Conditions: Filariasis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 77
Healthy volunteers: yes

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

Detailed description:
There is an urgent need for a macrofilaricidal drug, killing or sterilizing permanently O. volvulus adult worms, which could be used in individual case management and, after appropriate testing, as an alternative drug to ivermectin in MDA programs. Emodepside is a promising candidate to kill the adult and sexually mature O. volvulus. Emodepside was shown to be macrofilaricidal against a variety of filarial nematodes and is a registered drug for animal health, commercialized by Bayer AG under the name of Profender® (in combination with praziquantel) or Procox® (in combination with toltrazuril).

A first-in-human (FIH) double-blind, placebo-controlled study of single ascending doses of emodepside in healthy Caucasian men has been conducted and the preliminary results are favourable, and support continuing the Phase I development program. For this reason, new tablet formulations have been developped and the present study will evaluate bioavailability, PK safety and tolerability, and as well food effect of single doses of 2 new immediate release (IR)-tablet formulations of emodepside compared to the oral liquid service formulation (LSF) used in the FIH study.

Arms:
arm 1: 5 mg emodepside LSF, fasted arm 2: 5 mg emodepside IR-tablet #406, fasted arm 3: 5 mg emodepside IR-tablet #416, fasted arm 4: 5 mg emodepside IR-tablet #406, fed arm 5: 5 mg emodepside IR-tablet #416, fed arm 6: 2 x 5 mg emodepside IR-tablet #406, fasted (may be tested or not, depending on the results of the part 1) arm 7: 2 x 5 mg emodepside IR-tablet #416, fasted (may be tested or not, depending on the results of the part 1)

Interventions: intervention 1: Emodepside (BAY 44-4400)
Intervention descriptions: intervention 1: 2 tablets compared to the liquid formulation

Protocol document:
Prot_000.pdf: 
Confidential  
Page 1 of 69 
Protocol template_Version 1.2_24 April 2014 
 
CLINICAL TRIAL PROTOCOL 
 
A Phase 1, Randomized, Open-Label, Parallel-Group, Relative 
Bioavailability Study to Investigate the Pharmacokinetics, including 
Food Effect, as well as the Safety and Tolerability of Single Doses 
of New Immediate Release Tablet Formulations of Emodepside 
(BAY 44-4400), compared to Oral Solution, in Healthy Male Subjects 
 
Short title 
Relative Bioavailability Study of Emodepside IR-tablets and 
Solution 
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-03 
EudraCT 
2017-003091-31 
Sponsor 
DNDi, Chemin Louis Dunant, 15,  
1202 Geneva Switzerland 
Phone: +41 22 906 9230 
Principal Investigator 
Dr Jeremy Dennison, 
Hammersmith Medicines Research (HMR), 
Cumberland Avenue, Park Royal, London, NW10 7EW, 
United Kingdom 
Phone : +44 (0) 20 8961 4130 
Clinical Trial Protocol 
Version / Date 
Version 3, 01 February 2018 
Protocol Amendment 
Number / Date 
N/A 
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-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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CONTACT DETAILS 
 
 Principal Investigator: 
Dr Jeremy Dennison  
Senior Research Physician and Principal Investigator 
Hammersmith Medicines Research (HMR) Limited 
Cumberland Avenue, Park Royal, 
London, NW10 7EW, United Kingdom 
 Investigator Site 24-Hour Medical Contact: 
On-call physician tel: +44 (0) 7930 323 244 
 Co-Investigators: 
(See Study Reference Manual) 
 Name and address of Monitor (if other than the Sponsor) 
Niche Science & Technology 
Unit 26, Falstaff House, Bardolph Road, 
Richmond TW9 2LH, United Kingdom 
Tel.: + 44 (0)20 8332 2588 
 Name, title, address, and telephone number(s) of the Sponsor's medical 
expert for the trial (24 h) 
Nathalie Strub-Wourgaft MD, 
Medical Director, 
15 Chemin Louis Dunant, 1211 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, 1211 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, 1211 Geneva, Switzerland  
Switchboard: +41 22 906 92 30  
Mobile:  +41 79 219 52 59 
 
Jean-Yves Gillon PharmD, PhD,  
Head of Translational Sciences,  


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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15 Chemin Louis Dunant, 1211 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 (HMR) Limited 
Cumberland Avenue, Park Royal, 
London, NW10 7EW, United Kingdom 
Switchboard:  +44 (0) 20 8961 4130 
Clinical Laboratory 
The HMR Analytical Laboratory 
Cumberland Avenue, Park Royal, 
London, NW10 7EW, United Kingdom 
Switchboard:  +44 (0) 20 8961 4130 
Bioanalytic Laboratory 
Analytical Services International Ltd 
St. George’s, University of London, Cranmer Terrace, 
London, SW17 0RE, United Kingdom 
Switchboard:  +44 (0) 20 8725 2845 








Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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TABLE OF CONTENTS  
ABBREVIATIONS – GLOSSARY OF TERMS ........................................................ 10 
PROTOCOL SUMMARY .......................................................................................... 13 
1. 
BACKGROUND AND STUDY RATIONALE ................................................. 19 
2. 
STUDY OBJECTIVES AND ENDPOINTS .................................................... 28 
2.1. 
Objectives ........................................................................................................................... 28 
2.1.1. 
Primary Objective .................................................................................................. 28 
2.1.2. 
Secondary Objectives........................................................................................... 28 
2.2. 
Study Endpoints ................................................................................................................. 28 
2.2.1. 
Primary Endpoint .................................................................................................. 29 
2.2.2. 
Secondary Endpoints ........................................................................................... 29 
3. 
STUDY DESIGN AND STUDY DESIGN RATIONALE .................................. 29 
3.1. 
Study design ....................................................................................................................... 29 
3.2. 
Study duration and duration of subject participation .................................................... 30 
3.3. 
Definition of the end of trial .............................................................................................. 31 
3.4. 
Rationale of study design ................................................................................................. 31 
4. 
SELECTION OF SUBJECTS ........................................................................ 32 
4.1. 
Inclusion criteria ................................................................................................................ 32 
4.2. 
Exclusion criteria ............................................................................................................... 33 
4.3. 
Dietary and lifestyle guidance .......................................................................................... 35 
5. 
SCHEDULE OF ASSESSMENTS ................................................................. 36 
6. 
ENROLMENT PROCEDURES ...................................................................... 38 
7. 
STUDY TREATMENTS ................................................................................. 38 
7.1. 
Doses and treatment regimens ........................................................................................ 38 
7.2. 
Emodepside Liquid Service Formulation ........................................................................ 39 
7.3. 
Emodepside Immediate Release Tablets ......................................................................... 40 
7.4. 
IMP supply and handling ................................................................................................... 40 
7.5. 
Dose decision ..................................................................................................................... 41 
7.6. 
Trial stopping criteria ........................................................................................................ 41 
7.7. 
Study treatment labelling, packaging .............................................................................. 41 
7.8. 
Accountability .................................................................................................................... 41 
7.9. 
Storage ................................................................................................................................ 42 
7.10. 
Blinding and procedures for unblinding ......................................................................... 42 
7.11. 
Concomitant treatments .................................................................................................... 42 
8. 
STUDY ASSESSMENTS ............................................................................... 43 
8.1. 
Subject Information and Consent Form .......................................................................... 43 
8.2. 
Timing of Assessments ..................................................................................................... 43 
8.3. 
Screening Visit ................................................................................................................... 44 
8.4. 
Admission to Ward (Day 1) ............................................................................................. 44 


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8.5. 
Profile day (Day 0) .............................................................................................................. 45 
8.6. 
Post-dosing days (Days 1–3) ............................................................................................ 45 
8.7. 
Outpatient (ambulatory) visit (Day 5) and Follow-up visit (Day 7) ................................ 45 
8.8. 
Sampling time points and additional tests ...................................................................... 46 
8.9. 
PK assessments ................................................................................................................. 47 
8.10. 
Total blood volume ............................................................................................................ 49 
8.11. 
Assessment of Safety ........................................................................................................ 49 
8.11.1. 
12-lead ECG Safety recording ............................................................................. 50 
8.11.2. 
Vital signs .............................................................................................................. 50 
8.11.3. 
Physical examination and neurological examination ....................................... 50 
8.11.4. 
Clinical Laboratory Safety Assessments ........................................................... 51 
9. 
ADVERSE EVENT DEFINITIONS AND REPORTING .................................. 51 
9.1 
Adverse Event definition ................................................................................................... 51 
9.2 
Serious Adverse Event (SAE) ........................................................................................... 52 
9.3 
Eliciting Adverse Event information ................................................................................ 52 
9.4 
Adverse Event reporting period ....................................................................................... 53 
9.5 
Serious Adverse Event reporting requirements ............................................................. 53 
9.6 
Grading of Adverse Event severity .................................................................................. 54 
9.7 
Adverse Event causality assessment .............................................................................. 54 
9.8 
Exposure in utero ............................................................................................................... 55 
9.9 
Adverse event follow up .................................................................................................... 56 
10. 
WITHDRAWAL CRITERIA ............................................................................ 56 
11. 
DATA ANALYSIS AND STATISTICAL METHODS ...................................... 57 
11.1. 
Sample size determination ................................................................................................ 57 
11.2. 
Definition of study populations included in the analysis .............................................. 57 
11.3. 
Subject Disposition ............................................................................................................ 58 
11.4. 
Efficacy Analysis ................................................................................................................ 58 
11.5. 
Demographics and Other Baseline Characteristics ....................................................... 58 
11.6. 
Safety Analysis ................................................................................................................... 58 
11.6.1. 
Vital signs, 12-lead ECG safety parameters ....................................................... 58 
11.6.2. 
Haematology, Coagulation and Clinical Chemistry Parameters ...................... 59 
11.6.3. 
Urinalysis parameters........................................................................................... 59 
11.6.4. 
Physical and neurological examination.............................................................. 59 
11.6.5. 
Adverse events ...................................................................................................... 59 
11.7. 
Analysis of Human Pharmacokinetics of Emodepside .................................................. 60 
12. 
SAFETY REVIEW MEETINGS ...................................................................... 61 
13. 
QUALITY ASSURANCE AND QUALITY CONTROL PROCEDURES ......... 61 
13.1. 
Investigator’s file ................................................................................................................ 61 
13.2. 
Case report forms .............................................................................................................. 61 
13.3. 
Source documents ............................................................................................................. 62 
13.4. 
Record Retention ............................................................................................................... 62 
13.5. 
Monitoring, audits and inspections ................................................................................. 62 


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13.6. 
Audits and inspections ...................................................................................................... 63 
13.7. 
Data Management .............................................................................................................. 63 
13.8. 
Confidentiality of trial documents and subjects records .............................................. 63 
14. 
PROTOCOL DEVIATIONS AND AMENDMENTS ........................................ 64 
15. 
EARLY TERMINATION OF THE STUDY ...................................................... 64 
16. 
ETHICS .......................................................................................................... 65 
16.1. 
Informed consent process ................................................................................................ 66 
16.2. 
Compensation of volunteers............................................................................................. 67 
16.3. 
Insurance and Liability ...................................................................................................... 67 
16.4. 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP ......... 67 
16.5. 
Reporting and Publication of study results .................................................................... 67 
17. 
REFERENCES .............................................................................................. 68 
 
 
 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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ABBREVIATIONS – GLOSSARY OF TERMS 
 
ADME 
Absorption, Distribution, Metabolism, and Excretion 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase (SGPT) 
ANOVA 
Analysis of variance 
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 in die (twice-daily) 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
Creatinine Kinase 
CL 
Clearance 
Cmax 
Maximum observed concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CV 
Coefficient of Variation 
CYP3A4 
Cytochrome P450 3A4 
DNDi 
Drugs for Neglected Diseases initiative 
ECG 
Electrocardiogram 
IC20 
Inhibitory Concentration 20 
ICF 
Information Consent Form 
IMP 
Investigational Medicinal Product 
IR 
Immediate Release 
F 
Female 
FDA 
Food and Drug Administration 
FIH 
First-In-Human 
GABA 
Gamma-Aminobutyric Acid 
GCP 
Good Clinical Practice 
GDRC 
Generic Documents Review Committee 
GGT 
Gamma-Glutamyl Transpeptidase 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GP 
General Practitioner  
HDL 
High Density Lipoprotein 
hERG 
Human ether-a-go-go-related gene 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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HIV 
Human Immunodeficiency Virus 
HMR 
Hammersmith Medicines Research 
HR 
Heart Rate 
ICF 
Information and Consent Form 
ICH 
International Conference on Harmonization 
IR 
Immediate Release 
IRB 
Institutional Review Board 
LDH 
Low Density Lipoprotein 
LF 
Lymphatic filariasis 
LS-means 
Least Squares Means 
LSF 
Liquid Service Formulation 
M 
Male 
MCV 
Mean Corpuscular Volume 
MCH 
Mean Corpuscular Haemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MDA 
Mass Drug Administration 
MedDRA 
Medical Dictionary For Regulatory Activities 
mg 
Milligram 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MIC 
Minimum Inhibitory Concentration 
mL 
Millilitre 
MRT 
Mean Residence Time 
MTT 
4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide 
NOAEL 
No Observed Adverse Effect Level 
ng 
Nanogram 
OCP 
Onchocerciasis Control Programme 
OD 
Omnie die (once-daily) 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetics 
p.o 
Per Os (To Be Taken By Mouth) 
ppm 
Parts Per Million 
PT 
Prothrombin Time 
RBC 
Red Blood Cell 
REC 
Research Ethics Committee 
QTcB 
QT Corrected By Bazett’s Formula 
QTcF 
QT Correct By Fridericia's Formula 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SOC 
System Organ Class 
SRG 
Safety Review Group 
SUSAR 
Serious Unexpected Adverse Event 
Tmax 
Time of Maximum Observed Concentration 
TEAE 
Treatment Emergent Adverse Event 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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TSH 
Thyroid-Stimulating Hormone 
ULN 
Upper Limit Of Normal 
UV 
Ultraviolet 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WHO DD 
World Health Organisation Drug Dictionary 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
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PROTOCOL SUMMARY 
Trial 
Objectives Primary Objective 
 
To investigate the pharmacokinetics, including relative bioavailability and 
food effect, of two new immediate release (IR)-tablet formulations of 
emodepside in comparison to the liquid service formulation (LSF) oral 
solution.  
Secondary Objectives 
 
To investigate and compare safety and tolerability of single oral doses of 
emodepside formulations in healthy subjects. 
Trial 
Endpoints 
 
Primary Endpoint 
 
Based on the plasma concentration–time data, the following PK 
parameters of emodepside will be calculated: 
o Main:  AUC0-7d, AUC0-7d/Dose, Cmax, Cmax/Dose 
Secondary Endpoints 
 
Safety and Tolerability Variables: 
o Adverse Events (AEs) 
o Physical and neurological examination findings 
o Vital signs (BP and HR),  
o 12-lead ECG (HR, PR, QRS, QTcB, QTcF), will be analysed ad hoc for 
safety and for the final data base and report by central reading  
o 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); 
 
Coagulation:  activated partial thromboplastin time (aPTT), 
prothrombin time (PT); 
 
Biochemistry: serum aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (AP), gamma-
glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), 
creatine kinase (CK), amylase, lipase, glucose, cholesterol (HDL, 
LDL, total), triglycerides, creatinine, urea, uric acid, bilirubin (total 
and conjugated), total protein, sodium, potassium, calcium, 
chloride and magnesium; 
 
Urinalysis: by dipstick – glucose, ketone bodies, specific gravity, 
occult blood, pH, proteins, leucocytes, bilirubin, urobilinogen, 
nitrites and microscopy (reflex). 
Other and exploratory endpoints 
 
Pharmacokinetic: 
o AUC0-7d,norm, Cmax,norm, t1/2,0-24h, t1/2,0-7d, tmax, MRT, points terminal 
Trial 
Design  
 The study will be done in 2 parts, as follows: 
 
Part 1 – single oral doses of 5 mg emodepside will be tested: 
o Part 1a – the LSF (reference formulation) and 2 new IR-tablet 
formulations (test formulations) will be administered in the fasted 
state. 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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o Part 1b – the 2 new IR-tablet formulations will be administered in 
the fed state (high-fat, high-calorie meal). 
 
Part 2 – single oral doses of 10 mg emodepside will be tested:  depending 
on the results from Part 1, one or both IR-tablet formulations will be 
administered in the fasted state.  
The treatments in each study part are as follows: 
 
Part 
Treatment Formulation, dose and condition 
Number of 
subjects 
Part 
1a 
A 
5 mg emodepside LSF, fasted 
12 
 
B 
5 mg emodepside IR-tablet #406, fasted 
12 
 
C 
5 mg emodepside IR-tablet #416, fasted 
12 
Part 
1b 
D 
5 mg emodepside IR-tablet #406, fed 
12 
 
E 
5 mg emodepside IR-tablet #416, fed 
12 
Part 2 
F* 
2 x 5 mg emodepside IR-tablet #406, fasted 
12 
 
G* 
2 x 5 mg emodepside IR-tablet #416, fasted 
12 
* one or both treatments may be tested, depending on results from Part 1 
Up to 84 healthy volunteers will be enrolled, in up to 7 treatment arms made up of 
12 subjects each.   
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 (Body Mass Index (BMI); Quetelet index) in the range 
18.0 to 30.1 kg/m2 at screening 
4. Mean blood pressure and heart rate (from the triplicate readings) in the 
supine position at the screening assessment within the following ranges: 
 
90–140 mm Hg systolic BP 
 
60–90 mm Hg diastolic BP 
 
45–100 beats/min HR 
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 


Protocol number (DNDI-EMO-03)  
 
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Overvolunteering Prevention System (TOPS) 
8. Willingness to follow contraception requirements of the study, from the first 
dose of the IMP until 90 days after dosing and inform HMR as soon as 
possible if their partner becomes pregnant in the 90 days after dosing   
Exclusion:  
9. 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 
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 (e.g. stomach bypass) or medical condition that might affect 
absorption of the study drug when taken orally 
12. 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 
13. Loss of more than 400 mL of blood within the 3 months before admission 
14. Clinically relevant history of vital organ disease, or other organ or central 
nervous system disease (e.g. diabetes mellitus, liver disease, seizures, 
etc.) 
15. Current or previous medical or psychiatric disorder that, in the opinion of 
the Investigator or the Sponsor, would increase the risk and ability to 
participate in and/or complete the study 
16. Positive test for hepatitis B, hepatitis C or HIV 
17. Febrile illness (e.g. fever) within 1 week before the first dose of study 
medication 
18. History of a severe allergy, non-allergic drug reaction, severe adverse 
reaction to any drug, or multiple drug allergies 
19. 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 year, or intake of 
more than 21 units (1 unit = ½ pint of beer, 1 small glass of wine or 1 
measure of spirits) of alcohol weekly 
21. Regular daily consumption of more than one litre of beverages containing 
xanthine 
22. Daily consumption of more than 10 cigarettes or more than 6 grams (1/4 
ounce) of tobacco 
23. Use of a prescription medicine during the 28 days before the dose of study 
medication, or use of an over-the-counter medicine (with exception of 
acetaminophen (paracetamol)), during the 7 days before the dose of study 


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Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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medication 
24. Use, within 14 days before the dose of study medication, of dietary 
supplements or herbal remedies (such as St John’s Wort) that are known 
to be inducers or inhibitors of CYP3A4, or other co-medications known to 
be relevant substrates of CYP3A4 (see list in the Study Procedures 
Manual)  
25. Use, within 14 days before the dose of study medication,  of dietary 
supplements or herbal remedies that are known to be strong inhibitors of 
P-gp, or other co-medications known to be relevant substrates of P-gp 
(see list in the Study Procedures Manual) 
26. Relevant pathological abnormalities in the ECG at screening, such as: 
 
second or third-degree atrioventricular (AV) block  
 
prolongation of the QRS complex > 120 msec,  
 
QTc-interval (QTcB or QTcF)  
> 450 msec. 
The mean of the triplicate ECG readings will be used to assess eligibility. 
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 during 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 
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 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 5 weeks, and will 
include a Screening visit (within 4 weeks before dosing), a 5-day in-house 
evaluation period (Day –1 to Day 3), followed by an outpatient visits (on Days 
5), and a final Follow-up visit (on Day 7). 
 
Overall, including the recruitment period, the trial is expected to last 
approximately 6 months 
Study 
treatment
s 
 
Emodepside oral LSF will be provided as 0.1% (w/v) 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. 
Each bulk solution bottle contains 20 mg emodepside, corresponding to 20 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
Confidential  
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mL solution.  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 will be used for application of doses of 5 mg, corresponding to 
application of 5 mL of the solution. 
The solution is composed of the active substance emodepside and 
excipients. 
Detailed information on the drug substance emodepside (BAY 44–4400) is 
given in the Investigator’s Brochure. 
Emodepside tablet #406 contains granules of emodepside and the polymer 
hypromellose acetate succinate as a solid dispersion to enhance solubility.  
Tablets contain 5 mg active substance (emodepside), and excipients: 
Emodepside tablet #416 contains granules of emodepside and the polymer 
copovidone as a solid dispersion to enhance solubility.  Tablets contain 
5 mg active substance (emodepside) and excipients. 
Sample 
Size 
No formal statistical sample size estimation has been performed, due to the 
exploratory nature of this study.  
10 subjects per treatment arm is considered sufficient to examine the 
safety and tolerability of emodepside, as well as the PK after single doses.  
However, 12 subjects will be recruited and enrolled per treatment arm to 
ensure a minimum of 10 evaluable subjects complete the study. 
Statistics  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 PK sample has been analysed.  
 PK Parameter Population:  All subjects in the PK Concentration 
Population for whom PK parameters can be derived.  
In all populations, treatment will be assigned based upon the treatment 
subjects actually received, regardless of the treatment to which they were 
randomized. 
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 mean23; 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 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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Clinical Trial Protocol template_Version 1.2_02 June 2014 
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 will be listed 
and summarised, by treatment, using descriptive statistics.  Individual and 
mean plasma concentration–time profiles will be presented graphically. 
To assess the relative bioavailability, analysis of variance (ANOVA) models 
will be fitted to the tablet (test) and solution (reference) data with the 
logarithm of the pharmacokinetic parameters AUC0-7d/Dose or 
Cmax/Dose as the dependent variable, and formulation as a fixed effect.  
The point estimates least squares (LS)-means and 90% confidence 
intervals for the ratios “B / A” and “C / A” will be calculated in Part 1a.  In 
Part 2, “F/A” and/or “G/A” will be calculated. The acceptance range 80 – 
125% will be applied for these assessments.   
To assess the effect of food, ANOVA models will be fitted to the data with 
the logarithm of the pharmacokinetic parameters AUC0-7d/Dose or 
Cmax/Dose as the dependent variable, and fed (test) or fasted (reference) 
as a fixed effect.  In Part 1, the point estimates and 90% confidence 
intervals for the ratios “D/B” and “E/C”  will be calculated.  The acceptance 
range 80 – 125% will be applied for the assessment of a potential food 
effect.   
To assess dose proportionality, for each tablet type, exploratory ANOVA 
models will be fitted to the relevant fasted data in Parts 1 and 2 with the 
logarithm of the pharmacokinetic parameters AUC0-7d or Cmax as the 
dependent variable and dose as a fixed effect.  The ratios “F/B” and/or 
“G/C” will be calculated. 
 
 
 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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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 risk1,2. 
An estimated 18 million people suffer from onchocerciasis3, with 99% of cases in 31 
African countries, and 187 million at risk in 20154.  Although the disease is almost 
exclusively confined to Africa, some foci still exist in Yemen and South America 
(Brazil and Venezuela)5.  
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 and 
can even induce premature child weaning by affected mothers.  
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) estimates6 that 746,000 patients are visually 
impaired, 265,000 are blinded and more than 4 million suffer from severe itching due 
to onchocerciasis7.  
The burden associated with onchocerciasis is estimated at more than 1 million 
disability-adjusted life years (DALYs) in 2013 worldwide8. 
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 years9 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 160010 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.   
Ivermectin is the standard treatment for onchocerciasis patients.  The drug kills the 
microfilarial stage of the parasite and provides temporary sterilization of adult female 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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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 donation11 to 
African Control programs in 24 African countries under the direction of APOC/ WHO 
until 201512. 
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 
drug is therefore needed to kill the adult worm, stop the perpetual 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 disease that occurs exclusively in 
West and Central Africa; an estimated 13 million people are infected with Loa loa13. 
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 worm14.  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 
sequelae15.   
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 resistance13,16.  
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 is a relative bioavailability study to investigate the safety, 
tolerability, food effect and pharmacokinetics of emodepside (BAY44-4400) new 
immediately-release tablet formulations, compared to oral solution, after a single 
dose in healthy male Caucasian subjects. 
 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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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 lienalis17,18. 
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-119.  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)20.  
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 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 (PK).  
The preliminary results are favourable, and 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 relative bioavailability study, PK as well as safety and 
tolerability, and food effect of single doses of 2 new immediate release (IR)-tablet 
formulations of emodepside will be compared to the oral liquid service formulation 
(LSF) used in the FIH study.   
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 sigmodontis, and 
Acanthocheilonema viteae, are considered to represent a reasonable in vitro disease 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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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 i.e., 
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 (NOEL) 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 NOAEL 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 electrocardiogram (ECG) results in 
anesthetized dogs. However, a moderate vasodilatation (reduction of total resistance, 
slight decrease of arterial blood pressure (BP), 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 on BP or heart rate (HR) was seen in dogs following 
oral administration of emodepside for 4 weeks at up to 20 mg/kg body weight. 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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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 (P-gp) mediated.  Therefore, a role for P-gp in 
the PK 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 
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 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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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/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 
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 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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non-clinical studies (all pivotal studies were conducted under GLP conditions) are 
sufficient to support this phase I study in human subjects. 
1.4. Summary of human clinical data 
Results of the first in man single dose escalation study (ref. DNDI-EMO-001) 
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 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 and without treatment.  


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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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) 
Gastro-intestinal 
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 TEAEs 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 TEAEs 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 
receiving placebo reported dry eye (n=1).  All treatment-related eye disorders TEAEs 
were of mild intensity, resolved spontaneously (without treatment), and were more 
frequently reported with highest dose (40 mg).  Among them, the TEAEs of blurred 


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Emodepside (BAY 44-4400) 
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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 with 
regards to treatment 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 post-administration. 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 post-
administration (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 preliminary 
results suggest an increase of blood glucose and insulin, 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 in subjects exposed to 
treatment, regardless of the formulation. 
Preliminary 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 most cases close to Tmax and of various durations.  In addition, the 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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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 single doses of emodepside have been administered to 
humans and were well tolerated.  Based on the FIH single ascending dose 
clinical study, overall tolerability to emodepside has been acceptable up to 
20 mg of LSF formulation.  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. 
 Pre-clinical data suggests that plasma exposure following emodepside as 
IR-tablets is not high than the one observed after LSF administration at the 
same dose. 
 In Part 1 of this study, single doses of 5 mg emodepside will be 
administered in the fed and fasted states.  Based on PK data from the FIH 
study, exposure to emodepside following administration of the IR-tablet in 
the fed state is likely to be similar to or lower than the IR-tablet 
administered in the fasted state.  Therefore, it is acceptable to test the fed 
and fasted doses in parallel or sequentially in Part 1. 
 Part 2 of this study, in which single doses of 10 mg emodepside will be 
tested, will proceed only if the PK, safety and tolerability after single doses 
of 5 mg emodepside in Part 1 are acceptable, and provided the Investigator 
and Sponsor’s Medical Monitor agree that it is appropriate to give a higher 
dose.  The total dose of emodepside for any subject will not exceed 10 mg. 
2. Study Objectives and Endpoints 
2.1. 
Objectives 
2.1.1. Primary Objective 
 
To investigate the pharmacokinetics, including relative bioavailability 
and food effect, of two new immediate release (IR)-tablet formulations 
of emodepside in comparison to the liquid service formulation (LSF) oral 
solution.  
2.1.2. Secondary Objectives 
 
To investigate and compare safety and tolerability of single oral doses 
of emodepside formulations in healthy subjects. 
2.2. 
Study Endpoints 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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2.2.1. Primary Endpoint 
 
Based on the plasma concentration–time data, the following PK 
parameters of emodepside will be calculated: 
o Main:  AUC0-7d, AUC0-7d/Dose, Cmax, Cmax/Dose 
2.2.2. Secondary Endpoints 
 
Safety and Tolerability Variables: 
o Adverse Events (AEs) 
o Physical and neurological examination findings 
o Vital signs (BP and HR),  
o 12-lead ECG (HR, PR, QRS, QTcB, QTcF), will be analysed ad hoc 
for safety and for the final data base and report by central reading  
o 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); 
 Coagulation:  activated partial thromboplastin time (aPTT), 
prothrombin time (PT); 
 Biochemistry: serum aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (AP), gamma-
glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), 
creatine kinase (CK), amylase, lipase, glucose, cholesterol 
(HDL, LDL, total), triglycerides, creatinine, urea, uric acid, 
bilirubin (total and conjugated), total protein, sodium, potassium, 
calcium, chloride and magnesium; 
 
Urinalysis: by dipstick – glucose, ketone bodies, specific gravity, occult 
blood, pH, proteins, leucocytes, bilirubin, urobilinogen, nitrites and 
microscopy (reflex). 
2.2.3. Other and exploratory endpoints 
 
Pharmacokinetic: 
o AUC0-7d,norm, Cmax,norm, t1/2,0-24h, t1/2,0-7d, tmax, MRT, points terminal 
3. Study design and study design rationale 
3.1. 
Study design 
This is a single-centre, open-label, randomized, parallel-group relative bioavailability 
study in healthy men.  The study will be done in 2 parts, as follows: 
 Part 1 – single oral doses of 5 mg emodepside will be tested: 
o Part 1a – the LSF (reference formulation) and 2 new IR-tablet 
formulations (test formulations) will be administered in the fasted state. 
o Part 1b – the 2 new IR-tablet formulations will be administered in the 
fed state (high-fat, high-calorie meal). 
 Part 2 – single oral doses of 10 mg emodepside will be tested:  depending on 
the results from Part 1, one or both IR-tablet formulations will be administered 
in the fasted state.  
The treatments in each study part are summarised in Table 1. 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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Table 1. Planned treatments by dose, formulation and condition 
Part 
Treatment 
Formulation, dose and condition 
Number of subjects 
Part 1a 
A 
5 mg emodepside LSF, fasted 
12 
 
B 
5 mg emodepside IR-tablet #406, fasted 
12 
 
C 
5 mg emodepside IR-tablet #416, fasted 
12 
Part 1b 
D 
5 mg emodepside IR-tablet #406, fed 
12 
 
E 
5 mg emodepside IR-tablet #416, fed 
12 
Part 2 
F* 
2 x 5 mg emodepside IR-tablet #406, fasted 
12 
 
G* 
2 x 5 mg emodepside IR-tablet #416, fasted 
12 
* one or both treatments may be tested, depending on results from Part 1 
Up to 84 healthy volunteers will be enrolled, in up to 7 treatment arms made up of 12 
subjects each.   
The 36 subjects in Part 1a will be randomised to one of 3 treatments (A, B or C).  The 
24 subjects in Part 1b will be randomised to one of 2 treatments (D or E).  Parts 1a 
and 1b may proceed in parallel, or may be done sequentially. 
After at least 10 subjects have received each treatment in Part 1, and data up to 72 h 
after dosing are available, there will be a Dose Decision Meeting to determine which 
treatment(s) will be tested in Part 2 (see section 7.5). 
In Part 2, either treatment F, G or both F and G will be tested.  There will be 12 
subjects enrolled for each treatment tested.  If both treatments are tested, they will be 
done in parallel, and subjects will be randomised to one of the 2 treatments. 
The study will be performed in a single site specialized in Phase 1 studies.  
3.2. 
Study duration and duration of subject participation 
Each subject will attend a Screening visit within the 4 weeks before their dose of 
study medication (on Day 0). 
Eligible subjects will be admitted to the ward on the afternoon of Day –1 (the day 
before dosing).  They will remain on the ward until the morning of Day 3 (4 nights and 
5 days in a row); during that time, they will receive a single oral dose of emodepside. 
Safety, tolerability, and PK assessments will be done before and regularly after 
dosing.  Each subject will undergo a full day of assessments (including PK) on the 
day of dosing (Day 0). 
Subjects will be discharged from the study unit on Day 3, provided there are no 
medical objections.  Subjects will attend the ward for outpatient (ambulatory) visit on 
Day 5 and a final Follow-up visit on Day 7, at 1 week after their dose of emodepside. 
The study design is summarised schematically in Figure 1. 
The study Schedule of assessments (Section 5) provides a detailed overview of all 
study procedures, which are further discussed in Section 8 (Study Assessments). 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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Figure 1 – Overall study design   
 
3.3. 
Definition of the end of trial 
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 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 a randomized, open-label, parallel group design. 
The open design of the trial has the important disadvantage that both investigator 
and subjects are aware that active treatment is being given, and there is no placebo.  
The possibility of bias must therefore be taken into account in the assessment of AEs 
in particular.  However, the primary objective of the study is to compare the PK of 
emodepside after different formulations, which will be assessed using an objective 
test measured by an external laboratory.  Relative bioavailability and food effect form 
part of the PK assessment.  Most of the other assessments are also objective, either 
because they are measured by a laboratory or are measured using automated means 
(HR, BP, and ECG). 
After a single dose, emodepside is rapidly absorbed and peak plasma concentrations 
occur within a few hours after dosing.  There is a short half-life in the first 24 h 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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(distribution/elimination phase) followed by a long terminal elimination half-life (t1/2 
>500 h).  Crossover designs are attractive because they can enhance the power of a 
trial to distinguish between treatments; that is because within-subject variability is 
generally less than between-subject variability.  However, crossover designs are 
subject to carryover of effects from one treatment to the next, especially if the 
elimination half-life is long.  Because of this, a parallel group design was chosen for 
this study and PK samples will be taken at the Follow-up Visit (168 h after dosing).  
Treatments in Part 1 will be randomized to reduce the likelihood of period or 
seasonal effects confounding the study assessments.  Part 2 will also be randomized 
if both treatments are tested. 
The study will be performed in healthy male Caucasian volunteers, in order to avoid 
ethic and sex differences that may increase pharmacokinetic variability. 
In the FIH study, single doses of 5 and 10 mg emodepside, administered as LSF oral 
solution in the fasted state, were safe and well tolerated.  Since those doses are 
likely to fall within the dose range tested in later phase studies, and have previously 
been well tolerated in healthy volunteers, they have been selected for this relative 
bioavailability study.  It is anticipated that emodepside exposure following IR-tablets 
(in both fasted and fed states) will be no higher than exposure following the same 
dose of LSF oral solution.  Anticipated exposures for each formulation tested in this 
study are provided below.  
Following a single dose of 5 mg emodepside, administered as LSF oral solution in 
the FIH study, mean ± SD (CV%) Cmax was 93.2 ± 15.7 ng/mL (16.8%) and AUClast 
was 1736.2 ± 392.5 ng*h/mL (22.6%).  Exposures in Part 1 of this study are likely to 
be similar to, or lower than, these values. 
Following a single dose of 10 mg emodepside, administered as LSF oral solution in 
the FIH study, mean ± SD (CV%) Cmax was 178.6 ± 47.9 ng/mL (26.8%) and AUClast 
was 3165.2 ± 817.2 ng*h/mL (25.8%).  Exposures in Part 2 of this study are likely to 
be similar to, or lower than, these values. 
The highest single dose which has been shown to be well tolerated is 20 mg LSF oral 
solution, which resulted in mean ± SD (CV%) Cmax of 315.7 ± 87.6 ng/mL (27.7%) 
and AUClast of 7617.0 ± 1467.7 ng*h/mL (19.3%).  Even if exposures in Parts 1 and 2 
are higher than anticipated, they are unlikely to exceed these values. 
Therefore, the proposed doses to be tested in this study are considered acceptable. 
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 
DNDi Medical Monitor before the 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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Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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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. Mean blood pressure and heart rate (from the triplicate readings) in the supine 
position at the screening assessment within  the following ranges: 
a. 90–140 mm Hg systolic BP 
b. 60–90 mm Hg diastolic BP 
c. 45–100 beats/min HR 
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 follow contraception requirements of the study, from the first 
dose of the IMP until 90 days after dosing and inform HMR as soon as 
possible if partner becomes pregnant in the 90 days after dosing. 
4.2. 
Exclusion criteria 
The presence of 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 (e.g. 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 (e.g. diabetes mellitus, liver disease, seizures, etc.) 


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Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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7. Current or previous medical or psychiatric disorder that, in the opinion of the 
Investigator or the Sponsor, would increase the risk and ability to participate in 
and/or complete the study 
8. Positive test for hepatitis B, hepatitis C or HIV 
9. Febrile illness (e.g. 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 years, or intake of 
more than 21 units (1 unit = ½ pint of beer, 1 small glass of wine or 1 measure 
of spirits) of alcohol weekly 
13. Regular daily consumption of more than one litre of beverages containing 
xanthine 
14. Daily consumption of more than 10 cigarettes or more than 6 grams (1/4 
ounce) of tobacco 
15. Use of a prescription medicine during the 28 days before the dose of study 
medication, or use of an over-the-counter medicine (with exception of 
acetaminophen (paracetamol)), during the 7 days before the dose of study 
medication 
16. Use, within 14 days before the dose of study medication, of dietary 
supplements or herbal remedies (such as St John’s Wort) that are known to be 
inducers or inhibitors of CYP3A4, or other co-medications known to be 
relevant substrates of CYP3A4 (see list in the Study Procedures Manual)  
17. Use, within 14 days before the dose of study medication,  of dietary 
supplements or herbal remedies that are known to be strong inhibitors of P-gp, 
or other co-medications known to be relevant substrates of P-gp (see list in the 
Study Procedures Manual) 
18. Relevant pathological abnormalities in the ECG at screening, such as: 
 second or third-degree atrioventricular (AV) block  
 prolongation of the QRS complex > 120 msec,  
 QTc-interval (QTcB or QTcF)  
> 450 msec. 
The mean of the triplicate ECG readings will be used to assess eligibility. 
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 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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23. Possibility that subject will not cooperate with the requirements of the protocol 
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 from 24 h before 
Screening, and from 24 h before admission until after the Follow-up visit.  
No strenuous exercise will be allowed from 48 h before Screening until after the 
Follow-up visit. 
Subjects should fast (no food or drink, except water) for at least 10 h before 
Screening. 
On Day 0, subjects in Part 1a and Part 2 will fast (no food or drink, except water) 
overnight for at least 10 h before dosing, until at least 4 h after dosing.  Subjects in 
Part 1b will fast (no food or drink, except water) overnight until approximately 30 min 
before dosing, at which time they will be given a standard Food and Drug 
Administration high-calorie, high-fat breakfast consisting of:  2 fried eggs, 2 strips of 
bacon, 2 slices of toast and butter, 4 ounces of hash brown potatoes, and a glass of 
whole milk.  They must finish the breakfast at least 5 min before dosing. 
For all subjects, post-dose mealtimes on Day 0 will be as follows: 
 Lunch: approximately 5 h after dosing 
 Snack: approximately 8 h after dosing 
 Dinner: approximately 12 h after dosing 
The content of meals on Day 0 will be standardised:  the content of lunch, snack and 
dinner will be the same for each subject. 
On all other study days on which subjects are resident, 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.  
From the first dose until 90 days after the dose, subjects must not have sex without 
using a condom, unless they have had a vasectomy or their partner is not of 
childbearing potential. 


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Protocol Version/Date:  Version 3, 01 February 2018 
 
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5. Schedule of assessments  
Procedure 
Screening 
Inpatient 
Follow-up 
Day 28 to 2 Day –1 
Day 0 
Day 1 
Day 2 Day 3 Day 5 Day 7 
 
hours –1 
0 
0.25 0.5 
1 
1.5 
2 
2.5 
3 
4 
6 
8 
12 
24 
36 
48 
72 
120 
168 
Subject demographics and 
informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria - 
Eligibility check 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/prior medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient stay 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of emodepside1 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient visit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Drugs of abuse screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical and neurological 
examination2 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Vital signs3 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead safety ECG4 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Laboratory safety tests5,6 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
Serology7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood samples for assay of 
emodepside6 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE questioning8 
 
 
1. 
Subjects in Part 1a and Part 2 will fast for 10 h before until at least 4 h after dosing.  Subjects in Part 1b will be given a high-calorie, high-fat breakfast approximately 30 min 
before dosing, which they must finish at least 5 min before dosing.  Standard meals will be served at approximately 5 h (lunch), 8 h (snack) and 12 h (dinner) after dosing 
on Day 0.  Procedures scheduled at the same time as a meal will be completed before the meal. 
2. 
A full physical examination will be done at Screening and Follow-up.  A brief (symptom-directed) physical examination and short neurological examination will be 
undertaken at all other time points.  Any abnormalities will trigger a full neurological examination and/or opening of an AE as appropriate.  Height, weight and body mass 
index (BMI) will be assessed at screening, and weight will be assessed on Day –1.   
3. 
Vital signs will comprise supine blood pressure and heart rate.  Subjects should rest in the supine position for at least 10 min before vital signs measurements.  Vital signs 
will be measured in triplicate at screening and pre-dose (–1 h); single measurements at all other time points. Body temperature will be measured on day -1. 
4. 
Subjects should rest in the supine position for 10 min before ECG measurements.  Measurement in triplicate at screening and pre-dose (–1 h); single measurements all 
other time points.  


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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5. 
Blood and urine samples for clinical laboratory safety tests (haematology, biochemistry, coagulation and urinalysis). 
6. 
Subjects should rest in the supine position for 10 minutes before blood is drawn (if possible).  
7. 
Serology tests will comprise HIV 1 & 2 and hepatitis B & C. 
8. 
Adverse event monitoring will be done throughout the study, but scheduled questioning will be done at the time points of scheduled blood draws.  


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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6. Enrolment procedures  
The study will be carried out in healthy male subjects at the following Phase 1 unit:  
Hammersmith Medicines Research Limited (HMR),  
Cumberland Avenue, Park Royal 
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 ‘Enrolled’ – i.e., received treatment) or reason for not enrolling (Screen 
Failure) or not being randomised, whenever applicable. 
Screening should occur between 2 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 16.1 for Informed 
Consent Procedures) to participate in this trial.  Consent for screening evaluations 
may be obtained using the Information and Consent Form (ICF) for the HMR healthy 
volunteer panel (see Section 16). 
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 dose (‘Enrolled’ subjects).  Subject numbers in the trial will be as 
shown in Table 2.  In Part 1 only, subject numbers will be allocated to treatment 
according to a randomization schedule prepared by an independent HMR statistician, 
using a SAS program.  Sufficient subjects will be screened to ensure 12 subjects are 
enrolled per treatment arm tested. 
7. 
Study treatments 
7.1. Doses and treatment regimens 
The study will be done in 2 parts.  In Part 1, each subject will receive a single oral 
dose of 5 mg emodepside in the fasted state (Part 1a) or in the fed state (Part 1b).  In 
Part 2, each subject will receive a single oral dose of 10 mg emodepside in the fasted 
state. 
In Part 1, two new IR-tablet formulations of emodepside (#406 and #416) will be 
compared to LSF solution (concentration 1 mg/mL).  In Part 2, one or both IR-tablet 
formulations from Part 1 will be tested. 
Each subject will receive a single dose of emodepside.  The treatments in each study 
part will be as follows. 
 Part 1a: 
 
Treatment A:  5 mg emodepside LSF, fasted 
 
Treatment B:  5 mg emodepside IR-tablet #406, fasted 
 
Treatment C:  5 mg emodepside IR-tablet #416, fasted 
 Part 1b: 


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Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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 
Treatment D:  5 mg emodepside IR-tablet #406, fed 
 
Treatment E:  5 mg emodepside IR-tablet #416, fed 
 Part 2: 
 
Treatment F:  2 x 5 mg emodepside IR-tablet #406, fasted 
 
Treatment G:  2 x 5 mg emodepside IR-tablet #416, fasted 
In Part 1a, subjects will be randomized 1:1:1 to receive Treatment A, B or C.  In 
Part 1b, subjects will be randomized 1:1 to receive Treatment D or E.  Depending on 
the results from Part 1, all subjects in Part 2 may receive Treatment F, all subjects 
may receive Treatment G, or half of the subjects may receive each treatment.  If one 
treatment is tested, 12 subjects will be allocated to that treatment.  If both treatments 
are tested subjects will be randomized 1:1 to receive Treatment F or G.  Enrolled 
subjects will be given a unique ID (subject number; Table 2) that will be recorded in 
the case report form (CRF), and will be retained throughout the study.  This subject 
number will also appear on the study medication containers. 
Table 2.  Study treatment and subject numbers by study part 
Part 
Treatment 
Number of subjects 
Subject numbers 
Part 1a 
A, B or C 
36 (12 per treatment) 
1001–1036 
Part 1b 
D or E 
24 (12 per treatment) 
2001–2024 
Part 2 
F or G* 
24 (12 per treatment) 
3001–3024 
* one or both treatments may be tested, depending on results from Part 1.  If only one 
treatment is selected, the first 12 subject numbers will be used. 
Replacements for withdrawn subjects will be given a number equal to that of the 
subject that they replaced plus 100 (e.g. Subject 1036 would be replaced by 
Subject 1136). 
7.2. Emodepside Liquid Service Formulation 
Emodepside oral LSF will be provided as 0.1% (w/v) 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. 
Each bulk solution bottle contains 20 mg emodepside, corresponding to 20 mL 
solution.  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 will be used for 
application of doses of 5 mg, corresponding to application of 5 mL of the solution. 
The solution is composed of the active substance emodepside and the following 
excipients:  
 macrogol 400  
 polysorbate 20 
 levomenthol 
 butylhydroxyanisole 
Detailed information on the drug substance emodepside (BAY 44–4400) is given in 
the Investigator’s Brochure. 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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7.3. Emodepside Immediate Release Tablets 
Both emodepside tablets are IR forms with rapid dissolution in vitro. Both tablet 
formulations are expected to disintegrate in the acid milieu of the stomach and the 
resultant granules to dissolve rapidly in the upper intestine. 
Emodepside tablet #406 contains granules of emodepside and the polymer 
hypromellose acetate succinate as a solid dispersion to enhance solubility.  Tablets 
contain 5 mg active substance (emodepside), and the following excipients: 
 hypromellose acetate succinate 
 macrogol 15 hydroxystearate 
 croscarmellose sodium 
 microcrystalline cellulose 
 magnesium stearate 
Emodepside tablet #416 contains granules of emodepside and the polymer 
copovidone as a solid dispersion to enhance solubility.  Tablets contain 5 mg active 
substance (emodepside) and the following excipients: 
 copovidone 
 macrogol 15 hydroxystearate 
 croscarmellose sodium 
 microcrystalline cellulose 
 magnesium stearate 
Both tablets are film-coated with a coating composed of hypromellose, macrogol, 
ferric oxide red, and titanium dioxide.  They are identical in appearance: they are 
both round, pink, tablets with a diameter of 5 mm.  Bulk tablets are packaged in 
HDPE bottles with a desiccant capsule inside each bottle and the bottles are closed 
with child-resistant polypropylene screw cap closures with induction seal. 
Subjects will be instructed to swallow the IR-tablets whole, without chewing the 
medication prior to swallowing. 
Detailed information on the drug substance emodepside (BAY 44–4400) is given in 
the Investigator’s Brochure. 
7.4. IMP supply and handling 
Formulation and Supplier:   
Emodepside will be supplied by the Sponsor, DNDi, as emodepside LSF solution and 
IR-tablets (#406 and #416). 
The Sponsor will supply the bulk study drug to the study site.  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 and IR-tablets will be dispensed in the Phase 1 Unit into 
individual dosing containers by 2 appropriately qualified members of the pharmacy 
team.  Instructions provided in the Pharmacy Manual/Study Procedures Manual must 
also be followed. 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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7.5. 
Dose decision 
The decision to go ahead with one or both treatments in Part 2 will be made based 
on the safety, tolerability and PK of the treatments in Part 1. 
The dose decision will be made by the Safety Review Group (SRG) at the Safety 
Review Meeting.  The treatments will not be decided until the SRG has reviewed the 
safety, tolerability and PK data of at least 10 subjects per treatment.  Safety, 
tolerability and PK data up to a minimum of 72 h post-dose should be reviewed 
before a decision can be made. 
The treatments in Part 2 will be tested only if the Investigator and Sponsor’s medical 
representative agree that it is appropriate to give the higher dose. 
7.6. 
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 AEs, 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 Medicines and Healthcare products Regulatory 
Agency (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; 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
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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 Reference 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 CRF. 
7.9. 
Storage 
Emodepside oral LSF solution should be stored at 2°C – 8°C in the original container 
(upright storage).  
Emodepside IR-tablets should be stored in the original container, and the storage 
temperature should not exceed 25°C.  The tablets should be stored in the original 
packaging in order to protect them from moisture. 
7.10. 
Blinding and procedures for unblinding 
Not applicable – this is an open-label study. 
7.11. 
Concomitant treatments 
Prior therapy as indicated in the exclusion criteria section (Section 4.2) will not be 
permitted.  The only exception is acetaminophen (paracetamol), which may be taken 
at any time before the dose of trial medication. 
No medications (with the exception of acetaminophen (paracetamol) up to 2 g/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 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.  No dietary supplements or herbal remedies which are known to interfere 
with the CYP3A4 metabolic pathway and/or P-gp transport 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 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 dose of study medication will be 
documented as a prior medication.  Medications taken after the dose of study 
medication will be documented as concomitant medications. 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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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 16.1. 
8.2. 
Timing of Assessments  
All procedures will be conducted according the Schedule of assessments in 
Section 5. 
Baseline will be considered as the last assessment performed prior to randomisation. 
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 
be adhered to, where possible: 
 12-lead ECGs (single readings, with the exception of triplicate reading at 
screening and pre-dose) 
 HR/BP (single readings, with the exception of triplicate reading at 
screening and pre-dose) 
 AE monitoring (spontaneous and solicited AE monitoring will include 
specific questioning for tolerability and safety) 
 PK blood sampling (at the nominal time) 
 Laboratory safety blood and urine samples 
 Physical examinations 
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 time 
windows for study assessments are detailed in Section 8.8 of this protocol. 
To minimise variability, throughout the study, study staff should ensure a minimum 
10-minute supine period before the following assessments:  BP, HR, ECG; the rest 
period is also recommended before drawing blood samples. 
Throughout the study from the point of signing the ICF AEs 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, and at the specific time points 
detailed in the Schedule of assessments (Section 5). 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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8.3. 
Screening Visit 
All subjects will be screened within 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, within the allowed 4 weeks of 
screening period. 
Subjects will attend the ward, having fasted overnight for at least 10 h.   
The following assessments will be done to collect historical safety data, and to 
assess eligibility for the study: 
 Review of inclusion and exclusion criteria 
 Complete medical history:  including demographic data, previous and 
concomitant medications (i.e., prescription or non-prescription drugs, and dietary 
supplements taken within 28 days before the planned dose) 
 Full physical examination, including body weight and height:  see Section 8.11.3 
 Vital signs (BP and HR): see Section 8.11.2; 
 12-lead ECG: see Section 8.11.1 
 AE monitoring (spontaneous and solicited AE monitoring will include specific 
questioning for tolerability and safety) 
 Urinary drug screen (opiates, amphetamines, barbiturates, cannabis, 
benzodiazepines and cocaine-metabolites) and breath test for alcohol 
 Blood sampling for serology (HIV and hepatitis) 
 Blood sampling for clinical safety laboratory evaluations:   
 Haematology: haemoglobin, haematocrit, MCV, MCH, MCHC, platelets, 
reticulocytes, WBC including differential, RBC; 
 Coagulation:  aPTT, PT; 
 Biochemistry: serum AST, ALT, AP, GGT, LDH, CK, amylase, lipase, glucose, 
cholesterol (HDL, LDL, total), triglycerides, creatinine, urea, uric acid, bilirubin 
(total and conjugated), total protein, sodium, potassium, calcium, chloride and 
magnesium; 
 Urinalysis: by dipstick – glucose, ketone bodies, specific gravity, occult blood, 
pH, proteins, leucocytes, bilirubin, urobilinogen, nitrites.  Microscopy will be 
done only if the dipstick test for protein, blood, leukocyte esterase or nitrites is 
abnormal. 
To prepare for study participation, subjects will be instructed on the unit- and study-
specific restrictions described in Section 4.3 (Dietary and lifestyle guidance). 
8.4. 
Admission to Ward (Day 1) 
Subjects will be admitted to the ward at the Phase 1 Unit, on Day –1 at approximately 
1600 h, and will have a brief physical exam, urinary drug screen, and alcohol breath 
test. 
Subjects will fast according to the requirements in Section 4.3. 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
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8.5. 
Profile day (Day 0) 
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.  Subjects taking 
Treatment D and E will consume breakfast before their dose (see Section 4.3). 
Emodepside will be administered, with approximately 240 mL of water21, between 
0800–1100 h.  The following assessments will be done before and/or after dosing at 
the time points given in the Schedule of assessments (Section 5).  
 Scheduled AE monitoring 
 12-lead ECGs 
 Vital signs (BP and HR) 
 Clinical safety laboratory evaluations (haematology, coagulation, 
biochemistry, urinalysis) 
 Blood sampling to assay emodepside in plasma 
8.6. 
Post-dosing days (Days 1–3) 
Subjects will remain on the ward until the morning of Day 3, and have the following 
assessments at the time points given in the Schedule of assessments (Section 5). 
 Scheduled AE monitoring 
 12-lead ECG 
 Vital signs (BP and HR) 
 Clinical safety laboratory evaluations (haematology, coagulation, 
biochemistry, urinalysis) 
 Blood sampling to assay emodepside in plasma 
 Brief (directed) physical examination and short neurological examination 
A full neurological examination may be conducted, as required. 
8.7. 
Outpatient (ambulatory) visit (Day 5) and Follow-up visit (Day 7) 
Subjects will return to the clinic for an outpatient visit and the Follow-up Visit, as 
scheduled in the Schedule of assessments (Section 5).  The following assessments 
will be done. 
 Scheduled AE monitoring 
 12-lead ECG 
 Vital signs (BP and HR) 
 Clinical safety laboratory evaluations (haematology, coagulation, 
biochemistry, and urinalysis) 
 Blood sampling to assay emodepside in plasma  
 Physical examination (brief or full) and short neurological examination 
A full neurological examination may be conducted, if clinically indicated or to 
investigate treatment-emergent adverse events. 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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8.8. 
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 8.10 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 in the ward, and additional outpatient visits, will be 
permitted in the event of a technical failure, and/or if extra observations or samples of 
blood are needed for safety purposes.   
In the case of any post-dose samples for PK 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 dosing; 
 Deviations of not more than 15 min on measurements scheduled from 
after 4 h to 24 h after dosing; 
 Deviations of not more than 1 h on measurements scheduled more than 
24 h after dosing; and 
 Deviations of not more than 3 h on measurements scheduled on Day 5 
and Day 7. 
For all other procedures (including pre-dose PK sample), the following will not be 
regarded as protocol deviations: 
 
 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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Table 3.  Permitted allowed time windows for all other procedures 
Time point 
(Day 0) 
Deviation window in relation to the 
scheduled time point 
Pre-dose 
Within 75 min before dosing1 
(Part 1b: all procedures to be completed 
before breakfast) 
Up to and including 4 h 
after dosing 
± 10 min 
After 4 h to 24 h after 
dosing 
± 15 min 
More than 24 h after 
dosing 
± 1 hour 
Ambulatory visits 
Any time on the scheduled day 
1. Urine collection for laboratory safety tests will be within 2 h of the 
scheduled time point and Day 0 urine sample to be collected pre-dose. 
8.9. 
PK assessments 
Blood samples for assay of emodepside will be collected at the time points indicated 
in the Schedule of assessments (Section 5).  The exact date and time of PK blood 
sampling will be recorded in the CRF. 
Blood samples for emodepside assay will be taken from either arm.  Samples will be 
collected either via a cannula 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 Table 4.   
Plasma will be analyzed 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 the Profile Day 
(Day 0), frequent blood samples will be collected for PK estimation and emodepside 
plasma concentrations.  The following PK parameters of emodepside will be derived 
for each subject: 
Pharmacokinetic parameters 
Text Symbol 
Definition 
Calculation 
Concentrations and times 
Cmax 
Maximum (peak) 
plasma concentration 
The maximum (peak) plasma 
concentration will be obtained directly 
from the concentration–time data. 
Cmax/Dose 
Dose-normalised Cmax 
The dose-normalised Cmax will be 
calculated as Cmax /Dose 
administered 
Cmax,norm 
Observed maximum 
plasma concentration 
corrected by dose and 
body weight 
The Cmax normalised by dose and 
body weight will be calculated as  
Cmax/(Dose administered*body 
weight) 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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Text Symbol 
Definition 
Calculation 
tmax 
Time to reach maximum 
(peak) plasma 
concentration 
The first time of maximum (peak) 
plasma concentration will be obtained 
directly from the concentration–time 
data. 
Half-life 
Z 
Terminal rate constant 
The apparent terminal phase rate-
constant (Z) will be estimated by 
linear regression of logarithmically 
transformed concentration versus 
time data. 
t1/2,0-24h 
Dominant half-life 
The half-life calculated from the 
terminal slope of the log 
concentration-time curve (0–24 h), as 
follows: 
𝑡½ = log𝑒2
𝑧
 
t1/2 
Terminal elimination 
half-life  
The terminal half-life calculated from 
the terminal slope of the log 
concentration-time curve, as follows: 
𝑡½ = log𝑒2
𝑧
 
Points terminal 
Number of points for z 
The number of time points used in 
calculating Z 
Areas under the curve 
AUClast 
Area under the plasma 
concentration-time curve 
from time zero to time of 
last measurable 
concentration 
The area under the concentration-time curve 
from zero time (pre-dose) to the time of last 
quantifiable concentration will be calculated 
using the (specified) trapezoidal method.  
AUC0-7d 
Area under the plasma 
concentration–time 
curve from time zero to 
7 days 
The area under the concentration-
time curve from zero time (pre-dose) 
to 7 days will be calculated using the 
(specified) trapezoidal method.  
 
If z is not estimable, a partial AUC is 
not calculated (when tlast<t). 
AUC0-7d/Dose 
Dose-normalised AUC 
from time zero to 7 days 
The dose-normalised AUC from time 
zero to 7 days will be calculated as 
AUC0-7d/Dose administered 
AUC0-7d,norm 
Area under the 
concentration-time 
curve from time zero to 
7 days corrected by 
dose and body weight 
The AUC from time zero to 7 days 
normalised by dose and body weight 
will be calculated as  
AUC0-7d/(Dose administered*body 
weight) 
Mean residence time 
MRTlast 
Mean Residence Time 
The mean residence time will be 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
Confidential  
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Text Symbol 
Definition 
Calculation 
calculated using: 
last
AUC
AUMC
MRT 
 
8.10. 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 planned total blood volume to be taken from each subject during the study is 
158 mL. 
Additional blood may need to be collected for assay of emodepside, or for laboratory 
safety tests.  No more than an extra 80 mL blood will be taken. 
Table 4.  Blood volumes 
Test 
Planned 
number of tests 
Volume  
(mL) 
Total planned 
blood volume 
(mL) 
Haematology 
7 
2 
14 
Biochemistry 
7 
2.5 
17.5 
Coagulation 
7 
3 
21 
Serology  
1 
2.5 
2.5 
 
 
 
 
 
 
 
 
Emodepside PK 
18 
5 
90 
Discard (when using 
a cannula) 
13 
1 
13 
 
 
Total 
158 mL 
When using a cannula: after each blood sample, the cannula will be flushed with 3 to 
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 1 mL will be drawn via the cannula into the sampling syringe, and discarded. 
The definitive blood sample will then be taken. 
8.11. Assessment of Safety  
Safety of the treatments will be assessed through routine monitoring of adverse 
events.  
From screening (for AE onset after the subject signs the ICF), daily during the 
in-patient phase, then at the outpatient and Follow-Up Visits, the patients will be 
enquired about current adverse events or any events observed during the period 
previous to the visit.  
In addition, 12-lead ECG recording, regular measurement of vital signs and physical 
examinations, clinical laboratory parameters monitoring, will be made at scheduled 
follow-up visits. (See Section 9 for AE recording and reporting, and the descriptions 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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below.) 
8.11.1. 
12-lead ECG Safety recording 
Standard 12-lead ECGs will be recorded at the times given in the Schedule of 
assessments (Section 5).  Triplicate ECGs will be done at screening (about 1 minute 
between recordings); single readings will be done at all other time points.  
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 adverse event (see AE definition in 
Section 9.1).  If out of range at screening, the ECG may be repeated once. 
8.11.2. 
Vital signs 
BP and HR will be measured, in the supine position after 10 minutes rest, at times 
detailed in the Schedule of assessments (Section 5).   
BP and HR will be measured using using SpaceLabs oscillometric equipment. 
During the trial, vital signs will be repeated if they fall outside the following ranges: 
 Supine systolic BP:   
85 – 160 mm Hg 
 Supine diastolic BP:   40 – 90 mm Hg 
 Supine HR:   
 
35 – 100 beats/min 
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 adverse event) and decide on an appropriate 
course of action.  If out of range at screening, vital signs may be repeated once. 
Oral temperature will be measured using oral thermometers. 
8.11.3. 
Physical examination and neurological 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.  
At certain time points, as detailed in the Schedule of assessments (Section 5), a brief 
(symptom-directed) physical and short neurological examination will be performed. 
Height and body weight will also be measured at screening; body weight will be 
measured on Day –1. 
Neurological examination will be done by a physician, in case it is clinically indicated, 
or to investigate treatment-emergent AEs.  At the time-points in the Schedule of 
assessments (Section 5), a short neurological examination will be done, which 
includes an informal psychological assessment (e.g. orientation to place and time).  
Any abnormalities will trigger the full neurological examination or opening of an AE as 
appropriate.  The full neurological examination may include (but is not limited to) any 
of the following:  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); 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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mood; and sleepiness.  Abnormalities assessed as clinically significant will be 
reported as adverse event (see AE definition in Section 9.1). 
8.11.4. 
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 Reference 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).  Data from analysers that are not interfaced will be entered manually into the 
LIMS.  Confirmed abnormal laboratory results (after repeat) will be assessed for 
clinical significance and reported as AEs if necessary. 
Collection of samples for laboratory safety tests:  Blood will be taken for 
haematology (2 mL in EDTA), and biochemistry (2.5 mL in tubes with a gelatin plug), 
and coagulation (3 mL in sodium citrate).  At screening, blood will be taken for 
serology (2.5 mL in tubes with a gelatin plug).  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 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 
When reporting an abnormal lab, a clinical diagnosis should be recorded rather than 
the abnormal value itself, if available (for example, "anaemia" rather than "decreased 
red blood cell count"). 
9. 
Adverse Event definitions and reporting 
9.1 
Adverse Event definition 
An adverse event will be defined as: 
Any untoward medical occurrence in a clinical trial subject administered a medicinal 
product that does not necessarily have a causal relationship with that treatment.  An 
AE can therefore be any unfavourable and unintended sign (e.g.  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 (i.e., ECG, X-ray, etc.) 
or laboratory results which are assessed as "clinically significant".  Information on 
AEs must be evaluated by a physician.  Each AE is to be classified by the 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
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Investigator as serious or non-serious.  This classification will determine the reporting 
procedure for the event. 
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. 
9.2 
Serious Adverse Event (SAE) 
An AE will be defined as serious if it: 
 results in death 
i.e.  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 
i.e.  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 (i.e.  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 
i.e.  The AE resulted in a substantial disruption of the subject’s ability to 
conduct normal activities. 
 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 adverse event/reaction. 
9.3 
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 assessments (Section 5).  
Each AE will be assessed for severity, and causality (see definitions in Section 9.6 
and 9.7).  In addition, each AE is to be classified by the Investigator as serious or 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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non-serious (see definition in Section 9.2).  This classification will determine the 
reporting procedure for the event (see Section 9.5). 
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 adverse events are to be reported on the CRF, which is to be submitted 
to DNDi as specified in Section 13.2.  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. 
Serious AEs will be reported both on the AE CRF and the SAE forms. 
9.4 
Adverse Event reporting period 
The adverse events reporting period begins upon subject enrolment in the trial (after 
signature of the ICF) and ends at the Follow-up Visit.   
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. 
9.5 
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 
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 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 REC of SAEs 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 IMP (as defined in Section 9.7) 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 
MHRA and the European Medicines Agency (EMA) of all SUSARs, and will be 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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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 
calendar days after DNDi becomes aware of the event. 
9.6 
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 CRFs. 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 (e.g. 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. 
9.7 
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, i.e. 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. 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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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 IMP.  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. 
9.8 
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 90 days after the 
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 90 days after administration 
of the 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 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 (i.e. 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. 


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9.9 
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 (i.e. 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 IMP 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). 
10. 
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. 
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 (See the Schedule of assessments [Section 5]). 
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 and 
PK data, which should be collected if possible and in accordance with additional 
subject consent.  The Sponsor may retain and continue to use any data collected 
before any withdrawal of 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-emergent AE (TEAE), thorough efforts should be made to clearly 
document the outcome of that TEAE.The Investigator should inquire about the 
reason for withdrawal, request the subject to return for a final visit, if applicable, and 
follow-up with the subject regarding any unresolved TEAEs. 
Subjects who withdraw, or are withdrawn from the study, may be replaced at the 
discretion of the Investigator upon consultation with the Sponsor.  
Furthermore, the Investigator may withdraw a subject for the following 
reasons: 
 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 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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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. 
 
11. 
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. 
11.1. Sample size determination 
No formal statistical sample size estimation has been performed, due to the 
exploratory nature of this study.  
10 subjects per treatment arm is considered sufficient to examine the safety and 
tolerability of emodepside, as well as the PK after single doses.  However, 12 
subjects will be recruited and enrolled per treatment arm to ensure a minimum of 
10 evaluable subjects complete the study. 
11.2. 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 PK sample has been analysed.  
 PK Parameter Population:  All subjects in the PK Concentration Population for 
whom PK parameters can be derived.  
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 (e.g. Q1, and Q3) will be presented 


Protocol number (DNDI-EMO-03)  
 
Emodepside (BAY 44-4400) 
Protocol Version/Date:  Version 3, 01 February 2018 
 
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to one additional decimal place.  The standard deviation and standard error will be 
presented to 2 additional decimal places. 
11.3. Subject Disposition  
The disposition of all subjects in the safety population will be summarized including: 
number of subjects randomized (or treated, for non-randomised groups); 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. 
11.4. Efficacy Analysis 
Not applicable.  
11.5. Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics (e.g. medical history, physical 
examination, vital signs, weight and ECGs) 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. 
11.6. Safety Analysis 
Safety and tolerability data will be summarized using the following parameters:  
• 
Vital signs; 
• 
12-lead ECG; 
• 
Haematology; 
• 
Clinical chemistry; 
• 
Coagulation; 
• 
Urinalysis; 
• 
Physical examination; 
• 
Neurological examination; 
• 
AEs. 
No formal hypothesis testing of these parameters will be carried out. 
11.6.1. 
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.  


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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 1 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 msec22,23.   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. 
Abnormal physical examination findings (with or without clinical significance) will be 
listed. 
11.6.2. 
Haematology, Coagulation 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 (i.e. haematology or clinical chemistry). Frequencies of laboratory 
values of potential clinical importance will be summarised. 
11.6.3. 
Urinalysis parameters 
These parameters will be individually listed and summarized. 
11.6.4. 
Physical and neurological examination 
An individual data listing of abnormal physical and neurological examination findings 
(with or without clinical significance) will be provided. 
11.6.5. 
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 13.2. 
Adverse events will be coded using the version of the Medical Dictionary for 
Regulatory Activities (MedDRA) current at the time of database lock. 


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All AEs will be listed. 
An AE will be considered as treatment emergent if it appeared after the 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 on the dosing day, the AE will be 
considered as a 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 serious adverse events will be listed 
separately (fatal events will be listed separately from non-fatal events).   
11.7. 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 mean23; 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 will be listed and 
summarised, by treatment, using descriptive statistics.  Individual and mean plasma 
concentration–time profiles will be presented graphically. 
To assess the relative bioavailability, analysis of variance (ANOVA) models will be 
fitted to the tablet (test) and solution (reference) data with the logarithm of the 
pharmacokinetic parameters AUC0-7d/Dose or Cmax/Dose as the dependent variable, 
and formulation as a fixed effect.  The point estimates least squares (LS)-means and 
90% confidence intervals for the ratios “B / A” and “C / A” will be calculated in 
Part 1a.  In Part 2, “F/A” and/or “G/A” will be calculated. The acceptance range 80 – 
125% will be applied for these assessments.   
To assess the effect of food, ANOVA models will be fitted to the data with the 
logarithm of the pharmacokinetic parameters AUC0-7d/Dose or Cmax/Dose as the 
dependent variable, and fed (test) or fasted (reference) as a fixed effect.  In Part 1, 
the point estimates and 90% confidence intervals for the ratios “D/B” and “E/C”  will 


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be calculated.  The acceptance range 80 – 125% will be applied for the assessment 
of a potential food effect.   
To assess dose proportionality, for each tablet type, exploratory ANOVA models will 
be fitted to the relevant fasted data in Parts 1 and 2 with the logarithm of the 
pharmacokinetic parameters AUC0-7d or Cmax as the dependent variable and dose as 
a fixed effect.  The ratios “F/B” and/or “G/C” will be calculated. 
12. 
Safety Review Meetings 
Safety will be reviewed between Part 1 and Part 2 of the study in a Safety Review 
Meeting.  Participants in the Safety Review Meeting (‘the Safety Review Group’ 
[SRG]) 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. This meeting 
will follow DNDi SOP CL 26 (Safety Data Review during Phase I clinical trial) and will 
be described in the Safety Review Group charter. 
13. 
Quality Assurance and Quality Control Procedures 
13.1. 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. 
13.2. Case report forms 
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 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 predefined in the 
Source Data Agreement. 
For subjects who are subsequently enrolled, study-specific information will be 
entered into the CRF.  All CRF data should be anonymized, i.e., identified by study 
subject number only. 
The Investigator 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 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 screened subjects who leave 


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the study before enrolment, will be recorded in the CRF but not entered in to the 
database. 
13.3. Source documents 
Before the start of the study, the sponsor and investigator will sign an agreement 
listing the source documents to be used in this trial.  The verification of the 
CRF/SAE/pregnancy/child and query data must be by direct inspection of source 
documents.  Source documents include subject 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, General 
Practitioner, pharmacy records, 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. 
13.4. 
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. 
13.5. 
Monitoring, audits and inspections 
Monitoring visits to the trial site will be made periodically by DNDi representatives or 
designated clinical monitors to ensure that GCPs 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/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 
Investigator's obligations are being fulfilled.  Four visit types are planned: pre-study, 


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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 CRFs 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. 
13.6. 
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 REC. 
The Investigators will permit representatives of DNDi and/or designated clinical 
monitors to inspect all CRFs and 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. 
13.7. 
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. 
13.8. 
Confidentiality of trial documents and subjects records 
The Investigator must assure that subjects’ anonymity will be maintained and that 


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their identities are protected from unauthorized parties.  On CRFs/other forms 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.  
14. 
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 (e.g. 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.  
15. 
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 
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 


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 Following the recommendation of the Drug Safety and Monitoring Board 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 Visit are followed up with the necessary medical care. 
 Provide in writing the reasons for the decision to the national health authority 
and the Sponsor. 
16. 
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)24.  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 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 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 REC and subsequently 
by the 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 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 


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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 ICF which 
has been approved by London – Brent REC 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 9.5), 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 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 
serious adverse event that occurs during this trial (see Section 9.5). The Investigator 
will provide the REC with annual progress reports of the trial, if the trial lasts longer 
than a year. 
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. 
The Sponsor will supply a summary of the clinical trial report 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. 
16.1. 
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 


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(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.  
16.2. 
Compensation of volunteers 
The Sponsor agrees to abide by the Association of the British Pharmaceutical 
Industry Guidelines for medical experiments in healthy human volunteers 
(2012 edition)24 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. 
16.3. 
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. 
16.4. 
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 IMP, 
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. 
16.5. 
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. 
 
 


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17. 
References 
 
1. 
WHO. Global programme to eliminate lymphatic filariasis: progress report 
2014. Wkly. Epidemiol. Rec. 90, 489–504 (2015). 
2. 
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). 
3. 
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). 
4. 
Organisation Mondial de la Santé (OMS). Progress report on the elimination of 
human onchocerciasis, 2015-2016. 91, 501–516 (2016). 
5. 
Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-Antiarrhythmic Drugs. ICH Guidance for Industry E14, 2005. 
6. 
Okoye, I. C. & Onwuliri, C. O. Epidemiology and psycho-social aspects of 
onchocercal skin diseases in northeastern Nigeria. Filaria J. 6, 15 (2007). 
7. 
Amazigo, U. O. Detrimental effects of onchocerciasis on marriage age and 
breast-feeding. Trop. Geogr. Med. 46, 322–325 (1994). 
8. 
Alonso, L. M., Murdoch, M. E. & Jofre-Bonet, M. Psycho-social and economic 
evaluation of onchocerciasis : a literature review . Soc. Med. 4, 8–31 (2009). 
9. 
WHO. Working to overcome the global impact of neglected diseases - 
summary -  First WHO report on neglected tropical diseases. (2010). 
10. 
GBD 2015 DALYs and HALE Collaborators. Global, regional, and national 
disability-adjusted life-years (DALYs) for 315 diseases and injuries and 
healthy life expectancy (HALE), 1990-2015: a systematic analysis for the 
Global Burden of Disease Study 2015. Lancet (London, England) 388, 1603–
1658 (2016). 
11. 
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. 48, 271–84 (1991). 
12. 
Schulz-Key, H. & Soboslay, P. T. Reproductive Biology and Population 
Dynamics of Onchocerca Volvulus in the Vertebrate Host. PARASITE Biol. 
Biochem. 1, 53–55 (1994). 
13. 
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). 
14. 
Meredith, S. E. & Dull, H. B. Onchocerciasis: The First Decade of MectizanTM 
Treatment. Parasitol. Today 14, 472–474 (1998). 
15. 
Fobi, G. et al. Managing the Fight against Onchocerciasis in Africa: APOC 
Experience. PLoS Negl. Trop. Dis. 9, e0003542 (2015). 
16. 
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). 
17. 
Zahner et al. Filaricidal efficacy of anthelmintically active cyclodepsipeptides. 
Int J Parasitol. 31, 1515-22 (2001). 
18. 
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). 
19. 
Willson, et al. The effect of the anthelmintic emodepside at the neuromuscular 
junction of the parasitic nematode Ascaris suum. Parasitology 126, 79-86 


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(2003). 
20. 
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).  
21. 
Committee for Human Medicinal Products (CHMP) Guideline on the 
investigation of drug interactions. CPMP/EWP/560/95/Rev. 1 Corr. 2. 
European Union 2012. 
22. 
Statistical principles for clinical trials.  ICH harmonised tripartite guideline E9, 
1998.  
23. 
Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for  Non-Antiarrhythmic Drugs.  ICH Guidance for Industry  E14, 
2005. 
24. 
Integrated addendum to ICH E6(R1):  Guideline for Good Clinical Practice 
E6(R2) 
25. 
Guidelines for Phase 1 Clinical Trials, 2012 Edition.  Association of the British 
Pharmaceutical Industry. 
 

SAP_001.pdf: 
HMR code:  17-008  
Sponsor code:  DNDI-EMO-03 
Hammersmith Medicines Research  
23 March 2018  
Page 1 of 61 
Statistical Analysis Plan 
Clinical trial protocol title:  
A Phase 1, Randomized, Open-Label, Parallel-Group, 
Relative Bioavailability Study to Investigate the 
Pharmacokinetics, including Food Effect, as well as the 
Safety and Tolerability of Single Doses of New 
Immediate Release Tablet Formulations of Emodepside 
(BAY 44-4400), compared to Oral Solution, in Healthy 
Male Subjects 
HMR code: 
17-008 
Sponsor code: 
DNDI-EMO-03 
EudraCT no: 
2017-003091-31 
CRO details: 
Hammersmith Medicines Research 
Cumberland Avenue 
London NW10 7EW 
Sponsor details: 
DNDi, Chemin Louis Dunant, 15, 
1202 Geneva Switzerland 
Phone: +41 22 906 9230 
 
Issued:  
23 March 2018 
Version:  
1 
Based on: 
Protocol Version 3, 1 February 2018 
Number of pages:  
61 
Prepared by:  
Helen Topping 


HMR code:  17-008  
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Table of contents 
1 
LIST OF ABBREVIATIONS .............................................................................5 
2 
SIGNATURES ......................................................................................................7 
3 
INTRODUCTION ................................................................................................8 
4 
STUDY OBJECTIVE(S) AND ENDPOINT(S) ................................................8 
4.1 
Study Objective(s) .....................................................................................8 
4.1.1 
Primary Objective ............................................................................................... 8 
4.1.2 
Secondary Objectives ......................................................................................... 8 
4.2 
Study Endpoint(s) ......................................................................................9 
4.2.1 
Primary Endpoint ............................................................................................... 9 
4.2.2 
Secondary Endpoints .......................................................................................... 9 
4.2.3 
Exploratory Endpoints ........................................................................................ 9 
4.3 
Statistical Hypotheses ................................................................................9 
5 
STUDY DESIGN ................................................................................................10 
6 
TIME AND EVENTS TABLE ..........................................................................12 
7 
PLANNED ANALYSES ....................................................................................14 
7.1 
Interim Analyses ......................................................................................14 
7.1.1 
Persons responsible for analysis ....................................................................... 14 
7.2 
Final Analysis ..........................................................................................14 
7.2.1 
Persons responsible for analysis ....................................................................... 14 
8 
SAMPLE SIZE CONSIDERATIONS .............................................................15 
8.1 
Sample Size Assumptions .......................................................................15 
9 
ANALYSIS POPULATIONS ...........................................................................15 
9.1 
Analysis Datasets .....................................................................................15 
10 
TREATMENT COMPARISONS .....................................................................15 
11 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ........................16 
11.1 
Data Display Treatment and Other Subgroup Descriptors ......................16 
11.2 
Conventions for Summary Statistics and Data Displays .........................16 
12 
DATA HANDLING CONVENTIONS ............................................................17 
12.1 
Premature Withdrawal and Missing Data ................................................17 
12.2 
Derived and Transformed Data ...............................................................17 
12.3 
Assessment Windows ..............................................................................18 
12.4 
Values of Potential Clinical Importance ..................................................18 
13 
STUDY POPULATION ....................................................................................18 
13.1 
Disposition of Subjects ............................................................................18 


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13.2 
Protocol Deviations .................................................................................19 
13.3 
Demographic and Baseline Characteristics .............................................19 
13.4 
Treatment Compliance ............................................................................19 
14 
SAFETY ANALYSES .......................................................................................19 
14.1 
Extent of Exposure ..................................................................................20 
14.2 
Adverse Events ........................................................................................20 
14.3 
Deaths, Serious Adverse Events and Other Significant Adverse Events 20 
14.4 
Adverse Events Leading to Withdrawal from the Study .........................21 
14.5 
Clinical Laboratory Evaluations ..............................................................21 
14.6 
Other Safety Measures .............................................................................21 
14.6.1 Vital signs ......................................................................................................... 21 
14.6.2 ECG .................................................................................................................. 21 
14.6.3 Physical and neurological examination ............................................................ 22 
15 
PHARMACOKINETIC ANALYSES ..............................................................22 
15.1 
Pharmacokinetic Concentration Data ......................................................22 
15.2 
Pharmacokinetic Parameters ....................................................................23 
16 
REFERENCES ...................................................................................................23 
17 
ATTACHMENTS ..............................................................................................24 
17.1 
Table of Contents for Data Display Specifications .................................24 
17.2 
Data Display Specifications .....................................................................29 
17.2.1 Table Outlines .................................................................................................. 29 
17.2.2 Figure Outlines ................................................................................................. 40 
17.2.3 Listing Outlines ................................................................................................ 44 
APPENDIX A: LABORATORY RANGES ................................................................55 
APPENDIX B: PHARMACOKINETIC ANALYSIS ................................................57 
1 
CALCULATION METHODS ..........................................................................57 
1.1 
Data Handling Conventions .....................................................................57 
1.1.1 
Actual vs Planned Times .................................................................................. 57 
1.1.2 
Missing and BQL Concentrations .................................................................... 57 
1.2 
AUC Calculations ....................................................................................57 
1.3 
Lambda-z Calculations ............................................................................57 
1.4 
Observed v Predicted Values ...................................................................58 
2 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS .........................58 
2.1 
Derived and transformed data ..................................................................58 
2.2 
Summary data ..........................................................................................58 
3 
PARAMETER DEFINITIONS ........................................................................59 


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3.1 
Plasma Parameters ...................................................................................59 
3.1.1 
Emodepside ...................................................................................................... 59 
APPENDIX C: SAMPLE PAGE LAYOUT ...............................................................61 
 


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1 
List of abbreviations 
λz 
Terminal rate constant 
AE 
Adverse Event 
ANOVA 
Analysis of variance 
AUC 
Area under concentration-time curve 
AUC0-t 
AUC from time zero to time t 
AUC0-t/Dose 
AUC from time zero t to time t, corrected for dose 
AUC0-t,norm 
AUC from time zero t to time t, corrected for dose and body weight 
AUClast 
AUC from time zero to last measurable concentration 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BQL 
Below the limit of quantification 
CI 
Confidence Interval 
Cmax 
Maximum Plasma Concentration 
Cmax/Dose 
Cmax corrected by dose 
Cmax, norm 
Cmax corrected by dose and body weight 
CRF 
Case Report Form 
CTR 
Clinical Trial Report 
       ECG 
Electrocardiogram 
HMR 
Hammersmith Medicines Research 
HR 
Heart Rate 
ICH 
International Conference on Harmonization 
IR 
Immediate Release 
LLOQ 
Lower Limit of Quantification 
LSF 
Liquid Service Formulation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean residence time 
MRTlast 
Mean residence time at last measurable concentration 
N 
Number of subjects 
n 
Number of observations used in analysis 
PCI 
Potential clinical importance 
PK 
Pharmacokinetic(s) 
PR 
Portion of the ECG from the beginning of the P wave to the beginning of the 
QRS complex, representing atrioventricular node function. 
Q1 
Lower quartile 
Q3 
Upper quartile 
QRS 
The QRS complex of the ECG reflects the rapid depolarization of the right 
and left ventricles. 
QT 
Portion of the ECG between the onset of the Q wave and the end of the T 
wave, representing the total time for ventricular depolarization and 
repolarization. 
QTc 
Corrected portion of the ECG between the onset of the Q wave and the end 
of the T wave, representing the total time for ventricular depolarization and 
repolarization. 
QTcB 
QTc interval with Bazett's correction method 
QTcF 
QTc interval with Fridericia's correction method 
RR 
 
Portion of the ECG between consecutive R waves, representing the 
ventricular rate 


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SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SRG 
Safety Review Group 
t1/2 
Terminal elimination half-life 
t1/2,0-t 
 Dominant half-life 
TEAE 
Treatment-Emergent Adverse Event 
tmax 
Time to maximum plasma concentration 
 
 
 




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3 
Introduction 
This Statistical Analysis Plan (SAP) is based on the current trial protocol (version 3, 1 
February 2018).  Where statistical methods differ substantially between this SAP and the 
protocol, that will be identified in this document. 
This SAP describes the datasets and the statistical methods to be used for the reporting and 
analysis of all data collected during the trial.   
The randomisation code will not be broken before this SAP is finalised.  If a future protocol 
amendment necessitates a substantial change to the statistical analysis of the trial data, this 
SAP will be amended accordingly.  If, after database lock, additional analyses are required to 
supplement the planned analyses described in this SAP, those unplanned analyses will not be 
described in an amended SAP, but they will be identified in the integrated clinical study 
report (CSR).  Any deviations from this SAP will be documented in the CSR. 
This SAP has been written in consideration of the following guidelines:   
 International Conference on Harmonization (ICH) E9, Guidance for Industry:  Statistical 
Principles for Clinical Trials (ICH E9 1998)1; and  
 ICH E3, Guidance for Industry: Structure and Content of Clinical Study Reports (ICH E3 
1995)2. 
Pharmacokinetic analysis will be done using WinNonlin v7 on a Windows PC.  Statistical 
analysis will be done using SAS 9.3 on a Windows PC. 
4 
Study Objective(s) and Endpoint(s) 
4.1 
Study Objective(s) 
4.1.1 Primary Objective 
To investigate the pharmacokinetics, including relative bioavailability and food effect, of two 
new immediate release (IR)-tablet formulations of emodepside in comparison to the liquid 
service formulation (LSF) oral solution. 
4.1.2 Secondary Objectives 
To investigate and compare safety and tolerability of single oral doses of emodepside 
formulations in healthy subjects. 


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4.2 
Study Endpoint(s) 
4.2.1 Primary Endpoint 
 Based on the plasma concentration–time data, the following PK parameters of 
emodepside will be calculated: 
o Main:  AUC0-7d, AUC0-7d/Dose, Cmax, Cmax/Dose 
4.2.2 Secondary Endpoints 
 
Safety and Tolerability Variables: 
o Adverse Events (AEs) 
o Physical and  neurological examination findings 
o Vital signs (BP and HR),  
o 12-lead ECG (HR, PR, QRS, QTcB, QTcF), will be analysed ad hoc for safety 
and for the final data base and report by central reading  
o 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); 
 Coagulation:  activated partial thromboplastin time (aPTT), 
prothrombin time (PT); 
 Biochemistry: serum aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (AP), gamma-glutamyl 
transpeptidase (GGT), lactate dehydrogenase (LDH), creatine kinase 
(CK), amylase, lipase, glucose, cholesterol (HDL, LDL, total), 
triglycerides, creatinine, urea, uric acid, bilirubin (total and 
conjugated), total protein, sodium, potassium, calcium, chloride and 
magnesium; 
 Urinalysis: by dipstick – glucose, ketone bodies, specific gravity, occult 
blood, pH, proteins, leucocytes, bilirubin, urobilinogen, nitrites, and 
microscopy (reflex). 
4.2.3 Exploratory Endpoints 
 Pharmacokinetic: 
o AUC0-7d,norm, Cmax,norm, t1/2,0-24h, t1/2,0-7d, tmax, MRT, points terminal 
4.3 
Statistical Hypotheses 
Except for the analysis of pharmacokinetic data, no formal statistical testing will be done.  


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5 
Study Design 
This is a single-centre, open-label, randomized, parallel-group relative bioavailability study in 
healthy men.  The study will be done in 2 parts, as follows: 
 Part 1 – single oral doses of 5 mg emodepside will be tested: 
o Part 1a – the LSF (reference formulation) and 2 new IR-tablet formulations 
(test formulations) will be administered in the fasted state. 
o Part 1b – the 2 new IR-tablet formulations will be administered in the fed state 
(high-fat, high-calorie meal). 
 Part 2 – single oral doses of 10 mg (2 x 5 mg) emodepside will be tested:  depending 
on the results from Part 1, one or both IR-tablet formulations will be administered in 
the fasted state.  
The treatments in each study part are summarised in Table 1. 
Table 1. Planned treatments by dose, formulation and condition 
Part 
Treatment 
Formulation, dose and condition 
Number of subjects 
Part 1a 
A 
5 mg emodepside LSF, fasted 
12 
 
B 
5 mg emodepside IR-tablet #406, fasted 
12 
 
C 
5 mg emodepside IR-tablet #416, fasted 
12 
Part 1b 
D 
5 mg emodepside IR-tablet #406, fed 
12 
 
E 
5 mg emodepside IR-tablet #416, fed 
12 
Part 2 
F* 
2 x 5 mg emodepside IR-tablet #406, fasted 
12 
 
G* 
2 x 5 mg emodepside IR-tablet #416, fasted 
12 
* one or both treatments may be tested, depending on results from Part 1 
Up to 84 healthy volunteers will be enrolled, in up to 7 treatment arms made up of 12 subjects 
each.   
The 36 subjects in Part 1a will be randomised to one of 3 treatments (A, B or C).  The 24 
subjects in Part 1b will be randomised to one of 2 treatments (D or E).  Parts 1a and 1b may 
proceed in parallel, or may be done sequentially. 
After at least 10 subjects in each arm have received  treatment in Part 1, and data up to 72 h 
after dosing are available, there will be a Dose Decision Meeting to determine which 
treatment(s) will be tested in Part 2 (see section 7.5). 
In Part 2, either treatment F, G or both F and G will be tested.  There will be 12 subjects 
enrolled for each treatment tested.  If both treatments are tested, they will be done in parallel, 
and subjects will be randomised to one of the 2 treatments. 


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The study will be performed in a single site specialized in Phase 1 studies. 


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6 
Time and Events Table  
Procedure 
Screening 
Inpatient 
Follow-up 
Day 28 to 2 Day –1 
Day 0 
Day 1 
Day 2 Day 3 Day 5 Day 7 
 
hours –1 
0 
0.25 0.5 
1 
1.5 
2 
2.5 
3 
4 
6 
8 
12 
24 
36 
48 
72 
120 
168 
Subject demographics and 
informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria - 
Eligibility check 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/prior medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient stay 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of emodepside1 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient visit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Drugs of abuse screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical and neurological 
examination2 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Vital signs3 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead safety ECG4 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Laboratory safety tests5,6 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
Serology7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood samples for assay of 
emodepside6 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE questioning8 
 
1. 
Subjects in Part 1a and Part 2 will fast for 10 h before until at least 4 h after dosing.  Subjects in Part 1b will be given a high-calorie, high-fat breakfast approximately 30 min 
before dosing, which they must finish at least 5 min before dosing.  Standard meals will be served at approximately 5 h (lunch), 8 h (snack) and 12 h (dinner) after dosing 
on Day 0.  Procedures scheduled at the same time as a meal will be completed before the meal. 
2. 
A full physical examination will be done at Screening and Follow-up.  A brief (symptom-directed) physical examination and short neurological examination will be 
undertaken  at all other time points. Any abnormalities will trigger a full neurological examination and/or opening of an AE as appropriate.  Height, weight and body mass 
index (BMI) will be assessed at screening, and weight will be assessed on Day –1.   
3. 
Vital signs will comprise supine blood pressure and heart rate.  Subjects should rest in the supine position for at least 10 min before vital signs measurements.  Vital signs 
will be measured in triplicate at screening and pre-dose (–1 h); single measurements at all other time points. Body temperature will be measured on day -1. 


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4. 
Subjects should rest in the supine position for 10 min before ECG measurements.  Measurement in triplicate at screening and pre-dose (–1 h); single measurements all 
other time points.  
5. 
Blood and urine samples for clinical laboratory safety tests (haematology, biochemistry, coagulation and urinalysis). 
6. 
Subjects should rest in the supine position for 10 minutes before blood is drawn (if possible).  
7. 
Serology tests will comprise HIV 1 & 2 and hepatitis B & C. 
8. 
Adverse event monitoring will be done throughout the study, but scheduled questioning will be done at the time points of scheduled blood draws.  
 
 
 


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7 
Planned Analyses 
7.1 
Interim Analyses 
The decision to go ahead with one or both treatments in Part 2 (10mg [2 x 5mg] of IMP) will 
be made based on the safety, tolerability and PK of the treatments in Part 1 (5mg of IMP). 
The dose decision will be made by the Safety Review Group (SRG) at the Safety Review 
Meeting. The treatments will not be decided until the SRG has reviewed the safety, 
tolerability and PK data of at least 10 subjects per treatment. Safety, tolerability and PK data 
up to a minimum of 72 h post-dose should be reviewed before a decision can be made. 
 
7.1.1 Persons responsible for analysis 
Toni Mitchell (HMR) 
Statistician 
Nick Jackson (HMR) 
SAS Programmer 
7.2 
Final Analysis 
Each part of the study (Part 1 and Part 2) will have a separate database and will be analysed 
and reported separately.  Each database will be locked once all subjects have completed, data 
have been entered, all queries resolved and protocol deviations identified for that part of the 
study.  Final analyses will be carried out following database lock for each individual part of 
the study.  
7.2.1 Persons responsible for analysis 
Helen Topping  (HMR) 
Statistician 
Nick Jackson (HMR) 
SAS Programmer 
Duyen Unsworth  (HMR) 
Data Manager 
 


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8 
Sample Size Considerations 
8.1 
Sample Size Assumptions 
No formal statistical sample size estimation has been performed, due to the exploratory nature 
of this study.  
10 subjects per treatment arm is considered sufficient to examine the safety and tolerability of 
emodepside, as well as the PK after single doses.  However, 12 subjects will be recruited and 
enrolled per treatment arm to ensure a minimum of 10 evaluable subjects complete the study. 
9 
Analysis Populations 
The following populations 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 PK sample has been analysed.  
 
PK Parameter Population:   
All subjects in the PK Concentration Population for 
whom PK parameters can be derived.  
 
In all populations, treatment will be assigned based upon the treatment subjects actually 
received, regardless of the treatment to which they were randomized. 
 
The primary endpoint will be analysed using the PK Parameter population. 
 
 
9.1 
Analysis Datasets 
All analysis datasets will be based on observed data, except as outlined in Section 12.2. 
10 
Treatment Comparisons 
The treatment comparison of interest is test (IR-tablet formulations) versus reference (LSF). 


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11 
General Considerations for Data Analyses 
11.1 Data Display Treatment and Other Subgroup Descriptors 
The sort order for treatment groups will be treatment in ascending dose order.  When a total 
column is included, it immediately follows the treatment groups which it aggregates. 
Listings of data will be sorted and displayed by treatment group, subject number, and also by 
date and time if applicable.   
The treatment descriptions to be used on all tables and listings are:  
 
Treatment Groups  
 
Short Description 
Emodepside LSF 5 mg [fasted] 
LSF 5 mg [fasted] 
Emodepside IR-tablet #406 5 mg [fasted] 
IR #406 5 mg [fasted] 
Emodepside IR-tablet #416 5 mg [fasted] 
IR #416 5 mg [fasted] 
Emodepside IR-tablet #406 5 mg [fed] 
IR #406 5 mg [fed] 
Emodepside IR-tablet #416 5 mg [fed] 
IR #416 5 mg [fed] 
Emodepside IR-tablet #406 10 mg [fasted] 
IR #406 10 mg [fasted] 
Emodepside IR-tablet #416 10 mg[fasted] 
IR #416 10 mg [fasted] 
 
11.2 Conventions for Summary Statistics and Data Displays 
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 with the same number of decimal 
places as the raw data collected on the CRF (or to 3 significant figures for derived parameters 
less than 100 and as integers for values more than 99). The mean and percentiles (e.g. median, 
Q1, and Q3) will be presented using one additional decimal place. The standard deviation and 
standard error will be presented using two additional decimal places.  


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12 
Data Handling Conventions 
12.1 Premature Withdrawal and Missing Data 
All subjects who withdraw prematurely from the study and received the study drug will be 
included in the statistical analyses.  
If a subject completes the treatment period but has missing data, then this will be made 
apparent in the subject listings. Missing data will not be imputed except for as outlined in 
Section 12.2.   
If the study is prematurely discontinued, all available data will be listed and a review will be 
carried out to assess which statistical analyses are still considered appropriate. 
Data collected at unscheduled time points during the study will not be used in the summaries 
or data analyses.  They will be included in the listings. 
If time information (i.e. hours and/or minutes) for adverse events or concomitant medication 
is missing, but the day is present, then the time will be calculated in days.  If date information 
is partial or missing, then any derived times (e.g. AE start time from last study medication) 
will be listed as missing.  
Conventions for handling missing plasma concentrations are given in Appendix B. 
12.2 Derived and Transformed Data 
Baseline will be considered to be the latest value obtained before study drug administration 
(e.g. Day 0, pre-dose; or Day -1 if not recorded pre-dose; or Screening if not recorded 
elsewhere (e.g. body weight)).   
Laboratory data will be reported in standard units.  Out-of-range laboratory tests may be 
repeated.  If a test is out-of-range at a baseline time point and repeated before dosing, the 
latest repeat value before dosing will be used as baseline.  However, if a test is out-of-range 
and repeated at any other time during the study, the out-of-range value (not the repeat value) 
will be included in statistical summaries. 
Triplicate ECG and vital sign measurements will be made at pre-dose on Day 0 and the mean 
of the three measurements for each subject will be used as their baseline value for that 
session. 
The pharmacokinetic parameters to be derived are given in Appendix B. 


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12.3 Assessment Windows 
No assessment windows are defined for this report. 
12.4 Values of Potential Clinical Importance 
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 (Day 0 pre-dose) by more than 
a predetermined amount (as defined by the Principal Investigator, Appendix A), 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.   
A vital signs result will be considered to be of potential clinical importance if it falls outside 
the relevant range below: 
Vital Sign 
Range 
Supine/semi-recumbent systolic blood pressure 
85–160 mm Hg 
Supine/semi-recumbent diastolic blood pressure 
40–90 mm Hg 
Supine/semi-recumbent heart rate 
35–100 beats/min 
Respiration rate 
8–20 per min 
Oral temperature 
35.5–37.8°C 
 
QT, QTcB or QTcF > 450 msec  and increases in QT, QTcB or QTcF from baseline (Day 1 
pre-dose) of > 30 msec will be considered to be potentially clinically important.   
13 
Study Population 
13.1 Disposition of Subjects 
The disposition of all subjects in the safety population will be summarized including: number 
of subjects randomized (or treated, for non-randomised groups); 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. 


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All subjects who withdraw or are withdrawn from the study will be listed, by treatment, with 
the reason for withdrawal.  
A listing of analysis populations will be provided. 
 
13.2 Protocol Deviations 
Before closing the database, data listings will be reviewed to identify any significant 
deviations and determine whether the data should be excluded from any analysis populations.   
Major protocol deviations include subjects who: 
 Entered the study even though they did not satisfy the entry criteria. 
 Met the criteria for withdrawal from the study but were not withdrawn. 
 Received the wrong treatment or incorrect dose. 
 Received an excluded concomitant therapy. 
 Received investigational product(s) past the expiration date. 
 
In addition, subjects with minor time deviations (measurements taken outside the allowable 
windows) will be identified.  Allowable time windows for pharmacokinetic samples and other 
procedures are given in section 8.8 of the study protocol. 
 
13.3 Demographic and Baseline Characteristics 
Demographic and baseline characteristics (e.g. physical examination, vital signs and ECGs) 
will be listed and summarised.  
Subjects who take concomitant medication will be listed.  All non-trial medication will be 
coded using the version of the WHODrug Global that is current when the database is locked. 
13.4 Treatment Compliance 
Dates and times of dosing will be listed.  
14 
Safety Analyses 
Summaries and listings of safety data will use the safety population.  
 


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14.1 Extent of Exposure 
The dates and times of treatment dosing will be listed to indicate exposure to the study 
medication. 
14.2 Adverse Events 
Adverse events will be coded using the version  of the Medical Dictionary for Regulatory 
Activities (MedDRA) which is current at the time of database lock (version 20.1 or higher).   
All adverse events will be listed. 
The number of subjects with at least one treatment-emergent adverse event (TEAE) will be 
tabulated by actual treatment and MedDRA system organ class.  A treatment-emergent 
adverse event is defined as an event emerging during treatment having been absent pre-
treatment or having worsened relative to pre-treatment1.  
For each of the following, the number of adverse events and the number of subjects with 
adverse events will be summarised: 
 TEAEs by system organ class and preferred term 
 TEAEs by system organ class, preferred term and severity 
 Drug-related (“Related” as recorded by the Investigator) TEAEs by system organ class      
and preferred term 
Subjects with more than one TEAE will be counted only once, at the greatest severity or 
causality, for each system organ class/preferred term.  Multiple TEAEs in a subject will be 
counted once per system organ class and preferred term.  Adverse events with missing 
severity and/or causality will be treated as severe and related, respectively. 
Summaries will be sorted by system organ class and decreasing total incidence of preferred 
term. 
14.3 Deaths, Serious Adverse Events and Other Significant Adverse 
Events 
Deaths and serious adverse events will be listed separately (fatal events separate from non-
fatal events).  Other significant adverse events, as identified by the investigator in the CRF, 
will be listed separately. 


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14.4 Adverse Events Leading to Withdrawal from the Study 
Adverse events leading to withdrawal will be listed separately.   
14.5 Clinical Laboratory Evaluations 
Data from haematology, coagulation, clinical chemistry and urinalysis will be summarised by 
treatment. 
Urinalysis parameters will also be listed  
All laboratory values of potential clinical importance will be listed and all related laboratory 
results (i.e. haematology or clinical chemistry) for subjects with values of potential clinical 
importance will be listed, separately.  Frequencies of laboratory values of potential clinical 
importance will be summarised. 
 
14.6 Other Safety Measures 
14.6.1 Vital signs 
Vital signs evaluation at each planned assessment, and change in vital signs from baseline 
(Day 0 pre-dose in the current treatment period) at each planned post-baseline assessment 
(with or without potential clinical significance) will be summarised by actual treatment.  
 
Vital signs data of potential clinical importance will be listed.  
14.6.2 ECG 
QT interval data will be presented using Bazett's (QTcB) and Fridericia's (QTcF) corrections.   
ECG data will be summarised by treatment and  time point.  Differences from baseline (Day 0 
pre-dose) will be summarised by treatment and time point.   
The number of subjects with a potentially clinically important ECG value 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 msec3.  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. 


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14.6.3 Physical and neurological examination 
Abnormal physical and neurological examination findings will be listed. 
 
15 
Pharmacokinetic Analyses 
Analytical Services International Ltd, London, U.K will measure the plasma concentrations of 
emodepside.  The pharmacokinetic analysis will be done by HMR.  Pharmacokinetic 
parameters will be calculated using WinNonlin, version 7 or higher.   
The pharmacokinetic parameters to be derived are given in Appendix B. 
PK Concentration data will be summarised using the PK concentration population. PK 
parameters will be summarised using the PK Parameter population.  
For log normally distributed parameters, the primary measure of central tendency will be the 
geometric mean4; for other parameters, it will be the arithmetic mean or median. 
For all variables N (number of subjects receiving the treatment/formulation in the population),  
n (number of observations), arithmetic mean, median, minimum, maximum, SD, %CV, and 
the 95% confidence interval for the arithmetic mean will be provided.  For log-transformed 
variables, all of the above plus the geometric mean, which is the anti-logged arithmetic mean 
of log-transformed variables, its 95% confidence interval and the SD of the logs will be 
provided. 
The between-subject CV will be calculated using: 
1. %CVb = 100 * (SD/Mean) with SD and Mean of untransformed data 
2. %CVb = 100 * √ (exp(SD)2 -1) with SD of log-transformed data 
15.1 Pharmacokinetic Concentration Data 
The plasma concentrations will be listed and summarised by treatment. Individual and mean 
plasma concentration–time profiles will be presented graphically. 
 


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15.2 Pharmacokinetic Parameters 
The pharmacokinetic parameters will be listed and summarised by treatment.  
To assess the relative bioavailability, analysis of variance (ANOVA) models will be fitted to 
the tablet (test) and solution (reference) data with the logarithm of the pharmacokinetic 
parameters AUC0-7d/Dose or Cmax/Dose as the dependent variable, and formulation as a fixed 
effect. The point estimates least squares (LS)-means and 90% confidence intervals for the 
ratios “B/A” and “C/A” will be calculated in Part 1a. In Part 2, “F/A” and/or “G/A” will be 
calculated. The acceptance range 80 – 125% will be applied for these assessments. 
In part 1, to assess the effect of food, ANOVA models will be fitted to the data with the 
logarithm of the pharmacokinetic parameters AUC0-7d/Dose or Cmax/Dose as the dependent 
variable, and fed (test) or fasted (reference) as a fixed effect. The point estimates and 90% 
confidence intervals for the ratios “D/B” and “E/C” will be calculated. The acceptance range 
80 – 125% will be applied for the assessment of a potential food effect. 
To assess dose proportionality, for each tablet type, exploratory ANOVA models will be 
fitted to the relevant fasted data in Parts 1 and 2 with the logarithm of the pharmacokinetic 
parameters AUC0-7d or Cmax as the dependent variable and dose as a fixed effect. The ratios 
“F/B” and/or “G/C” will be calculated, with their 95% confidence interval. 
16 
References 
1. International Conference on Harmonization, 1998.  Statistical Principles for Clinical 
Trials - ICH Harmonised Tripartite Guideline. Guidance for Industry, E9, FDA federal 
register, Vol 63, 1998, p49583.  Available at: http://www.fda.gov/cder/guidance. 
2. International Conference on Harmonization, 1995.  Structure and Content of Clinical 
Study Reports - ICH Harmonised Tripartite Guideline. Guidance for Industry, E3, FDA 
federal register, Vol 61, 1996, p37320.  Available at: http://www.fda.gov/cder/guidance. 
3. International Conference on Harmonisation, 2005.  Clinical Evaluation of QT/QTc 
Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs.  
Concept paper, Guidance for Industry, E14, Center for Drug Evaluation and Research 
(CDER).  Available at:  http://www.fda.gov/cder/guidance/6922fnl.htm. 
4. Julious, SA & Debarnot, CAM (2000) “Why are Pharmacokinetic Data Summarised by 
Arithmetic Means?”, Journal of Biopharmaceutical Statistics, 10 (1), p55-71 


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17 
ATTACHMENTS 
17.1 Table of Contents for Data Display Specifications 
For overall page layout refer to Appendix C. 
Tables, figures and listings will be labelled A (for Part 1) and B (for Part 2), e.g. 14.1A, 
14.1B.  Separate tables will be produced for Parts A and B. 
The numbering  in the tables below will take precedence over the numbering in the shells. 
The following tables and figures will be produced (templates provided in Section 17.2.1 and 
17.2.2):


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Table 
Description 
Population 
Source 
Listing 
Template 
(Shells below) 
10.1   
Summary of Subject Disposition 
Safety 
16.2.1.2, 
16.2.3.1 
T_SD1 
14.1  
 DEMOGRAPHIC DATA 
 
 
14.1 
Summary of Demographic Characteristics 
Safety 
16.2.4.1 
T_DM1 
14.2  
 PHARMACOKINETIC AND PHARMACODYNAMIC DATA 
 
 
 
14.2.1 
Summary of Emodepside Plasma Pharmacokinetic Concentration-
Time Data (ng/mL) 
PK Concentration 
16.2.6.1 
T_PK1 
14.2.2 
Summary of Derived Emodepside Plasma Pharmacokinetic Parameters 
PK Parameter 
16.2.6.2 
T_PK3 
14.2.3 
Summary of Log-Transformed Derived Emodepside Plasma 
Pharmacokinetic Parameters 
PK Parameter 
16.2.6.2 
T_PK4 
14.2.4 
Summary of Relative Bioavailability of Emodepside 
PK Parameter 
16.2.6.2 
T_PK6 
14.2.5 
Assessment of the Effect of Food on the PK of Emodepside 
PK Parameter 
16.2.6.2 
T_PK6 
14.2.6 
Summary of Dose Proportionality Analysis of Emodepside 
PK Parameter 
16.2.6.2 
T_PK8 
14.3  
 SAFETY DATA 
 
 
14.3.1.1 
Summary of Treatment-Emergent Adverse Events 
Safety 
16.2.7.1 
T_AE1 
14.3.1.2 
Summary of Treatment-Emergent Adverse Events by Severity 
Safety 
16.2.7.1 
T_AE1 
14.3.1.3 
Summary of Drug-Related Treatment-Emergent Adverse Events 
Safety 
16.2.7.1 
T_AE1 
14.3.2.1 
Listing of Fatal Adverse Events 
Safety 
16.2.7.1 
L_AE1_PG  
14.3.2.2 
Listing of Non-Fatal Serious Adverse Events 
Safety 
16.2.7.1 
L_AE1_PG  
14.3.2.3 
Listing of Other Significant Adverse Events 
Safety 
16.2.7.1 
L_AE1_PG  
14.3.3   
Narratives of deaths, other serious and significant adverse events 
Safety 
 
- 
14.3.4   
Summary of Laboratory Values of Potential Clinical Importance 
Safety 
16.2.8.1 
16.2.8.3 
T_LB1  
14.3.5.1 
Summary of Chemistry Laboratory Values 
Safety 
16.4 
T_LB2  
14.3.5.2 
Summary of Haematology Laboratory Values 
Safety 
16.4 
T_LB2  
14.3.5.3 
Summary of Coagulation Values 
Safety 
16.4 
T_LB2 
14.3.5.4 
Summary of Urinalysis Dipstick Results 
Safety 
16.2.8.5 
T_UR1 
14.3.6 
Summary of Vital Signs 
Safety 
16.4 
T_VS1 
14.3.7.1 
Summary of ECG Values 
Safety 
16.4 
T_EG2 


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Table 
Description 
Population 
Source 
Listing 
Template 
(Shells below) 
14.3.7.2 
Summary of ECG Values and Changes in ECG Values of Potential 
Clinical Importance  
Safety 
16.2.9.2 
T_EG3 
 
Figure 
Description 
Population 
Source 
Listing 
Template 
(Shells below) 
14.3 
PHARMACOKINETIC AND PHARMACODYNAMIC DATA 
 
 
 
14.2.1 
Individual Emodepside Plasma Concentration-Time Plots (Linear and 
Semi-log) 
PK 
Concentration  
16.2.6.1 
F_PK1 
14.2.2 
Geometric mean (+/- SD) Emodepside Plasma Concentration-Time 
Plots (Linear and Semi-log) 
PK 
Concentration 
16.2.6.1 
F_PK2 
14.3 
SAFETY DATA 
 
 
 
14.3.1 
Individual Systolic Blood Pressure-Time Plots 
Safety 
16.4 
F_SAF1 
14.3.2 
Individual Diastolic Blood Pressure-Time Plots 
Safety 
16.4 
F_SAF1 
14.3.3 
Individual Heart Rate-Time Plots  
Safety 
16.4 
F_SAF1 
14.3.4 
Individual QTcF-Time Plots 
Safety 
16.4 
F_SAF1 
14.3.5 
Individual QTcB-Time Plots 
Safety 
16.4 
F_SAF1 
 
 
The following abbreviated listings will be produced (templates provided in Section 17.2.3): 
Listing 
Description 
Template 
(Shells below) 
16.2.1  
 Study dates & disposition of subjects 
 
16.2.1.1 
Listing of Study Dates 
L_SD1_PG 
16.2.1.2 
Listing of Reasons for Withdrawal 
L_SD2_PG 


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Listing 
Description 
Template 
(Shells below) 
16.2.2  
 Protocol deviations 
 
16.2.2.1 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
L_DV1_PG 
16.2.2.2 
Listing of Subjects with Time Deviations 
L_TD1_PG 
16.2.2.3 
Listing of Subjects with Other Protocol Deviations 
L_DV2_PG 
16.2.3  
 Analysis sets, including subjects excluded from analysis 
 
16.2.3.1 
 Listing of Analysis Populations 
L_AN1_PG 
16.2.4  
 Demographic data & concomitant medication 
 
16.2.4.1 
Listing of Demographic Characteristics 
L_DM1_PG  
16.2.4.2 
Listing of Concomitant Medications 
L_CM1_PG  
16.2.5  
 Study drug administration 
 
16.2.5.1 
Listing of Exposure Data 
L_EX1_PG  
16.2.6  
 Pharmacokinetic and pharmacodynamic data 
 
16.2.6.1 
Listing of Emodepside Plasma Pharmacokinetic Concentration-Time Data  
L_PK1_PG  
16.2.6.2 
Listing of Derived Emodepside  Plasma Pharmacokinetic Parameters  
L_PK4_PG  
16.2.6.3 
Individual Emodepside Plasma Concentration-Time Plots (log scale) for Estimation of 
λz, with Regression Line 
F_PK10 
16.2.7  
 Adverse events 
 
16.2.7.1 
Listing of All Adverse Events 
L_AE1_PG  
16.2.7.2 
Listing of Serious Adverse Events 
L_AE1_PG 
16.2.7.3 
Listing of Adverse Events Leading to Withdrawal from Study 
L_AE1_PG  
16.2.8  
 Laboratory values 
 
16.2.8.1 
Listing of Clinical Chemistry Abnormalities of Potential Clinical Importance  
L_LB1_PG  
16.2.8.2 
Listing of All Clinical Chemistry Laboratory Data for Subjects with PCI Abnormalities* 
L_LB2_PG  
16.2.8.3 
Listing of Haematology Abnormalities of Potential Clinical Importance 
L_LB1_PG  
16.2.8.4 
Listing of All Haematology Laboratory Data for Subjects with PCI Abnormalities* 
L_LB2_PG  
16.2.8.5 
Listing of Urinalysis Data 
L_URI_PG 
16.2.9  
 Vital signs, ECG variables, physical and neurological findings 
 
16.2.9.1 
Listing of Vital Signs of Potential Clinical Importance 
L_VS1_PG  
16.2.9.2 
Listing of ECG Values of Potential Clinical Importance 
L_EG1_PG  


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Listing 
Description 
Template 
(Shells below) 
16.2.9.3 
Listing of Abnormal ECG Findings  
L_EG2_PG  
16.2.9.4 
Listing of Abnormal Physical Examination Findings 
L_PE1_PG 
16.2.9.5 
Listing of Abnormal Neurological Examination Findings 
L_NE1_PG 
 
*  ICH does not require full listings of lab data so only subjects with double-flagged values will be listed. 
 
Complete listings of all data collected in this study will also be produced. 
 
 
 
 
 
 
 


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17.2 Data Display Specifications 
17.2.1 Table Outlines 
Template T_SD1 
Table   10.1 
Summary of Subject Disposition 
Population 
Status 
Reason for Withdrawal 
Treatment 1 
Treatment 2 
Etc 
All Subjects 
 
 
 
n (%) 
n (%) 
 
n (%) 
Safety  
Included 
 
xx 
xx 
 
xx 
Completed 
 
xx (xx) 
xx (xx) 
 
xx (xx) 
Withdrawn 
 
 
 
 
 
Death 
xx (xx) 
xx (xx) 
 
xx (xx) 
Adverse Events 
xx (xx) 
xx (xx) 
 
xx (xx) 
Withdrawal by subject 
xx (xx) 
xx (xx) 
 
xx (xx) 
Physician decision 
xx (xx) 
xx (xx) 
 
xx (xx) 
Protocol violation 
xx (xx) 
xx (xx) 
 
xx (xx) 
Pregnancy 
xx (xx) 
xx (xx) 
 
xx (xx) 
Study terminated by 
Sponsor 
xx (xx) 
xx (xx) 
 
xx (xx) 
Lost to follow-up 
 
 
 
 
 
 
Other 
xx (xx) 
xx (xx) 
 
xx (xx) 
 
 
 
 
 
 
 
Alternative 1 (if applicable) 
Included 
 
xx (xx) 
xx (xx) 
 
xx (xx) 
Alternative 2 (if applicable) 
Included 
 
xx (xx) 
xx (xx) 
 
xx (xx) 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatment groups 
 
 
 
 


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Template T_DM1 
Table   14.1 
Summary of Demographic Characteristics 
Variable 
Statistics 
Treatment 1 
(N=xx) 
Treatment 2 
(N=xx) 
Etc 
All Subjects (N=xx) 
Age (y) 
n 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Median  
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
Gender 
n 
 
 
 
 
Female 
 
 
 
 
Male 
 
 
 
 
Race 
American Indian or Alaskan 
Native 
 
 
 
 
 
Asian 
 
 
 
 
 
Black 
 
 
 
 
 
Native Hawaiian or other 
Pacific Islander 
 
 
 
 
 
White 
 
 
 
 
 
Other 
 
 
 
 
Ethnicity 
Hispanic or Latino 
 
 
 
 
Not Hispanic or Latino 
 
 
 
 
Height (cm) 
n 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Median  
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
Weight (kg) 
n 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Median  
 
 
 
 


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Variable 
Statistics 
Treatment 1 
(N=xx) 
Treatment 2 
(N=xx) 
Etc 
All Subjects (N=xx) 
Min 
 
 
 
 
Max 
 
 
 
 
BMI (kg/m2) 
n 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Median  
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
Smoker 
n 
 
 
 
 
% 
 
 
 
 
Cigarettes* 
(daily) 
n 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Median  
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
Alcohol* 
(units/week) 
n 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Median  
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
Xanthine* 
(units/week) 
n 
 
 
 
 
 
Mean 
 
 
 
 
 
SD 
 
 
 
 
 
Median  
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
*includes only those subjects who smoke/drink alcohol/drink beverages containing xanthine 
Source: Listing 16.2.xx 


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Programming notes: 
Continued with all treatment groups and additional demographic characteristics 
 
 
Template T_PK1 
Table   14..2.xx 
Summary of Emodepside Plasma Pharmacokinetic Concentration-Time Data [units]  
 
 
Treatment 
(N=xx) 
 
Planned  
Relative 
Time 
 
 
 
n 
 
 
No. 
Imputed 
 
 
 
Mean 
 
 
 
95% CI 
 
 
 
SD 
%CVb 
 
 
 
Median 
 
 
 
Min 
 
 
 
Max 
Treatment 1 
(N=xx) 
Treatment 2 
(N=xx) 
1h 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all dose levels and timepoints 
                                            Means, SD, CI and CV should only be calculated if ≥2/3 individual values are >LLOQ 
 
Template T_PK3 
Table   14..2.xx 
Summary of Derived Emodepside Plasma Pharmacokinetic Parameters  
 
 
Parameter 
 
 
Treatment (N=xx) 
 
 
n 
 
 
 Mean 
 
 
95% CI 
 
 
SD 
%CVb 
 
 
Median 
 
 
Min 
 
 
Max 
AUClast (units) 
Cmax (units) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
Programming notes: 
Continued with all dose levels and parameters 
 
 
 


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Template T_PK4 
 
Table   14..2.xx 
Summary of Log-Transformed Derived Emodepside Plasma Pharmacokinetic Parameters 
 
Parameter 
 
 
Treatment (N=xx) 
 
 
n 
 
Geom Mean 
 
 
95% CI 
 
 
SD (logs) 
 
 
%CVb 
AUClast(units) 
 
 
 
 
 
 
Cmax (units) 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all dose levels and parameters 
 
 
 
Template T_PK6 
Table   14.2.xx 
Summary of Relative Bioavailability of Emodepside 
 
 
 
 
LSMeans 
Test  vs Reference 
Parameter 
Test Formulation 
Reference 
Test 
Ref 
Ratio (%) 
90% CI 
Cmax/Dose 
(units) 
#406 5 mg  
LSF 
xx.x 
xx.x 
xxxx.x 
xxxx.x, xxxx.x 
 
#416 5 mg 
 
xx.x 
xx.x 
xxxx.x 
xxxx.x, xxxx.x 
AUC0-7d/Dose 
(units) 
#406 5 mg 
LSF 
xx.x 
xx.x 
xxxx.x 
xxxx.x, xxxx.x 
 
#416 5 mg 
 
xx.x 
xx.x 
xxxx.x 
xxxx.x, xxxx.x 
 
Source: Listing 16.2.xx 
 
Programming notes: 
For bioavailability In part 1a calculate values for “B/A” and “C/A” 
 
In part 2 calculate values for “F/A” and “G/A” 
 
For food effect calculate for part 1 only values for “D/B” and “E/C” 
 


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Template T_PK8 
Table   14.2.xx 
Summary of Dose Proportionality Analysis of Emodepside 
 
 
 
10mg vs 5 mg 
Formulation 
Parameter 
Ratio (%) 
95% CI 
#406 5 mg 
Cmax(units) 
xxxx.x 
xxxx.x, xxxx.x 
 
AUC0-7d(units) 
xxxx.x 
xxxx.x, xxxx.x 
Source: Listing 16.2.xx 
 
Programming notes: 
 
Continue with all formulations. Calculate “F/B” and/or “G/C” 
 
 
 
 
 
 
 
 


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Template T_AE1 
Table  14.3.3.xx 
Summary of Treatment-Emergent Adverse Events 
 
 
Treatment 1 (N=xx) 
Treatment 2 (N=xx) 
Etc 
System Organ Class 
Preferred Term 
n (%) 
 
n (%) 
 
 
Number of subjects with AEs 
 
x (xx.x)  
x (xx.x)  
 
Gastrointestinal disorders 
Total number of subjects 
x (xx.x)  
x (xx.x)  
 
 
Abdominal discomfort 
x (xx.x) [xx] 
x (xx.x) [xx] 
 
 
Abdominal pain 
x (xx.x) [xx] 
x (xx.x) [xx] 
 
 
 
 
 
 
 
 
Nervous system disorders 
Total number of subjects 
 
 
 
 
 
 
Dizziness 
 
 
 
 
 
 
Headache 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
n = number of subjects (subjects with 1 adverse event are counted only once per system organ class and preferred term 
[ ] = number of adverse events  
Based on MedDRA version xx.x 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatment groups 
 
SOCs and PTs are sorted in decreasing order of frequency 
 
Presented for all applicable MedDRA system organ classes and terms.  


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Template T_LB1 
Table  14.3.4.xx 
Summary of Laboratory Values of Potential Clinical Importance 
 
 
Planned Relative 
 
Double Flags 
Laboratory Test (units) 
Treatment 
Time 
n 
HI 
LD 
 
Treatment 1  (N=xx) 
 
 
 
 
 
 
 
 
 
 
 
H = Above reference interval, L = Below reference interval, I = Increase from baseline greater than pre-defined limit, D = Decrease from baseline greater than pre-defined limit 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all tests, treatment groups and time points. n = total number of results for that parameter 
 
Template T_LB2 
Table  14.3.5.xx 
Summary of Chemistry Laboratory Values 
 
 
 
 
 
 
 
 
 
Change from Baseline 
Laboratory Test 
(units) 
Treatment 
Planned 
Relative Time 
n 
Mean 
SD 
Median Min 
Max 
n 
Mean 
SD 
Median 
Min 
Max 
 
Treatment 1  (N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatments and time points 
 
 


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Template T_UR1 
Table  14.3.5.xx 
Summary of Urinalysis Dipstick Results 
 
Planned Relative 
Time 
Result 
Treatment 1 (N=xx) 
Treatment 2 (N=xx) 
Laboratory Test 
n 
% 
n 
% 
 
Time 1 
Positive 
X 
x 
 
 
 
 
Negative 
X 
X 
 
 
 
 
Not Done 
x 
 
 
 
 
Time 2 
Positive 
 
 
 
 
 
 
Negative 
 
 
 
 
 
 
Not Done 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Results recorded as received, e.g. Negative, Trace, etc; urine pH summarized as <5, 5-8, >8 
Continued with all treatment groups and time points.  The n’s sum to N but the calculated percentages exclude Not Done. 
 
Template T_VS1 
Table  14.3.6.xx 
Summary of Vital Signs 
 
 
 
 
Change from Baseline 
Variable (units) 
Treatment 
Planned 
Relative Time 
n 
Mean 
SD 
Median 
Min 
Max 
n 
Mean 
SD 
Median Min 
Max 
Systolic BP (mmHg) 
Treatment 1  (N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all variables, treatments and time points 
 
 


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Template T_EG2 
Table  14.3.7.xx 
Summary of ECG Values 
 
 
 
 
Change from Baseline 
Variable (units) 
Treatment 
Planned Relative 
Time 
n 
Mean 
SD 
Median 
Min 
Max 
n 
Mean 
SD 
Median 
Min 
Max 
Heart Rate  (bpm) 
Treatment 1 (N=xx)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 2 (N=xx)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PR Interval  (msec) 
Treatment 1 (N=xx)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 2 (N=xx)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatment groups and time points 
 
Do not summarise RR or QRS axis 
 
 


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Template T_EG3 
Table  14.3.7.xx 
Summary of ECG Values and Changes in ECG Values of Potential Clinical Importance 
Variable 
Treatment 
Planned 
Relative 
Time 
451 – 480 msec 
481 – 500 msec 
> 500 msec 
>30-60 msec 
Increase 
>60 msec  
Increase 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
QT interval 
Treatment 1 
(N=xx) 
Time 1 
 
 
 
 
 
 
 
 
 
 
Time 2 
 
 
 
 
 
 
 
 
 
 
Time 3 
 
 
 
 
 
 
 
 
 
 
Treatment 2 
(N=xx) 
Time 1 
 
 
 
 
 
 
 
 
 
 
Time 2 
 
 
 
 
 
 
 
 
 
 
Time 3 
 
 
 
 
 
 
 
 
 
 
QTcB interval 
 
Treatment 1 
(N=xx) 
Time 1 
 
 
 
 
 
 
 
 
 
 
Time 2 
 
 
 
 
 
 
 
 
 
 
Time 3 
 
 
 
 
 
 
 
 
 
 
Treatment 2 
(N=xx) 
Time 1 
 
 
 
 
 
 
 
 
 
 
Time 2 
 
 
 
 
 
 
 
 
 
 
Time 3 
 
 
 
 
 
 
 
 
 
 
QTcF interval 
 
Treatment 1 
(N=xx) 
Time 1 
 
 
 
 
 
 
 
 
 
 
Time 2 
 
 
 
 
 
 
 
 
 
 
Time 3 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatments and time points.  n = total number of results for that parameter 
 
 
 
 
 
 
 
 
 
 
 


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17.2.2 Figure Outlines 
Template F_PK1 
Figure  16.2.4 .xx 
Individual Emodepside Plasma Concentration-Time Plots (Linear and Semi-log) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming note: Plot will include all subjects for a given treatment group 
 
 
 
 
0
2
4
6
8
10
12
14
16
18
20
22
24
26
0
4
8
12
16
20
24
28
Concentration (units) 
Actual Time (hour) 
Treatment x  
Subject 1
Subject 2
LLOQ 
1
10
100
0
4
8
12
16
20
24
28
Concentration (units) 
Actual Time (hour) 
Subject 1
Subject 2
LLOQ 


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 Template F_PK2 
Figure 16.2.4.xx 
Geometric mean (+ SD) of Emodepside Plasma Concentration-Time Plots (Linear and Semi-log) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BLQ values are imputed to zero 
 
Programming note: The SD is the geometric standard deviations 
                                  In Part 1, the following treatment comparisons will be plotted separately: LSF vs #406 5mg [fasted] and #416 5 mg [fasted], LSF vs #406 5 mg [fed] and #416 5 mg [fed],  
                                 LSF vs #406 5mg [fasted] and #406 5 mg [fed], LSF vs #416 5 mg [fasted] and #416 5 mg [fed]. 
0
5
10
15
20
25
30
0
4
8
12
16
20
24
Mean Concentration (units) 
Scheduled Time (hour) 
Treatment 1
Treatment 2
1
10
100
0
4
8
12
16
20
24
Mean Concentration (units) 
Scheduled Time (hour) 
Treatment 1
Treatment 2


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Template F_PK10 
Figure  16.2.xx 
Individual Emodepside Plasma Concentration-Time Plots (log scale) for Estimation of Lambda-z, with Regression Line 
 
 
 
 
 
 
 
 
 
 
 
 
 
0.1
1
10
100
1000
10000
0
24
48
72
96
Emodepside Concentration (ng/mL) 
Actual Time (hour) 
Treatment X Subject X 
Observed
Predicted
0.1
1
10
100
1000
0
24
48
72
96
Emodepside Concentration (ng/mL) 
Actual Time (hour) 
Treatment X Subject X 
Observed
Predicted


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Template F_SAF1 
Figure  14.3.1 
Individual Systolic Blood Pressure-Time Plots 
Treatment = x 
                                            
 
 
Programming note: Plots are by treatment groups 
 
 
Continue with all parameters 
 
 


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17.2.3 Listing Outlines 
Template L_SD1_PG 
Listing 16.2.x.xx 
Listing of Study Dates 
Treatment 
Subject 
Screening 
First dose 
Follow Up 
 
Programming notes: 
Lists dates for screening, each dosing period and follow up 
 
Template L_SD2_PG 
Listing 16.2.x.xx 
Listing of Reasons for Withdrawal 
 
Treatment       
 
Subject 
Date of 
Withdrawal     
Study 
Day 
 
Reason 
 
Programming notes: 
Reason for withdrawal is concatenation of reason and details 
 
 
Template L_DV1_PG 
Listing 16.2.x.xx 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
Treatment 
Subject 
Type 
Criterion 
 
 
Inclusion 
 
 
 
Exclusion 
 
 


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Template L_TD1_PG 
Listing 16.2.x.xx 
Listing of Subjects with Time Deviations 
Treatment 
Subject 
 
Planned 
Relative 
Time 
Procedure 
Allowed 
deviation 
(h:min) 
Actual 
deviation 
(h:min) 
 
Programming notes: 
Only include time deviations which exceed the allowed deviation 
 
Template L_DV2_PG 
Listing 16.2.x.xx 
Listing of Subjects with Other Protocol Deviations 
Treatment 
Subject 
Protocol Deviation 
 
 
Template L_AN1_PG 
Listing 16.2.x.xx 
Listing of Analysis Populations 
Treatment 
Subject 
Safety 
Population 
Population 1 
Population 2 
Etc. 
 


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Template L_DM1_PG 
Listing 16.2.x.xx 
Listing of Demographic Characteristics 
Treatment  
Subject 
Date of visit 
Date of birth 
Age 
(y) 
Gender 
Race 
Ethnic origin 
Height 
(cm) 
Weight 
(kg) 
BMI (kg/m2) 
Etc (units) 
Treatment 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming notes: 
A by-subject listing of demographic characteristics including: 
Treatment 
Subject 
Date of visit 
Date of birth 
Age 
Gender 
Race / Ethnic Origin 
Height (if collected only once during the study) 
Weight (if collected only once during the study) 
Smoking History 
Alcohol Consumption 
Xanthine 
Additional study-specific demography characteristics included on the CRF 
 


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Template L_CM1_PG 
Listing 16.2.x.xx 
Listing of Concomitant Medications 
Treatment 
Subject 
ATC Class/  
Medication Code* 
Drug Name/ 
Indication 
Dose/ 
Freq/Route 
Date/time Started/ 
Date Stopped 
Time Since Last 
Dose 
Started Pre- 
Trial? 
Ongoing 
Medication? 
 
Coded using WHODrug Global version xx.x* 
 
Programming notes: 
* only include this column and the footnote if coding used 
Include dose and units (e.g. 5 mg)/Freq/Route 
 
Template L_EX1_PG 
Listing 16.2.x.xx 
Listing of Exposure Data 
Treatment 
Subject    
Start Date/  
Start Time of Dose 
Stop Date/  
Stop Time of Dose 
Dur- 
ation 
(days) 
Dose 
Dose 
Unit 
Formulation/ 
Route 
Frequency 
Treatment 1   
1001     
01JAN2002   
15FEB2002  
46  
25     
mg     
Tablet/       
2xday 
                             
 
23:59        
15:30 
 
 
 
Oral 
 
 
 
 
 
 
 
 
 


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Template L_PK1_PG 
Listing  16.2.4.xx 
Listing of Emodepside Plasma Pharmacokinetic Concentration-Time Data 
 
Treatment 
Subject 
 
{Add. 
time 
var.} 
 
 
Date 
 
 
Study Day 
Planned 
Relative Time 
 
Actual time 
(hh:mm) 
Time Deviation 
(min) 
Actual Relative 
Time 
(hh:mm) 
 
Concentration (units) 
 
 
 
 
 
 
 
 
 
 
 
Below the Limit of Quantification (BLQ) is < xx units (e.g. 1 ng/mL) 
 
Programming notes: 
Values below LLOQ are shown as BLQ 
 
 
 
 
Template L_PK4_PG 
Listing 16.2.4.xx Listing of Derived Emodepside Pharmacokinetic Parameters 
Treatment 
Subject 
{Add. 
time 
var.} 
AUCinf 
(units) 
AUCt 
(units) 
Cmax 
(units) 
t1/2 
(units) 
tmax 
(units) 
 
Programming notes: 
Continue with all parameters 
 
 
 
 
 


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Template L_AE1_PG 
Listing 16.2.x.xx 
Listing of All Adverse Events 
Treatment  
Subject 
System Organ Class / 
Preferred Term/ 
Verbatim Text 
Outcome/  
Onset Date/Time/  
Resolved Date/Time/ 
Duration 
Time Since Last 
Dose 
Severity/ 
Serious/ 
Withdrawal 
Frequency/  
Action Taken (1)/ 
Other Action 
Taken 
Related to Study 
Drug/ 
Treatment 
Emergent? 
Treatment 1 
1001 
Gastrointestinal Disorders / 
Intestinal Spasm / 
Entero-spasm 
Resolved/ 
24SEP2003 13:05/ 
27OCT2003 7:50/ 
34d 4h 5m  
10d 7h 3m 
Mild/ 
No/ 
Yes 
Intermittent/ Dose 
not changed/ 
None  
Possibly/ 
Yes 
(1) Action Taken with Study Treatment 
 
Programming notes:  
For the listing of “other significant AEs” include (from ICH E3) AEs leading to withdrawal, AEs leading to dose reduction (including drug withdrawn, interrupted, 
reduced or similar) and AEs with AEOSE=Y.  If AEOSE has not been collected then use “Otherwise significant” in the CRF. 


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Template L_LB1_PG 
Listing 16.2.x.xx 
Listing of Clinical Chemistry Abnormalities of Potential Clinical Importance 
Treatment 
Subject 
Laboratory test (units) 
Planned  
Relative  
Time 
Date/Time 
Study 
Day 
 
 
Value 
Reference Interval 
RI 
BL 
Clinically 
Significant? 
Treatment 1 
1001  
Alk Phos (U/L) 
Time 1 
01JAN2002 
13:34 
 -1        
 64.00  
 32.0 - 92.0       
 
 
 
 
 
 
Time 2 
01APR2002 
07:22 
 85       
 84.00  
 32.0 - 92.0       
 
 
 
 
 
ALT (U/L) 
Time 1 
01JAN2002 
18:56 
 -1         
 29.00  
 10.0 - 40.0       
 
 
 
 
 
 
Time 2 
01APR2002 
09:22 
 85        
 70.00  
 10.0-  40.0       
H 
I 
Y 
 
 
 
 
 
 
 
 
 
 
 
RI for Reference Interval flag, BL for Change from Baseline flag;  
H = Above reference interval, L = Below reference interval, I = Increase from baseline greater than pre-defined limit, D = Decrease from baseline greater than pre-defined limit 
 
Programming notes: 
Lists only double-flagged subjects 
 
 


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Template L_LB2_PG 
Listing 16.2.x.xx 
Listing of All Clinical Chemistry Laboratory Data for Subjects with PCI Abnormalities 
Treatment 
Subject 
Planned 
Relative 
Time 
Date/Time 
 
Alkaline Phosphatase (IU/L) 
Alanine Amino Transferase 
(IU/L) 
Aspartate Amino Transferase 
(IU/L) 
Total Bilirubin (UMOL/L) 
Result 
RI 
BL 
Result 
RI 
BL 
Result 
RI 
BL 
Result 
RI 
BL 
 
Treatment 
Subject 
Planned 
Relative 
Time 
Date/Time 
 
Chloride (MMOL/L) 
Glucose (MMOL/L) 
Potassium (MMOL/L) 
Sodium (MMOL/L) 
Result 
RI 
BL 
Result 
RI 
BL 
Result 
RI 
BL 
Result 
RI 
BL 
 
Treatment 
Subject 
Planned 
Relative 
Time 
Date/Time 
 
Calcium (MMOL/L) 
Creatinine (UMOL/L) 
Etc. 
Result 
RI 
BL 
Result 
RI 
BL 
Result 
RI 
BL 
 
RI for Reference Interval  flag, BL for Change from Baseline flag;  
H = Above reference interval, L = Below reference interval, I = Increase from baseline greater than pre-defined limit, D = Decrease from baseline greater than pre-defined limit 
 
Programming notes: 
Lists only double-flagged subjects 
Include all parameters for the study following the order from the lab report (above is a guide only) 
 
 
 
 
 
 


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Template L_URI_PG 
Listing 16.2.x.xx 
Listing of Urinalysis Data 
Treatment 
Subject 
Planned 
Relative 
Time 
Date/Time 
Specific Gravity 
pH 
Protein 
Glucose 
Result 
RI 
Result 
RI 
Result 
RI 
Result 
RI 
 
 
RI for Reference Interval flag, H = Above reference interval, L = Below reference interval, A = Abnormal result 
 
Programming notes: 
Include all parameters for the study following the order from the lab report (above is a guide only) 
 
 
 
Template L_VS1_PG 
Listing 16.2.x.xx 
Listing of Vital Signs of Potential Clinical Importance 
Treatment 
Subject 
 
Planned Relative 
Time 
 
 
Date/Time 
Systolic 
Blood Pressure 
(mmHg) 
Diastolic 
Blood Pressure  
(mmHg) 
 
Etc 
(units) 
 
 
24 H 
26SEP2012:09:57 
63 
148* 
 
* Value of potential clinical importance 
 
 
 
 


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Template L_EG1_PG 
Listing 16.2.x.xx 
Listing of ECG Values of Potential Clinical Importance 
 
 
 
 
 
QT Int. (msec) 
QTcB (msec) 
QTcF (msec) 
Treatment  
 
Subject 
Planned 
Relative Time 
Date/Time 
Heart 
Rate 
(bpm) 
PR Int. 
(msec) 
QRS 
Dur. 
(msec) 
QRS 
Axis 
(deg) 
Observed 
Change 
from 
Baseline 
Observed 
Change 
from 
Baseline 
Observed 
Change 
from 
Baseline 
 
 
24 H 
26SEP2012:09:57 
63 
148 
78 
50 
390 
32.7 * 
399 
-27.7 
396 
-6.5 
 
* Value of potential clinical importance 
Programming notes: 
Do not list RR 
 
 
 
Template L_EG2_PG 
Listing 16.2.x.xx 
Listing of Abnormal ECG Findings 
Treatment 
Subject 
 
Planned Relative 
Time 
 
 
Date/Time 
ECG Finding 
 
Comment on Clinical 
Significance  
 
Programming notes: 
Lists only values with Normal variant=’No’ or with comment on ECG result 
 
ECG Finding contains Physician’s Opinion from CRF and relates to whole trace (not individual parameters), e.g. Normal, Abnormal -  NCS or  Abnormal - CS 
 
 
 
 


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Template L_PE1_PG 
Listing 16.2.x.xx  
Listing of Abnormal Physical Examination Findings 
Treatment 
Subject 
 
Planned Relative 
Time 
 
 
Date/Time 
Site 
 
Details  
 
Programming Notes: 
List only findings with an ‘abnormal’ result. 
If subjects have multiple abnormal sites at a given time, create a separate row for each site. 
 
 
 
 
 
 
 
 
Template L_NE1_PG 
Listing 16.2.x.xx  
Listing of Abnormal Neurological Examination Findings 
Treatment 
Subject 
Planned 
Relative Time 
Date/Time 
Type 
Assessment 
Details 
 
Programming Notes:  
Type = (Mental Status, Cranial Nerves ,etc.) 
List only findings with an ‘abnormal’ result. 
If subjects have multiple abnormal assessment at a given time, create a separate row for each assessment. 
 
 
 
 
 
 
 


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Appendix A: Laboratory Ranges 
Pre-determined Changes for Laboratory Data (from FL140 v3) 
Test 
Test Code 
Unit 
Sex 
Delta ranges 
Acceptable 
decrease 
Acceptable 
increase 
Activated partial thromboplastin time APTTT 
sec 
Both 
− 8.0 
+ 8.0 
Alanine transferase 
ALTN 
IU/L 
F 
- 
+ 30 
Alanine transferase 
ALTN 
IU/L 
M 
- 
+ 30 
Albumin 
ALB 
g/L 
Both 
− 8 
+ 8 
Alkaline phosphatase 
ALPN 
IU/L 
Both 
− 30 
+ 30 
Amylase 
AMY 
U/L 
Both 
- 
+ 150 
Aspartate transferase 
ASTN 
IU/L 
F 
− 30 
+ 30 
Aspartate transferase 
ASTN 
IU/L 
M 
− 30 
+ 30 
Basophils 
BASO 
109/L 
Both 
- 
+ 0.30 
Bilirubin conjugated 
DBIL 
µmol/L 
Both 
- 
+ 4.0 
Bilirubin total 
TBIL 
µmol/L 
F 
− 20.0 
+ 10.0 
Bilirubin total 
TBIL 
µmol/L 
M 
− 20.0 
+ 10.0 
Bilirubin unconjugated 
IBIL 
µmol/L 
Both 
- 
- 
C-reactive protein 
CRP 
mg/L 
Both 
- 
- 
CK relative index 
CKMBR 
% 
Both 
- 
- 
Calcium 
CA 
mmol/L Both 
− 0.4 
+ 0.4 
Carbon dioxide 
CO2 
mmol/L Both 
− 8 
+ 8 
Chloride 
CL 
mmol/L Both 
− 10 
+ 10 
Cholesterol 
CHOL 
mmol/L Both 
- 
+ 0.7 
Creatine kinase 
CK 
IU/L 
F 
- 
+ 400 
Creatine kinase 
CK 
IU/L 
M 
- 
+ 400 
Creatinine 
CREA 
µmol/L 
Both 
- 
+ 40 
Creatinine (DOA urine) 
CREDA-U 
mmol/L Both 
- 
- 
Eosinophils 
EOS 
109/L 
Both 
- 
+ 0.50 
Erythrocyte sedimentation rate 
ESR 
mm/h 
Both 
- 
- 
Fibrinogen 
FIB-C 
g/L 
Both 
- 
- 
Free T3 
FT3 
pmol/L 
Both 
− 3.5 
+ 3.5 
Free T4 
FT4 
pmol/L 
Both 
− 15.0 
+ 15.0 
Gamma glutamyl transferase 
GGT 
IU/L 
F 
- 
+ 40 
Gamma glutamyl transferase 
GGT 
IU/L 
M 
- 
+ 40 
Globulin 
GLOB 
g/L 
Both 
− 8 
- 
Glucose 
GLU 
mmol/L Both 
− 1.5 
+ 2.5 
Haematocrit 
HCT 
L/L 
Both 
− 0.050 
- 
Haemoglobin 
HB 
g/L 
Both 
− 20 
- 
High density lipoprotein 
HDL 
mmol/L Both 
− 1.50 
+ 1.50 
International normalised ratio 
INRR 
ratio 
Both 
- 
- 
Lactate dehydrogenase 
LDH 
IU/L 
Both 
- 
+ 150 
Lymphocytes 
LYMP 
109/L 
Both 
− 1.50 
+ 1.50 
Magnesium 
MG 
mmol/L Both 
- 
- 
Mean cell haemoglobin 
MCH 
pg 
Both 
− 2.0 
+ 2.0 
Mean cell haemoglobin concentration MCHC 
g/L 
Both 
− 25 
+ 25 
Mean cell volume 
MCV 
fL 
Both 
− 10 
+ 10 


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Test 
Test Code 
Unit 
Sex 
Delta ranges 
Acceptable 
decrease 
Acceptable 
increase 
Monocytes 
MONO 
109/L 
Both 
− 0.50 
+ 0.50 
Neutrophils 
NEUT 
109/L 
Both 
− 2.00 
+ 8.00 
Phosphate 
PHOS 
mmol/L Both 
− 1.00 
+ 1.00 
Platelets 
PLT 
109/L 
Both 
− 100 
+ 100 
Platelets (citrate tube) 
PLTC 
109/L 
Both 
− 100 
+ 100 
Potassium 
K 
mmol/L Both 
− 0.8 
+ 0.8 
Prolactin 
PROL 
µg/L 
Both 
- 
- 
Prothrombin time 
PTT 
sec 
Both 
− 4.0 
+ 4.0 
Red blood cells 
RBC 
1012/L 
Both 
− 1.0 
- 
Reticulocyte 
RET 
% 
Both 
- 
- 
Reticulocyte count 
RETC 
109/L 
Both 
- 
- 
Reticulocyte manual count 
RETM 
109/L 
Both 
- 
- 
Sodium 
NA 
mmol/L Both 
− 8 
+ 8 
Thrombin time 
TT 
sec 
Both 
- 
- 
Thyroid stimulating hormone 
TSH 
mIU/L 
Both 
− 3.00 
+ 3.00 
Total protein 
TP 
g/L 
Both 
− 15 
- 
Triglycerides 
TG 
mmol/L Both 
- 
+ 1.5 
Urea 
UREA 
mmol/L Both 
− 5.0 
+ 2.0 
Uric acid 
UA 
µmol/L 
Both 
− 100 
+ 100 
Urine pH 
UPH 
N/A 
Both 
− 4 
+ 4 
Urine red blood cells 
URBC 
106/L 
Both 
- 
+ 10 
Urine white blood cells 
UWBC 
106/L 
Both 
- 
+ 100 
White blood cells 
WBC 
109/L 
Both 
− 2.0 
+ 8.0 
 
 


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Page 57 of 61 
Appendix B: Pharmacokinetic Analysis 
1 
Calculation Methods 
1.1 
Data Handling Conventions  
1.1.1 Actual vs Planned Times 
Actual sample times will be used for the calculation of pharmacokinetic parameters 
and for individual concentration-time plots. 
Planned sampling times will be used to calculate the concentration-time summary 
statistics and summary concentration-time plots. 
1.1.2 Missing and BQL Concentrations 
Missing values will not be used in any way. 
For calculation of all pharmacokinetic parameters and individual profile plots, plasma 
concentrations below the quantifiable limit (BQL) of the assay will not be used for the 
calculation of PK parameters (except BQL values observed at time points before the 
maximum concentration, which will be taken as zero). 
BQL values observed post dose will be substituted by one half of the lower limit of 
quantification for calculation of plasma concentration summary statistics. Pre dose 
values will be taken as zero. The number of imputed values will be included in the 
summary table. 
1.2 
AUC Calculations 
The AUC will be calculated by a combination of linear and logarithmic methods.  The 
linear trapezoidal method will be employed for all incremental trapezoids arising from 
increasing concentrations and the logarithmic trapezoidal method will be used for 
those arising from decreasing concentrations 
1.3 
Lambda-z Calculations 
The apparent terminal phase rate-constant (z) will be estimated by linear regression 
of logarithmically transformed concentration versus time data.  Only those data points 


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which are judged to describe the terminal log-linear decline will be used in the 
regression. 
During the analysis, repeated regressions are carried out using the last three points 
with non-zero concentrations, then the last four points, last five, etc.  Points prior to 
Cmax are not used.  Points with a value of zero for the concentration are excluded. For 
each regression, an adjusted R2 is computed.  The λz using the regression with the 
largest adjusted R2 is selected.  If the adjusted R2 does not improve, but is within 
0.0001 of the largest adjusted R2 value, the regression with the larger number of points 
is used.  λz must be positive, and calculated from at least three data points. 
For non-compartmental analysis uniform weighting will be applied. 
1.4 
Observed v Predicted Values 
For parameters dependent on λz, the ‘predicted’ rather than the ‘observed’ parameters 
will be calculated.   
The ‘predicted’ parameters are calculated using 
tCˆ  (the predicted value of the 
concentration at time tn); whilst the ‘observed’ parameters use the last observed 
concentration.  
2 
General Considerations for Data Analysis 
2.1 
Derived and transformed data 
In general, concentration and concentration-related quantities, rate constants and half-
lives (e.g. Cmax, AUC, t1/2 and MRT) will be analysed after logarithmic transformation.  
Logarithmic transformations will use natural logarithms (loge).  A list of those 
parameters that will be log transformed are given below. 
2.2 
Summary data 
Means at any time will only be calculated if at least 2/3 of the individual data are 
measured and are above the lower of quantification (LLOQ). 


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3 
Parameter Definitions 
3.1 
Plasma Parameters 
3.1.1 Emodepside 
Text Symbol 
Definition 
Calculation 
Typical Units 
Log 
Transform 
WNL 
CDISC 
Controlled 
Terminology 
TFL 
Symbol 
Concentrations and times 
Cmax 
Maximum (peak) plasma 
concentration 
The maximum (peak) plasma concentration 
will be obtained directly from the 
concentration-time data. 
ng/mL 
Y 
Cmax 
CMAX 
Cmax 
Cmax/Dose 
Dose-normalised Cmax to 
infinity 
The dose-normalised Cmax will be calculated 
as Cmax /Dose administered 
(ng/mL)/mg 
Y 
Cmax_D 
CMAXD 
Cmax/D 
Cmax,norm 
Observed maximum plasma 
concentration corrected by 
dose and body weight 
The Cmax normalised by dose and body weight 
will be calculated as  
Cmax/(Dose administered*body weight) 
(ng/mL)/(mg*kg) 
Y 
N/A 
CMAXWD 
Cmax,norm 
tmax 
Time to reach maximum 
(peak) plasma concentration  
The first time of maximum (peak) plasma 
concentration will be obtained directly from 
the concentration-time data. 
h 
N 
Tmax 
TMAX 
tmax 
Half-life 
z 
Terminal rate constant 
The apparent terminal phase rate-constant 
(z) will be estimated by linear regression of 
logarithmically transformed concentration 
versus time data. 
1/h 
Y 
Lambda_z 
LAMZ 
z 
Point terminal 
Number of points for 
Lambda z 
The number of time points used in calculating 
Lambda z 
- 
- 
No_points_lambda
_z 
LAMZNPT 
npts 
t½,0-7d 
Terminal half-life 
The terminal half-life calculated from the 
terminal slope of the log concentration-time 
curve, as follows: 
𝑡½ = log𝑒2
𝑧
 
h 
Y 
HL_Lambda_z 
LAMZHL 
t1/2,0-7d 
t½,0-24h 
Dominant half-life 
The half-life calculated from the terminal 
slope of the log concentration-time (0-24h) 
curve, as follows: 
𝑡½ = log𝑒2
𝑧
 
h 
Y 
HL_Lambda_z 
LAMZHLD 
t1/2,0-24 


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Text Symbol 
Definition 
Calculation 
Typical Units 
Log 
Transform 
WNL 
CDISC 
Controlled 
Terminology 
TFL 
Symbol 
Areas under the curve 
AUClast 
Area under the plasma 
concentration-time curve 
from time zero to time of last 
measurable concentration 
The area under the concentration-time curve 
from zero time (pre-dose) to the time of last 
quantifiable concentration will be calculated 
using the (specified) trapezoidal method. 
h*ng/mL 
Y 
AUC_last 
AUCLST 
AUClast 
AUC0-7d 
Area under the plasma 
concentration-time curve 
from time zero to 7 days 
The area under the concentration-time curve 
from zero time (pre-dose) to 7 days will be 
calculated using the (specified) trapezoidal 
method.  
 
If z is not estimable, a partial AUC is not 
calculated (when tlast<t). 
h*ng/mL 
Y 
User specified 
area 
AUCINT 
AUC7d 
AUC0-7d/Dose 
Dose-normalised AUC from 
time zero to 7 days 
The dose-normalised AUC from time zero to 
7 days will be calculated as AUC0-7d/Dose 
administered 
(h*ng/mL)/mg 
Y 
N/A 
AUCINTD 
AUC7d/D 
AUC0-7d,norm 
Area under the 
concentration-time curve 
from time zero to 7 days 
corrected by dose and body 
weight 
The AUC from time zero to 7 days 
normalised by dose and body weight will be 
calculated as  
AUC0-7d/(Dose administered*body weight) 
(h*ng/mL)/(mg*kg) 
Y 
N/A 
AUCINTWD 
AUC7d,norm 
Clearance, volume of distribution and mean residence time 
MRTlast 
Mean Residence Time 
The mean residence time will be calculated 
using: 
last
last
AUC
AUMC
MRT 
 
h 
Y 
MRTlast 
MRTEVLST 
MRTlast 
 
 
 
 
 
 
 


HMR code:  17-008  
Sponsor code:  DNDI-EMO-03 
 
 
Hammersmith Medicines Research 
23 March 2018 
Page 61 of 61 
Appendix C: Sample Page Layout 
DNDi :  DNDI-EMO-03 Part 1 
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Population:  [Pop] 
____________________________________________________________________________________________________________________________ 
 
Table [number] [title] 
 
 
Column headers 
 
 
Main body of output 
 
 
 
Source: Listing [16.2.xx] 
 
 
Footnotes about the table or listing text go here. 
 
____________________________________________________________________________________________________________________________ 
Program:  [Prog Name] 
Produced By:[Username] 
[Date] 
HMR 17-008 Part 1 
 
*y = last page of individual output 
Font size will be Arial 9.5pt. The following margins will be used: Left:  1", Right:  1", Top: 1", Bottom:  1"