritation, visual difficulties, corneal opacity, ocular surface (corneal or conjunctival damage, with or without ocular symptoms).
29. Evidence of narrow anterior chamber angles causing increased risk of acute glaucoma.
30. Evidence of ocular media opacity including lens opacity/vitreous opacities.
31. Evidence of retinal or optic nerve pathology.
32. Evidence of pronounced colour blindness, as indicated by an Ishihara score of 9/13 or below.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: cohort 1 (8 subjects); 6 subjects with LSF emodepside 5mg, OD 2 subjects with matching placebo	Drug: LSF emodepside (BAY 44-4400) or matching placebo; Emodepside administered as an LSF oral solution (1mg/mL)
Experimental: cohort 2 (8 subjects); 6 subjects with LSF emodepside 10mg, OD 2 subjects with matching placebo	Drug: LSF emodepside (BAY 44-4400) or matching placebo; Emodepside administered as an LSF oral solution (1mg/mL)
Experimental: cohort 3 (8 subjects); 6 subjects with LSF emodepside 10mg, BID 2 subjects with matching placebo	Drug: LSF emodepside (BAY 44-4400) or matching placebo; Emodepside administered as an LSF oral solution (1mg/mL)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability of Emodepside After Multiple Doses as Measured by Number of Participants With Adverse Events	Death, serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs).	up to 120 days
Safety and Tolerability of Emodepside After Multiple Doses as Measured by Adverse Event Severity	Number of subjects with a TEAE, by highest level of severity.	Up to 120 days
Safety and Tolerability of Emodepside After Multiple Doses as Measured by Number of Participants With Vital Signs Findings	Vital signs included heart rate, systolic and diastolic blood pressure and temperature.	up to 120 days
Safety and Tolerability of Emodepside After Multiple Doses as Measured by Number of Participants With 12-lead Electrocardiogram Findings	The following variables were recorded in 12-lead ECGs: ventricular rate, PR interval, QRS interval, QTcB and QTcF interval.	up to 30 days
Safety and Tolerability of Emodepside After Multiple Doses as Measured by Number of Participants With Clinical Laboratory Tests Findings	Clinical laboratory parameters included clinical chemistry, hematology, coagulation and urinalysis.	up to 120 days
Safety and Tolerability of Emodepside After Multiple Doses as Measured by Number of Participants With Ophthalmology Assessment Findings	Ophthalmological examinations at Screening Visit 2 and Day 10 were done at a specialist eye hospital by a Consultant Ophthalmologist, or their assistant. Examinations included: ocular symptoms and history, autorefraction, best correct visual acuity, colour vision, Amsler grid, ocular alignment and motility, confrontation visual field, slit-lamp, measurement of intraocular pressure and an optical coherence tomography test.	up to 10 days
Safety and Tolerability of Emodepside After Multiple Doses as Measured by Number of Participants With Physical Examination Findings	Abnormal or clinically significant physical examination findings during the study or reported as an adverse event.	up to 120 days
Safety and Tolerability of Emodepside After Multiple Doses as Measured by Number of Participants With Neurological Examination Findings	Abnormal or clinically significant neurological examination findings during the study or reported as an adverse event.	up to 120 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Geometric Mean Emodepside Plasma Pharmacokinetic Concentration-Time Data During the Repeated Dosing Period	Summary of geometric mean emodepside plasma pharmacokinetic concentration-time data (ng/mL) during the repeated dosing period (Days 0-9) in healthy men. Subjects in the 10 mg emodepside BID dosing group had twice-daily doses on Days 0-8 and a single dose on the morning of Day 9. Therefore, the Day 9, 24 h post-dose value was not comparable to the previous value in that dosing group.	From Day 1, pre-dose to Day 9, 24 hours post-dose
The AUClast of Emodepside in Plasma	Summary of AUClast of emodepside after the last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120h (Day 14) after the morning dose. AUClast: the area under the concentration-time curve from time zero (pre-dose) to the time of last quantifiable concentration. PK=pharmacokinetic. The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	AUClast in plasma after the last dose (Day 9)
The AUClast/D of Emodepside in Plasma	Summary of AUClast/D of emodepside after the last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120h (Day 14) after the morning dose. AUClast/D: the area under the concentration-time curve from time zero (pre-dose) to the time of last quantifiable concentration corrected for dose. The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	AUClast /D in plasma after the last dose (Day 9)
The AUClast,Norm of Emodepside in Plasma	Summary of AUClast,norm of emodepside after the last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120h (Day 14) after the morning dose. AUClast,norm: the area under the concentration-time curve from time zero (pre-dose) to the time of last quantifiable concentration corrected by dose and body weight. The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	AUClast,norm in plasma after the last (Day 9) dose
The AUC12 of Emodepside in Plasma	Summary of AUC12 of emodepside after the first (Day 0) and last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 0 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 15h after the morning dose. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120h (Day 14) after the morning dose. AUC12: the area under the concentration-time curve from time zero (pre-dose) to 12h. Note: AUC12 was calculated only in Cohort 3. The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	AUC12 in plasma after the first (Day 0) and last (Day 9) dose
The AUC12/D of Emodepside in Plasma	Summary of AUC12/D of emodepside after the first (Day 0) and last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 0 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 15h after the morning dose. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120h (Day 14) after the morning dose. AUC12/D: the area under the concentration-time curve from time zero (pre-dose) to 12h, corrected for dose. Note: AUC12/D was collected only in Cohort 3. The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	AUC12/D in plasma after the first (Day 0) and last (Day 9) dose
The AUC12,Norm of Emodepside in Plasma	Summary of AUC12,norm of emodepside after the first (Day 0) and last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 0 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 15 h after the morning dose. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120 h (Day 14) after the morning dose. AUC12,norm: the area under the concentration-time curve from time zero (pre-dose) to 12 h corrected by dose and body weight. Note: AUC12,norm was calculated only in Cohort 3. The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	AUC12,norm in plasma after the first (Day 0) and last (Day 9) dose
The AUC24 of Emodepside in Plasma	Summary of AUC24 of emodepside after the first (Day 0) and last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 0 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 15 h after the morning dose. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120 h (Day 14) after the morning dose. AUC24: the area under the concentration-time curve from time zero (pre-dose) to 24 h. The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	AUC24 in plasma after the first (Day 0) and last (Day 9) dose
The AUC24/D of Emodepside in Plasma	Summary of AUC24/D of emodepside after the first (Day 0) and last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 0 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 15 h after the morning dose. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120 h (Day 14) after the morning dose. AUC24/D: the area under the concentration-time curve from time zero (pre-dose) to 24h corrected for dose. The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	AUC24/D in plasma after the first (Day 0) and last (Day 9) dose
The AUC24,Norm of Emodepside in Plasma	Summary of AUC24,norm of emodepside after the first (Day 0) and last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 0 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 15h after the morning dose. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120h (Day 14) after the morning dose. AUC24,norm: the area under the concentration-time curve from time zero (pre-dose) to 24h corrected by dose and body weight. The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	AUC24,norm in plasma at Day 0 and Day 9
The Cmax of Emodepside in Plasma	Summary of Cmax of emodepside after the first (Day 0) and last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 0 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 15 h after the morning dose. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120 h (Day 14) after the morning dose. Cmax: the observed maximum plasma concentration measured in a subject after dosing identified by inspection of the drug concentration vs. time data. The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	Cmax in plasma after the first (Day 0) and last (Day 9) dose
The Cmax/D of Emodepside in Plasma	Summary of Cmax/D of emodepside after the first (Day 0) and last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 0 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 15 h after the morning dose. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120 h (Day 14) after the morning dose. Cmax/D: the observed maximum plasma concentration measured in a subject after dosing identified by inspection of the drug concentration vs. time data, corrected for dose. The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	Cmax/D in plasma after the first (Day 0) and last (Day 9) dose
The Cmax,Norm of Emodepside in Plasma	Summary of Cmax,norm of emodepside after the first (Day 0) and last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 0 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 15 h after the morning dose. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120 h (Day 14) after the morning dose. Cmax,norm: the observed maximum plasma concentration measured in a subject after dosing identified by inspection of the drug concentration vs. time data, corrected for dose and body weight. The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	Cmax,norm in plasma after the first (Day 0) and last (Day 9) dose
The Ctrough of Emodepside in Plasma	Summary of Ctrough (log-transformed) of emodepside after last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120 h (Day 14) after the morning dose. Ctrough: trough plasma concentration (measured concentration at the end of a dosing interval on Day 9 [taken directly before next administration]) obtained directly from the concentration-time data. The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	Ctrough in plasma after the last (Day 9) dose
The Tmax of Emodepside in Plasma	Summary of tmax of emodepside after the first (Day 0) and last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 0 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 15 h after the morning dose. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120 h (Day 14) after the morning dose. tmax: the time at which Cmax was apparent, identified by inspection of the drug concentration vs. time data.	tmax in plasma after the first (Day 0) and last (Day 9) dose
The t1/2 of Emodepside in Plasma	Summary of t1/2 of emodepside after the last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120 h (Day 14) after the morning dose. t1/2: terminal half-life. The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	t1/2 in plasma after the last (Day 9) dose
The t1/2,(0-24) of Emodepside in Plasma	Summary of t1/2,(0-24) of emodepside after the last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120 h (Day 14) after the morning dose. t1/2,(0-24): half-life calculated from the terminal slope of the log concentration-time (0-24h) curve. The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	t1/2,(0-24) in plasma after the last (Day 9) dose
The λz of Emodepside in Plasma	Summary of λz of emodepside after the last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120 h (Day 14) after the morning dose. λz: terminal rate constant. The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	λz in plasma after the last (Day 9) dose
The CLss/F of Emodepside in Plasma	Summary of CLss/F of emodepside after the last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120 h (Day 14) after the morning dose. CLss/F: apparent total clearance from plasma on Day 9. The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	CLss/F in plasma after the last (Day 9) dose
The Vz/F of Emodepside in Plasma	Summary of Vz/F of emodepside after the last (Day 9) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 9 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120 h (Day 14) after the morning dose. Vz/F: apparent volume of distribution on Day 9. The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	Vz/F in plasma after the last (Day 9) dose
The MRTlast of Emodepside in Plasma	Summary of MRTlast of emodepside after the first (Day 0) dose for 10-day oral treatment courses in healthy men: PK parameter population. Data on Day 0 was collected at the following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 15 h after the morning dose. MRTlast: mean residence time from time zero (pre-dose) to the time of last quantifiable concentration (measurable up to 24h after dosing on Day 0). The geometric coefficient of variation is the between-subject coefficient of variation (%CVb).	MRTlast in plasma after the first (Day 0) dose
The Rac(AUC12) of Emodepside in Plasma	Summary of emodepside plasma Rac(AUC12) after 10 days' repeated doses of 10 mg emodepside (Day 9): PK parameter population. Rac(AUC12): accumulation ratio calculated from AUC12, where AUC12 is the area under the concentration-time curve from time zero (pre-dose) to 12h. Note: measure of dispersion is 'percentage coefficient of variation' (the between-subject coefficient of variation [%CVb]). Note: Rac(AUC12) was calculated only in Cohort 3.	Rac(AUC12) after 10 days' repeated doses of 10 mg emodepside (Day 9)
The Rac(AUC24) of Emodepside in Plasma	Summary of emodepside plasma Rac(AUC24) after 10 days' repeated doses of 10 mg emodepside (Day 9): PK parameter population. Rac(AUC24): accumulation ratio calculated from AUC24, where AUC24 is the area under the concentration-time curve from time zero (pre-dose) to 24h. Note: measure of dispersion is 'percentage coefficient of variation' (the between-subject coefficient of variation [%CVb]).	Rac(AUC24) after 10 days' repeated doses of 10 mg emodepside (Day 9)
The Rac(Cmax) of Emodepside in Plasma	Summary of emodepside plasma Rac(Cmax) after 10 days' repeated doses of 10 mg emodepside (Day 9): PK parameter population. Rac(Cmax): accumulation ratio calculated from Cmax, where Cmax is the observed maximum plasma concentration measured in a subject after dosing identified by inspection of the drug concentration vs. time data. Note: measure of dispersion is 'percentage coefficient of variation' (the between-subject coefficient of variation [%CVb]).	Rac(Cmax) after 10 days' repeated doses of 10 mg emodepside (Day 9)
Mean Glucose Concentration at Day -1	Mean glucose concentrations (mmol/L) after repeated once or twice daily dosing with up to 10 mg emodepside or placebo at Day -1.	Mean glucose at Day -1 after repeated once or twice daily dosing
Mean Glucose Concentration at Day 0	Mean glucose concentrations (mmol/L) after repeated once or twice daily dosing with up to 10 mg emodepside or placebo at Day 0. Baseline=predose on Day 0.	Mean glucose after repeated once or twice daily dosing for up to 10 days
Mean Glucose Concentration at Day 9	Mean glucose concentrations (mmol/L) after repeated once or twice daily dosing with up to 10 mg emodepside or placebo at Day 9.	Mean glucose at Day 9 after repeated once or twice daily dosing
Mean Glucose Concentration at Day 30	Mean glucose concentrations (mmol/L) after repeated once or twice daily dosing with up to 10 mg emodepside or placebo at Day 30.	Mean glucose at Day 30 after repeated once or twice daily dosing
Mean Insulin Concentration at Day -1	Mean insulin concentration (pmol/L) after repeated once or twice daily dosing with up to 10 mg emodepside or placebo at Day -1.	Mean insulin concentration at Day-1 after repeated once or twice daily dosing
Mean Insulin Concentration at Day 0	Mean insulin concentration (pmol/L) after repeated once or twice daily dosing with up to 10 mg emodepside or placebo at Day 0. Baseline=predose on Day 0.	Mean insulin concentration at Day 0 after repeated once or twice daily dosing
Mean Insulin Concentration at Day 9	Mean insulin concentration (pmol/L) after repeated once or twice daily dosing with up to 10 mg emodepside or placebo at Day 9.	Mean insulin concentration at Day 9 after repeated once or twice daily dosing
Mean Insulin Concentration at Day 30	Mean insulin concentration (pmol/L) after repeated once or twice daily dosing with up to 10 mg emodepside or placebo at Day 30.	Mean insulin concentration at Day 30 after repeated once or twice daily dosing
Mean Serum Glucose Concentration at Day -2	Oral glucose tolerance test: mean serum glucose concentration at Day -2, before and up to 4 hours after intake of a high-glucose solution, in subjects receiving repeated doses of emodepside or placebo for 10 days (Days 0-9). Baseline=pre-glucose intake on each respective day.	Mean serum glucose concentration at Day -2, before and up to 4 hours after intake of a high-glucose solution
Mean Serum Glucose Concentration at Day 1	Oral glucose tolerance test: mean serum glucose concentration at Day 1, before and up to 4 hours after intake of a high-glucose solution, in subjects receiving repeated doses of emodepside or placebo for 10 days (Days 0-9). Baseline=pre-glucose intake on each respective day.	Mean serum glucose concentration at Day 1, before and up to 4 hours after intake of a high-glucose solution
Mean Serum Glucose Concentration at Day 8	Oral glucose tolerance test: mean serum glucose concentration at Day 8, before and up to 4 hours after intake of a high-glucose solution, in subjects receiving repeated doses of emodepside or placebo for 10 days (Days 0-9). Baseline=pre-glucose intake on each respective day.	Mean serum glucose concentration at Day 8, before and up to 4 hours after intake of a high-glucose solution
Mean Serum Glucose Concentration at Day 120	Oral glucose tolerance test: mean serum glucose concentration at Day 120, before and up to 4 hours after intake of a high-glucose solution, in subjects receiving repeated doses of emodepside or placebo for 10 days (Days 0-9). Baseline=pre-glucose intake on each respective day. Note: At Day 120, serum glucose concentration was only measured in Cohort 3 (10 mg BID)	Mean serum glucose concentration at Day 120, before and up to 4 hours after intake of a high-glucose solution
Mean Serum Insulin Concentration at Day -2	Oral glucose tolerance test: mean serum insulin concentration at Day -2, before and up to 4 hours after intake of a high-glucose solution, in subjects receiving repeated doses of emodepside or placebo for 10 days (Days 0-9). Baseline=pre-glucose intake on each respective day.	Mean serum insulin concentration at Day -2, before and up to 4 hours after intake of a high-glucose solution
Mean Serum Insulin Concentration at Day 1	Oral glucose tolerance test: mean serum insulin concentration at Day 1, before and up to 4 hours after intake of a high-glucose solution, in subjects receiving repeated doses of emodepside or placebo for 10 days (Days 0-9). Baseline=pre-glucose intake on each respective day.	Mean serum insulin concentration at Day 1, before and up to 4 hours after intake of a high-glucose solution
Mean Serum Insulin Concentration at Day 8	Oral glucose tolerance test: mean serum insulin concentration at Day 8, before and up to 4 hours after intake of a high-glucose solution, in subjects receiving repeated doses of emodepside or placebo for 10 days (Days 0-9). Baseline=pre-glucose intake on each respective day.	Mean serum insulin concentration at Day 8, before and up to 4 hours after intake of a high-glucose solution
Mean Serum Insulin Concentration at Day 120	Oral glucose tolerance test: mean serum insulin concentration at Day 120, before and up to 4 hours after intake of a high-glucose solution, in subjects receiving repeated doses of emodepside or placebo for 10 days (Days 0-9). Baseline=pre-glucose intake on each respective day. Note: At Day 120, serum glucose concentration was only measured in Cohort 3 (10 mg BID)	Mean serum insulin concentration at Day 120, before and up to 4 hours after intake of a high-glucose solution

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Drug-related Adverse Events	Subjects presenting drug-related treatment-emergent adverse events listed by preferred term. Note: subjects with ≥1 adverse event are counted only once per preferred term.	Drug-related AEs were reported throughout the study

Collaborators and Investigators

• Sponsor: Drugs for Neglected Diseases
• Collaborators: Bayer; Bill and Melinda Gates Foundation
• Investigators: Principal Investigator: Jeremy Dennison, PhD MBChB, Hammersmith Medicines Research Limited

Study record dates

Study Major Dates

• Study Start (Actual): November 14, 2017
• Primary Completion (Actual): October 15, 2018
• Study Completion (Actual): October 15, 2018

Study Registration Dates

• First Submitted: November 29, 2017
• First Submitted That Met QC Criteria: December 19, 2017
• First Posted (Actual): December 26, 2017

Study Record Updates

• Last Update Posted (Actual): April 15, 2020
• Last Update Submitted That Met QC Criteria: April 1, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Parasitic Diseases; Spirurida Infections; Secernentea Infections; Nematode Infections; Helminthiasis; Filariasis; Anti-Infective Agents; Antiparasitic Agents; Emodepside
• Other Study ID Numbers: DNDI-EMO-02; 2017-003020-75 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No