Clinical trial NCT03383614
Conditions: Filariasis
Sponsor: Drugs for Neglected Diseases
Start date: 2017-11-14; Completion date: 2018-10-15
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

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.

Arms: arm 1: 6 subjects with LSF emodepside 5mg, OD 2 subjects with matching placebo arm 2: 6 subjects with LSF emodepside 10mg, OD 2 subjects with matching placebo arm 3: 6 subjects with LSF emodepside 10mg, BID 2 subjects with matching placebo
Interventions: intervention 1: LSF emodepside (BAY 44-4400) or matching placebo
Intervention descriptions: intervention 1: Emodepside administered as an LSF oral solution (1mg/mL)

Protocol documents:
Prot_000.pdf: 
Confidential  
 
Page 1 of 84 
Protocol template_Version 1.2_24 April 2014 
 
CLINICAL TRIAL PROTOCOL 
 
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 
 
Short title 
Safety, tolerability and PK of multiple-ascending doses of 
emodepside 
Name of product(s) 
Emodepside (BAY 44-4400) 
Drug Class 
Anthelmintic cyclooctadepsipeptide 
Phase 
1 
Indication 
Treatment of onchocerciasis (river blindness) and potentially 
other filarial diseases including lymphatic filariasis 
Clinical Trial Protocol 
Number 
DNDI-EMO-02 
EudraCT 
2017-003020-75 
Sponsor 
DNDi, Chemin Louis Dunant, 15,  
1202 Geneva, Switzerland 
Phone : +41 22 906 9230 
Global/National 
Coordinating 
Investigator/Principal 
Investigator 
Dr Jeremy Dennison, Hammersmith Medicines Research, 
Cumberland Avenue, London, NW10 7EW,  
United Kingdom 
Phone : +4420 8961 4130 
Clinical Trial Protocol 
Version / Date 
Version 5, 25 July 2018  
 
Protocol Amendment 
Number / Date 
Amendment 4 
The information contained in this document is confidential. It is to be used by Investigators, 
potential Investigators, consultants, or applicable independent ethics committees. It is 
understood that this information will not be disclosed to others without written authorisation 
from DNDi, except where required by applicable local laws 
 


Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 5, 25 July 2018 
Confidential  
Page 2 of 84 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
CONTACT DETAILS 
 
 Principal Investigator: Dr Jeremy Dennison,  
Senior Research Physician and Principal Investigator 
Hammersmith Medicines Research Limited 
Cumberland Avenue, London, NW10 7EW, United Kingdom 
 Investigator Site 24-Hour Medical Contact: 
On-call physician tel:  +44 7930 323 244 
 Co-Investigators: 
(See Study Procedures Manual) 
 Name and address of Monitor (if other than the Sponsor)  
Karen Chalk 
Niche Science & Technology 
Unit 26, Falstaff House, Bardolph Road, 
Richmond TW9 2LH, United Kingdom 
Tel.:  +44 20 8332 2588 
Mobile:  +44 (0)7872 970103 
 Name, title, address, and telephone number(s) of the Sponsor's medical 
expert for the trial (24 hours)  
Nathalie Strub-Wourgaft MD,  
Medical Director,  
15 Chemin Louis Dunant, 1202 Geneva, Switzerland  
Switchboard:  +41 22 906 92 30  
Mobile:  +41 79 874 05 39 
 Name, Title, Address, and Telephone Number(s) of the Sponsor's Clinical 
Project Manager for the Trial 
Sophie Delhomme, 
 Translation Manager,  
 15 Chemin Louis Dunant, 1202 Geneva, Switzerland  
 Switchboard:  +41 22 906 92 30  
 Direct:  +41 22 9026 92 79 
 Name, Title, Address, and Telephone Number(s) of other Sponsor 
Representatives 
 Frédéric Monnot PharmD,  
 Acting Head of Filariasis,  
 15 Chemin Louis Dunant, 1202 Geneva, Switzerland  
 Switchboard:  +41 22 906 92 30  
 


Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 5, 25 July 2018 
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Page 3 of 84 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
Jean-Yves Gillon PharmD, PhD,  
Head of Translational Sciences,  
15 Chemin Louis Dunant, 1202 Geneva, Switzerland  
 Switchboard:  +41 22 906 92 30 
 Name(s) and address(es) of the clinical laboratory(ies) and other medical 
and/or technical department(s) and/or Institutions involved in the trial 
(See Study Procedures Manual) 
Phase 1 Unit 
Hammersmith Medicines Research Limited 
Cumberland Avenue, London, NW10 7EW, United Kingdom 
Switchboard:  +44 20 8961 4130 
Clinical Laboratory 
The HMR Analytical Laboratory 
Cumberland Avenue, London, NW10 7EW, United Kingdom 
Switchboard: +44 20 8961 4130 
 
Bioanalytic Laboratory 
Analytical Services International Ltd 
St. George’s, University of London, Cranmer Terrace, London, SW17 0RE, 
United Kingdom 
Switchboard:  +44 20 8725 2845 
Ophthalmology Clinic 
(See Study Procedures Manual) 
Metabolite Analysis 
Swiss BioQuant AG 
Rägenstrasse 18, 4153 Reinach, Switzerland 
Switchboard:  +41 61 716 98 16 or 12








Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
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TABLE OF CONTENTS  
TABLE OF CONTENTS ............................................................................................. 7 
ABBREVIATIONS – GLOSSARY OF TERMS ........................................................ 11 
PROTOCOL SUMMARY .......................................................................................... 14 
1. 
BACKGROUND AND STUDY RATIONALE ................................................. 22 
1.1. 
BACKGROUND INFORMATION .................................................................. 22 
1.2. 
RATIONALE FOR THE DEVELOPMENT OF EMODEPSIDE ...................... 24 
1.3. 
SUMMARY OF NON-CLINICAL INFORMATION ......................................... 24 
1.4. 
SUMMARY OF CLINICAL HUMAN DATA ................................................... 28 
1.5. 
ASSESSMENT AND MANAGEMENT OF RISK ........................................... 31 
2. 
STUDY OBJECTIVES AND ENDPOINTS .................................................... 31 
2.1. 
Objectives ............................................................................................................................... 31 
2.1.1. 
Primary Objective ................................................................................................................... 31 
2.1.2. 
Secondary Objectives ............................................................................................................ 32 
2.2. 
Study Endpoints ..................................................................................................................... 32 
2.2.1. 
Primary Safety Endpoint(s) ................................................................................................... 32 
2.2.2. 
Other Safety  Endpoint(s) ...................................................................................................... 32 
2.2.3. 
Secondary Endpoint(s) .......................................................................................................... 33 
2.3. 
Exploratory PK variables ....................................................................................................... 33 
3. 
STUDY DESIGN AND STUDY DESIGN RATIONALE .................................. 33 
3.1. 
Study design ........................................................................................................................... 33 
3.2. 
Study duration and duration of subject participation ........................................................ 34 
3.3. 
Definition of the end of trial ................................................................................................... 34 
3.4. 
Rationale of study design ...................................................................................................... 34 
4. 
SELECTION OF SUBJECTS ........................................................................ 35 
4.1. 
Inclusion criteria ..................................................................................................................... 35 
4.2. 
Exclusion criteria .................................................................................................................... 36 
4.3. 
Dietary and lifestyle guidance ............................................................................................... 38 
5. 
SCHEDULE OF EVENTS .............................................................................. 40 
5.1. 
TABLE 2:  SCHEDULE OF EVENTS OVERVIEW........................................ 40 
5.2. 
Table 3:  Schedule of events expanded view:  pre-dosing period .................................... 44 
5.3. 
Table 4:  Schedule of events expanded view:  first dosing day ........................................ 44 
5.4. 
Table 5:  Schedule of events expanded view:  last dosing day ......................................... 45 
6. 
ENROLMENT PROCEDURES ...................................................................... 46 
7. 
STUDY TREATMENTS ................................................................................. 46 
7.1. 
Doses and treatment regimens ............................................................................................. 46 
7.2. 
Emodepside study treatment ................................................................................................ 47 
7.3. 
Placebo study treatment ........................................................................................................ 47 


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7.4. 
IMP supply and handling ....................................................................................................... 48 
7.5. 
Dose escalation ...................................................................................................................... 48 
7.6. 
Study stopping criteria .......................................................................................................... 48 
7.6.1. 
Dose escalation stopping criteria ......................................................................................... 48 
7.6.2. 
Trial stopping criteria ............................................................................................................. 49 
7.7. 
Study treatment labelling, packaging ................................................................................... 49 
7.8. 
Accountability ......................................................................................................................... 49 
7.9. 
Storage .................................................................................................................................... 50 
7.10. 
Blinding and procedures for unblinding .............................................................................. 50 
7.11. 
Concomitant treatments ........................................................................................................ 51 
8. 
STUDY ASSESSMENTS ............................................................................... 51 
8.1. 
Subject Information and Consent Form ............................................................................... 51 
8.2. 
Timing of Assessments ......................................................................................................... 51 
8.3. 
Study visits ............................................................................................................................. 52 
Baseline will be considered as the last assessment performed prior to randomisation. ........... 52 
8.3.1. 
Screening Visit 1 ..................................................................................................................... 52 
8.3.2. 
Screening visit 2:  Ophthalmological assessment ............................................................. 53 
8.3.3. 
Admission to Ward (Day 3) .................................................................................................. 54 
8.3.4. 
Day 2 ...................................................................................................................................... 54 
8.3.5. 
Pre-day (Day 1) ..................................................................................................................... 54 
8.3.6. 
Profile day (Day 0) .................................................................................................................. 54 
8.3.7. 
Repeat dosing period (Days 1–8) .......................................................................................... 55 
8.3.8. 
Profile day (Day 9) .................................................................................................................. 55 
8.3.9. 
Days 10–14 .............................................................................................................................. 56 
8.3.10. Outpatient Visits (Days 17, 20, 23 and 27), Follow-up Visit (Day 30), and Long-term 
Follow-Up Visits (Days 60, 90 and 120) ± 2 days .............................................................................. 57 
8.4. 
Assessments .......................................................................................................................... 57 
8.4.1. 
Sampling time points and additional tests .......................................................................... 57 
8.4.2. 
PK assessments ..................................................................................................................... 58 
8.4.3. 
PD assessments ..................................................................................................................... 61 
8.4.4. 
Total blood volume ................................................................................................................. 62 
8.5. 
Assessment of Safety ............................................................................................................ 62 
8.5.1. 
12-lead ECG Safety recording ............................................................................................... 63 
8.5.2. 
Vital signs ................................................................................................................................ 63 
8.5.3. 
Neurological and physical examination ............................................................................... 63 
8.5.4. 
Ophthalmological examination (Screening Visit 2 and Day 10) ........................................ 64 
8.5.5. 
Clinical Laboratory Safety Assessments ............................................................................. 64 
8.6. 
Adverse Event definitions and reporting ............................................................................. 65 
8.6.1. 
Adverse Event definitions ..................................................................................................... 65 
8.6.2. 
Serious Adverse Event (SAE) ............................................................................................... 65 


Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
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8.6.3. 
Eliciting Adverse Event information ..................................................................................... 66 
8.6.4. 
Adverse Event reporting period ............................................................................................ 66 
8.6.5. 
Serious Adverse Event reporting requirements ................................................................. 66 
8.6.6. 
Grading of Adverse Event severity ....................................................................................... 67 
8.6.7. 
Adverse Event causality assessment .................................................................................. 68 
8.6.8. 
Exposure in utero ................................................................................................................... 68 
8.6.9. 
Adverse event follow up ........................................................................................................ 69 
9. 
WITHDRAWAL CRITERIA ............................................................................ 69 
10. 
DATA ANALYSIS AND STATISTICAL METHODS ...................................... 71 
10.1. 
Sample size determination .................................................................................................... 71 
10.2. 
Definition of study populations included in the analysis ................................................... 71 
10.3. 
Subject Disposition ................................................................................................................ 72 
10.4. 
Efficacy Analysis .................................................................................................................... 72 
10.5. 
Demographics and Other Baseline Characteristics ........................................................... 72 
10.6. 
Safety Analysis ....................................................................................................................... 72 
10.6.1. Vital signs, 12-lead ECG safety parameters ........................................................................ 73 
10.6.2. Haematology and Clinical Chemistry Parameters .............................................................. 73 
10.6.3. Urinalysis parameters ............................................................................................................ 73 
10.6.4. Physical and neurological examination ............................................................................... 74 
10.6.5. Adverse events ....................................................................................................................... 74 
10.7. 
Analysis of Human Pharmacokinetics of Emodepside ...................................................... 74 
10.8. 
Pharmacodynamic Analysis .................................................................................................. 75 
11. 
SAFETY REVIEW MEETINGS ...................................................................... 75 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL PROCEDURES ......... 75 
12.1. 
Investigator’s file .................................................................................................................... 75 
12.2. 
Case report forms (CRFs) ...................................................................................................... 75 
12.3. 
Source documents ................................................................................................................. 76 
12.4. 
Record Retention .................................................................................................................... 76 
12.5. 
Monitoring, audits and inspections ...................................................................................... 76 
12.6. 
Audits and inspections .......................................................................................................... 77 
12.7. 
Data Management ................................................................................................................... 77 
12.8. 
Confidentiality of trial documents and subjects records ................................................... 77 
13. 
PROTOCOL DEVIATIONS AND AMENDMENTS ........................................ 78 
14. 
EARLY TERMINATION OF THE STUDY ...................................................... 78 
15. 
ETHICS .......................................................................................................... 79 
15.1. 
Informed consent process .................................................................................................... 81 
15.2. 
Compensation of volunteers ................................................................................................. 81 
15.3. 
Insurance and Liability........................................................................................................... 81 
15.4. 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP .............. 81 


Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
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15.5. 
Reporting and Publication of study results ......................................................................... 82 
16. 
REFERENCES .............................................................................................. 82 


Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 5, 25 July 2018 
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Abbreviations – Glossary of terms 
ADME 
Absorption, Distribution, Metabolism, and Excretion 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase (SGPT) 
AP 
Alkaline Phosphatase 
aPTT 
Activated Partial Thromboplastin Time 
APOC 
African Program for Onchocerciasis Control 
AST 
Aspartate Aminotransferase 
AV 
Atrioventricular 
AUC 
Area Under the Curve 
BID 
Bis indie (twice-daily) 
BMI 
Body Mass Index 
BP 
Blood pressure 
Bw 
Body weight 
14C 
Carbon-14 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
Creatinine Kinase 
CL 
Clearance 
Cmax 
Maximum concentration 
Cmin 
Minimum concentration 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CV 
Coefficient of Variation 
CYP3A4 
Cytochrome P450 3A4 
DALY 
Disability-Adjusted Life Years 
DNDi 
Drugs for Neglected Diseases initiative 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
F 
Female 
F (parameter) 
Bioavailability 
FDA 
Food and Drug Administration 
FIH 
First-In-Human 
GABA 
Gamma-Aminobutyric Acid 
GCP 
Good Clinical Practice 
GDRC 
Generic Document Review Committee  
GGT 
Gamma-Glutamyl Transpeptidase 
GI 
Gastro Intestinal 
GLDH 
Glutamate Dehydrogenase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 


Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 5, 25 July 2018 
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GP 
General Practitioner  
HDL 
High Density Lipoprotein 
hERG 
Human ether-a-go-go-related gene 
HbA1c 
Glycated Haemoglobin A1c 
HIV 
Human Immunodeficiency Virus 
HMR 
Hammersmith Medicines Research 
HR 
Heart Rate 
IR 
Immediate Release 
IC20 
Inhibitory Concentration 20 
ICF 
Information Consent Form 
ICH 
International Conferences on Harmonization 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IV 
Intravenous 
LDH 
Low Density Lipoprotein 
LF 
Lymphatic filariasis 
LFTs 
Liver function tests 
LSF 
Liquid Service Formulation 
M 
Male 
MCV 
Mean Corpuscular Volume 
MCH 
Mean Corpuscular Haemoglobin 
MCHC 
Mean Corpuscular Haemoglobin Concentration 
MDA 
Mass Drug Administration 
MedDRA 
Medical Dictionary For Regulatory Activities 
Mg 
Milligram 
MIC 
Minimum Inhibitory Concentration 
MIC100 
Minimum Concentration for 100% Inhibition  
mL 
Millilitre 
MRT 
Mean Residence Time 
MTT 
4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide 
NOAEL 
No Observed Adverse Effect Level 
NOEL 
No Observed Effect Level 
Ng 
Nanogram 
OCP 
Onchocerciasis Control Program 
OD 
Omnie die (once-daily) 
OGTT 
Oral Glucose Tolerance Test 
PD 
Pharmacodynamic 
P-gp 
P-glycoprotein 
PI 
Principal Investigator (See Note Section 13) 
PK 
Pharmacokinetics 
p.o 
Per Os (To Be Taken By Mouth) 
Ppm 
Parts Per Million 
PR  
PR Interval 
PT 
Prothrombin Time 


Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
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PTT 
Partial Thromboplastin Time 
RBC 
Red Blood Cell 
REC 
Research Ethics Committee 
QRS 
QRS Interval 
QTcB 
Qtc Corrected By Bazett’s Formula 
QTcF 
Qtc Correct By Fridericia's Formula 
SAD 
Single-Ascending Dose 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
SAR 
Serious Adverse Drug Reaction 
SD 
Standard Deviation 
SOC 
System Organ Class 
SRG 
Safety Review Group 
SST 
Serum-Separating Tube 
SUSAR 
Serious Unexpected Adverse Event 
t½  
Half-life 
TEAE 
Treatment-Emergent Adverse Event 
Tmax 
Time Of At Which Cmax Is Observed 
TSH 
Thyroid-Stimulating Hormone 
ULN 
Upper Limit Of Normal 
UV 
Ultraviolet 
Vz 
Volume of Distribution 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WNL 
Within Normal Limits 


Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
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PROTOCOL SUMMARY 
Trial 
Objectives 
Primary Objective:  
 
To investigate the safety and tolerability of emodepside (BAY44-4400) 
after multiple doses, administered as a Liquid Service Formulation 
(LSF) oral solution, in healthy male Caucasian subjects 
Secondary Objectives:  
 
To investigate the pharmacokinetics (PK) of emodepside 
(BAY44-4400) after multiple doses, administered as an LSF oral 
solution. 
 
To investigate the time-matched profiles of selected 
pharmacodynamics (PD) markers in plasma after multiple doses of 
emodepside (BAY44-4400), administered as an LSF oral solution. 
Trial 
Endpoints 
 
Safety and Tolerability Variables:  
 
Adverse events (AEs) 
 
Physical and neurological examination findings (including 
assessments of tremor of the hands and fingers, 
coordination/cerebellar function (finger to finger, finger to nose, with 
eyes open and closed), pupil size and reaction to light) 
 
Vital signs: heart rate (HR), systolic and diastolic blood pressure (BP) 
 
12-lead Electrocardiogram (ECG (including HR, PR, QRS, QTcB, 
QTcF))  
 
Clinical laboratory tests: 
Haematology: haemoglobin, haematocrit, mean corpuscular volume (MCV), 
mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin 
concentration (MCHC), platelets, reticulocytes, white blood cells (WBC) 
including differential, red blood cells (RBC), glycated haemoglobin (HbA1C) 
(at screening and Day 120 only);  
Coagulation:  activated partial thromboplastin time (aPTT), prothrombin time 
(PT);  
Biochemistry:  serum aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (AP), glutamate 
dehydrogenase (GLDH), gamma-glutamyl transpeptidase (GGT), lactate 
dehydrogenase (LDH), creatine kinase (CK), amylase, lipase, free T3 and T4, 
thyroid-stimulating hormone (TSH), glucose, cholesterol (HDL, LDL, total), 
triglycerides, creatinine, urea, uric acid, bilirubin (total and conjugated), total 
protein, sodium, potassium, calcium, chloride, and magnesium; 
At baseline (screening visit 1) and day 9 additional hormones: leptin and 
prolactin levels 
Urinalysis:  by dipstick – glucose, ketone bodies, specific gravity, occult blood, 
pH, proteins, leucocytes, bilirubin, urobilinogen, nitrites. 
 
Ophthalmology assessments, including visual symptoms, past ocular 
history, best corrected distance visual acuity, colour vision 
assessment, Amsler grid assessment 


Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 5, 25 July 2018 
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Pharmacodynamic Variables: 
 
Time-matched profiles of glucose, glucagon, insulin, and cortisol. 
 
Oral glucose tolerance test (OGTT) 
Pharmacokinetic Variables:  
Emodepside plasma concentration–time data will be used to derive the 
following PK parameters of emodepside: 
 
After the first dose of emodepside (Day 0):  
 
Main PK parameters:  
 
Cohorts 1 & 2:  AUC24, , AUC24/D, Cmax, Cmax/D 
 
Cohort 3:  AUC12, AUC12/D, Cmax, Cmax/D 
 
Exploratory PK parameters:  
 
Cohorts 1 & 2:  AUC24,norm, Cmax,norm, tmax, MRTlast, Vz/F 
 
Cohorts 3:  AUC12,norm, Cmax,norm, tmax, MRTlast, Vz/F 
 
After multiple doses of emodepside (Day 9):  
 
Main PK parameters:  
 
Cohorts 1 & 2:  AUC, AUC/D, AUC24, AUC24/D, Cmax,ss, 
Cmax,ss/D 
 
Cohort 3:  AUC, AUC/D, AUC12, AUC12/D, Cmax,ss, Cmax,ss/D 
 
Exploratory PK parameters:  AUC,norm, AUC12,norm, AUC24,norm, AUClast, 
AUClast/D, AUClast,norm, Cmax,ss,norm, t1/2, λz, tmax, MRT, Vz/F, CLss/F 
 
Other optional parameters: AUCt–inf, %AUCextra, points terminal 
 
Accumulation ratios RA(Cmax) and RA(AUCtau) will be calculated 
 
Ctrough will be derived from the concentration data (Days 19). 
The above parameters may be calculated for the metabolites of emodepside, 
as appropriate.  
In urine, the amount and concentration of emodepside and its metabolites 
may be measured for up to 24 h on up to 4 occasions during the study. The 
appropriate specific PK parameters to be calculated will be decided, according 
to the concentration. 
Trial Design 
This will be a single-centre, single-blind, randomized, placebo-controlled, 
parallel-group, multiple-dose, dose-escalation study.  
The study will evaluate safety, tolerability, PK and PD of emodepside, after 
administration as an LSF oral solution, over 10 days, in healthy male 
Caucasian subjects.  Treatment duration was defined based on single 
ascending dose PK data modelling as well as anticipated duration of 
treatment with emodepside for safety. 
The study will be performed in a single site specialized in Phase 1 studies. 
Each cohort will comprise 8 healthy Caucasian male subjects, 6 of whom will 
be allocated to receive emodepside, and 2 of whom will be allocated to 
receive placebo.  3 cohorts will be recruited, to test 3 multiple dose levels of 


Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 5, 25 July 2018 
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emodepside LSF oral solution. 
This will be a single-blind study.  The Investigator and Sponsor will remain 
blinded, so as not to potentially introduce bias.  However, the Investigator and 
Sponsor may choose to review unblinded data at the Safety Review Group for 
a particular cohort (the process will be described in the Safety Review Group 
Charter). 
Each subject will attend a screening visit within the 4 weeks before their first 
dose of study medication (on Day 0).   
Eligible subjects will be admitted to the ward on the evening of Day –3.  They 
will remain on the ward until the morning of day 14 (17 nights in a row), during 
which they’ll receive once- or twice-daily oral doses of emodepside or placebo 
for 10 days.  Safety, tolerability, PD and PK assessments will be done 
regularly before, during, and after dosing.  Each subject will undergo a full day 
of assessments (excluding PK) on the day before dosing (Day –1), and a 
similar full day of assessments (including PK) on the first (Day 0) and last 
days of dosing (Day 9).  In addition, they will undergo an Oral Glucose 
Tolerance Test (OGTT) on Day –2, Day 1, Day 8 and Day 120. 
Subjects will be discharged from the ward 5 days after their last dose of study 
medication, if the Investigator has no safety concerns.  Subjects will attend the 
ward for out-patient visits on Days 17, 20, 23 and 27 (+/- 2 days).  Subjects 
will attend a follow-up visit on Day 30 (+/- 2 days), and 3 long-term follow-up 
visits on Days 60, 90 and 120 (+/- 2 days). 
The end of the trial is defined as the final long-term follow-up visit by the last 
subject (or final contact with the subject if that is later).  If the trial is 
terminated early, the trial ends when the Sponsor notifies the Investigator in 
writing that the trial has finished, or when the last subject attends the final 
long-term follow-up visit, whichever is later. 
Main Entry 
Criteria 
Inclusion:  
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 


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discuss the trial with the Investigator or his delegate. 
7. Willingness to agree to the contraceptive requirements of the study 
from the first dose until 120 days after the last dose of study 
medication 
8. Willingness to give written consent to have data entered into the 
Overvolunteering Prevention System 
Exclusion:  
9. 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. 
10. 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. 
11. Past surgery (eg stomach bypass) or medical condition that might 
affect absorption of study drug taken orally. 
12. 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. 
13. Loss of more than 400 mL of blood within 3 months before admission. 
14. Clinically relevant history of vital organ disease or other disease of an 
organ or the central nervous system. 
15. Current or previous medical or psychiatric disorder, condition or history 
of such (eg 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. 
16. Positive test for hepatitis B, hepatitis C or HIV 
17. Febrile illness within 1 week before the first dose of study medication. 
18. History of severe allergy, non-allergic drug reactions, severe adverse 
reaction to any drug, or multiple drug allergies. 
19. Subjects with hypersensitivity to any ingredient of the study 
medication, including the active ingredient, emodepside. 
20. Presence or history of drug or alcohol abuse in the last 10 years, or 
intake of more than 21 units of alcohol weekly. 
21. Regular daily consumption of more than one liter of xanthine-
containing beverages. 
22. Regular daily consumption of more than 5 cigarettes daily, or use more 
than 3 grams (1/8 ounce) of tobacco. 
23. 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. 
24. Use of dietary supplements or herbal remedies (such as St John’s 


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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).  
25. 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).  
26. Relevant pathological abnormalities in the ECG at screening, such as 
a second or third-degree AV block or prolongation of the QRS complex 
over 120 msec or QTc-interval over 450 msec (QTcB or QTcF). 
27. Evidence of drug abuse (via urine testing) at the screening 
assessment or admission to the ward 
28. Use of excluded therapies that may impact on the interpretation of 
study results in the opinion of the Investigator or Sponsor. 
29. Objection by General Practitioner (GP) to subject entering trial. 
30. 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. 
31. Possibility that subject will not cooperate with the requirements of the 
protocol. 
32. No contact lenses wear within 1 month before dosing. Contact lenses 
wear is not permitted during the study. 
33. 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) 
34. Past history of ocular disease requiring ongoing treatment 
35. Past ocular surgery including laser or other refractive corneal surgery 
36. Evidence of eye irritation, visual difficulties, corneal opacity, ocular 
surface (corneal or conjunctival damage, with or without ocular 
symptoms) 
37. Evidence of narrow anterior chamber angles causing increased risk of 
acute glaucoma 
38. Evidence of ocular media opacity including lens opacity/vitreous 
opacities 
39. Evidence of retinal or optic nerve pathology 
40. Evidence of pronounced colour blindness, as indicated by an Ishihara 
score of 9/13 or below 
Removal of 
subjects 
from study 
 
Subjects may withdraw from the study at any time at their own request, or 
they may be withdrawn at any time at the discretion of the Investigator or 
Sponsor for safety, behavioural, or administrative reasons. 
 
Subjects who withdraw, or are withdrawn from the study may be replaced 


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at the discretion of the Investigator upon consultation with the Sponsor.  
Study 
Duration 
 
Each subject’s participation in the study will last for up to 21 weeks, and 
will include a screening visit (within 4 weeks before dosing), an in-house 
2-week evaluation period (Day –3 to Day 14), followed by 4 outpatient 
visits (on Days 17, 20, 23 and 27), a follow-up visit (on Day 30), and 3 
long-term follow-up visits (on Days 60, 90 and 120). 
Study 
treatments
 
 
Test-Drug: Emodepside LSF oral solution (1 mg/mL) or matching placebo. 
Planned dose levels:  
Cohort 
Dose level 
Formulation 
1 
5 mg, OD, for 10 days 
LSF oral solution (1 mg/mL) 
2 
10 mg, OD, for 10 days 
LSF oral solution (1 mg/mL) 
3 
10 mg, BID, for 10 days 
(single dose on Day 9) 
LSF oral solution (1 mg/mL) 
Emodepside administration will be given as fasted doses of LSF oral solution.  
Each morning dose will be given after an overnight fast of at least 9 h.  On 
Days 0, 1, 8 and 9, subjects will fast until at least 4 h after dosing.  On 
Days 2 to 7, subjects will fast until at least 1h after dosing.  In Cohort 3, 
subjects will also fast for 2 h before and until 1 h after their evening dose.  
Dose escalation will be decided by the Safety Review Group (SRG) at the 
Safety Review Meeting.  The dose will not be escalated until the SRG have 
reviewed safety, tolerability and PK data until 48 h after the final dose of study 
medication in at least 4 subjects on active treatment (ie, at least 6 subjects 
overall), and agree that it is appropriate to give a higher dose; that decision 
will be taken in the Safety Review Meeting, before dosing of the subsequent 
cohort.  The next planned dose level may be reduced, or a dose level may re-
tested or an intermediate dose level selected, based on emerging data.  
The dose level will not exceed 20 mg LSF oral solution (1 mg/mL) per day. 
If, within a treatment group, any of the following occurs, dose escalation will 
be stopped: 
Safety stopping criteria 
 
There is 1 or more SAE, considered to be related to emodepside; 
 
2 or more subjects in the same treatment group who present any 
severe or clinically significant AEs considered to be related to 
emodepside 
If a cohort fulfils a dose escalation stopping criterion, that dose level will not 
be repeated. 
PK stopping criteria 
 
predicted mean plasma concentrations in the subjects at the next 
scheduled dose level exceed or equal: Cmax 612 µg/L (based on the 
highest dose in the Single Ascending Dose (SAD) study DNDi-EMO-
001)) 
The scheduled dose of emodepside may be reduced if, for example, the 
results of safety tests give any cause for concern, or tolerability is poor.  


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If AEs occur that cause mild or moderate discomfort but do not in any way 
threaten the health of the subject, that dose level may be repeated with the 
aim of exploring further the relationship between dose and AE.  If, in the 
judgement of the Safety Review Group (SRG), it would not be reasonable to 
expose further subjects to the level of discomfort experienced by the subjects 
who have already received the dose, the next scheduled dose may be 
reduced.  The reduction may be either to one of the dose levels that has 
already been given, or to an intermediate level that has not previously been 
given; in either case, the aim is to learn more about the relationship between 
AE and dose (or plasma concentration) of drug. 
Sample Size 
Up to 24 healthy male subjects (not including replacement subjects), in up to 
3 cohorts, of 8 subjects. 
Statistics  
No formal statistical sample size estimation has been performed for this, due 
to the exploratory nature of this study.  
6 subjects per dose level (cohort) is considered sufficient to examine the 
safety and tolerability of emodepside as well as the pharmacokinetics after 
single and multiple doses.  Any withdrawn subjects will be replaced. 
Interim analyses will be performed. 
Safety: 
Safety and tolerability data will be summarized using the Safety Population. 
Safety and tolerability data will be summarized using the following 
parameters:  
 
Vital signs; 
 
12-lead ECG; 
 
Haematology; 
 
Clinical chemistry; 
 
Coagulation; 
 
Urinalysis; 
 
Physical and neurological examination; 
 
Ophthalmology assessments 
 
AEs. 
No formal hypothesis testing of these parameters will be carried out. 
Pharmacodynamic: 
PD data will be summarized using the Safety Population. PD variables at each 
planned assessment, and change in PD variables from baseline at each 
planned post baseline assessment, will be summarised by actual treatment. 
Pharmacokinetic: 
PK concentration data will be summarised using the PK Concentration 
population.  PK parameters will be summarised using the PK Parameter 
population.  
For log-transformed parameters, the primary measure of central tendency will 
be the geometric mean; for untransformed parameters, it will be the arithmetic 


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mean or median. 
For all variables, N (number of subjects in receiving the treatment/formulation 
in the population), n (number of observations), arithmetic mean, median, 
minimum, maximum, Standard Deviation (SD), % Coefficient of variance 
(%CV), and the 95% confidence interval of the arithmetic mean will be 
derived.  For log transformed variables, all of the above plus the geometric 
mean, its 95% confidence interval, and the SD of the log-transformed 
variables, will be provided. 
Plasma concentrations and PK parameters of emodepside and metabolites 
will be listed and summarised, by treatment, using descriptive statistics.  
Individual and mean plasma concentration–time profiles will be presented 
graphically. 
Concentrations of emodepside and its metabolites in urine may be determined 
and the amount of emodepside excreted in the urine will be estimated, if 
applicable 
 
 


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1. Background and Study Rationale 
1.1. 
Background information 
Filarial diseases cover infectious diseases caused by parasitic nematode worms 
transmitted by arthropod vectors:  onchocerciasis (river blindness), lymphatic 
filariasis (LF, or elephantiasis), and loiasis (African eye worm, or Loa loa filariasis).  
More than 1 billion of the world’s poorest people are at risk (WHO, 2015; 
Zouré et al, 2015). 
An estimated 18 million people suffer from onchocerciasis (Vos et al, 2015), with 
99% of cases in 31 African countries, and 187 million at risk in 2015 .  Although the 
disease is almost exclusively confined to Africa, some foci still exist in Yemen and 
South America (Brazil and Venezuela) (OMS, 2016).  
Severe visual impairment and blindness are considered the most severe 
complications of onchocerciasis and their control was the main objective of the initial 
international control program, the Onchocerciasis Control Programme (OCP) in West 
Africa.  Onchocerciasis is still the world's second-leading infectious cause of 
blindness. 
Onchocercal dermatitis and itching are the most common symptoms of the disease 
and represent a significant public health problem in affected communities.  Incessant 
itching may cause insomnia, can affect work productivity and social relationships 
(Okoye & Onwulirir, 2007) and can even induce premature child weaning by affected 
mothers (Amazigo, 1994; Alonso et al, 2009).  
The clinical manifestations of the disease have been attributed to the host immune 
response to dying or dead microfilariae in the skin and the eyes. 
The World Health Organization (WHO) estimates11 that 746,000 patients are visually 
impaired, 265,000 are blinded and more than 4 million suffer from severe itching due 
to onchocerciasis (Amazigo, 1994).  
The burden associated with onchocerciasis is estimated at more than 1 million 
disability-adjusted life years (DALYs) in 2013 worldwide (Alonso et al, 2009). 
Onchocerca volvulus (O. volvulus) is a helminth belonging to the nematode class 
(roundworm), causing onchocerciasis in humans.  The disease is contracted through 
the bite of an infected female blackfly (Simulium), which transmits infective larvae 
(L3) to a person.  Once it has penetrated into the host, the larvae moult twice before 
reaching the adult stage.  The average reproductive life span of an adult female 
worm in the human body is estimated to be 10 years (WHO, 2010) but they can live 
up to 15 years.  Adult worms induce the formation of subcutaneous or deeper 
nodules where they settle (in the former case, they seem to be particularly frequent 
near the joints).  Adult males migrate from nodule to nodule (explaining the F:M sex 
ratio of 2:1 in the nodules).  After mating, a female releases on average 1600 (GBD, 
2015) new microfilariae (first stage larvae, L1) per day (however, in O. volvulus, the 
release of microfilariae by the female worms is not constant, with one estimate that 
there are, on average, 4 reproductive cycles per year).  
The microfilariae migrate to the dermis where they are eventually ingested by a 
blackfly, in which the parasite completes its life cycle by moulting twice to become an 
infective larvae (L3).  During a subsequent blood meal, these larvae may then be 
transmitted to another host to continue the cycle.   


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Ivermectin is the standard treatment for onchocerciasis patients.  The drug kills the 
microfilarial stage of the parasite and provides temporary sterilization of adult female 
worms, preventing vector-borne transmission and re-population of the host’s skin 
with microfilariae, but only for several months.  Ivermectin relieves onchocerciasis-
associated itching and reversible skin and eye clinical manifestations, preventing 
blindness and chronic skin lesions.  However, skin microfilariae and itching may 
resume in some patients as soon as 3-6 months after ivermectin treatment.  
Therefore, the treatment must be repeated regularly for several years to control both 
the production of microfilariae and the clinical symptoms. 
The current treatment approach is a preventative chemotherapy based on the 
administration of ivermectin once or twice a year to all the population in endemic 
areas.  Widespread use was made possible with Merck’s ivermectin donation 
(Plaiser et al, 1991) to African Control programs in 24 African countries under the 
direction of APOC/WHO until 2015 (Schulz-Key & Soboslay, 1994). 
Control programs with ivermectin have been in place for over 20 years, resulting in 
an important reduction in transmission and morbidity.  However, treatment must be 
repeated at least yearly for 10 or more years, to break the transmission cycle and 
reach elimination, making implementation difficult in some endemic areas.  A new, 
longer-acting drug is therefore needed that would kill the adult worm, stop the 
production of new microfilariae and break the transmission of O. volvulus.  
Additionally, the programs have to be implemented with special measures in regions 
where onchocerciasis is co-endemic with loiasis.  
Loiasis, also called “eye worm”, is another filarial diseasethat occurs exclusively in 
West and Central Africa; an estimated 13 million people are infected with Loa loa 
(Gardon et al, 1997).  Humans contract the disease through the bite of a deer fly or 
mango fly (Chrysops spp).  
Serious adverse events (SAE) following the use of ivermectin in Loa loa-infected 
patients were observed in areas of high prevalence of eye worm 
(Meredith & Dull, 1998).  The most severe complication is an encephalopathy which 
is triggered by the massive death of microfilariae induced by the drug, and which can 
be fatal or leave long-term sequelae (Fobi et al, 2015).   
Loa loa infection limits the use of ivermectin in Mass Drug Administration (MDA) 
programs in co-endemic areas, and is an impediment to achieving WHO elimination 
goals for onchocerciasis.  Furthermore, reports of a suboptimal response of 
O. volvulus to ivermectin may be a sign of developing resistance (Hotez & Kamath, 
2009; Gardon et al, 1997).  
Thus, 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.  
A macrofilaricidal drug could reduce the number of MDA cycles needed, thereby 
easing control program implementation and enhancing chances in disease 
elimination, particularly in Loa loa co-endemic areas. 
Emodepside is a promising candidate to kill the adult and sexually mature O. volvulus 
as explained below.  This study investigates the safety, tolerability and 
pharmacokinetics of emodepside (BAY44-4400) after multiple doses, in healthy male 
Caucasian subjects. 


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1.2. 
Rationale for the development of emodepside 
Emodepside (BAY 44-4400) 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).  Emodepside was shown to be 
macrofilaricidal against a variety of filarial nematodes as investigated in both in vitro 
and in vivo studies:  Achatocheilonema vitae, Litomosoides sigmodontis, Brugia 
malayi, Onchocerca gutturosa, Onchocerca lienalis (Zahner et al, Int J 
Parasitol, 2001; Zahner et al, Acta Tropica, 2001). 
The mechanism of action of emodepside is complex and not fully understood. In 
gastrointestinal nematodes, as well as the free-living nematode Caenorhabditis 
elegans it has been shown that emodepside interacts with the g-protein coupled 
receptors latrophilin LAT-1 (Wilson et al, 2003).  It was indicated that this interaction 
is responsible for the paralytic effects on the pharynx.  However, it has not been 
investigated whether LAT-1-like proteins are expressed in all nematodes (e.g. 
filariae) or if emodepside is able to modulate those.  Emodepside also interacts with 
SLO-1, a calcium activated potassium channel, which finally results in flaccid 
paralysis (inhibition of locomotion, feeding, egg-laying and slowed development) 
(Guest et al, 2007).  
Therefore, emodepside targets different life stages of the parasites, including the 
adult stage.  This is a very important feature since treatments targeting adult worms 
should result in the reduction of the number of cycles required to free patients from 
infection and hopefully allow treatment in regions where Loa loa co-infection is 
present.  Hence, emodepside can be considered to be a promising drug candidate 
able to fulfil unmet medical needs for the treatment of filarial diseases. 
A first-in-human (FIH) double-blind, placebo-controlled study of single ascending 
doses of emodepside in healthy Caucasian men has been conducted in the UK in 
10 cohorts, with data from the final 2 cohorts (Cohorts 9 and 10) currently under 
evaluation.  However, the first 8 dose steps, single doses ranging from 1 to 40 mg, 
have been evaluated with respect to safety, tolerability and pharmacokinetics.  The 
preliminary results are favourable, support continuing the Phase I development 
program and merit the further development of emodepside.  Details of those interim 
results are presented in the Summary of Clinical Human Data section below.  In the 
present repeat dose study, pharmacokinetic as well as safety and tolerability of the 
liquid service formulation of emodepside, given over 10 days will be tested. 
1.3. 
Summary of non-clinical information 
Summary of Pharmacology Data 
A set of primary pharmacodynamic studies was performed to characterize and 
assess the efficacy and specificity of emodepside.  In vitro, emodepside showed 
potent anthelmintic activity on microfilariae and worms.  The Minimum Inhibitory 
Concentration (MIC100) value for motility was 0.1 µM emodepside, equivalent to 
111.9 ng/mL.  The biological viability test (enzymatic MTT assay) also showed 
significant anthelmintic potency in vitro with a clear dose-response in Litomosoides 
sigmodontis (MIC100 = 10 µM).  The worms were unable to recover as demonstrated 
in an extended 40-day in vitro assay.  The model organisms employed 
ie.  Onchocerca gutturosa, Brugia pahangi, Onchocerca lienalis, Litomosoides 


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sigmodontis, and Acanthocheilonema viteae, are considered to represent a 
reasonable in vitro disease model and predictor for efficacy against O. volvulus 
infection.  In vivo studies in BALB/c mice and jirds, naturally infected with 
Litomosoides sigmodontis, also showed the significant potential of emodepside as a 
macrofilaricidal drug for human use.  In these infection models, emodepside reduced 
peripheral microfilaremia, from 10 mg/kg onwards, in mice and jirds; even in immune 
compromised mice there was evidence of anthelmintic activity.  Furthermore, 
emodepside significantly reduced the number of recovered adult worms in mice 
(at 1 and 12.5 mg/kg) and in jirds (at 10, 50 or 100 mg/kg).  In mice, comparable 
macrofilaricidal potency was found at all tested doses and reduction of adult worms 
was approximately 80%.  
In conclusion, primary in vitro and in vivo pharmacology studies showed the 
significant potential of emodepside as a macrofilaricidal drug for human use.  This 
chemotherapeutic compound was active against both stages of parasites 
ie.  microfilariae and adult filarial nematodes in vitro and thus, non-clinical 
pharmacology data of emodepside supports its use for treatment of onchocerciasis in 
humans.  
A large number of safety pharmacology studies were performed in vitro 
(+ mechanistic studies) and in vivo in rats and dogs.  In addition, standard safety 
pharmacology parameters were included in the toxicity studies with emodepside in 
rats and dogs.  
The in vitro hERG assay showed no critical potential for QT prolongation 
(IC20 19 µM).  In vitro, emodepside weakly inhibited GABA-A receptor (46 % at 
10 mmol/L).  In pituitary neuroendocrine preparations, 500 nmol/L emodepside 
reduced GABAergic activity. 
Safety pharmacology and repeated dose toxicity studies revealed the central nervous 
system as a target organ, with changes in behaviour, activity, tremor and gait 
abnormalities in rats, mice and dogs.  A No Observed Adverse Effect Level (NOAEL) 
of 5 mg/kg. was defined in dogs and rats after repeated administration (4-week 
repeat oral dose toxicity study).  10 mg/kg body weight was established as the NOEL 
for effects on the nervous system in fasted rats after acute administration.  
Toxicokinetic (TK) analysis suggested an AUC of 1,611 ng.h/mL and Cmax of 
238 ng/mL after 5 mg/kg/day in dogs following 4-week exposure.  In rats, an AUC of 
1.9 g.h/mL and Cmax of 79 ng/mL was found following 4 weeks of emodepside given 
with food at 50 ppm, corresponding to 4.2 mg/kg in males and 5.0 mg/kg in females. 
After a single oral application of emodepside to rats, no biologically relevant effect on 
respiratory parameters was noted (10-100 mg/kg).  Also, in dogs, no effect on 
respiratory functions was observed at the tested doses.  Hyperglycaemia was 
observed in rats in acute and repeated dose fed studies.  Fasted rats were less 
sensitive with a NOEL of 10 mg/kg body weight compared to fed rats with a NOEL of 
1 mg/kg body weight.  Mechanistic studies showed that emodepside inhibited 
secretory activities in mouse and rat β-cells of the pancreas.  
Emodepside showed no adverse effect on ECG results in anesthetized dogs.  
However, a moderate vasodilatation (reduction of total resistance, slight decrease of 
arterial blood pressure, moderate, probably reflex tachycardia) was observed at 
≥1.5 mg/kg body weight.  A threshold plasma level of 0.1 µg/mL was determined for 
this effect. The clinical significance of the vasodilatory effects is unclear, as no effect 


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on blood pressure or heart rate was seen in dogs following oral administration of 
emodepside for 4 weeks at up to 20 mg/kg body weight.   
Summary of Pre-Clinical Pharmacokinetic Data 
In vitro studies showed moderate plasma protein binding of emodepside in all tested 
species, with similar values in mice, dogs and humans (fraction unbound of 
1.0−1.6 %).  In rats, gerbils and rabbits the fraction unbound was slightly higher 
(2.7−3.1 %).  The relevant Phase 1 biotransformation pathway of emodepside in 
humans, as well as in animal species, was oxidation, with no significant species 
differences in terms of metabolic pathways.  In humans, oxidative metabolism of 
emodepside was predominantly catalyzed by CYP3A4.  The hydrolysis of the ester 
bonds was observed as an additional metabolic clearance pathway.  Transport 
studies revealed a high permeability of Caco2-cells to emodepside as well as active 
efflux, which was characterized as being P-glycoprotein mediated.  Therefore, a role 
for P-glycoprotein in the pharmacokinetics of the compound cannot be excluded.  
Single dose PK of emodepside was studied in rats, and dogs after single intravenous 
(i.v.) and oral (p.o.) administration.  The absolute bioavailability of emodepside was 
moderate in rats and dogs with 44 % and 52 %, respectively.  Plasma clearance was 
low in rats (0.77 L/[kg·h]), and dogs (0.30 L/[kg·h]).  The volume of distribution was 
high in both species with 8.5 in dogs and 38.7 l/kg in rats.  The plasma elimination 
half-life was 33 to 43 h in rats and 42 to 35 h in dogs after p.o. and i.v. administration, 
respectively.  
Biodistribution studies with 14C-labeled emodepside in rats, revealed a moderate to 
high affinity to most tissues and organs after p.o. administration (1 or 15 mg/kg) with 
higher concentrations in tissues than in the blood.  The highest proportion of 
emodepside was found in brown and white adipose tissue, the liver and adrenals.  
There was also a low penetration of the blood-brain barrier.  The distribution patterns 
were similar in both sexes. 
The main excretion pathway after oral administration in rats was the faecal/biliary 
route (about 50 % within 24 h, 83–93 % within 168 h), with only 2–3 % of the dose 
being found in urine.  The unchanged compound emodepside accounted with 
45−56 % for most of the dose excreted into faeces.  The major metabolites in faeces 
were identified as the hydrolysis product, its dehydrated and oxidized derivatives as 
well as three oxidized metabolites. 
After repeated oral dosing of 14C labelled emodepside in rats, the parent compound 
was the major component found in rat plasma with a small amount of metabolite M1 
detected in rat plasma. 
Toxicokinetic data were obtained from Good Laboratory Practice (GLP) 4-week 
repeated dose studies in rats and dogs.  In rats, exposure was slightly less than 
dose-proportional after oral administration.  In dogs, the toxicokinetics showed a 
more than dose proportional increase in AUC0 24h and Cmax (5–20 mg/kg). 
Summary of Toxicology Data 
A comprehensive battery of repeated dose studies was conducted, in which, 
emodepside was orally applied (in diet) for up to 13 and 14 weeks in mice and rats, 
respectively, at doses up to 1000 ppm and 800 ppm (1000 ppm equals in mice 


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approx. 245-380 mg/kg, 800 ppm equals in rats approx. 77-95 mg/kg, both in 
13-week treatment schedule).  
The studies in rats revealed toxicities resulting from metabolic changes induced by 
emodepside indirectly, such as a decrement in bodyweight gain, but, in parallel, an 
increased feed and water consumption as well as deformation of teeth as a sign of a 
diabetic-like effect.  The main affected organs were kidney, pancreas and liver, with 
associated changes in haematological parameters, triglyceride and glucose levels in 
the plasma and lipid and glycogen stores.  These toxicological findings pointed to a 
diabetes-related condition (inhibition of insulin secretion followed by increased 
glucose levels and reduced leptin levels, as confirmed by mechanistic studies).  In 
mice, the NOAEL after 14 weeks of treatment was 50 ppm (10.5-16.8 mg/kg).  The 
NOAEL in the 14-week rat study was defined at 10 ppm (m:  0.73, f: 1.11 mg/kg per 
day); In 4-week rat studies 50 ppm (equals 4–5 mg/kg) was defined as the NOAEL. 
In dogs, doses starting from 10 mg/kg per day for 4 weeks resulted in clinical signs 
like vomiting, tremor and unsteady gait.  At 20 mg/kg, an effect on nutritional state, 
food intake and bodyweight gain was noted.  All effects were reversible after a 
recovery period of 4 weeks.  The NOAEL for this study was 5 mg/kg. 
Several reproductive and developmental toxicity studies were conducted in rats and 
rabbits.  Effects of emodepside on reproductive performance in rats occurred only at 
parentally toxic doses.  No primary effect on fertility and reproduction was observed.  
In this species, both ovarian weight and gestation rate were unaffected by treatment.  
Primary systemic parental effects were due to diabetes I like effects, which were well 
known from repeat dose studies in rats.  A battery of well-conducted, GLP-compliant 
teratogenicity studies revealed maternal toxicity, fetotoxicity, foetal malformations 
and various skeletal/visceral anomalies or deviations.  Clinical signs of systemic 
maternal toxicity were evident at dose rates ≥ 6 mg/kg.  Overall, severe maternal 
toxicity at 18 mg/kg resulted in adverse effects on foetal development.  The NOAEL 
for maternal toxicity in rats was 2 mg/kg and the NOAEL for developmental toxicity 
was 0.5 mg/kg.  However, as discussed above, diabetes like effects, which were not 
measured in developmental toxicity studies, occurred in lower dosages.  Therefore, it 
can be assumed that the maternal toxic dose was significantly lower (NOEL of 
1 mg/kg in safety pharmacology studies on glucose levels in the blood.  See also 
glucose level in pregnant rats).  In rabbits, the effects were similar to the rat studies.  
The NOEL for developmental toxicity in the rabbit was 5 mg/kg.  
Additional endocrinology studies confirmed the involvement of emodepside in 
hormone deregulation (reduced estradiol [E2], triiodothyronine [T3], insulin, leptin and 
prolactin levels and enhanced thyroid-stimulating hormone [TSH] and glucagon 
levels) while not having estrogenic/anti-estrogenic or androgenic/anti-androgenic 
potency.  This deregulation is assumed to be the cause for the observed 
developmental toxicity. 
In vitro and in vivo genotoxicity studies revealed no mutagenic potential for 
emodepside; no carcinogenicity studies were conducted. Local tolerance studies in 
rats and rabbits revealed no skin- or eye-irritating potential of emodepside.  In guinea 
pigs, emodepside was found to have no skin sensitization potential. 
General Pre-Clinical Summary 
The non-clinical data package of emodepside is comprehensive due to the 
authorization of 3 veterinary medicinal products (Profender Spot-on, Profender 


Protocol number (DNDI-EMO-02)  
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Tablets, Procox).  The safety pharmacology studies, ADME studies, acute and 
repeated-dose studies, studies on reproduction and development, genotoxicity 
studies, local tolerance and sensitization studies, as well as mechanistic studies on 
the toxicological mode of action are included in the submission package.  All these 
non-clinical studies (all pivotal studies were conducted under GLP conditions) are 
sufficiently to support this Phase I study in human subjects. 
1.4. 
Summary of clinical human data 
To date, a total of 79 healthy male volunteers have been exposed to the study 
treatment: either emodepside Liquid Service Formulation (LSF) solution or immediate 
release (IR) tablets (dose range 1.0–40 mg LSF solution, and doses of 5 mg and 
20 mg tablets; 59 volunteers) or placebo (20 volunteers).  Volunteers received the 
treatment in fasted conditions, or, for the 8 subjects of Cohort 9 (receiving 10 mg LSF 
solution or placebo), after a high-fat, high calories breakfast. 
 This study was divided into 2 parts: part 1 with cohorts 1 to 8 including 63 subjects 
(47 exposed to emodepside) and part 2 with cohorts 9 and 10 including 16 subjects 
(12 exposed to emodepside). 
Based on preliminary data, maximum exposure was observed with the 40 mg LSF 
solution (Cohort 8), with a mean Cmax of 612 ng/mL and AUC of 4,315 ng.h/mL.  So 
far, based on unblinded safety data from Part 1 of the study, those doses have been 
safe and tolerance was acceptable.  Based on an unblinded review of the safety 
data, total number of subjects with at least one Treatment Emergent Adverse Events 
(TEAEs) are summarised below by System Organ Class (SOC). 
Based on preliminary data, across all treatments within Part 1 (Cohorts 1-8), no 
serious AEs were reported.  Overall, 53 non-serious TEAEs were reported by 31 out 
of the 63 subjects (49%), of which 45 non-serious TEAEs reported by 25 out of the 
47 subjects (53%) exposed to emodepside and 8 non-serious TEAEs reported by 6 
out of the 16 subjects (37%) exposed to placebo.  All TEAEs (related or not) were 
mild or moderate in severity.  All the treatment-related TEAEs resolved 
spontaneously within less than 24 h and without treatment. 
A total of 14 subjects exposed to emodepside (22.2%) experienced 20 TEAEs that 
were considered by the Investigator to be related to emodepside treatment.  In 
addition 4 TEAEs, reported in 3 subjects exposed to placebo, were assessed as 
related to treatment.  All TEAEs, whether related or not, were mild or moderate in 
severity.  The most frequently reported TEAEs were eye disorders and nervous 
system disorders. 
All the treatment-related TEAEs resolved spontaneously within less than 24 h and 
without treatment.  


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Table 1: Total number of subjects with at least one TEAE (unblinded 
Cohorts 1 to 8 – by SOC 
SOC 
Placebo 
Emodepside 
Total 
n=63 
(%) 
LSF; 
n=12 
(%) 
tablet; 
n=4 
(%) 
0.1 mg* 
LSF; 
n=1 
(%) 
1 mg 
LSF; 
n=5 
(%) 
2.5 mg 
LSF; 
n=6 (%) 
5 mg 
LSF; 
n=5 
(%) 
5 mg 
tablet; 
n=6 
(%) 
10 mg 
LSF; 
n=6 
(%) 
20 mg 
LSF; 
n=6 
(%) 
20 mg 
tablet; 
n=6 
(%) 
40 mg 
LSF; 
n=6 
(%) 
Any TEAE 
5 
(41.7) 
1 
(25) 
1 
(100.0) 
3 
(60.0) 
0 
3 
(50.0) 
3 
(60.0) 
5 (83.3) 
3 (50.0) 
2 (33.3) 
5 (83.3) 
31 
(49.2) 
Eye disorders 
0 
1 
(25.0) 
0 
0 
0 
0 
1 
(20.0) 
2 (33.3) 
1 (16.7) 
0 
5 (83.3) 
10 
(15.9) 
Gastrointestinal 
disorders 
1 (8.3) 
1 
(25.0) 
0 
0 
0 
1 
(16.7) 
0 
0 
0 
1 (16.7) 
0 
4 (6.3) 
General 
disorders and 
administration 
site conditions 
0 
0 
0 
0 
0 
2 
(33.3) 
0 
0 
0 
0 
0 
2 (3.2) 
Infections and 
infestations  
0 
0 
1 
(100.0) 
0 
0 
1 
(16.7) 
0 
1 (16.7) 
1 (16.7) 
0 
1 (16.7) 
5 (7.9) 
Injury, poisoning 
and procedural 
complications 
1 (8.3) 
0 
0 
0 
0 
0 
0 
0 
1 (16.7) 
0 
0 
2 (3.2) 
Musculoskeletal 
and connective 
tissue disorders  
0 
0 
0 
1 
(20.0) 
0 
1 
(16.7) 
1 
(20.0) 
0 
0 
1 (16.7) 
1 (16.7) 
5 (7.9) 
Nervous system 
disorders 
2 
(16.7) 
0 
0 
2 
(40.0) 
0 
1 
(16.7) 
1 
(20.0) 
1 (16.7) 
1 (16.7) 
1 (16.7) 
3 (50.0) 
12 
919) 
Respiratory, 
thoracic and 
mediastinal 
disorders  
1 (8.3) 
0 
0 
0 
0 
0 
0 
1 (16.7) 
1 (16.7) 
1 (16.7) 
0 
4 (6.3) 
Psychiatric 
disorders 
0 
0 
0 
0 
0 
0 
1 
(20.0) 
0 
0 
0 
0 
1 (1.6) 
*After 0.1 ml of IMP was administered, it was discovered that the subject was not eligible for the study due 
to an AE, and dosing was stopped 
 
Preliminary interpretation: 
Non-serious TEAEs involving Central Nervous System (CNS) disorders were 
reported in 10 out of 47 subjects exposed to emodepside, and included headache 
(n=6 subjects), dizziness (n=4) and somnolence (n=1), while 2 out of 16 subjects 
receiving placebo reported headache.  The AEs were mild or moderate in severity 
and more frequent at the highest dose (40 mg).  The AEs that were considered as 
treatment related were dizziness (n=4), headache (n=2) and somnolence (n=1), all 
mild in severity, reported in 7 out of 47 subjects exposed to emodepside, and 
headache of moderate severity, reported in 1 out of 16 subjects exposed to placebo.  
No abnormal findings were found on objective neurological examination.  
Non-serious eye disorders AEs were reported in 9 out of 47 subjects receiving 
emodepside, and included: vision blurred (n=5 subjects), photophobia (n=2), visual 
impairment (n=2), accommodation disorder (n=1), whereas 1 out of 16 subjects 


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receiving placebo reported dry eye (n=1).  All eye disorders AEs were of mild to 
moderate intensity, resolved spontaneously (without treatment), and were more 
frequently reported with highest dose (40 mg).  Among them, the AEs of blurred 
vision, photophobia (“Increased ocular light sensitivity”), visual impairment (“distorted 
contrast perception”, “distorted colour perception”) reported by 8 out of 47 subjects 
receiving emodepside were considered as treatment-related by the Investigator.  
Also of note, at the highest dose (40 mg), lightheadedness (n=1), dizziness (n=1) or 
headache (n=1) were reported concomitantly to blurred vision. 
None of the volunteers met any of the protocol-specified withdrawal criteria and 
overall tolerability to emodepside has been acceptable up to 20 mg.  The presence of 
post-dose visual disturbances in subjects of Cohort 8 receiving either 40 mg solution 
or placebo may warrant some concern and escalation was stopped at this dose level. 
The pharmacokinetic results obtained so far show that Tmax for the LSF solution is 
consistently about 1 h post-dose when fasted. Mean Cmax and AUC for the LSF 
solution have been roughly dose-proportional, with low to moderate inter-individual 
variability.  The plasma half-life during the first 24 h is very short for a single dose of 
emodepside.  After 3, 7, 16 and 47 h the maximum plasma concentration is reduced 
to 50%, 25%, 12.5% and 6.25% respectively.  Terminal plasma half-life is 523 h.  
Although data of Cohort 9 (which was treated with a single dose of emodepside with 
food) are still under review, administration of the LSF of 10 mg with a high fat, high- 
calorie meal resulted in a clinically relevant food effect with a reduction of AUC to 
~67%, Cmax to 42% and a delay of the Tmax up to 2.33 h.  Therefore, the 
recommendation of administration of the emodepside (LSF) under fasted conditions 
is given.  
In fasting conditions, a dose and plasma concentration-dependent decrease in insulin 
plasma concentration (13 pmol/L or below) after emodepside administration was 
reported, with a maximum between 0 and 4 h. In parallel, dose and plasma 
concentration-dependent increases in fasting serum glucose levels above 5.8 mmol/L 
were observed, with a maximum between 0 and 4 h (none of these increases were 
considered clinically significant by the Investigator, and therefore were not reported 
as AE) and a maximum of 12.7 mmol/L at 2 h at the dose of 40 mg LSF solution.  In 
fasted conditions, both blood insulin decrease and glucose increases occurred over 
the 4 h after single dosing with emodepside in most cases.  In Cohort 9 (6 subjects 
exposed to emodepside, and 2 subjects to placebo), 10 mg LSF of emodepside was 
given with food and a physiological increase of glucose and insulin was observed, as 
expected under normal conditions.  A decrease in insulin due to emodepside could 
not be observed.  This is interpreted that administration of food overrules a possible 
effect of emodepside on the secretion of insulin under fasted condition. 
There was no report of clinically significant laboratory abnormalities, or abnormalities 
in vital signs, ECG parameters or physical examination throughout the study, 
regardless of the formulation. 
Data of Cohort 10 (treated with a single 40 mg dose of emodepside and focused at 
ocular system assessment) are still under analysis, however no serious AEs were 
reported following administration of the LSF of 40 mg.  6 subjects were exposed to 
emodepside, and, 2 subjects to placebo.  Overall in cohort 10, 22 non-serious AEs 
related to emodepside were reported, all mild or moderate in severity.  4 subjects 
reported AEs related to emodepside (eye disorders including blurred vision, 
photopsia, visual impairment, eye pain and reduced visual acuity), with an onset in 


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most cases close to Tmax and of various durations.  In addition, the following were 
considered related to emodepside:  2 subjects reported concomitant feeling of 
relaxation, 1 subject reported dizziness, 1 subject reported disturbance in attention 
and hypervigilance, 1 subject reported concomitant balance disorder and 
disorientation, and 1 subject reported oral paresthesia (of the tongue) that lasted for 
approximately 6 h. 
1.5. 
Assessment and management of risk 
The factors taken into account in the assessment of risk to subjects in this study are 
as follows: 
 The planned daily doses of emodepside have been administered to humans 
as single doses and were well tolerated.  Based on the first-in-human clinical 
study, overall tolerability to emodepside has been acceptable up to 20 mg.  
Post-dose visual disturbances were observed more frequently at 40 mg, and 
although these visual and nervous system disturbances were considered 
non-serious and mild in intensity, dose escalation was stopped at this dose 
level.  All visual disturbances were transient in nature and resolved 
spontaneously within 24 h, and without treatment. 
 During the study, the dose will be increased only if the PK, safety and 
tolerability of the previous dose is acceptable and if the investigator and 
sponsor’s medical representative agree that it is appropriate to give a higher 
dose.  The next planned dose level may be reduced, or a dose level may 
re-tested or an intermediate dose level selected, based on emerging data.  
The total daily dose will not exceed 20 mg emodepside (as LSF solution at a 
concentration of 1 mg/mL).  
 Subjects will undergo a comprehensive ophthalmology assessment at 
screening and will be excluded from the study if any ocular pathology is 
detected.  Additional ophthalmology assessments will be performed during the 
study, if clinically indicated. 
 Subjects will undergo a full neurological assessment at screening, Day 0 and 
at discharge from the ward in order to detect and assess any neurological 
disorder or change. 
 In the first-in-human trial (DNDI-EMO-01), emodepside was shown to undergo 
bi-phasic elimination with a dominant half-life (t1/2 0-24) estimated at 
approximately 11 h, and terminal half-life (t1/2 0–∞) over 520 h.  In order to 
comprehensively assess safety parameters over this period, volunteers will be 
followed up until Day 120. 
2. Study Objectives and Endpoints 
2.1. 
Objectives 
2.1.1. Primary Objective 
 To investigate the safety and tolerability of emodepside (BAY44-4400) after 
multiple doses, administered as a LSF oral solution, in healthy male 


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Caucasian subjects. 
2.1.2. Secondary Objectives 
 To investigate the pharmacokinetics (PK) of emodepside (BAY44-4400) after 
multiple doses, administered as an LSF oral solution. 
 To investigate the time-matched profiles of selected pharmacodynamic (PD) 
markers in plasma, after multiple doses of emodepside (BAY44-4400), 
administered as an LSF oral solution. 
2.2. 
Study Endpoints 
2.2.1. Primary Safety Endpoint(s) 
 Adverse events (AEs) 
2.2.2. Other Safety  Endpoint(s)  
 Physical examination findings  
 Neurological examination findings (including assessments of tremor of the 
hands and fingers, coordination/cerebellar function (finger to finger, finger to 
nose, with eyes open and closed), pupil size and reaction to light) 
 Vital signs:  heart rate (HR), systolic and diastolic blood pressure (BP) 
 12-lead ECG (including heart rate (HR), PR, QRS, QTcB, QTcF)  
 Clinical laboratory tests: 
 Haematology:  haemoglobin, haematocrit, mean corpuscular volume 
(MCV), mean corpuscular haemoglobin (MCH), mean corpuscular 
haemoglobin concentration (MCHC), platelets, reticulocytes, white 
blood cells (WBC) including differential, red blood cells (RBC), glycated 
haemoglobin (HbA1C; at screening and Day 120 only);  
 Coagulation:  activated partial thromboplastin time (aPTT), prothrombin 
time (PT);  
 Biochemistry:  serum aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (AP), glutamate 
dehydrogenase (GLDH), gamma-glutamyl transpeptidase (GGT), 
lactate dehydrogenase (LDH), creatine kinase (CK), amylase, lipase, 
free T3 and T4, thyroid-stimulating hormone (TSH), glucose, cholesterol 
(HDL, LDL, total), triglycerides, creatinine, urea, uric acid, bilirubin (total 
and conjugated), total protein, sodium, potassium, calcium, chloride, 
and magnesium; 
 At baseline (screening visit 1) and Day 9 additional hormones:  leptin 
and prolactin levels 
 Urinalysis:  by dipstick – glucose, ketone bodies, specific gravity, occult 
blood, pH, proteins, leucocytes, bilirubin, urobilinogen, nitrites. 
 Ophthalmology assessments:  including visual symptoms, past ocular history, 
best corrected distance visual acuity, colour vision assessment, Amsler grid 


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assessment 
2.2.3. Secondary Endpoint(s) 
Pharmacokinetic Variables:  
Emodepside plasma concentration–time data will be used to derive the following PK 
parameters of emodepside: 
 After the first dose of emodepside (Day 0):  
 
Main PK parameters:   
 Cohorts 1 & 2:  AUC24, AUC24/D, Cmax, Cmax/D 
 Cohort 3:  AUC12, AUC12/D, Cmax, Cmax/D 
 After multiple doses of emodepside (Day 9):  
 
Main PK parameters:   
 Cohorts 1 & 2:  AUC, AUC/D, AUC24, AUC24/D, Cmax,ss, Cmax,ss/D 
 Cohort 3:  AUC, AUC/D, AUC12, AUC12/D, Cmax,ss, Cmax,ss/D 
 Accumulation ratios RA(Cmax) and RA(AUCtau) will be calculated 
 Ctrough will be derived from the concentration data (Days 19). 
The above parameters may be calculated for the metabolites of emodepside, as 
appropriate.  
Pharmacodynamic Variables: 
 Time-matched profiles of glucose, glucagon, insulin, and cortisol 
 Oral glucose tolerance test (OGTT) 
2.3. 
Exploratory PK variables 
Emodepside plasma concentration–time data will be used to derive the following PK 
parameters of emodepside: 
 After a single dose of emodepside (Day 0):  
o Cohorts 1 & 2:  AUC24,norm, Cmax,norm, tmax, MRTlast, Vz/F 
o Cohorts 3:  AUC12,norm, Cmax,norm, tmax, MRTlast, Vz/F 
 After multiple doses of emodepside (Day 9):  
 AUC,norm, AUC12,norm, AUC24,norm, AUClast, AUClast/D, AUClast,norm, 
Cmax,ss,norm, t1/2, λz, tmax, MRT, Vz/F, CLss/F  
 Other optional parameters:  AUCt–inf, %AUCextra, points terminal 
3. Study design and study design rationale 
3.1. 
Study design 
This will be a single-centre, single-blind, randomized, placebo-controlled, 


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parallel-group, multiple-dose, dose-escalation study.  
The study will evaluate the safety, tolerability, PK and PD of emodepside, after 
administration as an LSF oral solution, over 10 days, in healthy male Caucasian 
subjects.  Treatment duration was defined based on single ascending dose PK data 
modelling as well as anticipated duration of treatment with emodepside for safety. 
The study will be performed in a single site specialized in Phase 1 studies. 
Each cohort will comprise 8 healthy Caucasian male subjects, 6 of whom will be 
randomised to receive emodepside, and 2 of whom will be randomised to receive 
placebo.  3 cohorts will be recruited, to test 3 multiple dose levels of emodepside LSF 
oral solution.   
This will be a single-blind study, where the Investigator and Sponsor will remain 
blinded in each cohort, so as not to potentially introduce bias.   
3.2. 
Study duration and duration of subject participation 
Each subject will attend a screening visit within the 4 weeks before their first dose of 
study medication (on Day 0). 
Eligible subjects will be admitted to the ward on the evening of Day –3.  They will 
remain on the ward until the morning of day 14 (17 nights in a row), during which 
they’ll receive daily oral doses of emodepside or placebo for 10 days.  Subjects in 
Cohorts 1 and 2 will receive emodepside once-daily and those in Cohort 3 will 
receive emodepside twice-daily (at 12 h intervals) during that time.  
Safety, tolerability, PD and PK assessments will be done regularly before, during, 
and after dosing.  Each subject will undergo a full day of assessments (excluding PK) 
on the day before dosing (Day –1), and a similar full day of assessments (including 
PK) on the first (Day 0) and last days of dosing (Day 9).  In addition, they will undergo 
an Oral Glucose Tolerance Test (OGTT) on Day -2, Day 1, Day 8 and Day 120. 
Subjects will be discharged from the ward 5 days after their last dose of study 
medication (Day 14), if the Investigator has no safety concerns.  Subjects will attend 
the ward for outpatient (ambulatory) visits on Days 17, 20, 23 and 27 (± 2 days).  
Subjects will attend a follow-up visit on Day 30 (± 2 days), approximately 3 weeks 
after their last dose of emodepside.  Subjects will also have long-term follow-up visits 
on Days 60, 90 and 120( 2 days). 
The study Schedule of events (Section 5) provides a detailed overview of all study 
procedures, which are further discussed in Section 8 (Study Assessments). 
3.3. 
Definition of the end of trial 
The end of the trial is defined as the final long-term follow-up visit (Day 120 +/- 2 
days) by the last subject (or final contact with the subject, if that is later),   
If the trial is terminated early, the trial ends when the Sponsor notifies the Investigator 
in writing that the trial has finished, or when the last subject attends the final follow-up 
visit, whichever is later. 
3.4. 
Rationale of study design  
The study will be performed in healthy male Caucasian volunteers.   


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The study is performed in a single-blinded design, in which the subjects are blinded 
and will not know which treatment (active or placebo) they are given.  The 
Investigator and Sponsor will remain blinded during each cohort, so as not to 
potentially introduce bias.  For safety and dose escalation purposes, the data may 
also be unblinded at the end of each cohort, for review by the Safety Review Group 
(detailed in Section 7.10).  Placebo has been included to assess whether any 
observed effects are treatment-related or simply reflect the study conditions. 
Subjects will be given an extensive ophthalmological assessment at Screening Visit 2 
and full neurological assessment at screening and Day 0, to ensure that they don’t 
have any pre-existing conditions that might confound the results of post-dose 
assessments. 
The decision about dose escalation will be taken in the Safety Review Meeting, 
before dosing of the subsequent cohort (see Section 11). 
Figure 1- Overall study flow chart 
 
Based on the data from the single dose-escalating FIH trial (DNDI-EMO-001), the 
dose level in this study will not exceed 20 mg LSF oral solution (at a concentration of 
1 mg/mL) per day. 
4. Selection of Subjects 
The following eligibility criteria were designed to select subjects for whom the 
protocol treatment is considered appropriate.  All relevant medical and non-medical 
conditions should be taken into consideration when deciding whether this protocol is 
suitable for a particular subject.  Eligibility criteria may not be waived by the 
Investigator.  Any questions regarding a subject’s eligibility should be discussed with 
the DNDi Medical Monitor before subject’s enrolment. 
4.1. 
Inclusion criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrolment 
into the study: 


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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 (Body Mass Index (BMI); Quetelet index) in the range 
18.0 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 (TOPS) 
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 
4.2. 
Exclusion criteria 
Any of the following will exclude a subject from study enrolment: 
1. 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. 
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 (eg stomach bypass) or medical condition that might affect 
absorption of the study drug when taken orally 
4. 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 
5. Loss of more than 400 mL of blood within the 3 months before admission 
6. Clinically relevant history of vital organ disease, or other organ or central 
nervous system disease 
7. Current or previous medical or psychiatric disorder (eg seizures) that, in the 
opinion of the Investigator or the Sponsor, would increase the risk and ability 


Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 5, 25 July 2018 
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to participate in and/or complete the study 
8. Positive test for hepatitis B, hepatitis C or HIV 
9. Febrile illness (eg fever) within 1 week before the first dose of study 
medication 
10. History of a severe allergy, non-allergic drug reaction, severe adverse reaction 
to any drug, or multiple drug allergies 
11. 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 litre (L) of beverages containing 
xanthine 
14. Daily consumption of more than 5 cigarettes or 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: 
 second or third-degree atrioventricular (AV) block; or  
 prolongation of the QRS complex > 120 msec; or  
 QTc-interval (QTcB or QTcF)  
> 450 msec. 
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 during 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. Wearing of contact lenses during the 1 month before the first dose of study 
medication.  Contact lens wear is not permitted during the study 
25. Presence of an ocular disorder for which topical ocular therapy is currently or 


Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 5, 25 July 2018 
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chronically prescribed, including inflammatory eye disease (dry eye allergic 
conjunctivitis [seasonal allergic conjunctivitis, vernal keratoconjunctivitis, 
atopic keratoconjunctivitis], uveitis and glaucoma) 
26. 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 
4.3. 
Dietary and lifestyle guidance 
Subjects will abide by HMR house rules during the in-house period. 
No food or drink containing grapefruit will be allowed from 7 days before dosing until 
after the Follow-Up Visit. 
No alcoholic or caffeinated drinks, or smoking, will be allowed during the period from 
24 h before admission until the end of each in-house period and for 24 h before each 
other visit including long-term follow-up visits.  Subjects must not drink more than 3 
units of alcohol daily at all other times during the study (1 unit = ½ pint of beer, 1 
small glass of wine or 1 measure of spirits). 
No strenuous exercise will be allowed from screening until after the Follow-up Visit, 
and from 48 h before each long-term follow-up visit. 
Subjects should not expose themselves to sunlight for longer than 15 minutes without 
using a strong sunblock (factor (SPF) 30 or above), use a sunbed, or expose 
themselves to other sources of UV light (such as UV lighting in clubs), while taking 
the study medicine and until 3 days after their last dose 
Standard meals will be provided at the usual times designated by the Investigator.  
Subjects will be allowed to drink water ad libitum at all times during the study.  
Subjects should fast (no food or drink, except water) for 10 h before Screening 
Visit 1.  During the in-house period (Days –3 to 14), subjects will fast on the following 
occasions: 
 
for at least 9 h overnight until the morning of Day 2, and until the OGTT 
has been administered; 
 
for at least 9 h before the morning of Day –1, and will have their first meal 
of the day after their morning assessments are complete. 
 
for at least 9 h overnight before their morning dose on Days 0–9, until 4 h 
after that dose on Days 0, 1, 8 and 9, and 1 h after the dose on other 
days; 
 
in Cohort 3, subjects will additionally fast for at least 2 h before and 1 h 


Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 5, 25 July 2018 
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Page 39 of 84 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
after their evening dose on Days 0–9; 
 
for at least 9 h before their assessments on Day 10, 11, 12, 13, and 14, 
Day 23 outpatient visit, and the Follow-up (Day 30 ±2 days) and long-term 
follow-up visits (Day 60, 90 and 120 ±2 days).   
On each occasion, subjects will be required to fast until scheduled assessments for 
the relevant time have been completed. 
During the study (according to HMR procedures), and for 120 days after the subject’s 
last dose of study medicine, subjects must not have sex without using a condom, 
unless they have had a vasectomy or their partner is not of childbearing potential. 
Subject’s near vision will be blurred for approximately 2 h (due to the use of mydriatic 
eye drops) following the eye-testing procedures at Screening Visit 2, so they should 
not drive or operate machinery for that time afterwards.  On Day 10, the 
ophthalmology assessments will be repeated post-dose, but without the use of 
mydriatic eye drops.  If subjects report visual AEs, ophthalmology assessments 
should be done at the ophthalmological clinic, as soon as an appointment can be 
scheduled.  
 


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5. Schedule of events  
5.1. Table 2:  Schedule of events overview 
Screening 
Day (s) 
Follow-up 
(Day 30 
±2 Days) 
Long-term 
follow-up 
visits 
(Days 60, 
90, and 120 
±2 Days)18 
Procedure 
Day 28 to 3 
–3 
–2 
–1 
0 
1 
2–8 
9 
10–14 
17 
 (±2) 
20  
(±2) 
23  
(±2) 
27  
(±2)  
Visit 1 Visit 2 
Subject demographics and 
informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient stay 
 
 
 
 
 
 
 
 
X 
Outpatient visit 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Drugs of abuse screen 
and alcohol breath test1 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Full physical examination2 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
Short physical 
examination2 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Full neurological 
examination3 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Short neurological 
examination4 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmological 
examination5 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Oral Glucose Tolerance 
Test (OGTT)6 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
X 
Glucose, insulin, glucagon 
and cortisol7 
 
 
 
 
X 
X 
X 
 
X 
X 
 
 
 
 
X 
 
Administration of 
emodepside8 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
12-lead safety ECGs9 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
 


Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 5, 25 July 2018 
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Page 41 of 84 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
Screening 
Day (s) 
Follow-up 
(Day 30 
±2 Days) 
Long-term 
follow-up 
visits 
(Days 60, 
90, and 120 
±2 Days)18 
Procedure 
Day 28 to 3 
–3 
–2 
–1 
0 
1 
2–8 
9 
10–14 
17 
 (±2) 
20  
(±2) 
23  
(±2) 
27  
(±2)  
Visit 1 Visit 2 
Vital signs10 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE monitoring11 
 
PK of emodepside in 
plasma12 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK of metabolites of 
emodepside in plasma13 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
PK of emodepside and 
metabolites in urine14 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Laboratory safety tests15 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
X 
Serology16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leptin and prolactin7,17 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
1. Alcohol breath tests and drugs of abuse screen will be performed at Screening Visit 1 and Day–3.  At long-term follow-up visits (Days 60, 90 and 120), only 
alcohol breath tests will be performed.  
2. A full physical examination will be done at Screening Visit 1 and Follow-up and before the morning dose on Days 3–8 inclusive, and on Day 14.  To include height 
at Screening Visit 1 and weight at Screening Visit 1 and on the morning of Day –1.  Short physical examinations will be done at the following time points: 
 
on Day –1:  at –24, –23, –22, –20 and –12 h before the morning dose on Day 0 
 
on Day 0:  before and at 1, 2, 4, and 12 h after the morning dose  
 
on Days 1 & 2:  before the morning dose 
 
on Day 9:  before and at the following times after the morning dose:  0.5, 1, 2, 4, 12, 24 h (Day 10), 48 h (Day 11), 72 h (Day 12) and 96 h (Day 13) 
 
at outpatients visits on Days 17, 20, 23, 27, and at long-term follow-up visits (Days 60, 90 and 120) (± 2 days) 
3. A full neurological examination will be done at screening Visit 1, before the morning dose on Day 0 and on Day 14 after the morning dose (120 h).  
4. A short neurological examination will be given at the following time points: 
 
on Day –1:  at –24, -23, -22, -20, and -12 h before the morning dose on Day 0 
 
on Day 0:  at 1, 2, 4, and 12 h after the morning dose  
 
on Days 1–8:  before the morning dose 
 
on Day 9:  before and at the following times after the morning dose:  1, 2, 4, 12, 24 (Day 10), 48 (Day 11), 72 (Day 12) and at 96 h (Day 13) 
 
at outpatient visits on Days 17, 20, 23, 27 and at Follow-up (Day 30 ± 2 days), and long-term follow-up visits (Days 60, 90 and 120 ±2 days) 


Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 5, 25 July 2018 
Confidential  
Page 42 of 84 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
5. Ophthalmological examination will be performed at the second screening visit after all other eligibility criteria have been met, and on Day 10.  If deemed necessary 
by the ophthalmologist, additional ophthalmology follow-up visit(s) may be scheduled for eye-related AEs.  Subjects will be given the Ishihara test at screening 
visit 1.  
6. Blood samples taken for glucose and insulin measurement will be used to complete an Oral Glucose Tolerance Test (OGTT).  Samples taken will be: 
 
on Day –2:  at –48, –47, –46 and –44 h before the morning dose on Day 0 
 
on Day 1:  before and at 1, 2 and 4 h after the morning dose 
 
on Day 8:  before and at 1, 2 and 4 h after the morning dose 
 
on Day 120 at 0, 1, 2 and 4 h timepoints relative to dosing 
Subjects will fast until completion of the OGTT test; lunch will be provided immediately afterwards 
7. Blood samples for measurement of glucose, insulin, glucagon and cortisol will be taken: 
 
on Day –1:  at –24, –23, –22, –20 and –12 h before the morning dose on Day 0 
 
on Day 0:  before and at 1, 2, 4 and 12 h after the morning dose 
 
on Day 1:  before the morning dose  
 
on Day 9:  before and at the following time points after the morning dose:  1, 2, 4, 12, 24 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 120 h (Day 
14); and at follow up (Day 30 (± 2 days)).  Subjects will fast for the Day 11, 12, 13,14 and 30 time points.  
Leptin and prolactin will also be measured at Screening Visit 1 and Day 9, as part of the insulin blood sample. 
8. Administration of the study medicine will be done in fasting conditions on Days 0–9 at approximatively the same time each morning (±15 mins): 
 
in Cohorts 1 & 2, emodepside will be giving in the morning only 
 
in Cohort 3, emodepside will be given in the morning and evening (at 12 h intervals).  On the last day (day 9), emodepside will be given only in the 
morning 
9. 12-lead ECGs will be recorded in triplicate (with 1 minute between recordings) at –24 h (Day –1) before the morning dose on Days 0 and 9; single recordings will 
be made at all other time points.  ECGs will be recorded:   
 
at Screening Visit 1 and at Follow-up (Day 30 ± 2 days) 
 
on Day –1:  at –24, –23.5, –23, –22.5, –22, –21, –20, –16 and –12 h before the morning dose on Day 0  
 
on Day 0:  before and at 0.5, 1, 1.5, 2, 3, 4, 8 and 12 h after the morning dose  
 
on Days 1–8:  before the morning dose 
 
on Day 9:  before and at the following times after the morning dose:  0.5, 1, 1.5, 2, 3, 4, 8, 12, 24 (Day 10), 72 (Day 12) and 120 h (Day 14) after the 
Day 9 dose 
Subjects should rest in the supine position for 10 minutes before ECG measurements.  
10. Vital signs will comprise blood pressure (BP) and heart rate (HR) at all time points, with oral temperature included at screening and –24 h before the morning dose 
on Day 0 (Day –1).  Subjects should rest in the supine position for 10 minutes before single BP and HR measurements are taken.  Vital signs will be measured:   
 
at the first screening visit and at Follow-up (Day 30 ± 2 days) 
 
on Day –1:  at –24, –23.5, –23, –22.5, –22, –21, –20, –16 and –12 h before the morning dose on Day 0  
 
on Day 0:  before and at 0.5, 1, 1.5, 2, 3, 4, 8 and 12 h after the morning dose  
 
on Days 1–8:  before the morning dose 
 
on Day 9:  before and at the following times after the morning dose:  0.5, 1, 1.5, 2, 3, 4, 8,12, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 
120 h (Day 14) 
 
at outpatients visits on Days 17, 20, 23 and 27 (± 2 days), and long-term follow-up visits (Days 60, 90 and 120 ±2 days) 
11. Adverse event monitoring will be done throughout the study, but scheduled questioning will be done at the following time points: 
 
at Screening Visit 1 and at Follow-up (Day 30 ± 2 days) 
 
on Day –1, at -24, -23, -22, -21, -20, -18, -16, -12 h before the morning dose on Day 0  


Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 5, 25 July 2018 
Confidential  
Page 43 of 84 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
 
on Day 0:  before and at 1, 2, 3, 4, 6, 8 and 12 h after the morning dose  
 
on Days 1–8:  before the morning dose 
 
on Day 9:  before and at the following times after the morning dose:  0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36 (Day 10), 48 (Day 11), 72 (Day 12), 96 (Day 13) and 
120 h (Day 14) 
 
at outpatients visits on Days 17, 20, 23 and 27 (± 2 days), and long-term follow-up visits (Days 60, 90 and 120 ±2 days) 
12. Blood samples for assay of emodepside in plasma will be taken: 
 
on Day 0:  before and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 15 h after the morning dose 
 
on Days 1–8:  before the morning dose 
 
on Day 9:  before and at the following times after the morning 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) 
 
at outpatients visits on Days 17, 20, 23 and 27 (± 2 days), and at Follow-up (Day 30 ± 2 days) 
Subjects should rest in the supine position for 10 minutes before blood is drawn (if possible).  
13. Blood samples for assay of metabolites of emodepside in plasma will be taken: 
 
on Day 0:  before and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 15 h after the morning dose 
 
on Day 9:  before and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 15 h after the morning dose 
14. Urine for assay of emodepside and its metabolites may be collected at the following time points: 
 
On Day 0:  from 0–4, 4–8, 8–12 and 12–24 h after the morning dose 
 
On Day 9:  from 0–4, 4–8, 8–12 and 12–24 h after the morning dose 
15. Blood and urine samples for clinical laboratory safety tests (haematology, biochemistry, coagulation & urinalysis) will be taken:  at Screening Visit 1; on Day –1 (–
24 h before the morning dose on Day 0); before the morning dose on Day 0; before the morning dose on Days 1, 5 and 8; before, 24 h (Day 10) and 120 h after 
the morning dose on Day 9 (Day 14); at the Day 23 outpatient visit (± 2 days); at Follow-up (Day 30 ± 2 days); and at long-term follow-up (Days 60, 90 and 120 ± 2 
days).   
Subjects should rest in the supine position for 10 minutes before blood is drawn (if possible).  
16. Serology tests will comprise HIV 1 & 2, hepatitis B & C, and HbA1c 
17. Blood samples for measurement of leptin and prolactin will be taken at Screening Visit 1 and before the morning dose on Day 9. 
18. Subjects will be admitted to the ward on Day 119, before the Day 120 long-term follow-up visit. 
 
 


Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 5, 25 July 2018 
Confidential  
Page 44 of 84 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
5.2. 
Table 3:  Schedule of events expanded view:  pre-dosing period 
 
Pre-dosing period 
 
Day –2 
Day –1 
Procedure 
–48 h –47 h –46 h –44 h –24 h –23.5 h 
–23 h 
–22.5 h 
–22 h 
–21 h 
–20 h 
–18 h 
–16 h 
–12 h 
Short physical examination2 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Short neurological examination4 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Oral Glucose Tolerance Test (OGTT)6 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Glucose, insulin, glucagon and cortisol7 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
12-lead safety ECGs9 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Vital signs10 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
AE monitoring11 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Laboratory safety tests15  
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
5.3. 
Table 4:  Schedule of events expanded view:  first dosing day 
 
First dosing day (Day 0) 
Procedure 
0 h 
0.25 h 0.5 h 
1 h 
1.5 h 
2 h 
2.5 h 
3 h 
4 h 
6 h 
8 h 
12 h 
15 h 
24 h 
Short physical examination2 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
Full neurological examination3  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Short neurological examination4 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
Glucose, insulin, glucagon and cortisol7 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
Administration of emodepside8 
X 
 
 
 
 
 
 
 
 
 
 
X* 
 
 
12-lead safety ECGs9 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
Vital signs10 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
AE monitoring11 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
PK of emodepside in plasma1212 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


Protocol number (DNDI-EMO-02)  
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 5, 25 July 2018 
Confidential  
Page 45 of 84 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
 
First dosing day (Day 0) 
Procedure 
0 h 
0.25 h 0.5 h 
1 h 
1.5 h 
2 h 
2.5 h 
3 h 
4 h 
6 h 
8 h 
12 h 
15 h 
24 h 
PK of metabolites of emodepside in plasma13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK of emodepside and metabolites in urine1414 
 
 
 
 
Laboratory safety tests15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Group 3 only.  Order of assessments at this time point is given in Section 8.2 
5.4. 
Table 5:  Schedule of events expanded view:  last dosing day 
 
Last dosing day (Day 9) 
Procedure 
0 h 
0.25 h 0.5 h 
1 h 
1.5 h 
2 h 
2.5 h 
3 h 
4 h 
6 h 
8 h 
12 h 
15 h 
24 h 
Short physical examination2 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
Short neurological examination4 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
Glucose, insulin, glucagon and cortisol7 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
Administration of emodepside8 
X 
 
 
 
 
 
 
 
 
 
 
X* 
 
 
12-lead safety ECGs9 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
Vital signs10 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
AE monitoring11 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
PK of emodepside in plasma1212 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK of metabolites of emodepside in plasma13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK of emodepside and metabolites in urine1414 
 
 
 
 
Laboratory safety tests15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leptin and prolactin7,17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Group 3 only.  Order of assessments at this time point is given in Section 8.2 


Confidential  
 
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Protocol template_Version 1.2_24 April 2014 
6. Enrolment procedures  
The study will be carried-out in healthy male subjects at the following Phase 1 unit:  
Hammersmith Medicines Research Limited,  
Cumberland Avenue,  
London, NW10 7EW, United Kingdom  
The Investigator or his/her delegate should document the date when informed 
consent was obtained (Screening), screening dates, subject initials, Screening 
Number, date of eligibility and inclusion in the study (Enrolment), Subject Number 
(when Randomised – received treatment) or reason for not enrolling (Screen Failure) 
or not being randomised, whenever applicable. 
Screening should occur between 3 and 28 days before the intended initiation of 
treatment:  detailed procedures are described in Section 8:  Study Assessments. 
All subjects must give written consent (see Sections 8.1 and 15.1 for Informed 
Consent Procedures) to participate in this trial.  Consent for screening evaluations 
may be obtained using the information and consent form for the HMR healthy 
volunteer panel, which was originally approved by London – Brent Research Ethics 
Committee (REC) and has subsequently been approved by the Generic Document 
Review Committee.  The trial-specific information and consent form will be signed by 
the subject either before any screening evaluation or after the Investigator assesses 
the eligibility of the subject for the trial, and before the subject is randomised to 
receive the first dose of emodepside or placebo.  Before giving consent, subjects 
must read the information sheet about the trial.  They must also read the consent 
form.  They will then discuss the trial with the Investigator, or his deputy, and be 
given the opportunity to ask questions.  The trial-specific information sheet and the 
consent form must be approved by the REC.   
All screened subjects will be allocated a Screening Number. 
After successful screening, subjects will be enrolled, and allocated to a cohort in the 
trial, according to their availability and the scheduled trial dates.  Subjects will be 
assigned Subject Numbers (in the order in which they are admitted to the ward), 
when they receive their first dose (‘Randomised’ subjects).  Subject numbers in the 
trial will be as shown in Table 6 .  Subjects will be allocated to treatment (active or 
placebo) according to a randomization schedule prepared by an independent HMR 
statistician, using a SAS program.  Sufficient subjects will be screened to ensure up 
to 24 subjects are randomized. 
7. Study treatments 
Subjects in Cohorts 1–3 will be randomised to receive either emodepside LSF 
solution, or matching placebo solution.  Subjects in Cohorts 1 and 2 will receive 
once-daily doses of LSF or placebo, and subjects in Cohort 3 will receive twice-daily 
doses of LSF or placebo, by mouth.  
The planned treatments to be administered are described below in Table 6 . 
7.1. 
Doses and treatment regimens 
Randomised subjects will be given a unique ID (subject number; Table 6 ) that will be 
recorded in the case report form (CRF), and will be retained throughout the study.  


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This subject number will also appear on the study medication containers. 
Table 6 .  Study treatment:  Subject numbers, Formulation, and Dose-Levels by 
Cohort 
Subject 
numbersa 
Formulation and route of 
administration 
Planned subjects 
Emodepside 
Matching 
placebo 
Cohort 1 
1001 – 1008 
5 mg LSF solution OD, or 
placebo, by mouth 
6 
2 
Cohort 2 
2001 – 2008 
10 mg LSF solution OD, or 
placebo, by mouth 
6 
2 
Cohort 3 
3001 – 3008 
10 mg LSF solution BID, 
or placebo, by mouth 
6 
2 
a Any subjects who are replaced in a cohort will have the subject number incremented by 100 
(eg,  1001 would be replaced by 1101) 
Subjects will receive the study medication according to fasting instructions given in 
Section 4.3:  On dosing days, following an 9 h overnight fast (no food or drink, except 
water), Investigator site personnel will administer study medication (active or 
placebo) to subjects with 240 mL ambient temperature water. 
Subjects in Cohort 3 will be given an evening dose approximately 12 h after their 
morning dose on Days 0–9: they’ll fast for 2 h before and 1 h after that evening dose. 
Study treatment will be administered under the supervision of Investigator site 
personnel, following site standard procedures to ensure treatment compliance. 
7.2. 
Emodepside study treatment  
Detailed information on the drug substance emodepside (BAY 44–4400) is given in 
the Investigator’s Brochure.  
The study treatment will be provided as 0.1% (w/v) emodepside oral (LSF) solution 
with 1 mg active pharmaceutical ingredient (emodepside, BAY 44-4400) per mL.  It is 
available as bulk solution in a brown glass container with a dosing adapter and 
child-resistant screw cap closure. 
Doses up to 20 mg, corresponding to 20 mL solution, can be dispensed from 1 bottle.  
The solution has to be withdrawn from the container using a syringe and is then 
administered directly from the syringe into the mouth of the subject.  The solution 
should not be diluted before application.  The solution may be used for application of 
doses up to a maximum of 20 mg per day corresponding to application of 20 mL of 
the solution per day, based on the results of the single-administration dose study 
(DNDI-EMO-001). 
The solution is composed of the active substance emodepside and the following 
excipients:  
 macrogol 400  
 polysorbate 20 
 levomenthol 
 butylhydroxyanisole. 
7.3. 
Placebo study treatment  
A corresponding placebo solution is available with excipients matching the 


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emodepside treatment, but lacking the active pharmaceutical ingredient.  
7.4. 
IMP supply and handling 
Formulation and Supplier:   
Emodepside will be supplied by the Sponsor, DNDi, as emodepside LSF solution and 
matching placebo solution. 
The study drug will be delivered by the Sponsor to the study site in bulk.  It will be the 
responsibility of a relevant member of the pharmacy/pharmacy delegate to prepare 
the individual treatments. 
Preparation and Dispensing:   
Emodepside LSF solution will be dispensed in the Phase 1 Unit to the individual 
dosing containers by 2 appropriately qualified, unblinded members of the pharmacy 
team. Instructions provided in the Pharmacy Manual/Study Procedures Manual must 
also be followed. 
7.5. 
Dose escalation 
During the study, the dose will be increased only if the safety, tolerability and PK of 
the previous dose are acceptable. 
Dose escalation will be decided by the Safety Review Group (SRG) at the Safety 
Review Meeting (see Section 11).  The dose will not be escalated until the SRG have 
reviewed the safety, tolerability and PK data until 48 h after the final dose of study 
medication in at least 4 subjects on active treatment (ie.  at least 6 subjects overall) 
and agree that it is appropriate to give a higher dose; that decision will be taken in 
the Safety Review Meeting, before dosing of the subsequent cohort.  The next 
planned dose level may be reduced, a dose level may be re-tested, or an 
intermediate dose level selected, based on the emerging data.  
The dose level will not exceed 20 mg LSF oral solution (1 mg/mL) per day. 
7.6. 
Study stopping criteria 
7.6.1. 
Dose escalation stopping criteria 
A dose level will not be repeated, or exceeded, if the results of safety tests give the 
Sponsor or Investigator cause for concern, or if one of the following dose escalation 
stopping criteria is met: 
 any of the trial stopping criteria in Section 7.6.2 are met. 
 the Investigator considers the dose level to be not well tolerated. 
 predicted mean plasma concentrations in the subjects at the next scheduled 
dose level exceed or equal:   
o Cmax:    
 
612 µg/L 
 (based on the highest dose in the Single-Ascending Dose (SAD) study:  
DNDI-EMO-001) 
If a cohort fulfils a dose escalation stopping criterion, that dose level will not be 
repeated.   


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The scheduled dose of emodepside may be reduced if, for example, the results of 
safety tests give any cause for concern, or tolerability is poor. 
If AEs occur that cause mild or moderate discomfort but do not in any way threaten 
the health of the subject, that dose level may be repeated, with the aim of further 
exploring the relationship between dose and AE.  If, in the judgement of the SRG, it 
would not be reasonable to expose more subjects to the level of discomfort 
experienced by those who have already received the dose, the next scheduled dose 
may be reduced.  The reduction may be either to one of the dose levels that has 
already been given, or to an intermediate level that has not previously been given; in 
either case, the aim is to learn more about the relationship between AE and dose (or 
plasma concentration) of drug. 
7.6.2. 
Trial stopping criteria 
The trial will be stopped if either of the following occurs: 
 one or more serious AE that is considered to be related to emodepside; or 
 2 or more subjects with a severe or clinically significant AE, considered to be 
related to emodepside, that occurs in the same treatment group 
If, after an internal safety review, it is appropriate to restart the trial, a substantial 
amendment will be submitted to the MHRA and REC.  The trial will not restart until 
the amendment has been approved by the MHRA and REC.   
7.7. 
Study treatment labelling, packaging 
Emodepside supplied by the Sponsor will be manufactured, packed, labelled and 
shipped according to the current GMP guidelines and local legal rules.  Bulk-supplies 
of emodepside will be delivered to the pharmacy of the Phase 1 Unit. 
7.8. 
Accountability 
All study treatments must be kept in a locked room that can be accessed only by the 
pharmacist or the Investigator.  The study treatments must not be used for other 
purposes other than this protocol.  Under no circumstances the Investigator or site 
staff may supply study treatments to other Investigators or sites, or allow the 
medications to be used other than as directed by this protocol without prior written 
authorization from DNDi.  Adequate records on receipt, use, return, loss, or other 
disposition of treatments must be maintained. 
Upon receipt of the study drugs, the Investigator or a relevant member of the 
pharmacy/pharmacy delegate, will send the Sponsor the corresponding 
acknowledgement of receipt form.  This form must be filled (including the date of 
receipt) and signed by a relevant member of the pharmacy/pharmacy delegate, or 
the Investigator.  An audit trail of all medication transported and dispensed during the 
study will be maintained. 
All investigational materials (medication and packaging) unused in the study will be 
destroyed by HMR (with the Sponsor’s approval), or returned to the Sponsor before 
or at the termination of the study, together with an accountability form documenting: 
 all administered units; 


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 all unused treatments; 
 all units returned after completion of the study, and the date of return. 
The study drug will be dispensed only under the restricted conditions defined in the 
present protocol and the Pharmacy Manual/Study Procedures Manual. Drug will be 
administered by the Investigator only or his/her delegate. 
Time of administration and initials of the person administering the study medication 
will be documented in the Case Report Form (CRF). 
7.9. 
Storage 
Emodepside oral solutions (active and placebo) should be stored at 2–8°C in the 
original container (upright storage).   
7.10. 
Blinding and procedures for unblinding 
The study drug and matching placebo will be identical in appearance in order to 
preserve the single blind with respect to the subject; the subjects are blinded and will 
not know which treatment (active or placebo) they are given.  The Investigator 
(including clinical, statistics and data management personnel) and the Sponsor 
(including the study monitor) will remain blinded during each cohort, so as not to 
potentially introduce bias, unless safety concerns necessitate unblinding (if the 
knowledge of the treatment administered is useful for the best medical care of an 
AE).  Investigator pharmacy staff, who’ll dispense the IMP, will not be blinded at any 
time.   
For safety and dose escalation purposes, the data may be unblinded at the end of 
each cohort for review by the SRG.  Optionally, a separate, unblinded monitor may 
be used to check drug accountability monitoring during the conduct of the study, 
following procedures to avoid unblinding other study personnel. 
A sealed copy of the randomisation code will be kept in a locked file in the HMR 
Pharmacy.  A copy will also be kept by the Sponsor.  The Investigator will be 
supplied with sealed envelopes, each one containing the treatment allocation for the 
subject whose number appears on the outside of the envelope.  Those envelopes will 
be kept in the trial master file, readily accessible to clinical staff.  Emergency 
procedures for revealing medication codes are specified later in this section. 
If required, as described in Section 11, advisor(s) independent from the study team 
may be appointed to review unblinded data to assist decision-making during Safety 
Review Meetings. 
When the database is locked at the end of cohorts 1 and 2 and again at the end of 
cohort 3, the HMR statistician will inform the Sponsor of his or her intention to break 
the randomisation code for the finished cohorts.  The statistician will break the code, 
and do the statistical analysis of those data. 
If unblinding is required in the interest of the safety of a subject, an Investigator will 
discuss the matter with the Sponsor before opening the individual code-break 
envelope for that subject.  In a medical emergency, the Principal Investigator or 
delegate may open the individual code-break envelope for that subject without prior 
consultation with the Sponsor.  In that event, the principal Investigator or delegate will 


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notify the Sponsor as soon as possible that the randomisation code has been broken 
for the subject. 
When the randomisation code is broken, the reason will be fully documented and 
entered in source documents and the CRF. 
7.11. 
Concomitant treatments 
Prior therapy as indicated in the exclusion criteria (Section 4.2) will not be permitted.  
The only exception is acetaminophen (paracetamol), which may be taken up to the 
first dose of trial medication. 
No medications (with the exception of acetaminophen (paracetamol) up to 2000 mg 
per day), will be allowed while the subject is participating in the study, except those 
medically indicated for the treatment of AEs.  If any medication is required, the 
subject may be withdrawn from the study drug at the discretion of the Investigator 
and the Sponsor, if use of that medication could compromise the safety of the subject  
or the scientific value of the trial, and will be followed up until the end of the study.  
No dietary supplements or herbal remedies that are known to interfere with the 
CYP3A4 and/or P-gp metabolic pathways will be allowed while the subject is 
participating in the study, except those medically indicated for the treatment of AEs.  
Further questions about concomitant medication can be directed to the Sponsor’s 
Medical Expert.  
Use of any concomitant medication will be recorded until the last long-term follow-up 
visit in the source data and CRF with the following information: 
 Reason for treatment; 
 Name of the drug, type of formulation, and unit strength; 
 Dose administered; 
 Time and duration of treatment. 
Medications taken within 28 days before the first dose of study medication will be 
documented as a prior medication.  Medications taken after the first dose of study 
medication will be documented as concomitant medications. 
8. Study Assessments 
8.1. 
Subject Information and Consent Form 
Before any procedures are conducted, the Investigator (or an appropriate delegate at 
the Investigator site) will obtain written informed consent from each subject in 
accordance with the procedures described in Section 15.1 on the Subject Information 
and Consent Form (ICF). 
8.2. 
Timing of Assessments 
All procedures will be conducted according the Schedule of events, in Section 5. 
General order of assessments 
For the study periods described below, when multiple procedures are scheduled at 
the same time point(s) relative to dosing, the following chronology of events should 


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be adhered to, where possible: 
 Neurological examination and physical examination   
 12-lead ECGs:  after 10 minutes rest in the supine position single 
readings, with the exception of one triplicate reading 
 Blood pressure/heart rate:  after 10 minutes rest in the supine position 
 AE monitoring (spontaneous and solicited AE monitoring will include 
specific questioning for tolerability and safety) 
 PK blood sampling (taken at, or closest to, the nominal time point) 
 PK blood sampling for metabolites 
 Blood sampling for profiles of glucose, insulin, glucagon, and cortisol; 
single samples for prolactin and leptin; Laboratory safety blood samples.  
Urine samples will be collected when possible (dependent on the subject) 
but within the allowed deviation times.  
Every effort should be made to ensure that protocol-required tests and procedures 
are completed as described.  However, it is anticipated that from time to time there 
may be circumstances outside the control of the Investigator that may make it 
unfeasible to perform the test.  In those cases, the Investigator must take all steps 
necessary to ensure the safety and well-being of the subject.  When a protocol 
required test cannot be performed, the Investigator will document the reason for the 
missed test and any corrective and preventative actions which s/he has taken to 
ensure that required processes are adhered to as soon as possible.  The Sponsor 
study team must be informed of these incidents in a timely manner.  Allowable 
deviations for study assessments are detailed in Section 8.4 of this protocol. 
To minimise variability, throughout the study, study staff should also ensure a 
minimum 10-minute supine period, where possible, before drawing any blood 
samples (including lab safety assessments). 
Throughout the study (from subject signature of the ICF) AEs and concomitant 
medication will be documented as they are reported by the subjects.  Subjects will 
also be questioned about AEs at the times that blood samples are taken, at follow-
up, at long-term follow-up, and at the specific time points detailed in the Schedule of 
events (Section 5). 
8.3. 
Study visits 
Baseline will be considered as the last assessment performed prior to randomisation.   
8.3.1. Screening Visit 1 
All subjects will be screened within the 28 days before administration of the study 
medication to confirm that they meet the subject selection criteria for the study.  
Subjects who fail screening by not meeting the inclusion and/or exclusion criteria 
may be rescreened at the Investigator’s discretion. 
Subjects will attend the ward, having fasted overnight for at least 10 h.  
The following assessments will be done in order to collect historical safety data, and 
to assess eligibility for the study: 


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 Review of inclusion and exclusion criteria 
 Complete medical history:  including demographic data, previous and 
concomitant medications (ie, prescription medicine taken within 28 days, or 
non-prescription drugs and dietary supplements taken within 7 days, before the 
planned first dose, and/or plan to continue taking throughout the study) 
 Full physical examination:  see Section 8.5.3.  A detailed description of the 
physical examination will be included in the Study  Procedures Manual 
 Full neurological examination:  see Section 8.5.3.  Also a detailed description of 
the neurological examination will be included in the Study Procedures Manual.  
Subjects will be given the Ishihara colour perception eye test.  
 Body weight and height, vital signs (oral temperature, blood pressure and heart 
rate will be determined; see Section 8.5.2) 
 12-lead ECGs  
 AE monitoring (spontaneous and solicited AE monitoring will include specific 
questioning for tolerability and safety) 
 Urinary drugs of abuse screen (opiates, amphetamines, barbiturates, cannabis, 
benzodiazepines and cocaine-metabolites) and breath test for alcohol 
 Blood sampling for serology (HIV and hepatitis) and for Hb1Ac 
 Blood sampling for clinical safety laboratory evaluations:   
 Haematology and coagulation:  haemoglobin, haematocrit, MCV, MCH, 
MCHC, platelets, reticulocytes, white blood cells (WBC) with differential, red 
blood cells (RBC), HbA1C, activated partial thromboplastin time (aPTT), 
prothrombin time (PT); 
 Biochemistry:  aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase (AP), glutamate dehydrogenase (GLDH), 
gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), 
creatinine kinase (CK), amylase, lipase, T4 (free), T3 (free), thyroid-
stimulating hormone (TSH), glucose, cholesterol (HDL, LDL, total), 
triglycerides, creatinine, urea, uric acid, bilirubin (total and conjugated), total 
protein, sodium, potassium, calcium, chloride and magnesium in serum 
 Leptin and prolactin 
 Urinalysis for clinical laboratory safety evaluations, via dipstick test:  glucose, 
ketone bodies, specific gravity, occult blood, pH, proteins, leucocytes, bilirubin, 
urobilinogen, nitrites 
All biological assessments will be performed in fasting state (at least 9 h), and with a 
10 minute supine rest before sampling.  
To prepare for study participation, subjects will be instructed on the use of the Dietary 
and Lifestyle Guidelines of the Phase 1 unit and for this study, and will be scheduled 
to report to the ophthalmology clinic for Screening Visit 2. 
8.3.2. Screening visit 2:  Ophthalmological assessment 
Details of the ophthalmological assessment are given in Section 8.5.4.  Screening 


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Visit 2 will take place after confirmation that all other eligibility criteria have been met 
and may take place up to and including Day –3. 
Subjects will be scheduled to report to the Investigator site for admission to the ward 
on Day 3. 
8.3.3. Admission to Ward (Day 3) 
Subjects will be admitted to the ward at the Phase 1 Unit, on Day –3 at approximately 
1600 h, and will have a urinary drug screen and alcohol breath test, and be 
monitored for AEs. 
Subjects will fast overnight from 2300 h until after their assessments are complete on 
the morning of Day –2 (about 13 h in total).  
8.3.4. Day 2 
Blood samples will be taken for measurement of glucose and insulin for the OGTT at 
times as per the Schedule of events in Section 5. 
Subjects will be given a high glucose liquid to drink after their first sample (–48 h) is 
taken.  The glucose and insulin measurements taken at 1, 2 and 4 h after the –48 h 
sample (–47, –46 and –44 h) will be used to complete the OGTT.  After those 
samples are taken, subjects will have their first meal of the day.  Subjects will be 
monitored for AEs.  
Subjects will fast overnight for at least 9 h before the –24 h time point on Day –1, 
until at least the –20 h timepoint on Day –1.  
8.3.5. Pre-day (Day 1) 
On the morning of Day 1, a cannula will be inserted into a forearm vein, under local 
anaesthesia with lidocaine 0.5%, for withdrawal of venous blood (for glucose, insulin, 
glucagon and cortisol measurements). 
Subjects will have the following procedures completed as scheduled in Section 5, 
time-matched to Day 0:  
 Scheduled AE monitoring 
 Short physical examination and neurological assessments  (including body 
weight, once in the morning) 
 12-lead ECGs (in triplicate only at –24 h) 
 Vital signs (including oral temperature) 
 Clinical safety laboratory evaluations (haematology, coagulation, 
biochemistry, urinalysis)  
 Blood samples will be taken for measurement of glucose, insulin, glucagon 
and cortisol 
Subjects will fast overnight as described in Section 4.3. 
8.3.6. Profile day (Day 0) 
Eligibility (based on inclusion and exclusion criteria) must be determined before 


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subject randomisation. 
On the morning of Day 0, a cannula will be inserted into a forearm vein, under local 
anaesthesia with lidocaine 0.5%, for withdrawal of venous blood.  The following will 
be done within 0.75 h before the morning dose of study medication and at the time 
points after administration outlined in the Schedule of Events (Section 5): 
 Scheduled AE monitoring (particularly any event related to the CNS) 
 Neurological examinations – full before the morning dose, and short at all 
other time points 
 Short physical examinations 
 12-lead ECGs (in triplicate only at the pre-dose measurement) 
 Vital signs (BP and HR) 
 Clinical safety laboratory evaluations (haematology, coagulation, 
biochemistry, urinalysis)  
 Blood sampling to assay glucose, insulin, glucagon and cortisol  
 Blood sampling to assay pre-dose emodepside and its metabolites in 
plasma (with frequent sampling after dosing) 
Subjects in Cohort 3 will have an additional evening dose of the study medication, 
approximately 12 h after their morning dose.   
Subjects will fast overnight, each night, as described in Section 4.3. 
8.3.7. Repeat dosing period (Days 1–8) 
Subjects will have the following assessments at the time points specified in the 
Schedule of Events (Section 5): 
 Scheduled AE monitoring (particularly any event related to the CNS) 
 Short neurological examination 
 Physical examination – full on Days 3–8 and short on Days 1 and 2 
 12-lead ECGs (single measurements) 
 Vital signs (BP and HR) 
 Blood sampling for the OGTT (Days 1 and 8 only). Subjects will be given a 
high glucose liquid to drink after their first sample is taken, as done on Day 
–2.   
 Blood sampling to assay glucose, insulin, glucagon and cortisol (Day 1 
only) 
 Blood sampling to assay pre-dose emodepside in plasma 
 Clinical safety laboratory evaluations (haematology, coagulation, 
biochemistry, urinalysis), on Days 1, 5, and 8 only  
Subjects will fast overnight, as described in Section 4.3. 
8.3.8. Profile day (Day 9) 


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On the morning of Day 9, a cannula will be inserted into a forearm vein, under local 
anaesthesia with lidocaine 0.5%, for withdrawal of venous blood.  The following will 
be done within 0.5 h before the morning dose of study medication and at the time 
points after administration outlined in the Schedule of Events (Section 5): 
 Scheduled AE monitoring (particularly any event related to the CNS) 
 Short neurological and physical examinations 
 12-lead ECGs (in triplicate only at the pre-dose measurement) 
 Vital signs (BP and HR) 
 Clinical safety laboratory evaluations (haematology, coagulation, 
biochemistry, urinalysis) 
 Blood sampling to assay glucose, insulin, glucagon, cortisol 
 Blood sampling to assay leptin and prolactin 
 Blood sampling to assay pre-dose emodepside and its metabolites in 
plasma  
Subjects in Cohort 3 will have a final morning dose of the study medication only on 
Day 9.  
Subjects will fast overnight, as described in Section 4.3. 
8.3.9. Days 10–14 
Subjects will remain on the ward for another 5 days, and have the following 
assessments at the time points outlined in the Schedule of Events (Section 5): 
 Scheduled AE monitoring (particularly any event related to the CNS) 
 Physical examination and neurological assessments – short on Days 
10-13 and full on Day 14 
 Ophthalmological assessments (Day 10 only) 
 12-lead ECGs (single measurements; on Days 10, 12 and 14 only) 
 Vital signs (BP and HR) 
 Clinical safety laboratory evaluations (haematology, coagulation, 
biochemistry, urinalysis) (on Days 10 and 14 only) 
 Blood sampling to assay glucose, insulin, glucagon and cortisol  
 Blood sampling to assay post-dose emodepside in plasma  
Subjects will fast during this period as described in Section 4.3.  
Subjects may be discharged from the ward following completion of their Day 14 
assessments. 


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8.3.10. 
Outpatient Visits (Days 17, 20, 23 and 27), Follow-up Visit 
(Day 30), and long-term follow-up Visits (Days 60, 90 and 120) ± 2 
days  
Subjects will return to the clinic for each ambulatory visit, and the Follow-up visit, as 
scheduled in the Schedule of events (Section 5), to have some or all of the following 
procedures: 
 Scheduled AE monitoring (particularly any event related to the CNS) 
 Physical examination – short on Days 17, 20, 23, 27, 60, 90 and 120,  and 
full at Day 30 
 Short neurological assessments  
 Vital signs (BP and HR) 
 12-lead ECGs (single measurements) 
 Clinical safety laboratory evaluations (haematology, coagulation, 
biochemistry, urinalysis) on Days 23, 30, 60, 90 and 120 only 
(haematology will include HbA1C on Day 120 only) 
 Blood sampling to assay post-dose emodepside in plasma  
 Alcohol breath tests on Days 60, 90 and 120 only 
 Blood sampling for the OGTT (Day 120 only). Subjects will be given a high 
glucose liquid to drink after their first sample is taken, as done on Days –2, 
1 and 8. 
Subjects will fast overnight before their Day 23 and Day 30 visit, and all long-term 
follow-up visits, as described in Section 4.3.  
If deemed necessary by the ophthalmologist additional ophthalmology follow-up 
visit(s) may be scheduled to characterize and assess any eye-related AEs. 
Subjects who terminate the study early will have the same assessments as at 
follow-up (Day 30).  
Subjects will be admitted on Day 119, before their Day 120 long-term follow-up visit. 
8.4. 
Assessments 
8.4.1. Sampling time points and additional tests 
With the Sponsor’s approval, additional time points may be introduced, and changes 
to time points may be made, if there is reason to believe that the change might 
improve the quality of the data (for example, if it is believed that an important effect of 
emodepside is occurring at a time when no measurements are scheduled), or if extra 
procedures are needed in the interest of subject safety.  However, the total volume of 
blood taken in the trial will not exceed the value given in Section 8.4.4, unless in the 
opinion of the Investigator, it’s in the subject’s best interest that extra blood is taken 
for additional safety tests.   
An additional 48 h’ residence on the ward, and additional outpatient visits, will be 
permitted in the event of a technical failure, and/or if extra observations or samples of 


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blood are needed.   
In the case of any samples for pharmacokinetic analysis, the following will not be 
regarded as protocol deviations: 
 Deviations of not more than 5 min on measurements scheduled up to and 
including 4 h after a morning dose; 
 Deviations of not more than 15 min on measurements scheduled from 
after 4 h to 24 h after a morning dose; 
 Deviations of not more than 1 h on measurements scheduled more than 
24 h after a morning dose; and 
 Deviations of not more than 2 days on measurements scheduled for 
outpatient visits, the Follow-up visit, and long-term follow-up visits.  
For all other procedures, the following will not be regarded as protocol deviations: 
Table 7.  Permitted deviation windows for all other procedures1 
Time point 
Deviation window in 
relation to the scheduled 
time point 
Day –1 
Days 0–9 
Pre –24 h 
Pre-dose (0 h) 
Within 75 min before 
–24 h to –23.5 h 
Up to and including 
30 min after the 
morning dose 
± 5 min 
After –23.5 h to –20 h 
After 30 min to 4 h 
after the morning 
dose 
± 10 min  
After –20 to –12 h 
After 4 h to 24 h 
after the morning 
dose 
± 15 min 
NA 
more than 24 h 
after the morning 
dose 
± 1 hour2 
1. Urine collection for laboratory safety tests will be within 2 h of the scheduled time 
point and all pre-dose urine samples will be collected pre-dose.  
2. Deviations at outpatients visits (during Days 15 to 30) are ± 2 days, as shown in the in 
Schedule of events (Section 5) 
8.4.2. PK assessments 
Blood samples assaying the concentration of emodepside and its metabolites in 
plasma will be collected at the time points indicated in the Schedule of events 
(Section 5).  The exact date and time of PK blood sampling will be recorded in the 
CRF. 
Blood samples for PK purpose will be taken from either arm.  Samples will be 
collected either by cannulation or by venepuncture.  After processing, samples will be 
frozen and transported on dry ice to the Bioanalysis Laboratory.  Detailed instructions 
for collection, processing, storage, and transport of samples will be provided in the 
Study Procedures Manual.  Blood volumes for PK samples are shown in 
Section 8.4.4.   


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Plasma will be analysed for emodepside using a validated assay method.  Full details 
of the method will be presented in a separate document and all the results will be 
reported in the bioanalytical report at the end of the study.  On Profile Days (Day 0 
and Day 9), frequent blood samples will be collected for PK estimation and 
emodepside plasma concentrations.  On each treatment period, the following PK 
parameters of emodepside will be derived for each subject: 
Single Dose Day 0 parameters 
AUC12  
 The area under the concentration-time curve from time zero 
(pre-dose) to 12 h will be calculated using a trapezoidal method. 
AUC24  
 The area under the concentration-time curve from time zero 
(pre-dose) to 24h will be calculated using a trapezoidal method. 
AUC12/D  
 The area under the concentration-time curve from time zero (pre-
dose) to 12 h, corrected for dose 
AUC24/D  
 The area under the concentration-time curve from time zero (pre-
dose) to 24h, corrected for dose 
AUC12,norm  
The area under the concentration-time curve from time zero 
(pre-dose) to 12 h corrected by dose and body weight 
AUC24,norm  
The area under the concentration-time curve from time zero (pre-
dose) to 24h corrected by dose and body weight 
Cmax  
The observed maximum plasma concentration measured in a 
subject after dosing identified by inspection of the drug 
concentration vs. time data. 
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. 
Cmax,norm  
The observed maximum plasma concentration corrected by dose 
and body weight 
tmax  
 The time at which Cmax was apparent, identified by inspection of 
the drug concentration vs. time data. 
MRTlast 
 Mean Residence Time from time zero (pre-dose) to the time of 
last quantifiable concentration will be calculated using  
t
t
t
AUC
AUMC
MRT 
 
 
Where AUMCt is the area under the first moment of the 
concentration-time curve from time zero (pre-dose) to the time of 
last quantifiable concentration 
Vz/F  
 Apparent volume of distribution will be calculated using the 
following formula: 



AUC
Dose
F
V
z
z

/
 
Multiple Dose Day 9 parameters 


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λz  
 The terminal rate constant will be estimated by log-linear 
regression analysis on data points visually assessed to be on the 
terminal log-linear phase. 
t1/2  
 The terminal half-life will be calculated according to the following 
equation:  t1/2 = ln2 / λz. 
t1/2,dom 
 The dominant half-life will be calculated from the terminal slope 
of the log concentration-time (0-24h) curve according to the 
following equation:  t1/2,dom = loge2 / λz 
AUClast  
 The area under the concentration-time curve from time zero (pre-
dose) to the time of last quantifiable concentration will be 
calculated using a trapezoidal method. 
AUClast/D  
 The area under the concentration-time curve from time zero (pre-
dose) to the time of last quantifiable concentration, corrected for 
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 
AUC12 
Area under the plasma concentration-time curve during a 12 h 
dosing interval  
AUC12/D  
Area under the plasma concentration-time curve during a 12 h 
dosing interval corrected for dose 
AUC12,norm  
Area under the plasma concentration-time curve during a 12 h 
dosing interval corrected by dose and body weight 
AUC24 
Area under the plasma concentration-time curve during a 24 h  
dosing interval  
AUC24/D  
Area under the plasma concentration-time curve during a 24 h  
dosing interval corrected for dose 
AUC24,norm  
Area under the plasma concentration-time curve during a 24 h 
dosing interval corrected by dose and body weight 
AUC∞  
The area under the plasma drug concentration vs. time curve 
from time zero to infinity. 
AUC∞/D  
The area under the plasma drug concentration vs. time curve 
from time zero to infinity, corrected for dose. 
AUC∞,norm  
The area under the concentration-time curve from time zero to 
infinity corrected by dose and body weight 
%AUCextrap 
Percentage of AUC∞ extrapolated from from tlast to infinity, using 
the following formula 





AUC
AUC
AUC
t
extrap
100
%
 
Cmax,ss  
The observed maximum plasma concentration measured in a 
subject at steady state, identified by inspection of the drug 
concentration vs. time data. 
Cmax,ss/D  
The observed maximum plasma concentration measured in a 


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subject at steady state, identified by inspection of the drug 
concentration vs. time data, corrected for dose. 
Cmax,ss,norm  
The observed maximum plasma concentration at steady state, 
corrected by dose and body weight 
tmax  
 The time at which Cmax was apparent, identified by inspection of 
the drug concentration vs. time data. 
MRT∞  
 The mean residence time extrapolated to infinity 
CLss/F  
Apparent total clearance from plasma at steady state will be 
calculated using the following formula: 

AUC
Dose
F
/
CLss
 
Vz/F  
 Apparent volume of distribution will be calculated at steady state 
using the following formula: 



AUC
Dose
F
V
z
z

/
 
RA(Cmax) 
Accumulation ratio for Cmax, calculated from Cmax at steady state 
and Cmax after single dose 
RA(AUCtau) 
Accumulation ratio for AUCtau, calculated from AUCtau at steady 
state and AUCt after single dose, where t = tau. 
Steady state (days 1 – 9) 
Ctrough 
Trough plasma concentration (measured concentration at the 
end of a dosing interval at steady state [taken directly before 
next administration]) obtained directly from the concentration-
time data. 
8.4.3. PD assessments 
Blood samples for the determination of levels of glucose, insulin, glucagon and 
cortisol, and prolactin and leptin (Days 1 and 9 only) will be collected from each 
subject during the study, at the time points indicated in the Schedule of events 
(Section 5).  In addition, glucose and insulin measurements will be used in the OGTT 
on Days –2, 1, 8 and 120.  
The exact date and time of sampling will be recorded in the CRF.  Blood volumes for 
those samples are shown in Section 8.4.4. 
Collection of samples for pharmacodynamic assessments:  Blood for glucose, insulin, 
cortisol, prolactin and leptin will be collected in serum-separating tubes (SST) with a 
gelatin plug.  Samples will then be transferred to the laboratory.  


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8.4.4. Total blood volume  
The blood volume planned to be collected from each subject during the course of this 
study is detailed in Table 4 .  Additional samples may be required in the event of 
AEs.  The total blood volume to be taken during the study will be 538.5 mL. 
Additional blood may need to be collected for assay of emodepside, its metabolites, 
or for laboratory safety tests.  No more than an extra 50 mL blood will be taken. 
After collection, samples (blood and urine) may be stored for up to approximately 
12 months after end of study before being destroyed.   
Table 4 .  Blood volumes for Cohorts 1–3 
Test 
Planned 
number of tests 
Volume  
(mL) 
Total planned 
blood volume 
(mL) 
Haematology 
14 
2 
28 
Hb1Ac 
2 
2 
4 
Biochemistry 
including free T3 
and T4, and glucose 
40 
2.5 
100 
Coagulation 
14 
3 
42 
Serology  
1 
2.5 
2.5 
Insulin, cortisol and 
prolactin 
23 
2.5 
57.5 
Glucagon 
22 
2 
44 
Leptin 
2 
2.5 
5 
Emodepside PKa 
45 
3  
135 
Metabolites of 
emodepside  
26 
5 
130 
 
 
Total 
548 mL 
a optional samples can be taken from PK blood collections in up to 3 cohorts, to cover a whole PK 
profile.  Those samples may be retained for possible future bioanalytical method development.  No 
additional blood will be collected for those optional samples. 
After each blood sample, the cannula will be flushed with 3–5 mL normal saline, to 
keep it patent.  In order to minimise dilution of each subsequent blood sample with 
normal saline, the following procedure will be used:  about 2 mL will be drawn via the 
cannula into the sampling syringe, and immediately re-injected gently via the 
cannula.  The definitive blood sample will be taken after a 10-second delay. 
8.5. 
Assessment of Safety  
Safety of the treatments will be assessed through routine monitoring of AEs.  
From screening (for AE onset after the subject signs the ICF), daily during the 
in-patient phase, then at each visit, and at the Follow-Up and long-term follow-up 
Visits, the patients will be asked about current AEs or any events observed during 
the period previous to the visit.  
In addition, 12-lead ECG recording, regular measurement of vital signs and 


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neurological and physical examinations, ophthalmological evaluation, clinical 
laboratory parameters monitoring, will be made at scheduled follow-up visit. (see 
Section 8.6.1 for AE recording and reporting) and as described below.  At long-term 
follow-up visits, there will be a short physical examination and clinical laboratory 
parameters will be monitored. 
8.5.1. 12-lead ECG Safety recording 
Standard 12-lead ECGs will be recorded as per the Schedule of events in Section 5.  
Most will be single readings, but where triplicate ECGs are specified, 3 repeat ECGs, 
with a time difference of about 1 minute between them, will be captured.  Instructions 
for recording and handling of the ECGs will be included in the Study Procedures 
Manual.  Any ECG abnormality confirmed by repeat will be assessed for clinical 
significance and if so reported as an AE (see AE definition in Section 8.6.1).  If out of 
range at screening, the ECG may be repeated once. 
8.5.2. Vital signs 
Blood pressure and heart rate will be measured, in the supine position after 
10 minutes rest, at times detailed in the Schedule of events (Section 5). 
Oral temperature will be measured at screening and on Day 1 (24 h before the 
morning dose on Day 0). 
Blood pressure and heart rate will be measured using using SpaceLabs oscillometric 
equipment. 
Oral temperature will be measured using oral thermometers 
During the trial, vital signs will be repeated if they fall outside the following ranges: 
 Supine systolic BP:   
90–140 mm Hg 
 Supine diastolic BP:   40–90 mm Hg 
 Supine heart rate:   
40–100 beats/min 
 Oral temperature:   
35.5–37.8°C 
If the result of the repeat measurement is still out of range, the Investigator will make 
an assessment of clinical significance (if the abnormality is assessed as clinically 
significant, it will be reported as an AE) and decide on an appropriate course of 
action.  If out of range at screening, vital signs may be repeated once. 
8.5.3. Neurological and physical examination  
Physical examination: will be done by a physician.  The following will be examined:  
general appearance; head, ears, eyes, nose and throat; thyroid; lymph nodes; back 
and neck; heart; chest; lungs; abdomen; skin; and extremities; and the following 
systems will be assessed:  musculoskeletal and neurological (see below).  
Height and body weight will also be measured (at screening) and body weight only 
on the morning of Day 1.  At certain time points, as detailed in the Schedule of 
events (Section 5), a short physical examination will be performed (to be detailed in 
the Study Procedures Manual). 
Neurological examination will be done by a physician, and will include the following:  


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alertness, speech, language, and comprehension; cranial nerves; motor exam; 
coordination/cerebellar function; tremor of the hands, legs and head (postural, kinetic 
and rest tremor); sensation; gait and postural stability (Pull test); mood; and 
sleepiness.  Full details of the full and short neurological exams will be in the Study 
Procedures Manual.  Abnormalities assessed as clinically significant will be reported 
as AE (see AE definitions in Section 8.6.1). 
8.5.4. Ophthalmological examination (Screening Visit 2 and Day 10) 
For Screening Visit 2, subjects will attend a specialist eye hospital for ophthalmology 
assessments (see Section 8.3.2) to be performed by a Consultant Ophthalmologist 
(and described in the Study Procedures Manual). 
Subjects will be informed that they will need to bring their distance glasses (if 
applicable) and that, at Screening Visit 2, their near vision will be blurred for 
approximately 2 h (due to the use of mydriatic eye drops) following the eye-testing 
procedures.  Abnormalities assessed as clinically significant will be reported as AE 
(see AE definitions in Section 8.6.1).   
Subjects will also have an ophthalmological assessment on Day 10.  
8.5.5. Clinical Laboratory Safety Assessments 
Processing of samples will be done by the HMR Analytical Laboratory in accordance 
with the laboratory’s standard operating procedures, and additional information may 
be found in the Study Procedures Manual.  
The HMR Analytical Laboratory will do safety tests on blood and urine samples using 
instruments interfaced to a validated laboratory information management system 
(LIMS).  Confirmed abnormal laboratory results (after repeat) will be assessed for 
clinical significance (CS; see CS assessment below) and reported as AEs if 
necessary (see AE definition in Section 8.6.1). Data from analysers that are not 
interfaced will be entered manually into the LIMS. 
Collection of samples for laboratory safety tests:  Blood will be taken for 
haematology (2 mL in EDTA), and biochemistry and serology (2 × 2.5 mL in tubes 
with a gelatin plug).  Blood will be taken to measure Hb1Ac (2 mL in EDTA), and for 
coagulation (3 mL in sodium citrate).  Blood samples will be collected into 
13 × 75 mm tubes.  Urine will be collected in Universal containers.  Samples will then 
be transferred to the laboratory. 
Laboratory abnormalities considered AEs: 
Laboratory abnormalities assessed as "clinically significant" have to be reported as 
an AE (refer to AE definition in section 8.6.1) only if they meet at least one of the 
following conditions: 
 The abnormality suggests a disease and/or organ toxicity AND this 
abnormality was not present at the screening visit, or is assessed as 
having evolved since the screening visit 
 The abnormality results in discontinuation of the study drug 
 The abnormality requires medical intervention or concomitant therapy 


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When reporting an abnormal laboratory result, a clinical diagnosis should be 
recorded rather than the abnormal value itself, if available (for example, "anaemia" 
rather than "decreased red blood cell count") 
8.6. 
Adverse Event definitions and reporting 
8.6.1. Adverse Event definitions 
An adverse event will be defined as: 
Any untoward medical occurrence in a clinical trial subject administered a medicinal 
product, and which does not necessarily have a causal relationship with that 
treatment.  An AE can therefore be any unfavourable and unintended sign (eg.  an 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal 
product.  
Furthermore the definition of an AE includes worsening (in severity and frequency) of 
pre-existing conditions ("Medical history") before first Investigational Medicinal 
Product (IMP) administration and abnormalities of procedures (ie,, ECG, X-ray, 
ophthalmologic or neurological examination etc.) or laboratory results which are 
assessed as "clinically significant".  Information on AEs must be evaluated by a 
physician.   
What is not an AE? 
 Medical conditions present at the initial study visit that do not worsen in 
severity or frequency during the study are NOT considered as AEs. 
8.6.2. Serious Adverse Event (SAE)  
An AE will be defined as serious if it is  
 results in death 
ie Causes or contributes to the death. 
 is life-threatening 
Refers to an AE in which the subject was at risk of death at the time of the 
AE; it does not refer to an AE that hypothetically might have caused death 
if more severe. 
 requires in-patient hospitalisation or prolongation of existing 
hospitalisation 
ie The AE requires at least an overnight admission or prolongs a 
hospitalisation beyond the expected length of stay.  Hospital admissions 
for surgery planned before study entry, for social reasons, for any elective 
surgery (ie.  plastic surgery) or per protocol or for normal disease 
management ( (including treatment adjustment) are NOT to be considered 
as SAE according to this criterion (ie.  if the protocol requires planned 
hospitalisation). 
 results in persistent or significant disability or incapacity 
ie The AE resulted in a substantial disruption of the subject’s ability to 
conduct normal activities. 


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 is an important medical event, i.e. is medically significant. 
Medical and scientific judgment should be exercised in deciding whether 
other situations should be considered serious events/reactions, such as 
important medical events that might not be immediately life-threatening or 
result in death or hospitalisation, but might jeopardise the subject or might 
require intervention to prevent one of the other outcomes listed above.   
Any suspected transmission via a medicinal product of an infectious agent 
is also considered a serious AE/reaction. 
 
8.6.3. Eliciting Adverse Event information 
The Investigator is required to report all directly observed AEs and all AEs 
spontaneously reported by the trial subject using concise medical terminology.   
In addition, each trial subject will be questioned about the occurrence of AEs using 
non-leading questions (eg.  “How are you feeling?”), at times specified in the 
Schedule of events (Section 5).  
Each AE will be assessed for severity, and causality (see definitions in Section 8.6.6 
and 8.6.7).  In addition, each AE is to be classified by the Investigator as serious or 
non-serious (see definition in Section 8.6.2).  This classification will determine the 
reporting procedure for the event (see Section 8.6.5). 
Information on AEs must be evaluated by a physician.  Each AE is to be classified by 
the Investigator as serious or non-serious.  This classification will determine the 
reporting procedure for the event. 
Non-serious AEs are to be reported on the CRF, which is to be submitted to DNDi as 
specified in Section 12.2.  In the CRF, a given AE will be recorded only one time per 
subject, and the severity recorded will be the maximum level reached.  If several 
distinct episodes of the same condition occur, their number will be recorded in the 
CRF. 
SAEs will be reported both on the AE CRF and the SAE forms. 
8.6.4. Adverse Event reporting period 
The AE reporting period begins upon subject enrolment in the trial (after signature of 
the ICF) and ends at the last Long-term Follow-up Visit (Day 120 ±2 days).   
All AEs that occur during the AE reporting period specified in the protocol must be 
reported to DNDi, whether or not the event is considered medication related.  In 
addition, any AE that occurs subsequent to the AE reporting period that the 
Investigator assesses as possibly related to the investigational medicinal product 
should also be reported as an AE. 
8.6.5. Serious Adverse Event reporting requirements 
All serious adverse events (SAE) are to be reported immediately (within 24 
hours of awareness of SAE by the Investigator) to the Sponsor Clinical Team 
(via SAEEMOHVstudies@dndi.org), and to DNDi Pharmacovigilance (via 
pharmacovigilance@dndi.org), using the SAE report form.  This includes a 


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description of the event, onset date and type, duration, severity, relationship to study 
drug, outcome, measures taken and all other relevant clinical and laboratory data.  
The initial report is to be followed by submission of additional information (follow-up 
SAE form) as it becomes available.  Any follow-up reports should be submitted as 
soon as possible, and if possible within 5 working days.  
SAEs should also be reported on the clinical trial AE case report form (CRF).  It 
should be noted that the form for reporting of SAE (SAE form) is not the same as the 
AE section of the CRF.  Where the same data are collected, the two forms must be 
completed in a consistent manner, and the same medical terminology should be 
used. 
In addition to immediately reporting SAEs to DNDi, the Investigator will 
immediately notify the Research Ethics Committee (REC) of serious adverse 
events that occur during this trial, if applicable, in accordance with the standard 
operating procedures issued by the Research Ethics Service (RES). 
A suspected unexpected serious adverse reaction (SUSAR) is a suspected 
adverse reaction related to an investigational medicinal product (as defined in 
Section 8.6.7) that is both unexpected and serious.  
DNDi is responsible for determining the expectedness of the event, using the 
reference safety information in the Investigator's Brochure.  DNDi will notify the 
Medicines and Healthcare products Regulatory Agency (MHRA) and the European 
Medicines Agency (EMA) of all SUSARs, and will be responsible for ensuring that the 
REC is notified of SUSARs, if applicable. 
 
SUSARs that are fatal or life-threatening must be notified to the 
MHRA/EMA and REC within 7 calendar days after DNDi becomes aware 
of the event.  Follow-up reports should be provided within another 8 
calendar days. 
 Other SUSARs must be reported to the REC and MHRA/EMA within 15 
days after DNDi becomes aware of the event. 
8.6.6. Grading of Adverse Event severity 
The Investigator will use the terminology MILD, MODERATE, or SEVERE to describe 
the maximum severity of the AE. This information will be entered in the AE case 
report forms. For purposes of consistency, these severity grades are defined as 
follows:  Severity is a clinical determination of the intensity of an AE to describe its 
maximum severity.  Please note the distinction between severity and seriousness of 
AEs.  A severe AE is not necessarily a serious AE.   
MILD 
Does not interfere with subject's usual functions.  The subject is 
aware of the event or symptom, but the event or symptom is 
easily tolerated (eg. no reduction in daily activities is required). 
MODERATE 
Interferes to some extent with subject's usual functions.  The 
subject experiences sufficient discomfort to interfere with or 
reduces his or her usual level of activity. 
SEVERE 
Interferes significantly with subject's usual functions.  The 
subject is unable to carry out usual activities and/or the subject's 
life is at risk from the event. 


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8.6.7. Adverse Event causality assessment  
For both serious and non-serious AEs, the Investigator is required to assess if there 
is a causal relationship between the AE and the study drug, ie. to determine whether 
there exists a reasonable possibility that the study drug caused or contributed to 
the AE.   
To help Investigators with the decision binary tree in the evaluation of causality, the 
CIOMS VI group recommends that Investigators be asked to consider the following 
before reaching a decision: 
 Medical history (including presence of risk factors) 
 Lack of efficacy/worsening of existing condition 
 Study medications 
 Other medications (concomitant or previous) 
 Withdrawal of study medication, especially following trial discontinuation / end 
of study medication 
 Erroneous treatment with study medication (or concomitant) 
 Protocol related procedure 
The decision to suspend, resume, or permanently interrupt treatment due to an AE 
will be left to the clinician in charge. 
The following categories for relationship to treatment will be used during AE 
reporting: 
Related  
There is at least a reasonable possibility of a causal relationship 
between an AE and an investigational medicinal product.  This 
means that there are facts (evidence) or arguments to suggest 
a causal relationship. 
Not related   
There is no reasonable possibility of causal relationship. 
The following categories will be used to document outcome of each AE: 
Action taken: 
  
None, drug treatment, subject withdrawn, other (specified). 
Outcome: 
 Completely recovered; recovered with sequelae; ongoing; death; 
unknown    
8.6.8. Exposure in utero 
Not applicable for this trial (subjects are all male).  Study subjects must use 
contraceptive method (condoms) from first dose of study drug to 120 days after the 
last dose of study drug. 
Should their female partner become pregnant despite this preventive measure, the 
following instructions must be followed:  
All pregnancies started in partners of trial subjects within 120 days after 
administration of the last dose of IMP to the study male healthy subject, should be 
reported using the Pregnancy form (as per the same process and timelines for SAEs) 
and consent from the subject’s partner sought to follow-up the outcome for the new 


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born (up to the age of 2 years).   
This must be done irrespective of whether an AE has occurred.  The information 
submitted should include the anticipated date of delivery. 
The investigator will follow the subject’s partner until completion of the pregnancy or 
until pregnancy termination (ie.  induced / spontaneous abortion).  The investigator 
will provide pregnancy outcome information in the Child report form.  In the case of a 
live birth, a paediatrician should assess the infant at the time of birth and submit a 
Child report, and the new born will be followed up to the age of 2 years. 
Pregnancies are not considered to be a SAE.   
An SAE should be declared in the case of unfavourable pregnancy outcome 
(abortion, still birth) or congenital abnormality. 
In addition, pregnancies considered related to study treatment by the Investigator 
(ie.  resulting from a drug interaction with a contraceptive medication) are considered 
as AEs and should be recorded on the AE pages of the CRF.   
If this might be considered as an AE and assessed as a serious one, an SAE form is 
to be completed in addition to these two forms.  
8.6.9. Adverse event follow up 
All AEs should be followed until: 
 they are resolved; or 
 the Investigator assesses them as “chronic” or “stable”; or  
 the subject participation in the trial ends (ie until their follow-up visit is 
complete, or otherwise the last contact with the subject).  
In addition, all SAEs (related or not), and those non-serious events assessed by the 
Investigator as having a reasonable possibility of relationship to the investigational 
drug, must continue to be followed even after the subject participation in the trial is 
over.  Such events should be followed until they resolve or until the Investigator 
assesses them as “chronic” or “stable.”  The outcome of these events is to be 
documented on the CRF and SAE form (if required). 
9. Withdrawal criteria 
Subjects may withdraw from the study at any time at their own request, or they may 
be withdrawn at any time at the discretion of the Investigator or Sponsor for safety, 
behavioural, or administrative reasons. 
If a subject does not return for a scheduled visit, every effort should be made to 
contact the subject.  In any circumstance, every effort should be made to document 
subject outcome, if possible. 
If the subject withdraws consent, no further evaluations should be performed and no 
attempts should be made to collect additional data, with the exception of safety data, 
which should be collected if possible and in accordance with subject consent.  The 
Sponsor may retain and continue to use any data collected before any withdrawal of 


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consent.  However if the subject consents to follow-up but asks the Investigator to 
destroy all identifiable samples taken from the subject and/or not enter into the CRF 
results of the follow-up examinations, the Investigator will comply with the subject’s 
requests. 
If a subject withdraws from the study, the reason must be noted in the source 
documents and on the CRF.  If a subject is withdrawn from the study because of a 
treatment limiting AE, thorough efforts should be made to clearly document the 
outcome of that AE. 
The Investigator should inquire about the reason for withdrawal, and request the 
subject to return for a final visit, if applicable, and follow-up with the subject regarding 
any unresolved AEs. 
It may be appropriate for the subject to return to the clinic for final safety 
assessments which may include all assessments normally scheduled for the study 
Follow-Up Visit (Day 30 ±2 days) (See the Schedule of events (Section 5)). 
Subjects who withdraw, or are withdrawn from the study may be replaced at the 
discretion of the Investigator upon consultation with the Sponsor. 
For any subject who meets any of the following criteria, the subject will be 
withdrawn from the study drug  and followed up until resolution of the adverse 
event.   
 ALT ≥ 5 x Upper Limit of Normal (ULN). 
 ALT ≥ 3 x ULN and total bilirubin ≥ 2 x ULN or international normalised 
ratio (INR) > 1.5 x ULN.  (If a subject meets that withdrawal criterion, 
serum bilirubin fractionation should be performed.) 
 ALT ≥ 3 x ULN if associated with the appearance or worsening of rash or 
hepatitis symptoms (fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash or eosinophilia).   
Note that all AEs must nevertheless be reported and followed-up as per 
Section 8.6(unless the subject withdraws consent for further assessments). 
Subjects who have ALT ≥ 3 x ULN and < 5 x ULN, and total bilirubin 2 x ULN, who do 
not exhibit hepatitis symptoms or rash, must not receive another dose of IMP, but 
can continue in the study and be monitored until the last long-term Follow-Up visit, or 
followed up until resolution of the adverse event, as specified in Section 8.6.9, 
whichever applies. 
Furthermore, the Investigator may withdraw a subject for the following 
reasons: 
 AEs that are considered by the Investigator to be related to trial 
medication and meet one of the following 2 criteria: 
 serious or severe; or 
 otherwise clinically significant, such as signs of allergic reaction or 
important bleeding events 
 Clinically significant intercurrent illness which could compromise the safety 
of the subject or the scientific value of the trial 
 Need for, or use of, contraindicated medication which could compromise 


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the safety of the subject or the scientific value of the trial 
 Withdrawal of consent 
 Significant non-compliance of the subject with the requirements of the trial 
If a subject is withdrawn, the Investigator will make all necessary arrangements to 
ensure that the subject receives the appropriate treatment for the relevant medical 
condition. 
A subject should be withdrawn from the study treatment if, in the opinion of the 
Investigator, it is medically necessary, or if it is the wish of the subject.  
10. Data Analysis and Statistical Methods 
Detailed methodology for summary and statistical analyses of the data collected in 
this study will be documented in a Statistical Analysis Plan.  This document may 
modify the plans outlined in the protocol; however, any major modifications of the 
primary endpoint definition and/or its analysis will also be reflected in a protocol 
amendment. 
10.1. 
Sample size determination 
No formal statistical sample size estimation has been performed, due to the 
exploratory nature of this study.  
Missing data will be described in the Statistical Analysis Plan (SAP). 
6 subjects per dose level (cohort) is considered sufficient to examine the safety and 
tolerability of emodepside, as well as the pharmacokinetics after single and multiple 
doses.  Subjects who withdraw, or are withdrawn from the study, may be replaced at 
the discretion of the investigator upon consultation with the sponsor. 
Interim analyses will be performed:  after each dose, a safety assessment will be 
made using the primary PK parameters, AEs, vitals, ECGs, safety lab 
measurements, glucose and insulin measurements, and any abnormal findings.  An 
additional interim analysis (including interim database lock) will be performed after 
Cohorts 1 and 2 have completed, to evaluate the progression into later phase 
studies. 
In each cohort of up to 8 subjects, 6 are randomised to emodepside and 2 are 
randomised to placebo. 
10.2. 
Definition of study populations included in the analysis 
The following population sets will be identified:  
 Safety Population:  All subjects who received at least one dose of IMP.  
 PK Concentration Population:  All subjects who received at least one dose of 
IMP and for whom a pharmacokinetic sample has been analysed.  
 PK Parameter Population:  All subjects in the PK Concentration Population for 
whom pharmacokinetic parameters can be derived.  


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In all populations, treatment will be assigned based upon the treatment subjects 
actually received, regardless of the treatment to which they were randomized.  
General considerations for data analyses 
The minimum set of summary statistics for numeric variables will be:  n, mean, 
standard deviation (or standard error), median, minimum, and maximum.  95% 
confidence intervals will be presented where appropriate for data interpretation.  
Categorical data will be summarised in frequency tables with n and percentage.  
Summaries of a categorical variable will include all recorded values. 
The minimum and maximum values will be presented to the same number of decimal 
places as the raw data collected on the CRF (or to 3 significant figures for derived 
parameters).  The mean, median and percentiles (eg Q1, and Q3) will be presented 
to one additional decimal place.  The standard deviation and standard error will be 
presented to 2 additional decimal places.  
10.3. 
Subject Disposition  
The disposition of all subjects in the safety population will be summarized including: 
number of subjects randomized; number completing the study, by treatment; and 
number discontinued from the study. The number of subject in each analysis 
population will be summarized by treatment 
All subjects who withdraw or are withdrawn from the study will be listed, by treatment, 
with the reason for withdrawal. 
10.4. 
Efficacy Analysis 
Not applicable 
 
10.5. 
Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics (eg medical history, physical examination, 
vital signs, weight, ECGs and ophthalmology results) will be summarised.  
Subjects who take concomitant medication will be listed.  All non-trial medication will 
be coded using the World Health Organisation Drug Dictionary (WHO DD). 
Medical history will be coded using the version of the Medical Dictionary for 
Regulatory Activities (MedDRA current at the time of database lock. 
10.6. 
Safety Analysis 
Safety and tolerability data will be summarized using the following parameters:  
• 
Vital signs; 
• 
12-lead ECG; 
• 
Haematology; 
• 
Clinical chemistry; 
• 
Coagulation; 


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• 
Urinalysis; 
• 
Physical examination; 
• 
Neurological examination; 
• 
Ophthalmology assessments; 
• 
AEs. 
No formal hypothesis testing of these parameters will be carried out. 
10.6.1. 
Vital signs, 12-lead ECG safety parameters 
Vital signs at each planned assessment, and change in vital signs from baseline at 
each planned post baseline assessment (with or without potential clinical 
significance), will be summarised by actual treatment.  
Vital signs of potential clinical importance will be listed separately.  
QT interval will be corrected using Bazett's (QTcB) and Fridericia's (QTcF) formulae.   
ECG variables of clinical significance will be summarised by treatment and time point.  
Differences from baseline will be summarised by treatment and time point. 
QT, QTcB or QTcF > 450 msec  and increases in QT, QTcB or QTcF from baseline 
(Day 0 pre-dose) of > 30 msec will be considered to be potentially clinically important.  
The number of subjects with a potentially clinically important QT, QTcB or QTcF will 
be summarised by actual treatment and time point, giving the numbers of subjects 
with QT, QTcB or QTcF > 450 msec, > 480 msec and > 500 msec, and the numbers 
of subjects with increases in QT, QTcB or QTcF from baseline of > 30 msec and 
> 60 msec (ICH Tripartite Guideline, 1998).   A supporting listing of all subjects with 
an ECG value of potential clinical importance, and a separate listing of ECG findings 
classified as abnormal by the investigator, will also be provided. 
10.6.2. 
Haematology and Clinical Chemistry Parameters   
Data from haematology, coagulation and clinical chemistry will be summarised by 
treatment.  
Any laboratory value outside the reference interval for that variable will be flagged 
with an ‘H’ if it is higher than the reference interval, and with an ‘L’ if it is lower. 
Additionally, if, during the course of the trial, a variable changes from baseline by 
more than a predetermined amount (as defined by the Principal Investigator), that 
value will receive a flag ‘I’ if increased, or ‘D’ if decreased. Therefore, if a value both 
falls outside the reference interval and alters from the baseline value by more than 
the predetermined amount, it will attract a double flag and will be considered to be 
potentially clinically important. 
All laboratory values of potential clinical importance will be listed.  In a separate 
listing, laboratory values of potential clinical importance will be listed with all related 
laboratory results (ie haematology or clinical chemistry).  Frequencies of laboratory 
values of potential clinical importance will be summarised. 
10.6.3. 
Urinalysis parameters 
These parameters will be individually listed and summarized. 


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10.6.4. 
Physical and neurological examination 
An individual data listing of abnormal physical and neurological examination findings 
(with or without clinical significance) will be provided. 
10.6.5. 
Adverse events 
Throughout the study, all AEs observed by either medical staff or professional 
collaborators, or reported by the subject spontaneously or in response to a direct 
non-leading question, will be evaluated by the Investigator and noted in the AE 
section of the CRF, as described in Section 12.2. 
AEs will be coded using the version of the Medical Dictionary for Regulatory Activities 
(MedDRA) current at the time of database lock. 
All AEs will be listed. 
An AE will be considered as treatment emergent if it appeared after the first dosing, 
or if appeared before dosing and worsened after dosing. In case of missing onset 
date of AE or missing onset time of AE when it appeared the first dosing day, the AE 
will be considered as treatment emergent (TEAE). 
The number of subjects with at least one TEAE will be tabulated by actual treatment 
and MedDRA system organ class and preferred term.   
For each of the following, the number of AEs and the number of subjects with AEs 
will be summarised by actual treatment as follows: 
 TEAEs, by system organ class and preferred term 
 drug-related TEAEs, by system organ class and preferred term 
Subjects with more than one TEAE will be counted only once, at the maximum 
causality, for each system organ class and preferred term.  AEs with missing severity 
and/or causality will be treated as severe and possibly related, respectively. 
AEs leading to withdrawal, deaths and SAEs will be listed separately (fatal events will 
be listed separately from non-fatal events).   
10.7. 
Analysis of Human Pharmacokinetics of Emodepside 
PK concentration data will be summarised using the PK Concentration population. 
PK parameters will be summarised using the PK Parameter population.  
For log-transformed parameters, the primary measure of central tendency will be the 
geometric mean (ICH Guidance For Industry E14, 2005); for untransformed 
parameters, it will be the arithmetic mean or median. 
For all variables, N (number of subjects in receiving the treatment/formulation in the 
population), n (number of observations), arithmetic mean, median, minimum, 
maximum, SD, %CV, and the 95% confidence interval of the arithmetic mean will be 
derived.  For log transformed variables, all of the above plus the geometric mean, its 
95% confidence interval, and the SD of the log-transformed variables, will be 
provided. 
Plasma concentrations and PK parameters of emodepside and metabolite (if 
available) will be listed and summarised, by treatment, using descriptive statistics.  
Individual and mean plasma concentration–time profiles will be presented 


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graphically. 
Concentrations of emodepside and its metabolites in urine may be determined and 
the amount of emodepside excreted in the urine will be estimated, if applicable. 
 
10.8. 
Pharmacodynamic Analysis  
Pharmacodynamic variables at each planned assessment, and change in 
pharmacodynamic variables from baseline at each planned post baseline 
assessment, will be summarised by actual treatment. 
 
11. Safety Review Meetings 
Safety will be reviewed throughout the study in Safety Review Meetings.  Participants 
in the Safety Review Meeting  (‘the Safety Review Group’) will be at a minimum the 
Principal Investigator (or his/her deputy), and at least one medically-qualified 
Sponsor representative.  Optionally, independent advisor(s) may be appointed to 
advise on dose escalation decisions, if required.  Those meetings will follow DNDi 
SOP CL 26 (Safety Data Review during Phase I clinical trial) and will be described in 
the Safety Review Group charter. 
12. Quality Assurance and Quality Control Procedures 
12.1. 
Investigator’s file 
The Investigator must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified.  
These documents include Investigator’s Site File, subject clinical source documents 
and screening / enrolment logs.  The Investigator’s Site File will contain the 
protocol/protocol amendments, CRF and SAE/query forms, REC and regulatory 
approval with correspondence, sample informed consent, drug accountability 
records, staff curriculum vitae and authorization forms and other appropriate 
documents / correspondence etc.  The Investigator is responsible for storing the 
Investigator’s Site File and other study documentation in a secure location.  
12.2. 
Case report forms (CRFs) 
Data will be collected by authorized staff at the clinical site. It will be supervised by 
the Investigator and signed by the Investigator or by an authorized staff member. 
After informed consent, data for all screened subjects will be recorded in either the 
panel screening case report form (CRF) or the screening section of the study-specific 
CRF and additional source documents.  The CRF is the source document for the 
majority of recorded data. Source documents other than the CRF will be defined in 
the Source Data Agreement. 
For subjects who are subsequently randomized, study-specific information will be 
entered into the CRF.  All CRF data should be anonymized, ie, identified by study 
subject number only.  
The Investigator at each trial site should ensure the accuracy, completeness, 
legibility, and timeliness of all data reported to the sponsor in the CRFs and any other 
additional information that is required.  The Investigator is responsible for keeping all 


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consent forms, screening forms, CRF and the completed subject identification code 
list in a secure location.  
Data from subjects who are screening failures, or from enrolled subjects who leave 
the study before randomization will be recorded in the CRF but not entered into the 
Database.  
12.3. 
Source documents 
The verification of the CRF/SAE/pregnancy/child and query data must be by direct 
inspection of source documents.  Source documents include subject hospital/clinic 
records, physician's and nurse's notes, appointment book, original laboratory reports, 
ECG, X-ray, pathology and special assessment reports, signed informed consent 
forms, consultant letters, and subject screening and enrolment logs. 
The Investigator must maintain source documents such as laboratory and 
consultation reports, history and physical examination reports, etc., for possible 
review and/or audit by DNDi and/or Regulatory Authorities.  The Investigator / 
designee will record the date of each subject’s visit together with a summary of their 
status and progress in the study. 
12.4. 
Record Retention 
The Investigator must keep all study documents on file for at least 25 years after 
completion or discontinuation of the study.  After that period of time the documents 
may be destroyed with prior permission from DNDi, subject to local regulations. 
Should the Investigator wish to assign the study records to another party or move 
them to another location, DNDi must be notified in advance. 
12.5. 
Monitoring, audits and inspections 
Monitoring visits to the trial site will be made periodically by DNDi representatives or 
designated clinical monitors to ensure that GCP and all aspects of the protocol are 
followed.  Source documents will be reviewed for verification of consistency with data 
on CRFs, and SAE/pregnancy/child and query forms.  The Investigator will ensure 
direct access to source documents by DNDi or designated representatives.  It is 
important that the Investigators and their relevant personnel are available during the 
monitoring visits. 
The Investigators will permit representatives of DNDi and/or designated clinical 
monitors to inspect all CRFs, medical records, laboratory work sheets and to assess 
the status of drug storage, dispensing and retrieval at any time during the study.  The 
corresponding source documents for each subject will be made available provided 
that subject confidentiality is maintained in accordance with local regulations.  The 
inspections are for the purpose of verifying the adherence to the protocol and to 
ensure the study is conducted according to GCP.  It is important that the 
Investigators and other trial site staff are available at these visits. 
The monitoring visits provide DNDi with the opportunity to evaluate the progress of 
the study, verify the accuracy and completeness of CRFs and 
SAE/pregnancy/child/query forms, resolve any inconsistencies in the study records, 
as well as to ensure that all protocol requirements, applicable regulations, and 


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Investigator's obligations are being fulfilled.  Four visit types are planned: pre-study, 
study start, during the study, and study end.  Visits may also be performed by 
regulatory authorities. 
It will be the clinical monitor’s responsibility to inspect the CRF and 
SAE/pregnancy/child/query forms at regular intervals throughout the study, to verify 
the adherence to the protocol and the completeness, consistency and accuracy of 
the data being entered on them.  The Investigator agrees to cooperate with the 
clinical monitor to ensure that any problems detected in the course of these 
monitoring visits are resolved. 
12.6. 
Audits and inspections 
The trial site may also be subject to quality assurance audits by DNDi or designated 
representatives and/or to inspection by regulatory authorities or Research Ethics 
Committees (REC). 
The Investigators will permit representatives of DNDi and/or designated clinical 
monitors to inspect all CRFs/SAE/pregnancy/child/query forms, medical records, 
laboratory work sheets and to assess the status of drug storage, dispensing and 
retrieval at any time during the study.  The corresponding source documents for each 
subject will be made available provided that subject confidentiality is maintained in 
accordance with local regulations. 
It is important that the Investigators and their relevant personnel are available for 
possible audits or inspections. 
12.7. 
Data Management   
The data will be securely stored within HMR. 
After the CRF has been completed and monitored by the clinical monitor, CRFs will 
be collected and data will be entered onto a database using double independent data 
entry.  The trial data will be stored in a computer database maintaining confidentiality 
in accordance with national data legislation. 
Only data from Randomised subjects will be entered in to the clinical database. 
Data will be double-entered into a clinical database management system (ClinPlus).  
Edit checks and generation of queries will be done in ClinPlus.  Tabulations and 
listings will be produced using validated, trial-specific SAS programs.  
The database will be locked after all the following have been completed:  all expected 
CRF data have been entered and accounted for; all discrepancies have been 
resolved; data have been coded as appropriate; SAEs have been reconciled 
between the clinical database and DNDi safety database; all site audit findings 
impacting the database have been closed; and QC inspection has been completed.  
Data in source documents will be checked by the HMR QA Department.  In addition, 
the HMR QA Department will audit the trial report; that audit will include checks to 
ensure that statistical output is correctly reproduced in the report.  If requested, the 
investigator will provide the sponsor, MHRA, and REC with direct access to the 
original source documents. 
12.8. 
Confidentiality of trial documents and subjects records 


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The Investigator must assure that subjects’ anonymity will be maintained and that 
their identities are protected from unauthorized parties.  On CRFs or other 
documents submitted to the Sponsor, subjects should not be identified by their 
names, but exclusively by an identification code.  The Investigator should keep a 
subject enrolment list showing codes, names, and addresses.  The Investigator 
should maintain documents for submission to Sponsor authorized representative, 
and subject’s signed written consent forms, in strict confidence.  
13. Protocol Deviations and Amendments 
The Principal Investigator will ensure that the study protocol is strictly adhered to 
throughout, and that all data are collected and recorded correctly on the CRF.   
After the protocol has been approved by the main REC and the Regulatory Authority 
(MHRA), no changes may be made without the agreement of both the Investigator 
and the Sponsor.  All protocol modifications must be documented in writing.  Any 
protocol amendment must be approved and signed by the Sponsor and the Principal 
Investigator.  It should be submitted to the appropriate REC for information and 
approval, in accordance with local requirements, and to regulatory agencies if 
required.  Approval by REC (and the Regulatory Authority, if applicable) must be 
received before any changes can be implemented, except for changes necessary to 
eliminate an immediate hazard to trial subjects, or when the change involves only 
logistical or administrative aspects of the trial (eg. change in clinical monitor[s], 
change of telephone number[s]). 
The protocol amendment can be initiated by either the Sponsor or the Principal 
Investigator.  
The Investigator will provide in writing the reasons for the proposed amendment and 
will discuss with the Sponsor.  
The standard text in the ICF template explains that the planned doses may change 
during the trial, and that subjects may be given any dose that has been approved by 
the MHRA and REC for the trial.  However, if the SRG decide to reduce the planned 
dose, HMR consider it essential to fully inform the subject why; a reduction in dose 
might be due to poor tolerability; and that might affect the subject’s decision to 
remain in the trial.  HMR will obtain prior approval from the REC for the information 
update consent form that will be given to subjects before the dose is reduced.  But, 
owing to the nature of trials on healthy subjects, sometimes an urgent amendment to 
lower the planned dose will have to be implemented, to avoid immediate hazard to 
the subjects.  In that case, subjects will be fully informed of the reason for reducing 
the dose, and HMR will notify the REC and MHRA promptly of the urgent 
amendment, in accordance with statutory requirements. 
14. Early Termination of the Study 
Premature termination of this study may occur because of a regulatory authority 
decision, change in opinion of the REC, or drug safety problems. 
Both the Sponsor and the Investigator reserve the right to terminate the study at any 
time before inclusion of the intended number of subjects, but intend to exercise this 
right only for valid scientific or administrative reasons.  Should early termination be 
necessary, both parties will arrange the procedures on an individual study basis after 
review and consultation.  In terminating the study, the Sponsor and the Investigator 


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will assure that adequate consideration is given to the protection of the subject’s 
interests. 
Reasons for early termination by the Sponsor(s) may include but not be limited to:  
 Enrolment rate is too low 
 Protocol violations 
 Inaccurate or incomplete data 
 Unsafe or unethical practices 
 Questionable safety of the test article 
 Suspected lack of efficacy of the test article 
 Following the recommendation of the Safety Review Committee or the REC 
 Administrative decision 
Reasons for early termination by the Investigator may be: 
 Insufficient time or resource to conduct the study 
 Lack of eligible subjects 
In the event that a study is terminated early, either by the Sponsor or by the 
Investigator, the Investigator must: 
 Complete all CRFs to the fullest possible extent 
 Return all test articles, CRFs, and related study materials to the Sponsor  
 Answer all questions from the Sponsors or their representatives related to 
subject data collected before the termination of the study 
 Ensure that subjects enrolled in the study who had not yet reached the Follow-
up and long-term Follow-up Visits are followed up with the necessary medical 
care. 
 Provide in writing the reasons for the decision to the national health authority 
and the Sponsor. 
15. Ethics 
The experimental protocol for this study has been designed in accordance with the 
general ethical principles outlined in the Declaration of Helsinki and ICH guidelines 
for Good Clinical Practice (International Committee for Harmonization; addendum to 
ICH E6(R1):  Guideline for Good Clinical Practice E6(R2)).  DNDi assures that it will 
comply with all applicable state, local and foreign laws for protecting the rights and 
welfare of human subjects.  This protocol and any protocol amendments will be 
reviewed / approved by an REC before its implementation.  
It is the responsibility of the Global or National Coordinating Investigator/Investigator 
to apply for review to the REC of the country where the study takes place regarding 
local rules and regulations.  Written approval from all involved RECs must be 
obtained before implementation of any protocol-specified intervention or investigation 


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provided to the subject (such as subject information sheets or descriptions of the 
study). 
Any modifications made to the protocol after receipt of the REC approval must also 
be submitted by the Investigator in writing to the REC in accordance with local 
procedures and regulatory requirements. 
All subjects must give written consent to participate in this trial.  Consent for 
screening evaluations may be obtained using the generic ICF for the HMR healthy 
volunteer panel that has been approved by London – Brent Research Ethics 
Committee and subsequently by the Generic Document Review Committee (GDRC).  
The trial-specific ICF will be signed by the subject either before any screening 
evaluation or after the Investigator confirms the eligibility of the subject for the trial, 
and before the subject is randomized to receive the first dose of IMP.  Before giving 
consent, subjects must read the information sheet about the trial. They must also 
read the consent form.  They will then discuss the trial with the Investigator or his 
deputy and be given the opportunity to ask questions.  The trial-specific information 
sheet and the consent form must be approved by the REC. 
Each subject is free to withdraw from the trial at any time, without giving a reason.  If 
a subject withdraws, the Investigator will ask the subject to consent to a follow-up 
examination.  For withdrawn subjects, the Investigator will use a special information 
and consent form which has been approved by London – Brent Research Ethics 
Committee and by the GDRC.   If the subject consents to the follow-up examination 
but asks the Investigator to destroy all identifiable samples taken from the subject 
and/or not enter into the CRF results of the follow-up examination, the Investigator 
will comply with the subject’s requests. 
The Sponsor or Investigator will ensure that the MHRA and the REC are informed 
promptly of SUSARs (see Section 8.6.5), and that any new reports of SUSARs from 
other ongoing trials of the IMPs under investigation in this trial are notified to the 
MHRA, and to the REC, if applicable.  The Sponsor will provide the Investigator, the 
REC and the MHRA with annual Development Safety Update Reports (DSURs) of 
each IMP under investigation.  The Sponsor will also inform the Investigator promptly 
of any new safety or toxicology data that might affect the safety of the subjects in this 
study. 
The Investigator will promptly inform the Sponsor and, if applicable, the REC of any 
SAE that occurs during this trial (see Section 8.6.5). The Investigator will provide the 
REC with annual progress reports of the trial, if the trial lasts longer than a year. 
The Investigator will report to the REC any protocol deviation that is, in his opinion, of 
clinical significance.  The Investigator will also inform the REC in the event of several 
deviations which, although of no clinical significance, cause inconvenience and/or 
discomfort to the subjects.  The Sponsor will notify the MHRA and REC of any 
serious breach of GCP (for example, the Investigator puts subjects’ safety at risk, 
falsifies data, or persistently fails to comply with this protocol or good clinical 
practice). 
Within 90 days after the end of the trial, the Sponsor will ensure that the REC and the 
MHRA are notified that the trial has finished.  The end of the trial is defined as the 
final follow-up visit by the last subject (or final contact with the subject if that is later).  
If the trial is terminated prematurely, those reports will be made within 15 days after 
the end of the trial. 


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The Sponsor will supply a summary report of the clinical trial to the MHRA and REC 
within 1 year after the end of the trial. 
Trial procedures at HMR will be subject to audits by the HMR QA Department, to 
ensure compliance with the protocol and applicable regulatory requirements. 
15.1. 
Informed consent process 
Inclusion in the study will occur only if the subject gives written informed consent.  It 
is the responsibility of the Investigator / designee to obtain written informed consent 
from each individual participating in this study, after adequate presentation of aims, 
methods, anticipated benefits, and potential hazards of the study.  If needed, the 
person will be given time to discuss the information received with members of the 
community or family before deciding to consent.  The subject will be asked to provide 
written and signed consent. 
If new safety information results in significant changes in the risk/benefit assessment, 
the consent form should be reviewed and updated if necessary.  All subjects 
(including those already being treated) should be informed of the new information, 
given a copy of the revised form and give their consent to continue in the study.  
15.2. 
Compensation of volunteers 
The Sponsor agrees to abide by the Association of the British Pharmaceutical 
Industry Guidelines for medical experiments in healthy human volunteers (Guidelines 
for Phase 1 Clinical Trials, 2012 edition) and undertakes to compensate the subjects 
for injuries which are considered, on the balance of probabilities, to have arisen as a 
result of their participation in the trial.  
15.3. 
Insurance and Liability 
DNDi is insured to indemnify the Investigator against any claim for damages brought 
by a subject who suffers from a research related injury during the performance of the 
trial according to the protocol, except for claims that arise from malpractice and/or 
negligence. 
In accordance with local regulations, DNDi will contract insurance for all study 
participants. 
15.4. 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP 
In the event of any prohibition or restriction imposed by an applicable Competent 
Authority in any area of the World, or if the Investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, DNDi should be informed immediately. 
In addition, the Investigator will inform DNDi immediately of any urgent safety 
measures taken by the Investigator to protect the study subjects against any 
immediate hazard, and of any serious breaches of this protocol or of ICH GCP that 
the Investigator becomes aware of. 
DNDi is responsible for reporting any serious breaches of the protocol or of ICH GCP 
to the UK Regulatory Authorities. 


Protocol number (DNDI-EMO-02)  
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15.5. 
Reporting and Publication of study results 
HMR will prepare a draft Clinical Study Report for discussion with the Sponsor.  The 
report will contain results and discussion of the trial, to which will be attached a full 
listing of all data recorded in the CRFs, and summary tables of all important data. 
Completed CRFs will be supplied separately to the Sponsor by HMR. 
DNDi encourages the communication and/or publication of the results, in accordance 
with the Clinical Trial Agreement for the study. 
All clinical trials will be registered with a recognised clinical trial registry such as 
www.clinicaltrials.gov. 
16. References 
 
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evaluation of onchocerciasis : a literature review . Soc. Med. 4, 8–31 (2009). 
Amazigo, U. O. Detrimental effects of onchocerciasis on marriage age and breast-
feeding. Trop. Geogr. Med. 46, 322–325 (1994). 
Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for  
Non-Antiarrhythmic Drugs.  ICH Guidance for Industry  E14, 2005. 
Fobi, G. et al. Managing the Fight against Onchocerciasis in Africa: APOC 
Experience. PLoS Negl. Trop. Dis. 9, e0003542 (2015). 
Gardon, J. et al. Serious reactions after mass treatment of onchocerciasis with 
ivermectin in an area endemic for Loa loa infection. Lancet 350, 18–22 (1997). 
GBD 2015 DALYs and HALE Collaborators. Global, regional, and national disability-
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2015. Lancet (London, England) 388, 1603–1658 (2016). 
Guest, et al. The calcium-activated potassium channel, SLO-1, is required for the 
action of the novel cyclo-octadepsipeptide anthelmintic, emodepside, in 
Caenorhabditis elegans. Int J Parasitol. 37, 1577-88 (2007).  
Guidelines for Phase 1 Clinical Trials, 2012 Edition.  Association of the British 
Pharmaceutical Industry. 
Hotez, P. J. & Kamath, A. Neglected tropical diseases in sub-saharan Africa: review 
of their prevalence, distribution, and disease burden. PLoS Negl Trop Dis 3, e412 
(2009). 
ICH E2A - CPMP/ICH/377/95 modifié, Note for Guidance on Clinical Safety Data 
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Meredith, S. E. & Dull, H. B. Onchocerciasis: The First Decade of MectizanTM 
Treatment. Parasitol. Today 14, 472–474 (1998). 
Okoye, I. C. & Onwuliri, C. O. Epidemiology and psycho-social aspects of 
onchocercal skin diseases in northeastern Nigeria. Filaria J. 6, 15 (2007). 
Organisation Mondial de la Santé (OMS). Progress report on the elimination of 
human onchocerciasis, 2015-2016. 91, 501–516 (2016). 
Plaisier, A. P., van Oortmarssen, G. J., Remme, J. & Habbema, J. D. F. The 
reproductive lifespan of Onchocerca volvulus in West African savanna. Acta Trop. 


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Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 5, 25 July 2018 
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48, 271–84 (1991). 
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Onchocerca Volvulus in the Vertebrate Host. PARASITE Biol. Biochem. 1, 53–55 
(1994). 
Statistical principles for clinical trials.  ICH harmonised tripartite guideline E9, 1998.  
Vos, T. et al. Global, regional, and national incidence, prevalence, and years lived 
with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-
2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet 
386, 743–800 (2015). 
WHO. Global programme to eliminate lymphatic filariasis: progress report 2014. 
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WHO. Working to overcome the global impact of neglected diseases - summary -  
First WHO report on neglected tropical diseases. (2010). 
Willson, et al. The effect of the anthelmintic emodepside at the neuromuscular 
junction of the parasitic nematode Ascaris suum. Parasitology 126, 79-86 (2003). 
Zahner et al. Filaricidal efficacy of anthelmintically active cyclodepsipeptides. Int J 
Parasitol. 31, 1515-22 (2001). 
Zahner et al. Effects of Bay 44-4400, a new cyclodepsipeptide, on developing stages 
of filariae (Acanthocheilonema viteae, Brugia malayi, Litomosoides sigmodontis) in 
the rodent Mastomys coucha. Acta Tropica 80,19-28 (2001). 
Zouré, H. G. M. et al. The Geographic Distribution of Loa loa in Africa: Results of 
Large-Scale Implementation of the Rapid Assessment Procedure for Loiasis 
(RAPLOA). PLoS Negl. Trop. Dis. 5, e1210 (2011). 
 
 


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Appendices 
 
Changes introduced in protocol version  
 
 
 

SAP_001.pdf: