Conditions: Healthy Volunteers
Keywords: Parasitic Diseases Helminthiasis Nematode Infections Secernentea Infections Spirurida Infections Filariasis Skin Diseases, Parasitic Skin and Connective Tissue Diseases Skin Diseases Skin Diseases, Infectious Depsipeptides Emodepside Neglected disease Africa New drug Oral drug Parasite Anthelmintic drug Cyclooctadepsipeptide Single ascending dose Volunteers Phase 1 Safety Tolerability Pharmacokinetics Relative bioavailability Onchocerciasis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 79
Healthy volunteers: yes

Brief summary:
This study will investigate the safety, tolerability, and pharmacokinetics of single ascending doses of emodepside (BAY 44-4400) in healthy male volunteers. This study will also conduct an exploratory investigation of the relative bioavailability of emodepside administered as tablets and determine the effect of food on the pharmacokinetics.

Detailed description:

Arms:
arm 1: Up to 10 cohorts with single ascending dose arm 2: Up to 10 cohorts with single ascending dose

Interventions: intervention 1: emodepside (BAY 44-4400) intervention 2: placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
 
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Protocol template_Version 1.2_24 April 2014 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
A Phase 1, Blinded, Randomized, 
Placebo-Controlled, Parallel-Group, Single-Dose, 
Dose-Escalation Study to Investigate Safety, 
Tolerability, and Pharmacokinetics of Emodepside 
(BAY 44-4400) After Oral Dosing in Healthy Male 
Subjects 
 
Short title 
Emodepside Single Dose-Escalation in Healthy Male 
Subjects 
Name of product(s) 
Emodepside (BAY 44-4400) 
Drug Class 
Anthelmintic cyclooctadepsipeptide 
Phase 
1,  First-in-Human study (FiH) 
Indication 
Treatment of onchocerciasis (river blindness)  
Clinical Trial Protocol 
Number 
DNDI-EMO-001 
EudraCT 
2015-003592-29 
Sponsor 
DNDi, Chemin Louis Dunant, 15,  
1202 GENEVA Switzerland 
Phone: +41 22 906 9230 
Principal Investigator 
Dr. Malcolm Boyce 
Clinical Trial Protocol 
Version / Date 
Version 5.0, Final / Date: 18 January 2017 
Protocol Amendment 
Number / Date 
Not Applicable 
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-001) 
 
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CONTACT DETAILS 
 
 Principal Investigator: 
Malcolm Boyce, MD, BSc, FRCP, FFPM, FBPharmacolS, FCMI FCIPD 
‎Managing and Clinical Director  
Hammersmith Medicines Research Limited 
Cumberland Avenue, London, NW10 7EW, United Kingdom 
Switchboard: +44 20 8961 4130 
 Investigator Site 24-Hour Medical Contact: 
On-call physician tel:  +44 7930 323 244 
 Co-Investigators: 
(See Team Contact List) 
 Name, Title, Address, and Telephone Number(s) of the Sponsor's 
Medical Expert for the Trial (24 Hours)  
Nathalie Strub-Wourgaft MD,  
Medical Director, 
Chemin Louis Dunant, 15, 1202 Geneva, Switzerland  
Switchboard: +41 22 906 92 30 
Mobile: +41 79 874 05 39 
 Name, Title, Address, and Telephone Number(s) of the Sponsor's 
Clinical Project Manager for the Trial 
Karen Dequatre Cheeseman 
Chemin Louis Dunant, 15, 1202 Geneva, Switzerland  
Switchboard: +41 22 906 92 30 
Mobile: +41 79 916 19 35 
 Name, Title, Address, and Telephone Number(s) of other Sponsor 
Representatives 
Robert Don 
Head of Filarial Diseases Program 
Chemin Louis Dunant, 15, 1202 Geneva, Switzerland  
Switchboard: +41 22 906 92 30 
 
Jean-Yves Gillon  
Head of Translation 
Chemin Louis Dunant, 15, 1202 Geneva, Switzerland  
Switchboard: +41 22 906 92 30 
 
Frédéric Monnot 
Senior Clinical Project Manager 
Chemin Louis Dunant, 15, 1202 Geneva, Switzerland 


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Switchboard: +41 22 906 92 30 
 Name and Address of Monitor  
(See Team Contact List) 
 Name(s) and Addressee(s) of the Clinical Laboratory(ies) and Other 
Medical and/or Technical Department(S) and/or Institutions Involved 
in the Trial 
(See Team Contact List) 
Phase 1 Unit 
Hammersmith Medicines Research Limited 
Cumberland Avenue, London, NW10 7EW, United Kingdom 
Switchboard: +44 20 8961 4130 
Clinical Laboratory 
The HMR Analytical Laboratory 
Cumberland Avenue, London, NW10 7EW, United Kingdom 
Switchboard: +44 20 8961 4130 
Bioanalytic Laboratory 
Analytical Services International Ltd 
St.‎George’s,‎University‎of‎London,‎Cranmer‎Terrace,‎London,‎SW17‎0RE, 
United Kingdom 
Switchboard: +44 20 8725 2845 
Centralised ECG Reading 
(See Team Contact List) 
Ophthalmology Clinic 
(See Team Contact List) 
Metabolite Analysis  
Swiss BioQuant AG 
Rägenstrasse 18, 4153 Reinach, Switzerland 
 
Switchboard: +41 61 716 98 16 or 12 
 
 
 






Protocol number (DNDI-EMO-001)
Protocol, Version 5.0, Final / Date: 18 January 2017
Statistician
Signature
Name
Title
Institution
Address
Principal investigator
Investigator
Signature
Name
Title
Institution
Address
Confidential
Protocol template_Verslon 1.2_24 April 2014
Emodepside
Date of Signature
(DD/mmmAT)
Stephen Sah BSc, MSc
Senior Statistician
Hammersmith Medicines Research Limited
Cumberland Avenue, London, NW10 7EW, United Kingdom
t
Date of Signature
(DD/mmmAT)
Malcolm Boyce, MD, BSc, PROP, FFPM, FBPharmacolS, FGMI
FCIPD
Managing and Clinical Director
Hammersmith Medicines Research Limited
Cumberland Avenue, London, NW10 7EW, United Kingdom
Page 6 of 90




Protocol number (DNDI-EMO-001) 
 
Emodepside 
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TABLE OF CONTENTS  
 
TABLE OF CONTENTS ............................................................................................. 8 
ABBREVIATIONS – GLOSSARY OF TERMS ........................................................ 11 
PROTOCOL SUMMARY ......................................................................................... 13 
1. 
BACKGROUND AND STUDY RATIONALE................................................. 23 
1.1. 
Background Information ................................................................................................... 23 
1.2. 
Summary of Non-Clinical Information ............................................................................. 26 
1.3. 
Summary of Human Clinical Information ........................................................................ 29 
1.4. 
Assessment and Management of Risk ............................................................................ 30 
2. 
STUDY OBJECTIVES AND ENDPOINTS .................................................... 33 
2.1. 
Primary Objectives ............................................................................................................ 33 
2.2. 
Secondary Objectives ....................................................................................................... 33 
2.3. 
Study Endpoints ................................................................................................................ 33 
2.3.1. 
Safety and Tolerability Variables: ....................................................................... 33 
2.3.2. 
Pharmacokinetic Variables: ................................................................................. 34 
2.3.3. 
Pharmacodynamic Variables: ............................................................................. 34 
3. 
STUDY DESIGN AND STUDY DESIGN RATIONALE ................................. 34 
3.1. 
Study Design ...................................................................................................................... 34 
3.2. 
Study Duration and Duration of Subject Participation .................................................. 37 
3.3. 
Rationale of Study Design and Dosing ........................................................................... 37 
4. 
SELECTION OF SUBJECTS ........................................................................ 40 
4.1. 
Inclusion Criteria ............................................................................................................... 40 
4.2. 
Exclusion Criteria .............................................................................................................. 40 
4.3. 
Dietary and Lifestyle Guidelines ...................................................................................... 42 
5. 
SCHEDULE OF EVENTS ............................................................................. 44 
6. 
ENROLMENT PROCEDURES ...................................................................... 49 
7. 
STUDY TREATMENTS ................................................................................. 49 
7.1. 
Study Treatment Doses and Regimens ........................................................................... 49 
7.2. 
Allocation to Treatment ..................................................................................................... 50 
7.3. 
Drug Supplies .................................................................................................................... 51 
7.4. 
Dose Escalation and Stopping Rules .............................................................................. 51 
7.5. 
Blinding and Procedures for Unblinding ........................................................................ 52 
7.6. 
Drug Storage and Drug Accountability ........................................................................... 53 
7.7. 
Prior and Concomitant Treatments ................................................................................. 54 
8. 
STUDY PROCEDURES ................................................................................ 54 
8.1. 
Subject Information and Consent Form .......................................................................... 54 
8.2. 
Screening visit 1 (all cohorts in Parts 1 and 2) ............................................................... 54 
8.3. 
Screening visit 2 (Part 2, Cohort 10 only) ....................................................................... 56 


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8.4. 
Admission to Ward (Day -2) .............................................................................................. 56 
8.5. 
Pre-Day (Day -1) ................................................................................................................. 56 
8.6. 
Profile Day (Day 0) ............................................................................................................. 57 
8.7. 
Day 1 (24 & 36 Hours after Study Drug Administration) ................................................ 58 
8.8. 
Day 2 Through Day 6 ......................................................................................................... 59 
8.9. 
Day 7 (or Day X for Option 3: Prolonged In-House Phase) ........................................... 59 
8.10. 
Evaluation Visit(s) for Option 3 (Discharge from Ward) and Option 2 (Ambulatory 
Visit[s]Scheduled as Needed) ...................................................................................................... 60 
8.11. 
Follow-Up Visit (3 weeks [+3 Days] after dosing) ........................................................... 61 
8.12. 
Sampling time points and additional tests ..................................................................... 62 
8.13. 
Subject Withdrawal (see also Section 9.5) ...................................................................... 63 
8.14. 
Study Assessments ........................................................................................................... 65 
8.15. 
Assessment of Efficacy .................................................................................................... 65 
8.16. 
PK Assessments ................................................................................................................ 65 
8.17. 
Pharmacodynamic Assessments .................................................................................... 67 
8.18. 
Collection Method and Total Volume of Blood ............................................................... 68 
8.19. 
Assessments of Safety ..................................................................................................... 69 
8.19.1. 
12-lead Safety ECG Recording ............................................................................ 69 
8.19.2. 
Extracted 12-lead ECG for Central Evaluation .................................................. 70 
8.19.3. 
Vital Signs ............................................................................................................. 70 
8.19.4. 
Neurological and Physical Examination ............................................................ 71 
8.19.5. 
Ophthalmology testing (Part 2, Cohort 10 only) ................................................ 71 
8.19.6. 
Laboratory Safety Assessments ......................................................................... 72 
9. 
ADVERSE EVENT DEFINITION AND REPORTING .................................... 72 
9.1. 
Definitions of Adverse Events .......................................................................................... 72 
9.2. 
Procedures for Recording Adverse Events .................................................................... 74 
9.3. 
Adverse Event Reporting Period ..................................................................................... 75 
9.4. 
Procedures for Dealing With Serious Adverse Events .................................................. 75 
9.5. 
Procedures for Handling Withdrawals due to Adverse Events .................................... 76 
9.6. 
Exposure in utero .............................................................................................................. 76 
9.7. 
Adverse Event Follow Up .................................................................................................. 76 
10. 
DATA ANALYSIS AND STATISTICAL METHODS ...................................... 77 
10.1. 
Sample Size Determination............................................................................................... 77 
10.2. 
Definition of Study Populations Included in the Analysis ............................................. 77 
10.3. 
Subject Disposition ........................................................................................................... 78 
10.4. 
Efficacy Analysis ............................................................................................................... 78 
10.5. 
Analysis of Human Pharmacokinetics of Emodepside ................................................. 78 
10.6. 
Pharmacodynamic Analysis ............................................................................................. 79 
10.7. 
Demographics and Other Baseline Characteristics ....................................................... 79 
10.8. 
Safety Analysis .................................................................................................................. 79 
10.8.1. 
Vital Signs and 12-Lead ECG Safety Parameters .............................................. 79 
10.8.2. 
Extracted 12-lead ECG for Central Evaluation .................................................. 80 
10.8.3. 
Hematology and Clinical Chemistry Parameters .............................................. 80 


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10.8.4. 
Urinalysis Parameters .......................................................................................... 81 
10.8.5. 
Physical and Neurological Examination ............................................................ 81 
10.8.6. 
Adverse Events ..................................................................................................... 81 
11. 
SAFETY REVIEW MEETINGS ...................................................................... 82 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL PROCEDURES ......... 82 
12.1. 
Investigator’s File .............................................................................................................. 82 
12.2. 
Case Report Forms (CRFs) ............................................................................................... 82 
12.3. 
Source Documents ............................................................................................................ 83 
12.4. 
Record Retention ............................................................................................................... 83 
12.5. 
Monitoring .......................................................................................................................... 83 
12.6. 
Audits and Inspections ..................................................................................................... 84 
12.7. 
Data Management .............................................................................................................. 84 
12.8. 
Confidentiality of Trial Documents and Subjects Records ........................................... 84 
13. 
PROTOCOL DEVIATIONS AND AMENDMENTS ........................................ 84 
14. 
EARLY TERMINATION OF THE STUDY ..................................................... 85 
15. 
ETHICAL AND REGULATORY REQUIREMENTS ...................................... 86 
15.1. 
Informed Consent Process ............................................................................................... 87 
15.2. 
Subject Recruitment .......................................................................................................... 88 
15.3. 
Compensation of volunteers ............................................................................................ 88 
15.4. 
Insurance and Liability ...................................................................................................... 88 
15.5. 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP ......... 88 
16. 
REPORTING AND PUBLICATION OF STUDY RESULTS .......................... 88 
17. 
REFERENCES .............................................................................................. 89 
 
 


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ABBREVIATIONS – GLOSSARY OF TERMS 
ADME 
Absorption, Distribution, Metabolism, Excretion 
AE 
Adverse event 
ALT 
Alanine aminotransferase (SGPT) 
AP 
Alkaline Phosphatase 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the curve 
BMI 
Body mass index 
BP 
Blood pressure 
bw 
Body weight 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
Creatine kinase 
CL 
Clearance (total) 
Cmax 
Maximum concentration 
Cmin 
Minimum concentration 
CNS 
Central nervous system 
CRF 
Case report form 
CTA 
Clinical Trial Application 
CV 
Coefficient of variation 
DALY 
Disability Adjusted Life Years 
DNDi 
Drugs for neglected diseases initiative 
ECG 
Electrocardiogram 
EDTA 
Ethylenediaminetetraacetic acid 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
Frel 
The average relative bioavailability 
ICF 
Informed Consent Form 
IEC 
Independent ethics committee 
FIH 
First in Human 
FIM 
First in Man 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
GLDH 
Glutamate dehydrogenase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GP 
General Practitioner 
HbA1C 
Glycated haemoglobin  
HDL 
High density lipoprotein 
HED 
Human equivalent dose 
HIV 
Human immunodeficiency virus 
HMR 
Hammersmith Medicines Research Ltd 
HR 
Heart rate 
ICH 
International Conferences on Harmonisation 


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IMP 
Investigational Medicinal Product 
IR 
Immediate Release 
IV 
Intravenous 
LDH 
Lactate dehydrogemnase  
LDL 
Low density lipoprotein 
LF 
Lymphatic Filariasis 
LIMS 
Laboratory Information Management System 
LSF 
Liquid Service Formulation 
MCH 
Hemoglobin amount per red blood cell  
MCHC 
The amount of hemoglobin relative to the size of the cell 
(hemoglobin concentration) per red blood cell  
MCV 
Average red blood cell size  
MDA 
Massive Drug Administration 
MedRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MIC 
Minimum Inhibitory Concentration 
MRT 
Mean residence time 
NOAEL 
No Observed Adverse Effect Level 
NOEL 
No Observed Effect Level 
NRES 
National Research Ethics Service 
OCP 
Onchocerciasis Control Programme  
PI 
Principal investigator  
PK 
Pharmacokinetics 
PT 
Prothrombin Time 
QA 
Quality Assurance 
QTcB 
QTc‎Bazett’s‎formula 
QTcF 
QTc Fridericia's formula 
RBC 
Red blood cell 
REC 
Research Ethics Committee  
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SRG 
Safety Review Group 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
TK 
Toxicokinetic 
Tmax 
Maximum Time 
TSH 
thyroid stimulating hormone  
ULN 
Upper limit of normal 
UV 
Ultraviolet 
Vs 
Volume 
WBC 
White blood cell 
WHO 
World Health Organization 


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PROTOCOL SUMMARY 
 
Background 
Information 
Background Information 
Filarial diseases cover infectious diseases caused by parasitic nematode 
worms onchocerciasis (river blindness), lymphatic filariasis (LF, or 
elephantiasis), and loiasis (African eye worm, or Loa loa). More than 1 billion 
of‎the‎world’s‎poorest people are at risk.24,25 An estimated 120 million people 
suffer from LF, and about 80% of people at risk live in the following 
10 countries: Bangladesh, Democratic Republic of Congo, Ethiopia, India, 
Indonesia, Myanmar, Nigeria, Nepal, Philippines, and the Republic of 
Tanzania.25 Loiasis occurs exclusively in West and Central Africa, an 
estimated 13 million are infected with Loa loa.12 
An estimated 37 million20 suffer from onchocerciasis, with 99% cases in 
31 African countries, and 169 million at risk. Although the disease is almost 
exclusively confined to West and Central Africa, some foci exist in Yemen 
and South America (Brazil and Venezuela). 12,23  
The‎burden‎associated‎to‎onchocerciasis‎is‎estimated‎at‎nearly‎600’000‎
disability-adjusted life years (DALYs) worldwide.22 Severe visual impairment 
and blindness are considered the most severe complication of the disease 
and their control was the main objective of the initial control program: the 
Onchocerciasis Control Programme (OCP) in West Africa. However skin 
lesion and itching represent a significant public health problem in affected 
communities. Incessant itching may cause insomnia, affects work productivity 
and social relationships and can even induce a premature child weaning by 
affected mothers.1 Onchocerciasis is still the world's second-leading 
infectious cause of blindness. The World Health Organization (WHO) 
estimates‎that‎746’000‎patients‎are‎visually‎impaired,‎265’000‎are‎blinded‎
and more than 4 million suffer from severe itching.22 
Onchocerca is a helminth of the genus nematode (roundworm), causing 
onchocerciasis in humans. The disease is contracted through the bite of an 
infected vector, a female blackfly of the genus Simulium, which transmits 
infective larvae (L3) to a person. Once injected in the host, the larvae molt 
twice before reaching adult stage. An adult worm can then live for 15 years in 
the human body.9 Adult worms settle into fibrous nodules in the human body 
close to the surface of the skin or near the joints. Adult males migrate from 
nodule to nodule. After mating, a female releases about 1,000 new 
microfilariae larvae per day. The microfilariae migrate through the skin where 
they are eventually ingested by a blackfly in which the parasite completes its 
life cycle by molting twice into an infective larvae. These larvae may then be 
transferred to another host to continue the cycle. 
Rationale for 
the Develop-
ment of 
Emodepside 
The programs for the treatment and control of filarial diseases through Mass 
Drug Administration (MDA) have been in place for over 20 years with an 
important success in reducing transmission and morbidity. However, current 
treatments must be repeated at regular intervals for the life of the adult worm 
(up to 15 years), making implementation extremely difficult in endemic 
countries. 
Additionally, the programs have to be implemented with special measures in 
regions of Onchocerca infection where patients are co-infected with Loa loa.16 
This limits the use of ivermectin in MDA programs in co-endemic areas, and 


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is an impediment to achieving WHO elimination goals for onchocerciasis. 
Furthermore, reports of a suboptimal parasite response to ivermectin may be 
a sign of developing resistance.16 Thus, there is an urgent need for a 
macrofilaricide, targeting onchocerciasis worms for use in  individual case 
management and, after appropriate testing, as an alternative treatment in 
MDA programs. A macrofilaricidal drug could reduce the number of MDA 
cycles needed, thereby easing program implementation and enhancing 
chances in disease elimination, particularly in Loa loa co-endemic areas.  
Emodepside (BAY 44-4400) 
Emodepside is a registered drug for animal health, commercialized by Bayer 
Health Care under the name of Profender® (in combination with praziquantel) 
or Procox® (in combination with toltrazuril). 
Emodepside is a cyclooctadepsipeptide anthelmintic drug stimulating 
presynaptic receptors belonging to the secretin receptor family, resulting in 
flaccid paralysis of parasitic nematodes. Emodepside also interacts with 
SLO1, a calcium activated potassium channel. Emodepside is being 
investigated for the oral treatment of onchocerchiasis caused by nematode 
parasites‎(“river‎blindness”).‎The‎advantage‎of‎emodepside‎over‎ivermectin,‎
is to target different life stages of the parasites including the adults at lower 
concentrations. Targeting the adult form of the worm parasite should result in 
the reduction of the number of treatment cycles required to free the patient of 
infection and hopefully in allowing for treatment in regions Loa loa co infection 
is present.  
Hence, emodepside can be considered as a promising drug candidate able to 
fulfill unmet medical needs for the treatment of onchocerciasis. 
Study 
Objectives 
Primary Objective:   
 
To investigate the safety and tolerability of emodepside 
(BAY 44-4400) after single oral doses administered as solution or 
immediate release (IR) tablets in healthy male subjects.  
Secondary Objectives:   
 
To investigate the pharmacokinetics (PK) of emodepside 
(BAY 44-4400), after administration as oral solution, and IR tablet 
(optional). 
 
To conduct an exploratory investigation of the relative bioavailability of 
the 5 mg and 20 mg IR tablet formulation using data generated in this 
study (optional). 
 
Possibility to determine the effect of food on the bioavailability of 
emodepside (BAY 44-4400) after single oral doses administered as 
solution or IR tablets. 
Study 
Endpoints 
Safety and Tolerability Variables:  
 
Adverse Events (AEs). 
 
Physical and Neurological examination findings (including 
assessments of 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; and gait and postural stability (Pull test); mood; and 


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sleepiness.) 
 
Vital signs: heart rate (HR), systolic and diastolic blood pressure (BP) 
in supine and sitting position (Part 2, Cohort 10 only in supine 
position), weight, body mass index (BMI; height at screening only), 
oral temperature. 
 
12-lead ECG (HR, PR, QRS, QTcF); and for selected cohorts 12-lead 
ECG continuous recording (for emodepside exposure response 
analysis - heart rate, PR, QRS and QTcF) 
 
Clinical laboratory parameters: 
Hematology: hemoglobin, hematocrit, MCV, MCH, MCHC, platelets, 
reticulocytes, white blood cells (WBC) including differential, red blood 
cells (RBC), glycated haemoglobin (HbA1C) (at screening); 
Coagulation: activated partial thromboplastin time (aPTT), 
prothrombin time (PT);  
Biochemistry: aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (AP), glutamate 
dehydrogenase (GLDH), gamma-glutamyl transpeptidase (GGT), 
lactate dehydrogenase (LDH), creatine kinase (CK), amylase, lipase, 
free T3 and T4, thyroid-stimulating hormone (TSH), glucose, 
cholesterol (HDL, LDL, total), triglycerides, creatinine, urea, uric acid, 
bilirubin (total and conjugated), total protein, sodium, potassium, 
calcium, chloride, and magnesium in serum;  
Urinalysis: by dipstick - glucose, ketone bodies, specific gravity, occult 
blood, pH, proteins, leucocytes, bilirubin, urobilinogen, nitrites; 
 
Ophthalmology assessments (Part 2, Cohort 10)  
 
Pharmacodynamic Variables:  
 
Profiles of glucose and insulin (Parts 1 and 2, all cohorts), and 
glucagon and cortisol (Part 1, and Part 2, Cohort 9 only), only on Pre-
Day (Day -1), Profile Day (Day 0), and Day 1. 
 
Single samples of prolactin and leptin, only on Pre-Day (Day -1), 
Profile Day (Day 0), and Day 1 (Part 1 and Part 2, Cohort 9 only). 
 
PK Variables:  
Based on the plasma concentration time data (collected after administration 
of oral solution, or IR tablet), the following PK parameters will be calculated, 
and compared between the 2 different administrative forms of emodepside. 
 
Main PK parameters: AUC∞, AUC∞/D, Cmax, Cmax/D, of emodepside 
(BAY 44-4400) 
 
Exploratory PK parameters: Cmax,norm, Tmax, t½, MRT, CL/F, AUC∞,norm, 
AUCt, AUC t,norm, Vz/F of emodepside (BAY 44-4400) 
 
Other parameters: z, AUC t-∞, points terminal 
Optionally, the relative bioavailability of the IR tablet will be calculated:  Frel 
The following PK parameters of metabolites may be calculated: 
AUC∞, AUC∞/D, Cmax, Cmax/D, Cmax,norm ,Tmax, t½, AUC∞,norm, AUCt, AUCt,norm.  
In urine, the amount and concentration of emodepside and possibly its 
metabolites will be measured. The appropriate specific PK parameters to be 
calculated will be decided according to the concentration. 
Study Design  This will be a single-center, blinded, randomized, placebo-controlled, 


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parallelgroup, single-dose, dose-escalation, comparison study investigating 
safety, tolerability, and PK of emodepside, after administration as fasted or 
fed doses of oral liquid service formulation (LSF) or immediate release (IR) 
tablets in healthy male subjects. Optionally, a single dose of a 5 and 20 mg 
IR tablet formulation will be tested subsequently to the completion of the 
respective dose steps of the single-dose escalation with oral solution. 
Because emodepside has never been given to humans before, the first dose 
will be staggered. Two leading subjects will be dosed no later than the day 
before the remaining subjects in Cohort 1 will be dosed. To maintain the blind 
nature of the study, it will be ensured that 1 of the leading subjects, and 1 of 
the remaining subjects, are randomized to receive placebo.  
The study will be performed in a single site specialized in Phase 1 studies. 
For each subject the study starts with the Screening Visit, which can be up to 
4 weeks before the profile day (dosing). Subjects who participate in Cohort 
10, will attend a second Screening visit for ophthalmology assessments, if all 
other‎screening‎assessments‎show‎that‎they’re‎suitable.  
For eligible subjects, admission to the ward will be at latest the evening 
before the Pre-Day. One dose step per subject consists of one Pre-Day, one 
Profile Day and an in-house observation period of 7 days after administration 
of test substance. Subjects will be discharged from the study ward 7 days 
after administration of test substance provided there are no medical 
objections (Day 7) (Follow-Up Option 1). 
However, if it is observed that mean half-life of emodepside in any previous 
cohort is longer than expected from the preclinical PK of 36 hours, and 
plasma concentrations of emodepside are still present 7 days after dosing, 
2 alternative options may be employed to follow subjects after Day 7 
(Figure 2) from Cohort 5 onwards and for all subjects in subsequent cohorts 
(this decision will be made during the Safety Review Meetings): 
 
Option 2: addition of up to 4 out-patient follow-up visits with 
measurements for safety and blood samples for PK over a period up to 
an additional 14 days (ie, up to Day 21); or 
 
Option 3: prolongation of the in-house period of up to an additional 7 
days (ie, up to Day 14) with additional measurements for safety and 
blood samples for PK on up to 4 days during that period 
In all cases, approximately three weeks after their dose of study medicine 
(Day 21) the subjects will undergo their final examinations in a Follow-Up 
Visit. In Part 2, Cohorts 9 and 10 will follow Option 2.  The out-patient visits 
for Cohort 9 will be decided at the dose decision meeting for that cohort.  
Cohort 10 will have outpatient visits on Days 10, 14 and 18. 
Rationale for  
Study Design 
This study applies a standard Phase I single dose escalation design. The 
data from this Single Ascending Dose study will be used to design 
subsequent Phase I studies of emodepside (eg, additional food effect and 
multiple ascending dose studies). 
The study is performed in a blinded design, in which the subjects and the 
study personnel (investigators and nurses) are blinded. The decision about 
dose escalation will be taken in the Safety Review Meeting prior to each new 
dose step (see‎‘Safety‎Review’‎section.) 
The rationale for the starting dose, and selection of study population are 


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covered in the section ”Rationale‎of‎study‎design‎and‎dosing”.  
The rationale for the 7 day in-house period is based on an assumed dominant 
half-life of emodepside of 36 hours, derived from pharmacokinetics in dog 
and rat after oral administration. Applying the convention of in-house stay 
corresponding to 5 half-lives: 36h x 5 = 180h, equivalent to 7.5 days. 
However this may be extended if subjects have relevant plasma 
concentrations in early dose steps. 
Main Entry 
Criteria 
Inclusion:   
 
Male, Caucasian volunteers, deemed healthy on the basis of a clinical 
history, physical examination, ECG, vital signs, and laboratory tests of 
blood and urine. Optionally, after further evaluation during the study, 
at‎the‎sponsor’s‎discretion‎other‎ethnic‎groups‎may‎be‎recruited. 
 
18 to 55 years of age 
 
Normal body weight (BMI; Quetelet index) in the range of 18 and 30.1 
kg/m2 at screening 
 
Sufficient intelligence to understand the nature of the trial and any 
hazards of participating in it. Ability to communicate satisfactorily 
with the investigator and to participate in, and comply with the 
requirements of, the entire trial. 
 
Willingness to give written consent to participate, after reading the 
information and consent form, and after having the opportunity to 
discuss the trial with the investigator or his delegate 
 
Willingness to give written consent to have data entered into The 
Overvolunteering Prevention System 
Exclusion:   
 
Participation in another clinical trial within 3 months prior and during 
the study, or 5-times the half-life of the drug tested in the previous 
clinical trial, whichever is longer. (time calculated relative to the last 
dose in the previous clinical trial) 
 
Clinically relevant abnormal medical history, concurrent medical 
condition, acute or chronic illness or history of chronic illness sufficient 
to invalidate the subject's participation in the trial or make it 
unnecessarily hazardous 
 
Surgery (eg stomach bypass) or medical condition that might affect 
absorption of study drug taken orally 
 
Presence of abnormal physical findings, ECG, or laboratory values at 
the pre-trial screening assessment that could interfere with the 
objectives of the trial or the safety of the subject 
 
Blood pressure and heart rate in supine position at the screening 
examination outside one (or more) of the ranges 90–140 mm Hg 
systolic, 60–90 mm Hg diastolic; heart rate 40-100 beats/min. Subject 
with vital signs outside the reference range for the population being 
studied‎may‎be‎included,‎at‎the‎investigator’s‎discretion,‎if‎it‎is‎unlikely‎
to introduce additional risk factors and will not interfere with study 
procedures 


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 
Loss of more than 400 mL of blood within the previous 3 months 
 
History of relevant diseases of vital organs, of the central nervous 
system or other organs 
 
Subjects with a medical or psychiatric disorder, condition or history of 
such that would increase the risk associated with study participation, 
or‎impair‎the‎subject’s‎ability‎to‎participate‎or‎complete‎this‎study,‎in‎
the opinion of the investigator or the sponsor 
 
Positive tests for hepatitis B & C, HIV 
 
Febrile illness within 1 week before the start of the study 
 
Subjects with a history of severe allergies, non-allergic drug reactions, 
severe adverse reaction to any drug, or multiple drug allergies 
 
Subjects with a hypersensitivity to the investigational drug, the control 
agent and/ or to inactive constituents 
 
Presence or history of drug or alcohol abuse in the last 10 years, or 
intake of more than 21 units of alcohol weekly 
 
Regular daily consumption of more than one liter of xanthine-
containing beverages 
 
Regular daily consumption of more than 5 cigarettes daily, or use 
more than 3 grams (1/8 ounce) of tobacco 
 
Use of a prescription medicine during the 28 days before the first dose 
of trial medication or use of an over-the-counter medicine (with the 
exception of acetaminophen (paracetamol), during the 7 days before 
the first dose of trial medication  
 
Use of dietary supplements or herbal remedies (such‎as‎St‎John’s‎
Wort) known to interfere with the CYP3A4 and/or P-gp metabolic 
pathways during the 28 days before the first dose of trial medication 
(see list in Study Procedures Manual) 
 
Relevant pathological abnormalities in the ECG such as a second or 
third-degree AV block, prolongation of the QRS complex over 
120 msec or of the QTc-interval over 450 msec (QTcB or QTcF) 
 
Subjects testing positive in the drug screening 
 
Excluded therapies which may impact on the interpretation of study 
results in the opinion of the investigator or sponsor 
 
Objection by General Practitioner (GP) to subject entering trial 
 
History of residing for 6 or more continuous months, within the last 
3 years, in regions with endemic parasitic infections as determined by 
the investigator 
 
Possibility that subject will not cooperate with the requirements of the 
protocol 
The following exclusion criteria are applicable only to subjects in Cohort 10: 
 
No contact lenses wear within 1 month prior to dosing. Contact lenses 
wear is not permitted during the study. 
 
Any ocular disorder for which topical ocular therapy is currently or 


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chronically prescribed, including inflammatory eye disease (dry eye 
allergic conjunctivitis [seasonal allergic conjunctivitis, vernal 
keratoconjunctivitis, atopic keratoconjunctivitis], uveitis and glaucoma) 
 
Past history of ocular disease requiring ongoing treatment 
 
Past ocular surgery including laser or other refractive corneal surgery 
 
Evidence of eye irritation, visual difficulties, corneal opacity, ocular 
surface (corneal or conjunctival damage, with or without ocular 
symptoms) 
 
Evidence of narrow anterior chamber angles causing increased risk of 
acute glaucoma 
 
Evidence of ocular media opacity including lens opacity/vitreous 
opacities 
 
Evidence of retinal or optic nerve pathology 
 
Evidence of pronounced colour blindness, as indicated by an Ishihara 
score of 9/13 or below 
Subjects must not expose themselves to sunlight (eg, go out of doors) for 
longer than 15 minutes without using a strong sunblock (sun protection factor 
(SPF) 30 or above), or use a sunbed, or expose themselves to other sources 
of UV light, while they are taking emodepside and until 3 days after their last 
dose. 
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, behavioral, 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.  
Safety Review Safety will be reviewed throughout the study in Safety Review Meetings. 
Participants in the Safety Review Meeting will be at a minimum the 
Principal Investigator or his/her deputy and at least one Sponsor's 
representative (medically qualified). As an option, independent advisor(s) will 
be appointed, who will have access to unblinded data to advise if required 
(eg, on dose escalation decisions.) 
Study 
Duration 
Subject participation in the study will be for up to 7 weeks, including a 
screening phase (within 4 weeks prior to dosing), an in-house 1week 
evaluation phase (Day -2 to Day 7), that will be followed by discharge on 
Day 7 for Options 1 and 2; with ambulatory evaluation visits scheduled as 
needed for Option 2 (up to maximally the follow-up visit on Day 21), or by a 
prolonged in-house evaluation phase (up to maximally Day 14) for Option 3, 
and a follow-up visit 3 weeks (+3 days) after dosing. 
 
Rationale for 
Dose 
Selection and 
Route of 
Rationale for Starting Dose 
The recommended starting dose in humans (70 kg) was calculated to be 
1.75 mg/day (0.025 mg/kg), based on the following data:  


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Administration 28 days rats study: No Observed Adverse Effect Level (NOAEL) = 5 mg/kg‎►‎
Human Equivalent Dose (HED)+ safety factor 10 = 0.082 mg/kg 
28‎days‎dog‎study:‎NOAEL‎=‎5‎mg/kg‎►‎HED‎+‎safety‎factor‎10‎=‎
0.27 mg/kg 
Dosages resulting in Margins of Safety of 10 from predicted human PK 
(unbound Cmax from dog scenario): 
- 28‎days‎rats‎study:‎NOAEL‎=‎5‎mg/kg‎►‎0.048‎mg/kg 
- 28‎days‎dog‎study:‎NOAEL‎=‎5‎mg/kg‎►‎0.075‎mg/kg 
- Single‎administration‎rat:‎NOAEL‎=‎10‎mg/kg‎►‎0.035‎mg/kg 
 
1.75mg is not practical to dose in the Liquid Service Formulation (LSF, 
solution), and it is not recommended to dose the LSF in less than 0.5mL 
(0.5mg) increments. 1mg is chosen as the starting dose. Two dose steps are 
required to reach the 5mg dose (tablet).  
 
Rationale for 
Study 
Population  
The study will be performed in healthy, male Caucasian volunteers. Currently 
there are no data to indicate that emodepside will be sensitive to ethnic 
factors,‎according‎to‎criteria‎in‎ICH‎Guideline‎E5‎‘Ethnic‎Factors‎in‎the‎
Acceptability‎of‎Foreign‎Clinical‎Data’.‎As‎per‎the‎ICH‎E5 guidelines, 
knowledge of the pharmacokinetic and pharmacodynamic properties, and the 
translation of these to clinical efficacy and safety, are required to assess if 
emodepside will be sensitive to ethnic factors. Therefore data gathered in the 
current study will contribute to an evaluation of the need for a bridging study 
in other ethnic groups. However optionally, after further evaluation during the 
study,‎at‎the‎sponsor’s‎discretion‎other‎ethnic‎groups‎may‎be‎recruited. 
Sample Size: 
Up to 80 subjects (up to 10 cohorts, each of up to 8 subjects). 


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Study 
Treatments 
Test-Drug: Emodepside Liquid Service Formulation (LSF) solution or 
matching placebo solution; emodepside immediate release (IR) tablets of 
5 and 20 mg or matching placebo tablets.  
Part 1 Dose-Escalation:  
1st dose-level: 1 mg (solution); up to 8 subjects  
2nd dose-level: 2.5 mg (solution); up to 8 subjects  
3rd dose-level: 5 mg (solution); up to 8 subjects  
4th dose-level: 5 mg (tablet); up to 8 subjects  
5th dose-level: 10 mg (solution); up to 8 subjects  
6th dose-level: 20 mg (solution); up to 8 subjects  
7th dose-level: 20 mg (tablet); up to 8 subjects  
8th dose-level: 40 mg (solution); up to 8 subjects  
Part 2 Doses 
9th dose-level: 10 mg fed (solution); up to 8 subjects  
10th dose-level: 40 mg (solution); up to 8 subjects 
Frequency of administration: Doses will be administered as a single oral dose 
to be taken while fasting.  
In addition, the 5 and 20 mg dose-levels will be repeated with 5 and 20 mg IR 
tablets (optional), in order to estimate the relative bioavailability of this 
formulation early, and for comparison within the same study. The IR tablet 
dose-levels will be inserted in the dose-escalation, depending on the 
availability of the IR tablets and the results of the respective doses (5 and 
20 mg) administered as oral solution.  
The effect of food on the bioavailability of the emodepside LSF solution will 
be assessed in Cohort 9. 
Cohort 10 will be used to further characterize and assess the relationship 
between emodepside and adverse events seen in earlier cohorts, as long as 
those adverse events were of mild or moderate intensity and do not in any 
way threaten the health of the subject. This Cohort will be used to investigate 
in particular the effect of emodepside on the eye system. To accommodate 
the additional ophthalmology assessments that will be needed this cohort will 
have a reduced number of timepoints for other assessments compared to the 
previous cohorts. In this Cohort, emodepside or placebo will be administered 
as a single oral dose to be taken while fasting. 
Decision to escalate the dose will be taken during a Safety Review Meeting 
before each new dose step after reviewing safety data collected following 
study drug administration. 
Based on safety considerations, a reduction in dose is always possible, after 
review of safety and tolerability data from the previous dose step.   
Statistics 
 
Sample size 
For evaluation, a minimum number of 6 evaluable subjects per cohort is 
required. 


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Randomization 
 
In each cohort of 8 subjects, 6 subjects will be randomised to receive 
emodepside and 2 subjects will be randomised to receive placebo.   
The sample size of up to 8 per dose step (cohort) is considered sufficient to 
examine the safety and tolerability of emodepside as well as the 
pharmacokinetics after single oral administration of the investigational drug. 
Safety: 
Safety and tolerability data will be summarized using the following 
parameters:  
 
Vital signs; 
 
12-lead ECG; 
 
Hematology; 
 
Clinical chemistry; 
 
Urinalysis; 
 
Physical and neurological examination; 
 
AEs. 
 
Ophthalmology assessments (Part 2, Cohort 10)  
No formal hypothesis testing of these parameters will be carried out. 
Pharmacodynamic: 
Pharmacodynamic variables at each planned assessment, and change in 
pharmacodynamic variables from baseline at each planned post baseline 
assessment, will be summarised by actual treatment. 
Pharmacokinetic: 
PK concentration data will be summarised using the PK Concentration 
population. PK parameters will be summarised using the PK Parameter 
population.  
For log-transformed parameters, the primary measure of central tendency will 
be the geometric mean; for untransformed parameters, it will be the 
arithmetic 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. 
Optionally, the relative bioavailability of the IR tablet will be calculated:  Frel 
Plasma concentrations and PK parameters of emodepside and metabolites 
will be listed and summarised, by treatment, using descriptive statistics. 
Individual and mean plasma concentration–time profiles will be presented 
graphically. 
If concentrations of emodepside and its metabolites in urine are determined, 
the amount of emodepside excreted in the urine will be estimated. 


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1. Background and Study Rationale 
 
1.1. Background Information 
Filarial diseases cover infectious diseases caused by parasitic nematode worms 
onchocerciasis (river blindness), lymphatic filariasis (LF, or elephantiasis), and 
loiasis (African eye worm, or Loa loa).‎More‎than‎1‎billion‎of‎the‎world’s‎poorest‎
people are at risk.24,25 An estimated 120 million people suffer from LF, and about 
80% of people at risk live in the following 10 countries: Bangladesh, Democratic 
Republic of Congo, Ethiopia, India, Indonesia, Myanmar, Nigeria, Nepal, Philippines, 
and the Republic of Tanzania.25 Loiasis occurs exclusively in West and Central 
Africa, where an estimated 13 million are infected with Loa loa.12 An estimated 37 
million20 suffer from onchocerciasis, with 99% cases in 31 African countries, and 
169 million at risk. Although the disease is almost exclusively confined to West and 
Central Africa, some foci exist in Yemen and South America (Brazil and 
Venezuela).12,23 
The‎burden‎associated‎to‎onchocerciasis‎is‎estimated‎at‎nearly‎600’000‎disability-
adjusted life years (DALYs) worldwide.22 Severe visual impairment and blindness are 
considered the most severe complication of the disease and their control was the 
main objective of the initial control programs in West Africa (OCP). However skin 
lesion and itching represent a significant public health problem in affected 
communities. Incessant itching may cause insomnia, affects work productivity and 
social relationships and can even induce a premature child weaning by affected 
mothers.1 Onchocerciasis is still the world's second-leading infectious cause of 
blindness.‎The‎World‎Health‎Organization‎(WHO)‎estimates‎that‎746’000‎patients‎
are visually impaired,‎265’000‎are‎blinded‎and‎more‎than‎4‎million‎suffer‎from‎severe‎
itching.22 
Onchocerca is a helminth of the genus nematode (roundworm), causing 
onchocerciasis in humans. The disease is contracted through the bite of an infected 
vector, a female blackfly of the genus Simulium, which transmits infective larvae to a 
person. Once injected in the host, the larvae molt twice before reaching adult stage. 
An adult worm can then live for 15 years in the human body.9 An adult worms settle 
into fibrous nodules in the human body close to the surface of the skin or near the 
joints. Adult male migrates from nodule to nodule. After mating, a female releases 
about 1,000 new microfilariae per day. The microfilariae migrate through the skin 
where they are eventually ingested by a blackfly in which the parasite completes its 
life cycle by molting twice into an infective larvae. These larvae may then be 
transferred to another host to continue the cycle.  
Clinical Manifestations 
Infection with O. volvulus can result in initial symptoms such as fever, neuralgic pain 
in joints, and temporary hives on the trunk and face. Pruritus is the most common 
early‎symptom‎of‎onchocerciasis.‎It‎usually‎develops‎after‎a‎latent‎or‎“prepatent”‎
interval of 1 to 2 years following initial infection.10 Some infected persons remain 
asymptomatic (about 10% of cases9) or can develop symptoms during the course of 
the infection (which last up to 14 years). Inflammatory responses due to dead or 


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dying microfilaria are responsible for the majority of the clinical manifestations, which 
can range from the dermatological to the ocular symptoms, briefly described below.  
Dermatological Symptoms 
Onchoceral Dermatitis is the most common symptom of the disease. The condition 
can appear anywhere on the body and usually begins with intense itching. A rash 
consisting of patches of papules can appear on the body at any time and often leads 
to incessant scratching. In West Africa, this condition is known as craw-craw. This 
acute dermatitis may progress into chronic dermatitis with large papules and, in a 
later stage, hyper-pigmentation and the thickening of the skin, popularly known as 
Lizard skin. More advanced stage is characterized by loss of elasticity, atrophy of the 
skin and depigmentation known as Leopard skin.15 
Onchocercomas are subcutaneous, fibrous nodules where adult worms dwell and 
breed. These nodules are most easily felt when they form over a bony part of the 
body. The location of the nodules on the body depends on the place that the fly 
bites, which varies by region. In America, the nodules are mostly found on the upper 
body in the head and neck region, whereas in Africa the nodules are mostly on the 
lower body, especially in the groin region. It is estimated that only 30% of existing 
nodules can be found by palpation (95% CI 16-41%).9 
Ocular Symptoms 
Ocular symptoms are severe reactions that occur only after several years of having 
the disease. Initially, dead microfilariae in the eye cause inflammation and keratitis. 
Then, if the infection persists over a number of years, sclerosing keratitis, 
iridocyclitis, chorioretinitis, and uveitis occur, resulting in permanent visual 
impairment, glaucoma, or blindness. It is estimated that the life expectancy of a 
person who becomes blind in endemic areas may be shortened by up to 10 years.19 
Diagnosis 
Standard diagnosis of onchocerciasis is made by examination for microfilariae in skin 
biopsies. This technique has low sensitivity in light infections and it is an invasive 
method with low acceptability among the population. Infection in the eyes can be 
diagnosed with a slit-lamp examination to detect microfilaria and onchocerciasis 
lesions. In patients presenting subcutaneous nodules, adult worms can be found 
inside the nodules surgically removed. Other diagnostic methods are PCR-based 
diagnosis of skin scrapings for O. volvulus, more sensitive than parasitological 
examination of skin snips, and Ov-16 antibody detection card tests or 
diethylcarbamazine (DEC) patch test. 
Treatment 
Ivermectin (150 mg/kg single, oral dose) is the standard treatment of onchocerciasis 
patients. The drug kills the microfilarial stage of the parasite and includes temporary 
sterilization of adult female worm, reducing disease transmission and morbidity. 
However, the drug fails to kill adult worms, as a consequence, onchocerciasis 
requires treatments for up to 15 years (the life span of adult worms), to eliminate the 
parasite from the body. 


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Programs directed by the WHO for the treatment and control of onchocerciasis have 
been in place for over twenty years. The African Program for Onchocerciasis Control 
(APOC) spans 24 countries in Central and Western Africa. The treatment approach 
is preventive chemotherapy based on the administration of ivermectin once or twice 
a year to all the population in endemic areas. 
In areas of Loa loa co-infection, serious adverse events (SAE) following the use of 
ivermectin were observed.4,6 The most severe complication is an encephalopathy 
which is triggered by the massive death of microfilariae that can be fatal or leave 
long-term sequelae.6 SAEs‎happen‎in‎1‎in‎10’000‎treatments‎among‎patients‎with‎
high Loa loa parasitemia in Western and Central Africa (Angola, Cameroon, 
Democratic Republic of Congo, South Sudan) where onchocerciasis and loiasis are 
often co-endemic (The Mectizan Expert Committe and the Technical Consultative 
Committee, 2004).18 Geographical areas in which prevalence of Loa loa is higher 
than 20% are considered as high risk for encephalopathy.5 These areas have been 
defined through an epidemiological survey called Rapid Assessment Procedure for 
Loa Loa (RAPLOA).17 In these areas the risk of SAEs is particularly high when mass 
drug administration (MDA) programs are implemented for the first or second time 
when microfilariae prevalence is highest within the treated population. 
Rationale for the Development of Emodepside 
The programs for the treatment and control of filarial diseases through MDA have 
been in place for over 20 years with an important success in reducing transmission 
and morbidity. However, current treatments must be repeated at regular intervals for 
the life of the adult worm (up to 15 years), making implementation extremely difficult 
in endemic countries. 
Additionally, the programs have to be implemented with special measures in regions 
of Onchocerca infection where patients are co-infected with Loa loa. This limits the 
use of ivermectin in MDA programs in co-endemic areas, and is an impediment to 
achieving WHO elimination goals for onchocerciasis. Furthermore, reports of a 
suboptimal parasite response to ivermectin may be a sign of developing resistance.16  
Thus, there is an urgent need for a macrofilaricide, targeting onchocerciasis worms 
for use in individual case management and, after appropriate testing, as an 
alternative treatment in MDA programs. A macrofilaricidal drug could reduce the 
number of MDA cycles needed thereby easing program implementation and 
enhancing chances of disease elimination, particularly in Loa loa co-endemic areas.   
Emodepside (synonym: BAY 44 4400) is a cyclooctadepsipeptide anthelmintic drug 
stimulating presynaptic receptors belonging to the secretin receptor family, resulting 
in flaccid paralysis of parasitic nematodes. Emodepside also interacts with SLO-1, a 
calcium activated potassium channel. Emodepside is a registered drug for animal 
health, commercialized by Bayer Health Care under the name of Profender® (in 
combination with praziquantel) or Procox® (in combination with toltrazuril) indicated 
for treatment of Toxocara cati, Toxocara canis, Toxascaris leonina, Uncinaria 
stenocephala, Trichuris vulpis and Ancylostoma tubaeforme infections. Emodepside 
is a semi-synthetic drug with the precursor isolated as fermentation products from 
Mycelia sterilia, a fungus that grows on leaves of Camellia japonica.  


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Emodepside was shown to be macrofilaricide against a variety of filarial nematodes 
as investigated in both in vitro and in vivo studies: Achatocheilonema viteae, 
Litomosoides sigmodontis, Brugia malayi, Onchocerca gutturosa, Onchocerca 
lienalis. These filarial models are the accepted models for filarial diseases in 
humans.3  
In conclusion, emodepside targets different life stages of helminths parasites 
including the adult stage. This is a very important feature since treatments targeting 
Onchocerca adult worms have the potential to eliminate infection. Hence, 
emodepside can be considered as promising drug candidate able to fulfill unmet 
medical needs for the treatment of onchocerciasis. 
There are currently no drugs targeting the adult stage of Onchocerca parasites in 
humans. Therefore the clinical development plan will consider a number of clinical 
endpoints to assess the effect of emodepside in humans. 
1.2. Summary of Non-Clinical Information 
An extended battery of nonclinical studies supported the marketing of emodepside 
as a veterinary drug. To support the clinical development of emodepside in healthy 
volunteers and patients suffering from river blindness, additional studies have been 
performed to ensure all requirements for administration in man are met. 
Pharmacology 
A surrogate filarial nematode species was used (Litomosoides sigmodontis) which 
represents a permissive disease model considered to be a reasonable predictor for 
Onchocerca volvulus infection. A comprehensive set of primary pharmacodynamic 
studies was performed to characterize and assess the efficacy of emodepside 
against different filarial nematode species. Emodepside was capable of reducing the 
motility of both adult worms and microfilariae in L. sigmodontis in vitro with a 
minimum inhibitory concentration (MIC) close to 0.1 µM (111.9 ng/mL). The MIC is 
defined‎as‎the‎minimum‎concentration‎inhibiting‎the‎worm’s‎motility‎completely.‎In 
vivo Balb/c mice and jirds, a well-established, anthelmintic rodent model, were 
naturally infected with L. sigmodontis and treated with emodepside at different doses 
and formulations. In these studies treatment with emodepside efficiently and dose 
dependently reduced number of adult parasites.  
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.  
Secondary pharmacology studies did not detect any off-target receptor binding at 
clinically relevant concentrations. The in vitro hERG assay showed no critical 
potential for QT prolongation (IC20 19 µM). 
Safety pharmacology and repeated dose toxicity studies revealed the central 
nervous system as a target organ with changes in behavior, activity, tremor and gait 
abnormalities in rats, mice and dogs. A No Observed Adverse Effect Level (NOAEL) 
of 5 mg/kg i.d. was defined in dogs and rats after repeated administration (4-week 
repeat oral dose toxicity study). 10 mg/kg body weight was established as NOEL for 
effects on the nervous system in fasted rats after acute administration. 


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After a single oral application of emodepside to rats no biologically relevant effect on 
respiratory parameters was noted (10-100 mg/kg bodyweight [bw]). Also in dogs, no 
effect on respiratory functions was observed at the tested doses. Hyperglycaemia 
was observed in rats in acute and repeated dose 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 
secretory‎activities‎in‎mouse‎and‎rat‎β-cells of the pancreas presumably consistent 
with a mode of action through secretin receptors. 
Emodepside showed no adverse effect on the ECG in anesthetized dogs. However, 
a moderate vasodilatation (reduction of total resistance, slight decrease of arterial 
blood pressure, moderate, probably reflex tachycardia) was observed at ≥1.5 mg/kg 
bw. A threshold plasma level of 0.1 µg/mL was determined for this effect. The 
significance of the vasodilatory effects is unclear as no effect on blood pressure or 
heart rate was seen in dogs following oral administration of emodepside for 4 weeks 
at up to 20 mg/kg bw.  
Absorption, Distribution, Metabolism, Excretion (ADME) 
In vitro studies showed moderate plasma protein binding of emodepside in all tested 
species with similar values in mice, dogs and human (fu 1.0 – 1.6%). In rats, gerbils 
and rabbits the fraction unbound was slightly higher (2.7% - 3.1%). The relevant 
Phase 1 biotransformation pathways of emodepside in humans as well as in animal 
species were oxidation with no significant species differences in terms of metabolic 
pathways. In humans, oxidative metabolism of emodepside was predominantly 
catalyzed by CYP3A4. The hydrolysis of the ester bonds was observed as an 
additional metabolic clearance pathway. Transport studies revealed a high 
permeability of Caco2-cells to emodepside as well as active efflux which was 
characterized as being P-glycoprotein mediated. Therefore, a role for P-glycoprotein 
in the pharmacokinetics of the compound cannot be excluded.  
Single dose pharmacokinetics (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 hours in rats and 42 to 
35 hours 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 fecal/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 the majority of the dose excreted into feces. The major metabolites in feces 


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were identified as the hydrolysis product, its dehydrated and oxidized derivatives as 
well as three oxidized metabolites. 
After repeated oral dosing of 14C labeled emodepside in rats, the parent compound 
was the major component found in rat plasma with a small amount of metabolite M 1 
detected in rat plasma. 
Toxicokinetic (TK) data were obtained from 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). 
Toxicology 
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 bw, 800 ppm equals in rats approx. 77-95 mg/kg bw, both in 
13-week treatment schedule).  
The studies in rats revealed toxicities resulting from metabolic changes induced by 
emodepside indirectly, such as a decrement in bodyweight gain but in parallel an 
increased feed and water consumption as well as deformation of teeth as a sign of a 
diabetic-like effect. The main affected organs were kidney, pancreas and liver, with 
associated changes in hematological parameters, triglyceride and glucose levels in 
the plasma and lipid and glycogen stores. These toxicological findings pointed to a 
diabetes-related condition (inhibition insulin secretion followed by increased glucose 
levels, reduced leptin levels, as confirmed by mechanistic studies). In mice, the 
NOAEL after 14 week of treatment was 50 ppm (10.5-16.8 mg/kg bw.). The NOAEL 
in the 14 week rat study was defined at 10 ppm (m: 0.73, f: 1.11 mg/kg bw per day); 
In 4-week rat studies 50 ppm (equals 4 – 5 mg/kg bw) was defined as NOAEL. 
In dogs, doses starting from 10 mg/kg bw per day for 4 weeks resulted in clinical 
signs like vomiting, tremor and unsteady gait. At 20 mg/kg bw, 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 bw. 
Several reproductive and developmental toxicity studies were conducted in rats and 
rabbits. Effects of emodepside on the 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, foetotoxicity, foetal 
malformations and various skeletal/visceral anomalies or deviations. Clinical signs of 
systemic‎maternal‎toxicity‎were‎evident‎at‎dose‎rates‎≥6  mg/kg bw. Overall, severe 
maternal toxicity at 18 mg/kg bw resulted in adverse effects on foetal development. 
The NOAEL for maternal toxicity in rats was 2 mg/kg bw and the NOAEL for 
developmental toxicity was 0.5 mg/kg bw. 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 


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significantly lower (NOEL of 1 mg/kg bodyweight 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 bw.  
Additional endocrinology studies confirmed the involvement of emodepside in 
hormone deregulation (reduced E2, T3, insulin, leptin and prolactin levels and 
enhanced 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. 
1.3. Summary of Human Clinical Information 
Before this study, no human clinical trials had been conducted with emodepside. In 
this FirstinHuman (FIH) trial (Part 1, Cohorts 1-8), the safety of emodepside is 
being tested in healthy volunteers (Clinical Phase 1). 
To date, a total of 71 healthy male volunteers have been exposed to emodepside 
(dose range 1.0 mg–40 mg LSF solution, and dose range 5 mg-20 mg tablet) or 
placebo ( in this study (unblinded data available from Cohorts 1-8 [n=63 subjects]).  
Maximum exposure was observed with the 40 mg LSF solution (Cohort 8), with a 
mean Cmax of 612 ng/mL and AUC of 4315 ng.h/mL. So far, based on unblinded 
safety data from Part 1 (cohorts 1-8), those doses have been safe and tolerance was 
acceptable (see Table 1).  
Across all treatments within Part 1 (cohorts 1-8), no serious adverse events were 
reported. The majority of Treatment Emergent Adverse Events (TEAEs) experienced 
were mild in severity (22 subjects [34.9%] versus 9 subjects [14.3%] who 
experienced events of moderate severity). A total of 14 subjects (22.2%) 
experienced 20 TEAEs that were considered by the investigator to be related to 
emodepside treatment. 
Across all treatments, the most frequent treatment-related TEAEs occurred within 
the System Organ Classes (SOCs) of eye disorders and nervous system disorders 
(8 subjects [12.7%] within each SOC, respectively). After a single fasted dose of 
40 mg LSF solution (Cohort 8), 4 subjects (66.7%) reported at least 1 TEAE of 
blurred vision (of mild severity), and 2 subjects (33.3%) reported at least 1 TEAE of 
impaired vision (of mild severity). In the 20 mg LSF group, 1 subject (16.7%) 
experienced a TEAE of blurred vision of mild severity, and no subjects (0%), 
reported visual impairment which is indicative of a dose-dependent trend. Those 
TEAEs resolved spontaneously within 24 hours without treatment, caused no 
discomfort to the subjects and there were no lasting effects upon ophthalmology 
review. As per Section 7.4 of the protocol, in the occurrence of mild or moderate 
intensity adverse events which do not in any way threaten the health of the subject, 
that dose level may be repeated with the aim of exploring further the relationship 
between dose and adverse event. Cohort 10 in Part 2 will be used to further explore 
the effect of emodepside on the eye system.   


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One subject (of 63 exposed to emodepside or placebo during cohorts 1-8) in Cohort 
1 (1 mg solution) was found to be ineligible due to a pre-treatment event, of 
prolonged pre-dose PR interval. The event was noted by the Investigator at the 
moment of dosing. Dosing was stopped immediately but the subject received 0.1 mg 
of emodepside. The event was not serious, was neither treatment-emergent nor 
related to study treatment, and was mild in severity. The subject was withdrawn from 
the study. Overall, tolerability of emodepside has been good to date. 
Table 1  Treatment-emergent drug-related adverse events reported by 2 or more 
subjects in any individual treatment group in Part 1 (Cohorts 1 to 8): 
Safety population 
System Organ 
Class 
Preferred Term  
Placebo 
Emodepside  
All 
Subjects  
  
  
1 mg 
2.5 
mg 
5 mg 
5 mg 
10 mg 
20 mg 
20 mg 
40 mg 
 
LSF 
IR 
LSF 
LSF 
LSF 
IR 
LSF 
LSF 
IR 
LSF 
N=12 
n (%) 
N=4 
n (%) 
N=5 
n (%) 
N=6 
n (%) 
N=6 
n (%) 
N=6 
n (%) 
N=6 
n (%) 
N=1 
n (%) 
N=6 
n (%) 
N=6 
n (%) 
N=63 
n (%) 
Eye disorders 
0 
0 
0 
0 
0 
0 
2 
(33.3) 
1 
(16.7) 
0 
5 
(83.3) 
8 
(12.7) 
Vision blurred 
0 
0 
0 
0 
0 
0 
0 
1 
(16.7) 
0 
4 
(66.7) 
5 
(7.9) 
Photophobia 
0 
0 
0 
0 
0 
0 
2 
(33.3) 
0 
0 
0 
2 
(3.2) 
Visual 
impairment 
0 
0 
0 
0 
0 
0 
0 
0 
0 
2 
(33.3) 
2 
(3.2) 
Nervous system 
disorders 
1 
(8.3) 
0 
1 
(20.0) 
0 
1 
(16.7) 
0 
1 
(16.7) 
1 
(16.7) 
0 
3 
(50.0) 
8 
(12.7) 
Dizziness 
0 
0 
0 
0 
1 
(16.7) 
0 
0 
1 
(16.7) 
0 
2 
(33.3) 
4 
(6.3) 
Subjects‎with‎≥1‎adverse‎event‎are‎counted‎once‎per‎system‎organ‎class‎and‎preferred‎term. 
 
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 has been roughly dose-proportional with low to moderate inter-individual 
variability. The dominant half-life (t1/2 0-24 h) is estimated at approximately 11 h, and 
the terminal half-life (t1/2 0-∞) is approximately 500700 h.  
Relative bioavailability of the tablet formulation was about 35% for 5 mg and about 
12% for 20 mg. Due to the lower bioavailability at the higher dose level, the LSF 
formulation will be used within the exploratory cohorts (Part 2 Cohort 9 and Part 2, 
Cohort 10). The results of PK analysis will be fully reported within the Clinical Study 
Report when the data is available from all cohorts.  
Dose- and plasma concentration-dependent changes in insulin (decrease) and 
glucose (increase) levels were observed between 0 and 12 hours, with changes 
becoming apparent at dose levels of 10 mg LSF solution and above, in all subjects 
who received emodepside.  No change in insulin or glucose levels was considered 
clinically significant by the investigator or to be an AE. The maximum glucose level 
reached in any subject was 12.7 mmol/L at 2 h post-dose at the 40 mg LSF solution 
dose level. No noticeable changes in cortisol, leptin or prolactin levels occurred and 
glucagon variations on pre and profile day did not show any particular trend. 
1.4. Assessment and Management of Risk 
Emodepside has never been given to humans before, so a sentinel dosing approach 
will be used at the first dose level. The dose in Cohort 1 will first be given to 2 


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sentinel subjects and the remaining subjects will not be dosed until at least 23 h later 
following review of available safety and tolerability data. To maintain the blinded 
nature of the study, the sentinel subjects will be randomized in a 1:1 ratio to receive 
emodepside:placebo. 
Subjects in the FiH study (Part 1, Cohorts 1-8) and part 2 cohort 9, will remain 
hospitalized and will be closely monitored during the 7 days after their dose. A Safety 
Review Group (SRG) will be set-up to review any safety signal. 
Part 2, Cohort 10:  
The previous version of the protocol (version 4.0, dated 05 October 2016) included 
an additional optional cohort (Cohort 10). This cohort will be included, in order to 
explore in detail the effect of emodepside on the eye system using a dose level that 
was already completed in a prior cohort (see Section 1.3). Therefore this cohort is 
exploratory in nature, and is not considered to be FIH because it will repeat a dose 
level already tested in Part 1 of the study. Subjects will be transported to an eye 
hospital for ophthalmology assessments approximately 2-2.5 h post-dose and then 
transported back to the phase 1 unit, otherwise subjects will remain hospitalized in 
the phase 1 unit for 7 days consecutively following the single dose. Subjects could 
potentially be off-site (at the eye hospital) during or after the expected Tmax, however 
they will be under the direct medical supervision of a physician and nurse from the 
phase 1 unit at all times (including transportation). A dose of 40 mg LSF solution was 
previously tested in Part 1, Cohort 8, and the safety and tolerability profile was found 
acceptable.  
As Part 1 of this study is considered FIH, before a subject can be dosed in Part 1 
(Cohorts 1-8) a General Practitioner (GP) reply must be obtained, or a valid GP reply 
must be on file. 
As the doses to be tested in Part 2 (Cohorts 9 and 10) will have already been tested 
within this study; those cohorts are not considered FIH. For‎those‎cohorts,‎subjects’‎
GPs will be contacted but a reply is not required prior to dosing. 
Any safety risk to study participants is mitigated by the following considerations: 
Emodepside is registered as veterinary product worldwide. Therefore, a complete 
toxicological package is available which also covers human requirements. 
It is shown in a set of genotoxicity studies that emodepside is not genotoxic. 
Additionally, developmental toxicity studies in rats and rabbits showed that 
emodepside had no teratogenic or primary embryo/ fetotoxic potential. However, 
contraception will be used during the study in accordance with MHRA request and 
HMR standard procedures (see Section 4.3 on Dietary and Lifestyle Guidelines). 
Based on the nonclinical safety data, the toxicological release conference gave the 
following recommendations for the first in men study:  
 The recommended starting dose in humans (70kg) is 1.75 mg/day.  


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 Monitoring of standard parameters, including blood pressure, glucose 
homeostasis (glucose, insulin, glucagon). Increased glucose levels and 
decreased insulin and glucagon levels have been observed in the non-clinical 
safety studies.  
 Once the dose escalation is approaching plasma concentrations which were 
pre-clinically associated with CNS effects, particular attention should be given 
to observations/investigations indicating prodromal signs of tremor and 
incoordination.  
 Due to missing data on phototoxicity clinical trial participants should avoid 
exposure to excessive sunlight 
 Strong CYP3A4 inducers and inhibitors as well as co-medications that are 
relevant substrates for CYP3A4 should be excluded or closely monitored until 
the drug-interaction potential has been assessed in more detail.  
 Strong P-gp inhibitors as well as co-medications that are relevant substrates 
for P-gp should be excluded or closely monitored until the drug-interaction 
potential has been assessed in more detail.  
 The potential of emodepside to inhibit CYP3A4 and P-gp has to be further 
assessed clinically once it becomes clearer which emodepside exposure will 
be achieved at the therapeutic dose in humans. 
The NOAEL of emodepside in dogs was AUC(0-24) 860 µg·h/L, Cmax 175 µg/L, after 1 
week at a dose level of 5 mg/kg. This dose resulted in an exposure after 4 weeks of 
AUC(0-24) 1611 µg●h/L,‎Cmax 238 µg/L.  
The maximal dose tested in dogs was 20 mg/kg. This dose resulted in an exposure 
after 4 weeks of AUC(0-24) 15887 µg●h/L,‎Cmax 1682 µg/L.  
(Note: The recommended starting dose in humans (70kg) is 1.75 mg/day, however 
for technical reasons (see Section 3.3) the dose of 1.0 mg is chosen as the starting 
dose) 


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2. Study Objectives and Endpoints 
 
2.1. Primary Objectives 
 To investigate the safety and tolerability of emodepside (BAY 44-4400) after 
single oral doses administered as solution or immediate release (IR) tablets in 
healthy male subjects.  
 
2.2. Secondary Objectives 
 To investigate the pharmacokinetics (PK) of emodepside (BAY 44-4400), after 
administration as oral solution, or IR tablet (optional). 
 To conduct an exploratory investigation of the relative bioavailability of the 
5 mg and 20 mg IR tablet formulation using data generated in this study 
(optional). 
 Possibility to determine the effect of food on the bioavailability of emodepside 
(BAY 44-4400) after single oral doses administered as solution or IR tablets. 
 
2.3. Study Endpoints 
2.3.1. 
Safety and Tolerability Variables:  
 Adverse Events (AEs),  
 Physical and Neurological examination findings (including 
assessments of 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; and gait and 
postural stability (Pull test); mood; and sleepiness.) 
 Vital signs: heart rate (HR), systolic and diastolic blood pressure 
(BP) in supine and sitting position (Part 2, Cohort 10 only in 
supine position), weight, body mass index (BMI; height at 
screening only), oral temperature. 
 12-lead ECG (HR, PR, QRS, QTcF), and for selected cohorts 
12-lead ECG continuous recording (for emodepside exposure 
response analysis - HR, PR, QRS and QTcF) 
 Clinical laboratory parameters: 
Hematology: hemoglobin, hematocrit, MCV, MCH, MCHC, 
platelets, reticulocytes, white blood cells (WBC) differential, red 
blood cells (RBC), glycated haemoglobin (HbA1C) (at 
screening);  
Coagulation: activated partial thromboplastin time (aPTT), 
prothrombin time (PT) 
 Biochemistry: aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (AP), glutamate 
dehydrogenase (GLDH), gamma-glutamyl transpeptidase 
(GGT), LDH, CK, amylase, lipase, free T4 and T3, 
thyroid-stimulating hormone (TSH), glucose, cholesterol (high-


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density lipoprotein [HDL], and low-density lipoprotein [LDL], 
total), triglycerides, creatinine, urea, uric acid, bilirubin (total and 
conjugated), total protein, sodium, potassium, calcium, chloride 
and magnesium in serum;  
Urinalysis: by dipstick - glucose, ketone bodies, specific gravity, 
occult blood, pH, proteins, leucocytes, bilirubin, urobilinogen, 
nitrites;. 
 
Ophthalmology assessments (Part 2, Cohort 10, only). 
 
 
2.3.2. 
Pharmacokinetic Variables:  
Based on the plasma concentration time data (collected after 
administration of oral solution, or IR tablet), the following PK parameters 
will be calculated, and compared between the 2 different administrative 
forms of emodepside. 
 Main PK parameters: AUC∞, AUC∞/D, Cmax, Cmax/D of 
emodepside (BAY 44-4400) 
 Exploratory PK parameters: Cmax,norm, Tmax, t½, MRT, CL/F, 
AUC∞,norm, AUCt, AUCt,norm, Vz/F of emodepside (BAY 44-4400) 
 Other parameters: z, AUCt-∞, points terminal 
Optionally, the relative bioavailability of the IR tablet will be calculated:  Frel 
The following PK parameters of metabolites of emodepside may be 
calculated:  AUC∞,, AUC∞,/D, Cmax, Cmax/D, Cmax,norm, Tmax, T½, AUC∞,norm, 
AUCt, AUCt,norm.  
In urine, the amount and concentration of emodepside and possibly its 
metabolites will be measured. The appropriate specific PK parameters to 
be calculated will be decided according to the concentration. 
2.3.3. 
Pharmacodynamic Variables:  
 Profiles of glucose and insulin (Parts 1 and 2, all cohorts), and 
glucagon and cortisol (Part 1 and Part 2, Cohort 9 only), only on 
Pre-Day (Day -1), Profile Day (Day 0), and Day 1. 
 Part 1 and Part 2, Cohort 9 only – Single samples of prolactin 
and leptin, only on Pre-Day (Day -1), Profile Day (Day 0), and 
Day 1 (Part 1 and Part 2, Cohort 9 only). 
3. Study Design and Study Design Rationale 
 
3.1. Study Design 
This will be a single-center, blinded, randomized, placebo-controlled, parallel-group, 
single-dose, 10-cohort, dose-escalation, comparison study investigating safety, 
tolerability, and PK of emodepside, after administration as oral liquid service 
formulation (LSF) solution in healthy male subjects (Figure 1).  
The study is divided into 2 parts; Part 1 (Cohorts 1-8) is considered the FIH, single 
ascending dose phase of the study, where subjects will receive a single oral fasted 
dose, and which includes different formulations to allow assessment of relative 


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bioavailability. Part 2 is considered exploratory and will involve doses already tested 
in Part 1, so it is therefore not considered to be FIH.  
Part 1 (Cohorts 1-8)  
Optionally, a single dose of a 5 mg and 20 mg immediate release (IR) tablet 
formulation (Cohort 4 and Cohort 7, respectively) will be tested, subsequently to the 
completion of the respective dose steps of the single-dose escalation with oral 
solution (Cohort 3 and Cohort 6, respectively). 
Because emodepside has never been given to humans before, the first dose will be 
staggered. Two leading subjects will be dosed no later than the day before the 
remaining subjects in Part 1, Cohort 1 will be dosed. To maintain the blind nature of 
the study, it will be ensured that 1 of the leading subjects, and 1 of the remaining 
subjects, are randomized to receive placebo. 
Part 2 (Cohorts 9 and 10) 
The effect of food on the bioavailability of the emodepside LSF solution will be 
assessed in Cohort 9.  
Cohort 10 will be used to further characterize and assess the relationship between 
emodepside and adverse events seen in earlier cohorts, as long as those adverse 
events were all of mild or moderate intensity and do not in any way threaten the 
health of the subject. This Cohort will be used to investigate the mechanism by which 
emodepside may cause eye disorders. To accommodate the additional 
ophthalmology assessments that will be needed this cohort will have a reduced 
number of timepoints for other assessments compared to the previous cohorts (see 
Schedule of Events, Table 5 and Section 8). 
The study will be performed in a single site specialized in Phase 1 studies. For each 
subject the study starts with the Screening Visit, which can be up to 4 weeks before 
the profile day (dosing). For eligible subjects, admission to the ward will be at latest 
the evening before the Pre-Day (Figure 2). One dose step per subject consists of 
one Pre-Day, one Profile Day and an in-house observation period of 7 days after 
administration of test substance.  
Subjects will be discharged from the study ward 7 days after administration of test 
substance provided there are no medical objections (Day 7) – “Option‎1”‎in‎Figure 2. 


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Figure 1- Study Design Overview 
 
 
Figure 2- Parts 1 and 2: Study Flow Chart – Subject Level 
 
 
 
*If eligible for study entry based on Screening Visit 1, subjects to be included in Part 2 Cohort 10 will have a second Screening 
Visit in order to undergo an ophthalmology assessment (within 7 days prior to Profile-Day [Day 0]) or on Pre Day at the latest.   
 
However, if it is observed that mean half-life of emodepside in any cohort is 
longer than expected from the preclinical PK, and plasma concentrations of 
emodepside are still present 7 days after dosing, 2 alternative options may be 
employed to follow subjects after Day 7 (Figure 2) from Cohort 5 onwards and for all 


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subjects in subsequent cohorts (this decision will be made during Safety Review 
Meeting(s) – Section 11): 
 Option 2: addition of up to 4 out-patient visits with  measurements for safety 
and blood samples for PK over a period up to an additional 14 days (ie, up to 
follow-up on Day 21); or 
 Option 3: prolongation of the in-house period for up to an additional 7 days (ie, 
up to Day 14) with additional measurements for safety and blood samples for 
PK taken on up to 4 days during that period. 
Cohort 9 will follow option 2, (up to 4 visits during the period from Day 8–21 
inclusive, as needed) and Cohort 10 will have outpatient visits on Days 10, 14 and 
18. 
In all cases, approximately three weeks after their dose of study medicine the 
subjects will undergo their final examinations in a Follow-Up Visit. 
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. The Study 
Schedule of Events is provided in Table 3 (Part 1 and Part 2, Cohort 9) and Table 5 
(Part 2, Cohort 10) and Table 4 (Section 5) provides a detailed overview of all study 
procedures, which is further discussed in Section 8 Study Procedures. 
3.2. Study Duration and Duration of Subject Participation 
Subject participation in Parts 1 and 2 of the study will be for up to 7 weeks, including 
a screening phase (within 4 weeks prior to dosing), an in-house 1-week evaluation 
phase (Day 1 to Day 7), that will be followed by discharge on Day 7 for Options 1 
and 2 (Figure 2, Table 4; with ambulatory evaluation visits scheduled as needed for 
Option 2 [up to maximally the follow-up visit on Day 21]), or by a prolonged in-house 
evaluation phase (up to maximally Day 14) for Option 3, and a follow-up visit three 
weeks (+3 days) after dosing (Figure 2, Table 3, Table 4). 
3.3. Rationale of Study Design and Dosing 
This study applies a standard Phase I single dose escalation design. The data from 
this Single Ascending Dose study will be used to design subsequent Phase I studies 
of emodepside (eg, additional food effect and multiple ascending dose studies.)  
The study will be performed in healthy male Caucasian volunteers. Currently there 
are no data to indicate that emodepside will be sensitive to ethnic factors, according 
to‎criteria‎in‎ICH‎Guideline‎E5‎‘Ethnic‎Factors‎in‎the‎Acceptability‎of‎Foreign‎Clinical‎
Data’.‎As‎per‎the‎ICH‎E5‎guidelines, knowledge of the pharmacokinetic and 
pharmacodynamic properties, and the translation of these to clinical efficacy and 
safety, are required to assess if emodepside will be sensitive to ethnic factors. 
Therefore data gathered in the current study will contribute to an evaluation of the 
need for a bridging study in other ethnic groups. However optionally, after further 
evaluation‎during‎the‎study,‎at‎the‎sponsor’s‎discretion‎other‎ethnic‎groups‎may‎be‎
recruited. 


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The study is performed in a blinded design, in which the subjects and the study 
personal (investigators and nurses) are blinded, in order to avoid bias in the 
collection and evaluation of data in its conduct. Placebo has been chosen as the 
control treatment to assess whether any observed effects are treatment-related or 
simply reflect the study conditions.  
The decision about dose escalation will be taken in the Safety Review Meeting, prior 
to dosing of the subsequent cohort (see Section 7.4).  
The rationale for the 7 day in-house period is based on an assumed dominant half-
life of emodepside of 36 hours, derived from pharmacokinetics in dog and rat after 
oral administration. Applying the convention of in-house stay corresponding to 
5 half-lives: 36h x 5 = 180h, equivalent to 7.5 days. However this may be extended if 
subjects have relevant plasma concentrations in early dose steps. 
The 7 day Follow-Up Visit is scheduled according to standard practice for this type of 
study. 
The recommended starting dose in humans (70 kg) was calculated to be 
1.75 mg/day (0.025 mg/kg), based on the following data:  
 28 days rats study: No Observed Adverse Effect Level (NOAEL) = 5 mg/kg 
► Human Equivalent Dose (HED) + safety factor 10 = 0.082 mg/kg 
 28‎days‎dog‎study:‎NOAEL‎=‎5‎mg/kg‎►‎HED‎+‎safety‎factor‎10‎=‎0.27‎mg/kg 
Dosages resulting in Margins of Safety of 10 from predicted human PK 
(unbound Cmax from dog scenario): 
 28‎days‎rats‎study:‎NOAEL‎=‎5‎mg/kg‎►‎0.048‎mg/kg 
 28 days‎dog‎study:‎NOAEL‎=‎5‎mg/kg‎►‎0.075‎mg/kg 
 Single‎administration‎rat:‎NOAEL‎=‎10‎mg/kg‎►‎0.035‎mg/kg 
The 1.75 mg dose is not practical in the Liquid Service Formulation (LSF, solution), 
and it is not recommended to dose the LSF in less than 0.5 mL (0.5 mg) increments. 
The dose of 1.0 mg is chosen as the starting dose. Therefore, two dose steps are 
required to reach the 5 mg dose (tablet).  
 
Estimation of Human Exposure to Emodepside 
The prediction of human PK was based on the data obtained from in vivo 
experiments after administration of emodepside to rats and dogs and from in vitro 
data (plasma protein binding, blood/plasma partitioning). 
The classical allometric species scaling approach (with fu correction) including both 
species resulted in implausible values for the exponent for both CL and Vss. 
Therefore, the key parameters CL and Vss were assessed by single species scaling. 


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In order to predict human PK parameters and c/t profiles, rat and dog plasma 
concentrations after intravenous and oral administration were fitted to a 
3 compartment model using Phoenix 6.3. In order to obtain a better fit the 96h values 
of the rat PK data were excluded. Fitted single parameters for CL, CLD1, CLD2, Vc, 
Vt1 and Vt2 were scaled to humans considering fu and using the fixed exponent 
approach with an exponent of 1 for scaling of volumes and 0.75 for scaling of 
clearances. The bioavailability used for the prediction of the oral concentration vs. 
time profiles in man was with 50% about the mean value from bioavailabilities 
observed in animal species. 
The predicted human CL is low for both species used for prediction. The differences 
in predicted human clearance ranging from 0.11 (rat) to 0.14 L/(kg·h) (dog) are 
minor. With the Cb/Cp distribution of 0.6 values for CLblood would be 0.18 (rat) and 
0.23 (dog), respectively. These predictions are in the same range as the human 
clearance obtained in vitro in hepatocytes (CLblood = 0.36 L/(kg·h)). The predicted 
volume of distribution in man is high covering a range of 15 L/kg (rat) to 11 L/kg 
(dog). However, individual parameters for volume (Vc, Vt1 and Vt2) showed 
differences according to the species used for prediction. Consequently, the C/t 
profiles predicted for man mainly differ in Cmax and tmax. The value for the absorption 
rate constant (ka, 0.8 h-1) was based on former experiences with PEG-based liquid 
service formulations. The bioavailability obtained from the animal species was 
directly used for the prediction of the human plasma concentration profiles. 
Description of the theoretical dose levels to be studied is presented in Table 2: 
Table 2. Study Treatment: Formulation and Dose-Levels by Cohort 
Part 
Cohort 
Formulation 
Dose 
Increase from 
Previous Dose 
Total mg 
mg/kga 
1 
Cohort 1 
LSF solution 
1.0 
0.014 
 
Cohort 2 
LSF solution 
2.5 
0.036 
+ 150% 
Cohort 3 
LSF solution 
5.0 
0.071 
+ 100% 
Cohort 4 
IR tablet 
5.0 
0.071 
+ 100% 
Cohort 5 
LSF solution 
10.0 
0.143 
+ 100% 
Cohort 6 
LSF solution 
20.0 
0.286 
+ 100% 
Cohort 7 
IR tablet 
20.0 
0.286 
+ 100% 
Cohort 8 
LSF solution 
40.0 
0.571 
+ 100% 
2b 
Cohort 9 
LSF solution (fed) 
10.0 
0.143 
Not applicable 
Cohort 10 
LSF solution 
40.0 
0.571 
Not applicable 
 
a  Dose levels are theoretical, as calculated based on an average weight of 70kg. 
b Part 2 (Cohorts 9 and 10) are considered exploratory 
 


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4. Selection of Subjects 
The following eligibility criteria were designed to select healthy male subjects aged 
18 to 55, selected from the panel of volunteers recruited by HMR, 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.‎Any‎questions‎regarding‎a‎subject’s‎eligibility‎should‎be‎discussed‎with‎
the‎Sponsor’s‎Medical Expert prior‎to‎subject’s‎enrolment. 
4.1. Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrolment 
into the study:  
1. Male, Caucasian volunteers, deemed healthy on the basis of a clinical history, 
physical examination, ECG, vital signs, and laboratory tests of blood and 
urine. Optionally,‎after‎further‎evaluation‎during‎the‎study,‎at‎the‎sponsor’s‎
discretion other ethnic groups may be recruited. 
2. Aged 18 to 55 years. 
3. With a body mass index (BMI; Quetelet index) in the range of 18 to 
30.1 kg/m2 at screening.  
Body Mass Index  = 
4. 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. 
5. 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 
6. Willingness to give written consent to have data entered into The 
Overvolunteering Prevention System 
 
4.2. Exclusion Criteria 
The presence of any of the following will exclude a subject from study enrolment: 
1. Participation in another clinical trial within 3 months prior and during the 
study, or 5-times the half-life of the drug tested in the previous clinical trial, 
whichever is longer (time calculated relative to the last dose in the previous 
clinical trial) 
2. Clinically relevant abnormal medical history, concurrent medical condition, 
acute or chronic illness or history of chronic illness sufficient to invalidate 
the subject’s‎participation in the trial or make it unnecessarily hazardous. 
3. Surgery (eg stomach bypass) or medical condition that might affect 
absorption of study drug taken orally. 
4. Presence of abnormal physical findings, ECG, or laboratory values at the 
pre-trial screening assessment that could interfere with the objectives of the 
trial or the safety of the subject. 
weight [kg]
(height [m])2


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5. Relevant pathological abnormalities in the ECG such as a second or third-
degree AV block, prolongation of the QRS complex over 120 msec or of the 
QTc-interval over 450 msec (QTcB or QTcF) 
6. Blood pressure and heart rate in supine position at the screening 
examination outside one (or more) of the ranges: 
 90–140 mm Hg systolic 
 60–90 mm Hg diastolic 
 heart rate 40-100 beats/min 
Subjects with vital signs outside the reference range for the population 
being studied may‎be‎included,‎at‎the‎investigator’s‎discretion,‎if‎it‎is‎
unlikely to introduce additional risk factors and will not interfere with study 
procedures. 
7. History of relevant diseases of vital organs, of the central nervous system 
or other organs 
8. Subjects with a medical or psychiatric disorder, condition or history of such 
that would increase the risk associated with study participation, or impair 
the subject's ability to participate or complete this study, in the opinion of 
the investigator or the sponsor 
9. Subjects with a history of severe allergies, non-allergic drug reactions, 
severe adverse reaction to any drug, or multiple drug allergies 
10. Subjects with a hypersensitivity to the investigational drug, the control agent 
and/ or to inactive constituents 
11. Positive tests for hepatitis B & C, HIV 
12. Subjects testing positive in the drug screening 
13. Presence or history of drug or alcohol abuse during the last 10 years, or 
intake of more than 21 units of alcohol weekly. 
14. Regular daily consumption of more than one liter of xanthine-containing 
beverages 
15. Regular daily consumption of more than 5 cigarettes daily, or use more 
than 3 grams (1/8 ounce) of tobacco 
16. Use of a prescription medicine during the 28 days before the first dose of 
trial medication or use of an over-the-counter medicine, with the exception 
of acetaminophen (paracetamol), during the 7 days before the first dose of 
trial medication 
17. Use of dietary supplements or herbal remedies (such‎as‎St‎John’s‎Wort)‎
known to interfere with the CYP3A4 and/or P-gp metabolic pathways during 
the 28 days before the first dose of trial medication (see list in Study 
Procedures Manual) 
18. Excluded therapies which may impact on the interpretation of study results 
in the opinion of the investigator or sponsor 
19. Febrile illness within 1 week before the start of the study 
20. Objection by General Practitioner (GP) to subject entering trial. 
21. Loss of more than 400 mL of blood within the previous 3 months 


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22. History of residing for 6 or more continuous months within the last 3 years, 
in regions with endemic parasitic infections as determined by the 
investigator 
23. Possibility that subject will not cooperate with the requirements of the 
protocol 
Part 2, Cohort 10:  
The following exclusion criteria are applicable only to those subjects: 
24. No contact lenses wear within 1 month prior to first dose of IMP. Contact 
lenses wear is not permitted during the study 
25. Any ocular disorder for which topical ocular therapy is currently or 
chronically prescribed, including inflammatory eye disease (dry eye allergic 
conjunctivitis [seasonal allergic conjunctivitis, vernal keratoconjunctivitis, 
atopic keratoconjunctivitis], uveitis and glaucoma) 
26. Past history of ocular disease requiring ongoing treatment 
27. Past ocular surgery including laser or other refractive corneal surgery 
28. Evidence of eye irritation, visual difficulties, corneal opacity, ocular surface 
(corneal or conjunctival damage, with or without ocular symptoms) 
29. Evidence of narrow anterior chamber angles causing increased risk of 
acute glaucoma 
30. Evidence of ocular media opacity including lens opacity/vitreous opacities 
31. Evidence of retinal or optic nerve pathology 
32. Evidence of pronounced colour blindness, as indicated by an Ishihara score 
of 9/13 or below 13 
4.3. Dietary and Lifestyle Guidelines 
Subjects will abide by HMR house rules during the in-house period.  
No food or drink containing grapefruit will be allowed from 7 days before dosing until 
after the Follow-Up Visit.  
No alcoholic or caffeinated drinks or smoking, will be allowed during the period from 
24 h before admission until the end of each in-house period and for 24 h before each 
other visit. Subjects must not drink more than 3 units of alcohol daily at all other 
times during the study.  
In fasted cohorts, during the in-house period, subjects will fast (no food or drink other 
than water) overnight : 
 At least 9h before –24h on Day -1 until at least –20h on Day –1.  
 At least 9h before dosing, until at least 4h after dosing.  
When emodepside is given in the fed state (Part 2, Cohort 9), during the in-house 
period, subjects fast (no food or drink other than water) overnight: 


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 At least 10h before –24h on Day -1 until 30 min before -24 h on Day –1.  At 
30 min before –24h on Day –1, subjects will have a standard FDA 
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 it within 20 min.  
 From the time that they finish their breakfast on Day –1, until at least –20h on 
Day –1. 
 At least 10h before dosing, until 30 min before dosing.  At 30 min before 
dosing, subjects will have a standard FDA high-calorie, high-fat breakfast, the 
contents of which will be the same as on Day –1 – they must finish it within 
20 min.  
 From the time that they finish their breakfast on Day 1, until at least 4 h after 
dosing. 
 Subjects will take their dose of emodepside or placebo with 240 mL water.  
Water will otherwise be restricted from 1 h before until 1 h after dosing.8,11  
Standard meals (in addition to the FDA breakfasts where applicable) will be provided 
at usual times, other than when subjects are fasting. However on Day −1 and 
Day 0:meals must be given at the same time on both days 
 meals must be given after any study procedures scheduled around that 
timepoint).  
Meal guidelines, including standard times, will be detailed in the Study Procedures 
Manual. Subjects will be allowed to drink water ad libitum at all times during the 
study, other than during any periods specified in Section 7. No strenuous exercise 
will be allowed from screening until after the Follow-up Visit. 
Subjects must not expose themselves to sunlight (eg go out of doors) for longer than 
15 minutes without using a strong sunblock (sun protection factor (SPF) 30 or 
above), or use a sunbed, or expose themselves to other sources of UV light, while 
they are taking emodepside and until 3 days after their last dose. 
According to HMR standard procedures, and MHRA request, during the study and 
until 90 days following dosing, subjects must not have sex without using a condom, 
unless they have had a vasectomy or their partner is not of childbearing potential. 
Part 2, Cohort 10 
Subjects will be informed that they will need to bring their distance glasses (if 
applicable) to ophthalmology assessment visits. Also, their near vision will be blurred 
for approximately 2 hours (due to the use of mydriatic eye drops) following the eye-
testing procedures at Screening Visit 2. Therefore subjects will not be able to drive or 
operate machinery afterwards for at least 2 hours. On Profile-Day (Day 0), the 
ophthalmology assessments will be repeated post-dose, but without the use of 
mydriatic eye drops.    


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5. Schedule of Events 
Table 3. Schedule of Events (Part 1, Cohorts 1-8, and Part 2, Cohort 9) 
Study Procedure 
Screen 
 
In-Patient Phasea 
See Table 4b Follow-
Up 
Visit 
 
Pre-Day 
Profile-Day 
Evaluation 
Day 
± allowable deviation -28 to -2 -2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
 
 
 
 
7 
+3 
Subject information 
and Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
(including 
demographics and 
previous / concomitant 
medications) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Neurological 
examinationd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Ward Admission 
(approx.16h) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drugs of abuse 
and alcohol breath 
test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hours a (pre/post 
drug) 
 
-36 -24* -23.5 -23 -22.5 -22 -21 -20 -18 -16 -12 
0* 0.5 
1 
1.5 
2 
2.5 
3 
4 
5 
6 
8 
12 
24 36 48 72 96 120 144 168 
 
 
 
 
 
Glucose, Insulin, 
Glucagon, and 
Cortisol profiles 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Samples for Prolactin 
& Leptin  
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of 
emodepsidee 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead safety ECGf 
X 
 
Xf 
X 
X 
X 
X 
X 
X 
 
X 
X 
Xf 
X 
X 
X 
X 
 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
ECGs extracted from 
continuous 
recordingsg 
 
 
 
 
 
 
 
 
 
 
 
 
Xg Xg Xg Xg Xg Xg Xg Xg 
 
Xg 
Xg 
Xg 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsh 
X 
 
Xh 
X 
X 
X 
Xh 
X 
Xh 
X 
X 
Xh 
Xh 
X 
X 
X 
Xh 
 
X 
Xh 
 
X 
X 
Xh 
Xh X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
Adverse event 
monitoringi 
X 
X 
X 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
PK and metabolitesj in 
plasma 
 
 
 
 
 
 
 
 
 
 
 
 
Xj 
X 
Xj 
X 
Xj 
X 
X 
Xj 
 
X 
Xj 
Xj 
Xj 
X 
Xj 
X 
X 
X 
X 
X 
 
 
 
 
X 
PK in urinek 
 
 
 
 
 
 
 
 
 
 
 
 
0–4k 
4–8k 
8–12k 12–24k 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Safetyl,m 
X m 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
Neurologicald 
examination and short 
physical examinationc 
 
 
Xc 
 
 
 
X 
 
X 
 
 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 


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*: In fasted subjects, all assessments at Hour –24 on Day –1 and Hour 0 on Day 0 are immediately before the administration of study drug (emodepside). In fed subjects, all assessments 
at Hour –24 on Day –1 and at Hour 0 on Day 0 are before the FDA breakfast.  The only exception is the 12-lead ECG continuous recording (see footnote g).  
a: Including a 10-minute supine phase before supine BP, HR, body temperature, ECG; and for 5 minutes after each nominal timepoint for ECGs extracted from continuous recording (see 
footnote); and also recommended before drawing blood samples. Before sitting BP assessments minimum 3-minute sitting period. 
b: If mean half-life of emodepside in any cohort is longer than predicted, there are options to extend in-house period, or out-patient ambulatory visits up to Day 14 if necessary, from Cohort 
5 onwards and in subsequent cohorts. Refer to Option 1, Option 2, and Option 3 as outlined in Table 4.    
c: 
Height at screening only, for calculation of BMI. Weight at screening for calculation of BMI, also at -24h (Day -1) for PK calculations. 
d: Neurological examination designed for the study, see Section 8.19.4  and Study Procedures Manual 
e:  Administration of study drug while fasting or after a high-calorie, high-fat breakfast     
f: 
To include 3 repeat ECGs at these timepoints, with a time difference of about 1 minute, and single recordings at other timepoints 
g: For selected cohorts in Part 1 (see Section 8.19.2 continuous 12-lead ECG recording will be started 1 hour before dosing and continue for 24 hours post-dosing. ECGs will be extracted 
at predose, at three timepoints (-60, -45, and -30 minutes for fasted subjects or -90, -75, and -60 minutes for fed subjects) and at the timepoints at which PK blood samples are drawn. 
Subjects will be supine for 10 minutes prior to and 5 minutes after each nominal timepoint. When ECG extraction coincide with safety ECGs, vital signs and blood draws, procedures will 
be performed in said order. 
h: Vital‎signs‎to‎include‎BP‎(supine;‎‎plus‎sitting‎BP‎at‎the‎indicated‎timepoints‘h’) and HR. Oral temperature only at screening and -24h. 
i: 
Adverse Event (AE) monitoring will be throughout the study (spontaneous and solicited) to include questioning for tolerability and safety, however at these indicated timepoints will be 
specific questioning about AEs. 
j: 
In‎addition‎to‎the‎PK‎sample,‎metabolite‎samples‎are‎collected‎only‎for‎the‎indicated‎time‎points‎‘j’.‎As‎an‎option,‎at‎the‎sponsor’s discretion, an additional sample of no more than 1mL 
may be taken at each PK timepoint from all subjects in up to 2 cohorts. 
k: 
Start and end of urine collection for each bottle are indicated as hours post drug.. 
l: 
Hematology, Coagulation, Chemistry; Urinalysis by dip stick.  
m: At Screening only: HIV 1, 2, Hepatitis B, C, HbA1C,   in additional to hematology, coagulation, urinalysis, and chemistry. 
 


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Table 4. Follow-Up after Day 7 – Schedule Options 1, 2, or 3 Depending on Emodepside Plasma Concentrations at Day 7 in Previous 
Cohort(s) (from Cohort 5 onwards), Respectively. 
For Screening and Days -2 through Day 8 see Table 3 
OPTION 1 
 
Out-Patient Phase 
Day 
 
 
 
 
 
Follow-Up Visit  
at 3 weeks (+3 days) post-dose 
 
Discharge on Day 7  
Physical Examination 
 
 
 
 
 
(see Table 3) 
Neurological Examination 
 
 
 
 
 
(see Table 3) 
12-lead ECG 
 
 
 
 
 
(see Table 3) 
Vital signsh 
 
 
 
 
 
(see Table 3) 
Adverse event monitoringi 
 
 
 
 
 
(see Table 3) 
PK in plasma 
 
 
 
 
 
(see Table 3) 
Laboratory Safetyl,m 
 
 
 
 
 
(see Table 3) 
OPTION 2 
 
Out-Patient Phase 
Day 
Up to 4 visits during the period from Day 8–21 inclusive (as needed) 
Follow-Up Visit  
at 3 weeks (+3 days) post-dose 
 
Ambulatory Evaluation Visits, Scheduled As Needed 
Physical Examination 
 
 
 
 
 
(see Table 3) 
Neurological Examination 
 
 
 
 
 
(see Table 3) 
12-lead ECG 
 
 
 
 
 
(see Table 3) 
Vital signsh 
 
 
 
 
 
(see Table 3) 
Adverse event monitoringi 
X 
 
X 
X 
X 
(see Table 3) 
PK in plasma 
X 
 
X 
X 
X 
(see Table 3) 
Laboratory Safetyl,m 
X 
 
X 
X 
X 
(see Table 3) 
OPTION 3 
 
Discharge from Ward on Day X 
 
Day 
8 (±1) 
(as needed) 
 
10 (±1) 
(as needed) 
12 (±2) 
(as needed) 
14 (±2) 
(max.) 
Follow-Up Visit  
at 3 weeks (+3 days) post-dose 
 
Prolonged In-House Evaluation Phase  
with Discharge from Ward on Day X (8-14) 
Physical Examination 
 
 
 
 
 
(see Table 3) 
Neurological Examination 
 
 
 
 
 
(see Table 3) 
12-lead ECG 
 
 
 
 
 
(see Table 3) 
Vital signsh 
 
 
 
 
 
(see Table 3) 
Adverse event monitoringi 
X 
 
X 
X 
X 
(see Table 3) 
PK in plasma 
X 
 
X 
X 
X 
(see Table 3) 
Laboratory Safetyl,m 
X 
 
X 
X 
X 
(see Table 3) 
 
 


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Table 5. Schedule of Events (Part 2, Cohort 10) 
Study Procedure 
Screening
Visits  
 
In-Patient Phasea 
Out-patient 
phase 
Follo
w-Up 
1 
2 
 
Pre-Day 
Profile-Day 
Evaluation 
Day 
± allowable deviation 
-28 to 
-2 
-7 to 
1 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
10 
±1 
14 
±2 
18 
±2 
21 
+3 
Subject information 
and Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
(including 
demographics, 
previous/concomitant 
medications) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Neurological 
examinationc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Colour blindness testd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmology exame 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ward Admission 
(approx.16h) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drugs of abuse 
and alcohol breath test 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hoursa (pre/post 
drug) 
 
 
-36 -24* -23.5 -23 -22.5 -22 -21 -20 -18 -16 
-12 
0* 0.5 
1 
1.5 
2 
2.5 
3 
4 
5 
6 
8 
12 
24 36 48 72 96 120 144 168 
 
 
 
 
Glucose and Insulin 
profiles 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Administration of 
emodepsidef 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead safety ECG 
X 
 
 
Xg 
 
X 
 
 
 
 
 
 
X 
Xg 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Vital signsh 
X 
 
 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Adverse event 
monitoringi 
X 
 
X 
X 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK in plasmaj 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
(X) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Safetyk,l 
Xl 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurologicalc 
examination and short 
physical examinationb 
 
 
 
Xb 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Travel and stay at 
ophthalmology clinic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmology examm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* All assessments at Hour 0 on Day 0 are immediately before the administration of study drug (emodepside), and assessments at Hour –24 on Day –1 will be time-matched to Profile Day 
(dosing Day) 
a Including a 10-minute supine phase before supine BP, HR, body temperature, ECG; and also recommended before drawing blood samples. 


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b Height at screening only, for calculation of BMI. Weight at screening for calculation of BMI, also at -24h (Day -1) for PK calculations. 
c Neurological examination designed for the study, see Section 8.19.4 and Study Procedures Manual. 
d Colour blindness to be determined at Screening visit 1. 
e If subjects are eligible for study entry based on Screening visit 1 assessments, they will be asked to undergo an ophthalmology exam (Screening visit 2) within a week before Profile Day 
or on PreDay at the latest. All assessments for Screening Visit 1 will be performed prior to Screening Visit 2, but visits can be combined if necessary.  
f Administration of study drug is in the fasted-state only. 
g To include 3 repeat ECGs at these timepoints, with a time difference of about 1 minute, and single recordings at other timepoints. 
h Vital signs to include supine BP and HR. Oral temperature only at screening and -24h. 
i Adverse Event (AE) monitoring will be throughout the study (spontaneous and solicited) to include questioning for tolerability and safety, however at these indicated timepoints will be 
specific questioning about AEs. 
j Timepoint shown as (X) indicates sample will be taken off-site whilst at the ophthalmology clinic. As‎an‎option,‎at‎the‎sponsor’s‎discretion,‎an‎additional‎sample‎of‎no‎more‎than‎1‎mL‎may‎
be taken at each PK timepoint from all subjects in up to 3 cohorts. 
k Hematology, Coagulation, Chemistry; Urinalysis by dip stick. 
l At Screening only: HIV 1, 2, Hepatitis B, C, HbA1C, in additional to hematology, coagulation, urinalysis, and chemistry. 
m Ophthalmology exams will be performed on Profile-Day (Day 0) approximately 2-2.5 h post-dose. If deemed necessary by the ophthalmologist additional ophthalmology follow-up visit(s) 
may be scheduled for eye-related AEs. 
 


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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,  
Cumberland Avenue,  
London, NW10 7EW, United Kingdom 
The Investigator or his/her delegate should document the date when informed 
consent was obtained (Screening), screening dates, subject initials, Screening 
Number, date of eligibility and inclusion in the study (Enrolment), Subject Number 
(when Randomised – received treatment) or reason for not enrolling (screen failure) 
or not being randomized, whenever applicable. 
Screening should occur between 2 and 28 days before the intended initiation of 
treatment: detailed procedures are described in Section 8 “Study Procedures”. 
All subjects must give written consent (see Sections 8.1 and 15.1 for Informed 
Consent Procedures) to participate in this trial. Consent for screening evaluations 
may be obtained using the information and consent form for the HMR healthy 
volunteer panel, which was originally approved by London – Brent Research Ethics 
Committee (REC) and has subsequently been approved by the Phase 1 Advert 
Review Committee. The trial-specific information and consent form will be signed by 
the subject either before any screening evaluation or after the investigator confirms 
the eligibility of the subject for the trial and before the subject is randomized to 
receive the first administration of IMP. Before giving consent, subjects must read the 
information sheet about the trial. They must also read the consent form. They will 
then discuss the trial with the investigator or his deputy and be given the opportunity 
to ask questions. The trial-specific information sheet and the consent form must be 
approved by the REC. All screened subjects will be allocated a Screening Number. 
After successful screening, subjects will be enrolled, and allocated to the cohort in 
the trial, according to their availability and the scheduled trial dates. Subjects will be 
assigned Subject Numbers in the order in which they are admitted to the ward, when 
they receive their first dose (‘Randomised’‎subjects). Subject numbers for each part 
of the trial will be as shown in Table 6. Leading subjects in Cohort 1 will be numbered 
1001 and 1002. Subject numbers will be allocated to treatments (active or placebo) 
according to a randomization schedule prepared by an independent HMR statistician, 
using a SAS program. Sufficient subjects will be screened to ensure up to 
80 subjects are randomized.  
As this is a First in Human study, Sentinel Dosing will be applied. In Cohort 1, the 
leading subjects will be randomized so that one will receive placebo and the other will 
receive emodepside (see also Section 7.2 for more details). 
 
7. Study Treatments 
7.1. Study Treatment Doses and Regimens 
The study is divided into 2 parts; Part 1 (Cohorts 1-8) is considered the FIH, single 
ascending dose phase of the study, where subjects will receive a single oral fasted 
dose, and which includes different formulations to allow assessment of relative 
bioavailability. Subjects will be randomized to the following treatments: 


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Emodepside Liquid Service Formulation (LSF) solution (concentration of 1 mg/mL) or 
matching placebo solution for Cohorts 1, 2, 3, 5, 6 and 8; emodepside immediate 
release (IR) tablets of 5 and 20 mg or matching placebo tablets for Cohorts 4 and 7, 
respectively.  
Part 2 is considered exploratory and will involve doses already tested. Therefore it is 
not considered to be FIH.  The planned doses for Part 2 are 10 mg LSF solution or 
matching placebo solution in the fed state for Cohort 9 and 40 mg LSF solution or 
matching placebo solution (fasted) in Cohort 10.  
The planned and actual treatments administered are described below in Table 6. 
7.2.  Allocation to Treatment 
Randomised Subjects will be given a unique ID (subject number; Table 6) that will be 
recorded in the case report form (CRF), and will be retained throughout the study. 
This subject number will also appear on the study medication containers. 
Table 6. Study Treatment: Subject Numbers, Formulation, and Dose-Levels by Cohort 
Cohort 
Subject 
Numbersa 
Dose Level of 
Study Treatment 
Formulation and Route of 
Administration 
Planned Subjects 
Emodepside Matching 
Placebo 
Part 1* 
 
 
 
 
 
Cohort 1 
1001 - 1008 
1.0 mg 
LSF solution, p.o. 
6 
2 
Cohort 2 
2001 - 2008 
2.5 mg 
LSF solution, p.o. 
6 
2 
Cohort 3 
3001 - 3008 
5.0 mg 
LSF solution, p.o. 
6 
2 
Cohort 4 
4001 - 4008 
5.0 mg 
IR tablet, p.o. 
6 
2 
Cohort 5 
5001 - 5008 
10.0 mg 
LSF solution, p.o. 
6 
2 
Cohort 6 
6001 - 6008 
20.0 mg 
LSF solution, p.o. 
6 
2 
Cohort 7 
7001 - 7008 
20.0 mg 
IR tablet, p.o. 
6 
2 
Cohort 8 
8001 - 8008 
40.0 mg 
LSF solution, p.o. 
6 
2 
Part 2** 
 
 
 
 
 
Cohort 9 
9001 - 9008 
10.0 mg 
 LSF solution, p.o. 
6 
2 
Cohort 10 
9501 - 9508 
40.0 mg 
LSF solution, p.o. 
6 
2 
*Part 1 is the FIH, SAD part of the study. 
**Part 2 is the exploratory phase (including Cohorts 9 and 10). 
a Any subjects who are replaced in a cohort will have the subject number incremented by 100 (eg, 1001 would be 
replaced by 1101) 
 
The first two subjects in Cohort 1 (subjects 1001 and 1002), will be the leading 
subjects. The Investigator will review all safety and tolerability data (including 
laboratory safety tests) up to 23 h after dosing of leading subjects before dosing the 
remaining subjects in the cohort.  


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7.3. Drug Supplies 
Formulation and Supplier:  Emodepside will be supplied by the Sponsor, DNDi, as 
emodepside LSF solution and tablets, each with matching placebo.  
The study drug will be delivered by the sponsor to the study site in bulk. It will be the 
responsibility of a relevant member of the pharmacy/pharmacy delegate to prepare 
the individual treatments. 
Labelling, Packaging:  Emodepside supplied by the Sponsor will be manufactured, 
packed, labeled 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.  
A relevant member of the pharmacy/pharmacy delegate will dispense study drugs as 
individual doses for each subject according to the Pharmacy Manual. 
Preparation and Dispensing: Emodepside LSF solution and tablets will be 
dispensed in the Phase 1 Unit to the 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. 
Administration:  Following a fast overnight (of not less than 9 hours; fasted 
subjects) or an FDA breakfast (fed subjects), investigator site personnel will 
administer study medication to subjects on Day 0, with ambient temperature water to 
a total volume of approximately 240 mL.  
Subjects will swallow the study medication whole, for doses of tablets, the subject will 
not chew the medication prior to swallowing. All subjects will be required to refrain 
from drinking beverages other than water during the first 4 hours after dosing. 
Subjects will not eat until at least 4 hours after dosing, and not until all study 
assessments scheduled for that time have been completed. Instructions provided in 
Section 4.3. and the Study Procedures Manual regarding meals must also be 
followed. 
Compliance:  Study treatment will be administered under the supervision of 
investigator site personnel, who will monitor the subjects according to their standard 
procedures to ensure treatment compliance.  
7.4. Dose Escalation and Stopping Rules 
During the study, the dose will be increased only if the safety and tolerability and, 
from Cohort 3 onwards, the PK of the previous dose is acceptable.  
Planned dose levels may be changed based on emerging data. The top planned 
dose for the IR tablet is 20 mg and for the LSF solution is 40 mg. 
The first fed dose will not exceed half the highest dose, of the same formulation, that 
has previously been shown to cause no safety concerns in the fasted state. 
Decisions about dose escalation will be made by the participants in the Safety 
Review Meeting (SRG; see Section 11 on Safety Review Meetings). The dose will 
not be increased until the SRG have reviewed safety and tolerability data, up to a 


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minimum of 96 h after dosing and, from Cohort 3 onwards, a minimum of 24 h 
post-dose preliminary PK data from the highest dose level tested to date. The data 
reviewed by the SRG will be from at least 6 subjects in a Cohort (at least 4 subjects 
of whom have completed active treatment). 
If, within a treatment group, any of the following occurs, dose escalation will be 
stopped: 
Safety stopping criteria 
 There is 1 or more serious adverse event, considered to be related to 
emodepside; 
 2 or more subjects who present any severe adverse event considered to be 
related to emodepside 
If a cohort fulfils a dose escalation stopping criterion, that dose level will not be 
repeated. 
PK stopping criteria 
 predicted mean plasma concentrations in the subjects at the next scheduled 
dose level exceed or equal: Cmax 634 µg/L, AUC(0-24) 6025 µg·h/L  (based on 
the NOAEL level in dog toxicology studies, exposures resulting from 4 weeks 
of treatment at 10 mg/kg/d) 
The scheduled dose of emodepside may be reduced if, for example, the results of 
safety tests give any cause for concern, or tolerability is poor.  
If adverse events occur that cause mild or moderate discomfort but do not in any way 
threaten the health of the subject, that dose level may be repeated with the aim of 
exploring further the relationship between dose and adverse event. If, in the 
judgement of the SRG, it would not be reasonable to expose further subjects to the 
level of discomfort experienced by the subjects who have already received the dose, 
the next scheduled dose may be reduced. The reduction may be either to one of the 
dose levels that has already been given, or to an intermediate level that has not 
previously been given; in either case, the aim is to learn more about the relationship 
between adverse event and dose (or plasma concentration) of drug. 
Optionally, if further information is required to guide dose escalation decisions, an 
independent advisor(s) may be consulted, who will have access to unblinded data 
(see Section 11, Safety Review Meetings). 
7.5. Blinding and Procedures for Unblinding  
The study drug and matching placebo will be identical in appearance in order to 
preserve the blind. 
A sealed copy of the randomisation code will be kept in a locked file in the HMR 
Pharmacy. A copy will also be kept by the sponsor. The investigator will be supplied 
with sealed envelopes, each one containing the treatment allocation for the subject 
whose number appears on the outside of the envelope. Those envelopes will be kept 
in the trial master file, readily accessible to clinical staff. Emergency procedures for 
revealing medication codes are specified later in this section.  


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The investigators, Medical Monitor and Clinical Monitor will remain blinded until the 
database of finished cohorts is locked, unless safety concerns necessitate 
unblinding. 
Sponsor staff working on the study team, staff at the investigator site(s) and the study 
monitor(s) will be blinded to study treatment. Optionally, a separate, unblinded 
monitor may be used to check drug accountability monitoring during the conduct of 
the study, following procedures to avoid unblinding other study personnel. 
If required, as described in Section 11, advisor(s) independent from the study team 
may be appointed to review unblinded data to assist decision-making during Safety 
Review Meetings.  
When a trial database has been locked, the HMR statistician will inform the sponsor 
of his or her intention to break the randomisation code for the finished cohorts. The 
statistician will break the code, and do the statistical analysis of those data.  
If unblinding is required in the interest of the safety of a subject, an investigator will 
discuss the matter with the sponsor before opening the individual code-break 
envelope for that subject. In a medical emergency, the principal investigator or 
delegate may open the individual code-break envelope for that subject without prior 
consultation with the sponsor. In that event, the principal investigator or delegate will 
notify the sponsor as soon as possible that the randomisation code has been broken 
for the subject.  
When the blinding code is broken, the reason will have to be fully documented and 
entered in source documents and the CRF. 
7.6. Drug Storage and Drug Accountability 
Storage: The investigational product will be stored in a secure limited access area in 
accordance with required storage conditions. Storage and handling instructions will 
be included in the Pharmacy Manual. Pharmacy staff at the clinical center will be 
responsible for the correct storage and handling of the study drug. 
The study drug will be dispensed only under the restricted conditions defined in the 
present protocol and the Pharmacy Manual. Drug will be administered by the 
Investigator only or his/her delegate. Time of administration and initials of the person 
administering the drug will be documented in the CRF. 
Accountability:  Upon receipt of the study drugs, the Investigator or a relevant 
member of the pharmacy/pharmacy delegate will send to the Sponsor the 
corresponding acknowledgement of receipt form. This form must be duly filled 
(including the date of receipt) and signed by a relevant member of the 
pharmacy/pharmacy delegate or the Investigator. A drug movement form of all 
medication dispensed during the study will be maintained. 
All investigational materials (medication and packaging) unused in the study will be 
returned to the Sponsor before or at the termination of the study, together with an 
accountability form documenting: 
 all administered units; 


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 all unused treatments; 
 all units returned after completion of the study, and the date of return. 
7.7. Prior and 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 
up to the first dose of trial medication. 
No medications (with the exception of acetaminophen (paracetamol) up to 2000mg 
per day), will be allowed while the subject is participating in the study except those 
medically indicated for the treatment of AEs. If any medication is required, the subject 
may be withdrawn from the study at the discretion of the Investigator and the 
Sponsor if use of the concomitant 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 and/or P-gp metabolic pathways will 
be allowed while the subject is participating in the study except those medically 
indicated for the treatment of AEs. 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 first dose of study medication will be 
documented as a prior medication. Medications taken after the first dose of study 
medication will be documented as concomitant medications. 
8. STUDY PROCEDURES 
8.1.  Subject Information and Consent Form  
Before any procedures are conducted, the investigator (or an appropriate delegate at 
the investigator site) will obtain written informed consent from each subject in 
accordance with the procedures described in Section 15.1 on Subject Information 
and Consent Form.  
8.2. Screening visit 1 (all cohorts in Parts 1 and 2) 
Subjects will be screened within 28 days prior to administration of the study 
medication to confirm that they meet the subject selection criteria for the study.  
Subjects who fail screening due to failure to meet inclusion and/or exclusion criteria 
are not permitted to be rescreened. 
The following assessments will be done in order to collect historical safety data, and 
check inclusion and exclusion criteria. 
 Inclusion/exclusion criteria review; 


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 Complete medical history: including demographic data, previous and 
concomitant medications (ie, prescription or nonprescription drugs, and dietary 
supplements taken within 28 days prior to the planned first dose)  
 Complete Physical examination: See Section 8.19.4. 
 Neurological examination:  See Section 8.19.4. Also a detailed description of 
the neurological examination will be included in the Study Procedures 
Manual). 
 AE monitoring (spontaneous and solicited adverse event monitoring will 
include specific questioning for tolerabilty and safety) 
 Urinary drug screen (opiates, amphetamines, barbiturates, cannabis, 
benzodiazepines, cocaine-metabolites) and alcohol breath test; 
 Serology (HIV and hepatitis); 
 Body weight and height, vital signs (oral temperature, blood pressure and 
heart rate will be determined; Table 3); 
 Colour blindness test (Ishihara score) in Part 2, Cohort 10 only.    
 12-lead ECG recording; 
 Clinical safety laboratory evaluations: All biological assessments will be 
performed in fasting state:  
 Hematology and coagulation: hemoglobin, hematocrit, MCV, 
MCH, MCHC, platelets, reticulocytes, white blood cells (WBC) with 
differential, red blood cells (RBC), HbA1C, activated partial 
thromboplastin time (aPTT), prothrombin time (PT); 
 Biochemistry: aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (AP), glutamate 
dehydrogenase (GLDH), gamma-glutamyl transpeptidase (GGT), 
lactate dehydrogenase (LDH), creatinine kinase (CK), amylase, lipase, 
T4 (free), T3 (free), thyroid-stimulating hormone (TSH), glucose, 
cholesterol (HDL, LDL, total), triglycerides, creatinine, urea, uric acid, 
bilirubin (total and conjugated), total protein, sodium, potassium, 
calcium, chloride and magnesium in serum; 
 Urinalysis: 
o  dipstick test:  glucose, ketone bodies, specific gravity, occult 
blood, pH, proteins, leucocytes, bilirubin, urobilinogen, nitrites; 
To prepare for study participation, subjects will be instructed on the use of the Dietary 
and Lifestyle Guidelines of the Phase 1 unit and for this study, and will be scheduled 
to report to the clinic for admission to the ward on Day -2. 


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8.3. Screening visit 2 (Part 2, Cohort 10 only)  
For subjects in this exploratory cohort, in addition of differences in the timepoints the 
main difference compared to the other cohorts is the addition of ophthalmology 
assessments (see Section 8.19.5, a detailed description of the ophthalmology 
assessments will be added to the Study Procedures Manual. Cohort 10 procedures 
are described in detail in Table 5).  
 
8.4. Admission to Ward (Day -2) 
Subjects will be admitted to the ward at the Phase 1 Unit, on Day -2 approximately at 
16:00 h, and a urine drug screen (opiates, amphetamines, barbiturates, cannabis, 
benzodiazepines, cocaine-metabolites) and an alcohol breath test will be performed. 
Monitoring of AEs will be performed.  
General Order for all Assessments from Day -1 through Day 7:  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 (see also Table 3): 
 12-lead ECGs: obtain prior to vital signs and blood specimen collection, but as 
close as possible to scheduled time;  
 Blood pressure (supine)/heart rate/oral temperature: obtain as close as 
possible to scheduled time, but prior to blood specimen collection; 
 AE monitoring (spontaneous and solicited adverse event monitoring will 
include specific questioning for tolerability and safety)  
 For cohorts having continuous ECG reading, the minimum supine period prior 
to and after each nominal timepoint must be observed, and as close as 
possible to the blood draw for PK; 
 Blood draw for PK 
 Blood draw for profiles of glucose, insulin, glucagon, cortisol; single samples 
for  prolactin and leptin (For subjects in Part 2, Cohort 10, only glucose and 
insulin are required, see Table 5); and laboratory safety tests (taken at the 
same time, if scheduled at the same timepoint);  
 Blood pressure (sitting) 
 PK urine specimens: collect for scheduled time frame; 
 Neurological examination and short physical examination 
8.5. Pre-Day (Day -1) 
After their first night in the ward, subjects will be fasting overnight, fed subjects will 
then have a high-calorie, high-fat FDA breakfast, as described in section 4.3, and will 
have the following procedures completed as scheduled at various times during the 
day, which are all matching the schedule of procedures on the day of drug 
administration (Day 0, or Profile Day). The timing of all procedures must be as per 
the study Schedule of Events (Table 3) and Table 5 for Cohort 10: 


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 12-lead ECGs: as 3-repeat readings at one timepoint, and as a single 
readings at the others  
 Oral temperature 
 Blood pressure/heart rate: in both supine and sitting position, according to the  
timepoints specified in the Schedule of Events. For subjects in Cohort 10, 
measurements are only collected in the supine position 
 AE monitoring (spontaneous and solicited adverse event monitoring will 
include specific questioning for tolerability and safety):   
 Blood specimens for profiles of glucose, insulin, glucagon, and cortisol; single 
samples for prolactin and leptin (For subjects in Part 2, Cohort 10 only glucose 
and insulin are required, see Table 5) 
 Laboratory safety blood and urine specimens 
 Neurological examinations and short physical examinations:  
Subjects will receive meals at the same time points as on Profile Day, as per the 
Study Procedures Manual, and Section 4.3.  
8.6. Profile Day (Day 0) 
Part 1, Cohorts 1-8, and Part 2, Cohort 9 
Subjects will be fasting overnight, as described in section 4.3, and will have the 
following procedures completed pre-dose (within half an hour before [Cohorts 1–8] or 
before the FDA breakfast [Cohort 9], except the continuous ECG monitoring – see 
timings below) and at the time points after administration of Study Drug outlined in 
(Table 3): 
 In some cohorts (from Cohort 3 onwards, cohorts to be determined by the 
sponsor, in consultation with investigator – see Section 8.19.2), a continuous 
ECG recording (holter) will be started one hour prior to dosing and continue for 
24 hours post-dosing.  
 12-lead ECGs: single readings, with the exception of one triplicate reading  
 Blood pressure/heart rate: in both supine and sitting position according to the 
timepoint and specified in the Schedule of Events 
 AE monitoring (spontaneous and solicited adverse event monitoring will 
include specific questioning for tolerability and safety) 
 PK blood specimens 
 PK blood specimens for metabolites  
 PK urine specimen collections  
 Blood specimens for profiles of glucose, insulin, glucagon, and cortisol; single 
samples for prolactin and leptin; Laboratory safety blood and urine specimens 
 Neurological examination and short physical examination 
Subjects will receive meals at the same time points as on Day -1 (as per the Study 
Procedures Manual and Section 4.3) 


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Part 2, Cohort 10 
Subjects will be fasting overnight, as described in section 4.3, and will have the 
following procedures completed pre-dose (within half an hour before) and at the time 
points after administration of Study Drug outlined in Table 5.  
 12-lead ECGs: single readings, with the exception of one triplicate reading  
 Blood pressure/heart rate: in the supine position 
 AE monitoring (spontaneous and solicited adverse event monitoring will 
include specific questioning for tolerability and safety) 
 PK blood specimens 
 Blood specimens for profiles of glucose and insulin; Laboratory safety blood 
and urine specimens 
 Neurological examination and short physical examination 
 Ophthalmology assessments  
 
8.7. Day 1 (24 & 36 Hours after Study Drug Administration)  
Part 1, Cohorts 1-8, and Part 2, Cohort 9 
Subjects will have the following procedures completed at the timepoints specified in 
the Schedule of Events (Table 3): 
 12-lead ECGs 
 Blood pressure/heart rate: in both supine and sitting position, according to the 
timepoint and specified in the Schedule of Events, 
 AE monitoring (spontaneous and solicited adverse event monitoring will 
include specific questioning for tolerability and safety) 
 PK blood specimens 
 PK blood specimens for metabolites  
 PK urine specimen collections   
 Blood specimens for profiles of glucose, insulin, glucagon, and cortisol; single 
samples for prolactin and leptin  
 Laboratory safety blood and urine specimens 
 Neurological examination and short physical examination 
Subjects will receive meals at the standard time points (as per the Study Procedures 
Manual) 
Part 2, Cohort 10 
Subjects will have the following procedures completed at the timepoints specified in 
the Schedule of Events Table 5.  
 12-lead ECG (24h post-dose) 


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 Blood pressure/heart rate in the supine position (24 h and 36 h post-dose)  
 AE monitoring (spontaneous and solicited adverse event monitoring will 
include specific questioning for tolerability and safety (24 h and 36 h 
postdose) 
 PK blood specimens (24 h and 36 h postdose) 
 Blood specimens for profiles of glucose and insulin (24h post-dose);  
 Laboratory safety blood and urine specimens (24h post-dose); 
 Neurological examination and short physical examination (24 h and 36 h 
postdose);  
 
8.8. Day 2 Through Day 6  
Part 1, Cohorts 1-8, and Part 2, Cohort 9 
Subjects will have some or all of the following procedures completed as detailed in 
the Schedule of Events (Table 3). Procedures must be performed at the same time 
each morning: 
 12-lead ECGs: as a single reading. 
 Blood pressure/heart rate: in supine position  
 AE monitoring (spontaneous and solicited adverse event monitoring will 
include specific questioning for tolerability and safety)  
 PK blood specimens, 
 On Day 2 only: PK blood specimens for metabolites  
 Laboratory safety blood and urine specimens 
 On Day 2 only: Neurological examination and short physical examination:  
Subjects will receive meals at the standard time points of the ward of the Phase 1 
unit (as per the Study Procedures Manual) 
Part 2, Cohort 10 
Subjects will undergo the same procedures and assessments as for Part 1, Cohorts 
1-8, and Part 2, Cohort 9, with the exception that blood samples for PK metabolites 
are not required in this cohort.  
 
8.9. Day 7 (or Day X for Option 3: Prolonged In-House Phase) 
Parts 1 and 2 (all cohorts) 
The following procedures will be completed in the morning on the day the subject will 
be discharged from the ward: 
 12-lead ECGs: as a single reading 


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 Blood pressure/heart rate: in supine position 
 AE monitoring (spontaneous and solicited adverse event monitoring will 
include specific questioning for tolerability and safety) 
 PK blood specimens 
 Laboratory safety blood and urine specimens 
If a subject experiences any AE and/or clinically significant laboratory abnormality, 
which is considered related to emodepside by the investigator during the 1-week 
in-house evaluation phase that is planned to end on Day 7, the DNDi medical monitor 
(or designated representative) should be notified and the subject may be asked to 
remain in the Phase 1 Unit until such abnormalities are deemed not clinically 
significant, or it is safe to discharge the subject from the ward.  
In the event that results of assessments obtained‎after‎the‎subject’s‎discharge‎from‎
the ward indicate a significant safety concern (eg, a clinical laboratory result 
indicating an adverse event, or unexpectedly high levels of emodepside in plasma), a 
subject may be asked to return to the ward for readmission However, if a subject is 
unable or unwilling to remain on or return to the ward (including withdrawal of 
consent: Sections 8.13 and 15), and/or when outpatient follow-up is deemed 
appropriate, the DNDi medical monitor (or designated representative) should be so 
notified, and the Investigator should make every effort to arrange follow-up 
evaluations at appropriate intervals to document the course of ongoing AEs and/or 
abnormalities and/or clinically significant laboratory abnormality. 
Subjects will be discharged on Day 7, as outlined in Figure 2 and Table 4 for Option 
1. 
However, as detailed in section 3.1, if in previous cohorts plasma concentrations of 
emodepside are still present 7 days after dosing, 2 alternative options may be 
employed to follow subjects after Day 7 (from Cohort 5 onwards and for all subjects 
in subsequent cohorts (this decision will be made during Safety Review Meeting(s) – 
Section 11): 
Option 2: Subjects will be discharged on Day 7, as planned, as outlined in Figure 2 
and Table 4 for Option 2, but will return to the clinic for ambulatory evaluation visits 
that will be scheduled as needed.  
Option 3: Subjects will not be discharged on Day 7, as planned, but will be kept for a 
prolonged in-house evaluation phase of up to Day 14, as considered appropriate, 
before being discharged (Day X), as outlined in Figure 2 and Table 4 for Option 3. 
 
8.10. 
Evaluation Visit(s) for Option 3 (Discharge from Ward) and 
Option 2 (Ambulatory Visit[s]Scheduled as Needed) 
Option 2: Subjects (not fasting) will return to the clinic for each ambulatory 
evaluation visit as scheduled, to have some or all of the following procedures 
completed: 


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 AE monitoring (spontaneous and solicited adverse event monitoring will 
include specific questioning for tolerability and safety) 
 PK blood specimens, 
 Laboratory safety blood and urine specimens, 
Option 3: Subjects (not fasting) will remain on the ward for up to an additional 7 days 
(to Day 14). Starting from Day 8, subjects will have the following procedures every 
other day up to Day 12 as deemed necessary by the Investigator and Sponsor.  
 AE monitoring (spontaneous and solicited adverse event monitoring will 
include specific questioning for tolerability and safety) 
 PK blood specimens, 
 Laboratory safety blood and urine specimens 
Subjects will be discharged on Day 14 at the latest or earlier if PK data from previous 
cohorts support a shorter in-house stay. Procedures on the day of discharge will be 
as described in Section 8.9. (‘Day‎X’) 
Subjects in Cohort 9 will follow option 2, (up to 4 visits during the period from Day 8–
21 inclusive, as needed). Subjects in Cohort 10 will return to the unit for out-patient 
visits on Days 10, 14 and 18, to have the following assessments: 
 AE monitoring (spontaneous and solicited adverse event monitoring will 
include specific questioning for tolerability and safety) 
 PK blood specimens 
 Laboratory safety blood and urine specimens 
 
8.11. Follow-Up Visit (3 weeks [+3 Days] after dosing) 
Approximately three weeks after their dose the subjects will return to the Phase 1 
Unit for a Follow-Up Visit (all cohorts in Parts 1 and 2), and the following procedures 
will be completed: 
 Complete physical examination 
 Complete neurological examination 
 12-lead ECGs, as a single reading,  
 Blood pressure/heart rate: in supine position, 
 AE monitoring (spontaneous and solicited adverse event monitoring will 
include specific questioning for tolerability and safety), including any 
concomitant medications (ie, prescription or nonprescription drugs, and dietary 
supplements) taken during the duration of this study up to the follow-up visit,  
 Laboratory safety blood and urine specimens 
 PK blood specimens 


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For Cohort 10 only: If deemed necessary by the ophthalmologist additional 
ophthalmology follow-up visit(s) may be scheduled to characterize and assess any 
eye-related AEs. 
8.12. 
Sampling time points and additional tests 
With‎the‎sponsor’s‎approval,‎additional‎time‎points‎may‎be‎introduced,‎and‎changes‎
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 
the IMP 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 8.18, unless in the 
opinion‎of‎the‎Investigator,‎it’s‎in‎the‎subject’s‎best‎interest‎that‎extra‎blood‎is‎taken‎
for additional safety tests. Any additional urine collections may include continuous, 
total collections, if necessary. An‎additional‎48‎hours’‎residence‎in‎the‎ward‎and‎
additional outpatient visits, will be permitted, in the event of a technical failure, and/or 
if extra observations or samples of blood or urine are needed. Similarly, the interval 
between outpatient visits (Option 2 only, see Section 8.10) may be changed if data 
collected during the study support the change. 
In the case of any samples for pharmacokinetic analysis, the following will not be 
regarded as protocol deviations: 
1. deviations of not more than 5 min on measurements scheduled up to and 
including 4 h after dosing;  
2. deviations of not more than 15 min on measurements scheduled from after 4 h to 
24 h after dosing; 
3. deviations of not more than 1 h on measurements scheduled more than 24 h after 
dosing; and 
4. deviations of not more than 1 or 2 days on measurements scheduled for 
ambulatory visits in Option 2. Deviations are shown in the schedule of events in 
Table 4.   
For all other procedures, the following will not be regarded as protocol deviations:   


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Table 7. Permitted deviation windows for all other procedures1 
TIME POINT 
DEVIATION WINDOW IN 
RELATION TO THE 
SCHEDULED TIME POINT 
Day –1 
Day 0 
Pre –24 h 
Pre-dose (0 h) 
Within 75 min before2 
–24 h to –23.5 h 
Up to and including 
30 min after dosing 
+/– 5 min2 
After –23.5 h to –20 h 
After 30 min to 4 h after 
dosing5 
+/– 10 min2,3 
After -20 h to -12 h 
After 4 h to 24 h after 
dosing 
+/– 15 min2 
NA 
more than 24 h after 
dosing 
+/– 1 hour 
NA 
Ambulatory visits in 
Option 2 
1 or 2 days4 
1. Urine collection for laboratory safety tests will be within 2 h of the scheduled time point and all 
pre-dose urine samples will be collected pre-dose. 
2. On Day –1 and Day 0, for the neurological and brief physical examinations, and seated vital signs 
assessments, the window will be extended by 5 minutes beyond those specified in the table.   
3. For the cohorts that have PK urine collection, the window will be extended to +/- 15 min for the 4 h 
post dose neurological and brief physical examinations. 
4. Deviations are shown in the schedule of events in Table 4.  
5. For subjects in Cohort 10, ophthalmology tests may be done within 1.5 to 5 h following dosing.    
8.13. 
Subject Withdrawal (see also Section 9.5) 
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, 
behavioral, or administrative reasons.  
If a subject does not return for a scheduled visit, every effort should be made to 
contact the subject. In any circumstance, every effort should be made to document 
subject outcome, if possible.  
If the subject withdraws consent, no further evaluations should be performed and no 
attempts should be made to collect additional data, with the exception of safety data, 
which should be collected if possible and in accordance with patient subject consent. 
The sponsor may retain and continue to use any data collected before such 
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 
the‎subject’s‎requests. 


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If a subject withdraws from the study, the reason must be noted in the source 
documents and on the CRF. If a subject is withdrawn from the study because of a 
treatment limiting adverse event, thorough efforts should be made to clearly 
document the outcome of AE. 
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 adverse events. 
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 Schedule of Events, Table 3). 
Subjects who withdraw, or are withdrawn from the study may be replaced at the 
discretion of the investigator upon consultation with the sponsor. 
For any subject who meets any of the following criteria, the subject may be 
withdrawn from the trial (ie, have no further study assessments; and no dosing will 
occur if this has not already taken place). Note that all adverse events must 
nevertheless be reported and followed-up as per Adverse Event Reporting Section 9 
(unless the subject withdraws consent for further assessments). 
 ALT‎≥‎5‎x‎ULN. 
 ALT‎≥‎3‎x‎ULN‎and‎total‎bilirubin‎≥‎2‎x‎ULN‎or‎international‎normalised‎ratio‎
(INR) > 1.5 x ULN. (If a subject meets that withdrawal criterion, serum bilirubin 
fractionation should be performed.) 
 ALT‎≥‎3‎x‎ULN‎if‎associated‎with‎the‎appearance‎or‎worsening‎of‎rash‎or‎
hepatitis symptoms (fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness,‎fever,‎rash‎or‎eosinophilia).‎Subjects‎who‎have‎ALT‎≥‎3‎x‎ULN‎
and < 5 x ULN, and total bilirubin , 2 x ULN, who do not exhibit hepatitis 
symptoms or rash, can continue in the study as long as they can be monitored 
until Follow-Up visit,  or for the duration of follow-up as specified in Adverse 
Event Follow-Up Section 9, whichever applies. 
Furthermore, the investigator may withdraw a subject for the following reasons: 
 adverse events that are considered by the investigator to be related to trial 
medication and meet one of the following 2 criteria: 
 serious or severe; or 
 otherwise clinically significant, such as signs of allergic reaction 
or important bleeding events 
 clinically significant intercurrent illness which could compromise the safety of 
the subject or the scientific value of the trial 
 need for, or use of, contraindicated medication which could compromise the 
safety of the subject or the scientific value of the trial  


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 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. 
8.14. 
Study Assessments 
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 these cases, the investigator must take all steps 
necessary to ensure the safety and well-being of the subject. When a protocol 
required test cannot be performed, the investigator will document the reason for the 
missed test and any corrective and preventative actions which s/he has taken to 
ensure that required processes are adhered to as soon as possible. The Sponsor 
study team must be informed of these incidents in a timely manner. Allowable 
deviations for study assessments are detailed in Section 8.12 of this protocol.  
To minimise variability, throughout the study, study staff should ensure: 
 a minimum 10-minute supine period before the following assessments: supine 
BP, HR, oral temperature, ECG; and is also recommended before drawing 
blood samples 
 a minimum 10-minute supine period prior to, and 5 minutes after each nominal 
timepoint for the continuous ECG reading 
 a minimum 3-minute sitting period before sitting BP assessments 
Throughout the study, AEs and concomitant medication will be documented as they 
are reported by the subjects. Subjects will also be questioned about AEs at the times 
that blood samples are taken, at follow-up, and at the specific timepoints detailed in 
the Schedule of Events (Table 3). 
8.15. 
Assessment of Efficacy 
Not applicable 
8.16. 
PK Assessments 
Blood samples for the determination of emodepside concentration in plasma will be 
collected at the time points indicated in the Schedule of Assessments in Table 3. The 
exact date and time of PK blood sampling will be recorded in the CRF. 
Blood samples for PK purpose will be taken from either arm. Samples for measuring 
emodepside plasma concentration, and samples for measuring metabolites of 
emodepside will be collected either by cannulation or by venipuncture. 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. 


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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 Profile Day, blood samples will be collected for PK estimation and emodepside 
plasma concentrations. Overall, a total of 20-24 blood samples will be collected for 
PK purpose (plus an additional 8 samples for metabolites). 
On each treatment period, the following PK parameters of emodepside will be 
derived for each subject: 
z 
The terminal rate constant will be estimated by log-linear regression 
analysis on data points visually assessed to be on the terminal log-linear 
phase.  
t1/2 
The terminal half-life will be calculated according to the following equation: 
t1/2 = ln2/z. 
AUCt 
The area under the concentration-time curve from time zero (pre-dose) to 
the time of last quantifiable concentration will be calculated using a  
trapezoidal method. 
AUCt,norm The area under the concentration-time curve from time zero (pre-dose) to 
the time of last quantifiable concentration corrected by dose and body 
weight 
AUC 
The area under the plasma drug concentration vs. time curve from time 
zero to infinity. The percentage of extrapolation of AUC should normally 
not exceed 20%. 
AUC/D 
The area under the plasma drug concentration vs. time curve from time 
zero to infinity, corrected for dose.  
AUC,norm The area under the concentration-time curve from time zero to infinity 
corrected by dose and body weight 
Cmax 
The observed maximum plasma concentration measured in a subject after 
dosing identified by inspection of the drug concentration vs. time data. 
Cmax/D 
The observed maximum plasma concentration measured in a subject after 
dosing identified by inspection of the drug concentration vs. time data, 
corrected for dose. 
Cmax,norm The observed maximum plasma concentration corrected by dose and 
body weight 
Tmax 
The time at which Cmax was apparent, identified by inspection of the drug 
concentration vs. time data. 
MRT 
The mean residence time will be calculated using: 

AUC
AUMC
MRT
 


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Where AUMC is the area under the first moment of the concentration-time 
curve from zero time (pre-dose) extrapolated to infinite time. 
CL/F 
Apparent total clearance from plasma will be calculated using the following 
formula: 

AUC
Dose
F
CL /
 
Vz/F 
Apparent volume of distribution will be calculated using the following 
formula: 



AUC
Dose
F
V
z
z

/
 
As‎an‎option,‎at‎the‎sponsor’s‎discretion,‎an‎additional‎sample‎of‎no‎more‎than‎1mL 
may be taken at all PK time points, from all subjects in up to 3 cohorts. These 
samples may be used for future metabolite identification and/or further evaluation of 
the bioanalytical method. They will be stored and analysed, if required, at a 
laboratory designated by the Sponsor. These data will be used for internal 
exploratory purposes and will not be included in the clinical report. 
8.17. 
Pharmacodynamic Assessments 
Blood samples for the determination of levels of glucose, insulin, glucagon and 
cortisol, plus prolactin and leptin will be collected from each subject during the study, 
at the time points indicated in the Schedule of Assessments in Table 3 (for Part 1, 
Cohorts 1-8 and Part 2, Cohort 9), and Table 5 (Part 2, Cohort 10).  
The exact date and time of sampling will be recorded in the CRF. Blood volumes for 
those samples are shown in Table 8.  
Collection of samples for pharmacodynamic assessments:  Blood for glucose 
insulin, cortisol, prolactin and leptin will be collected in tubes with a gelatin plug. 
Blood for glucagon will be collected in aprotinin EDTA tubes. Samples will then be 
transferred to the laboratory.  
Processing and analysis of samples for laboratory safety tests:  Processing of 
samples will be done by the HMR Analytical Laboratory in accordance with the 
laboratory’s‎standard‎operating procedures. 
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.  


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8.18. 
Collection Method and Total Volume of Blood 
Blood collection:  Blood samples for pharmacokinetic, pharmacodynamic and 
laboratory safety samples will be drawn either via venipuncture or using a cannula. 
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. 
The blood volume planned to be collected from each subject during the course of this 
study is detailed in Table 8. Additional samples may be required in the event of 
adverse events. 
Table 8  Blood Volumes: Part 1 (Cohorts 1-8) and Part 2 (Cohort 9) 
Options for 
Follow-Up 
Option 1 Option 2 Option 3 
  
Option 1 Option 2 
Option 3 
Test 
Number of tests 
Blood 
volume 
Total planned blood volume 
(mL) 
(mL) 
Haematology  
11 
15 
15 
2.00 
22.00 
30.00 
30.00 
HbA1C 
1 
1 
1 
2.00 
2.00 
2.00 
2.00 
Biochemistry 
including free T3 
and T4 
11 
15 
15 
5.00 
55.00 
75.00 
75.00 
Coagulation 
11 
15 
15 
3.00 
33.00 
45.00 
45.00 
Serology 
1 
1 
1 
2.50 
2.50 
2.50 
2.50 
Glucose* 
8 
12 
12 
2.50 
20.00 
30.00 
30.00 
Insulin, cortisol, 
(prolactin** 
8 
8 
8 
2.50 
20.00 
20.00 
20.00 
Glucagon 
11 
11 
11 
2.00 
22.00 
22.00 
22.00 
Leptin 
3 
3 
3 
2.50 
7.50 
7.50 
7.50 
Emodepside PK 
20 
24 
24 
5.00 
100.00 
120.00 
120.00 
Samples for 
metabolites 
8 
8 
8 
5.00 
40.00 
40.00 
40.00 
Discard (when 
blood is taken via a 
cannula) 
17 
17 
17 
1.00 
17.00 
17.00 
17.00 
optional samples *** 
20 
24 
24 
1.00 
20.00 
24.00 
24.00 
 
Total 
(mL) 
361.00 
435.00 
435.00 
*Glucose included in biochemistry panel on Days -1, 0 (0-h timepoint) and 1  
**Prolactin only to be measured on Days -1, 0 (0-h timepoint) and 1; Insulin, cortisol and prolactin to be 
included in the biochemistry panel on Days -1, 0 and 1 
***optional samples taken from up to 3 cohorts, to cover a whole PK profile. To be retained for possible 
future metabolite identification/bioanalytical method development 
The total volume of blood taken from each subject in the trial will be about 361 mL 
(or 435 mL if Option 2 or Option 3 for follow-up is required). 


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Additional blood may need to be collected for assay of emodepside, its metabolites, 
or for laboratory safety tests. No more than an extra 80 mL blood will be taken. 
Subjects in Cohort 10 will provide less blood due to the fewer assessments required. 
The approximate total per subject in Cohort 10 will be about 286 mL. The blood 
volume to be collected is shown in Table 9. Additional samples may be required in 
the event of adverse events. 
Table 9  Blood Volumes (Part 2, Cohort 10) 
Test 
Number of tests 
Blood 
volume 
Total planned blood volume 
(mL) 
(mL) 
Haematology  
14 
2.00 
28.00 
HbA1C 
1 
2.00 
2.00 
Biochemistry 
including free T3 
and T4 
14 
5.00 
70.00 
Coagulation 
14 
3.00 
42.00 
Serology 
1 
2.50 
2.50 
Glucose* 
4 
2.50 
10.00 
Insulin* 
4 
2.50 
10.00 
Emodepside PK 
19 
5.00 
95.00 
Discard (when 
blood is taken via a 
cannula) 
7 
1.00 
7.00 
optional samples** 
19 
1.00 
19.00 
Total (mL) 
285.50 
*Glucose and insulin included in biochemistry panel on Days -1, 0 (0-h timepoint) and 1  
**optional samples taken from up to 3 cohorts, to cover a whole PK profile. To be retained for possible future 
metabolite identification/bioanalytical method development 
 
After collection, samples (blood and urine) may be stored for up to approximately 
12 months after end of study before being destroyed, with the exception of the limited 
number of optional samples retained for possible future metabolite 
identification/bioanalytical method development. If those samples are required, they 
may be retained for up to 15 years after end of study. No samples must be destroyed 
without prior approval of the Sponsor. 
8.19. 
Assessments of Safety  
General questioning about AE will be done at screening (for AE onset after ICF 
signature), daily during the in-patient phase, at each visit, and at the Follow-Up Visit 
(see Section for AE recording and reporting).  
8.19.1. 
12-lead Safety ECG Recording 
Standard 12-lead ECGs will be recorded as per Schedule of Events in Table 3 (Part 
1, Cohorts 1-8, and Part 2, Cohort 9) and Table 5 (Part 2, Cohort 10). Most will be 


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single readings, but where triplicate ECGs are specified, 3 repeat ECGs, with a time 
difference of about 1 minute between them will be captured. Instructions for recording 
and handling of the ECGs will be included in the Study Procedures Manual. 
A 3-repeat or single 12-lead ECG will be obtained on all subjects as specified in 
Table 3.  
8.19.2. 
Extracted 12-lead ECG for Central Evaluation 
Emodepside's effect on the placebo-corrected, change-from-predose baseline QTcF 
interval will be evaluated using a linear exposure response model. Cohorts in Part 1 
only (from Cohort 3 onwards) will be selected for continuous monitoring by the 
sponsor in consultation with the investigator, based on predicted exposure to 
emodepside. It is currently planned that the selected cohorts will include all those 
dosed with the IR tablet, but cohorts dosed with LSF solution may also be included. 
Subjects in these cohorts will have continuous 12-lead digital ECG recording on the 
profile day (Day 0), starting from 1 hour before dosing, until 24 hours after dosing. 
Instructions for placing the recording equipment will be included in the Study 
Procedures Manual. 
Depending on the exposure achieved, 12-lead ECGs will be extracted in up to 10 
replicates from predose and post-dosing timepoints as shown in the Schedule of 
Events for central evaluation of potential effects on ECG parameters (heart rate, PR, 
QRS and QTcF). ECGs to be used in the analyses will be selected by pre-determined 
time points as defined in the Schedule of Events, and will be read centrally by a 
specialised centre. 
8.19.3. 
Vital Signs 
Blood pressure (supine and at some time points, sitting), and heart rate will be 
measured at times specified in Table 3 (for Part 1, Cohorts 1-8 and Part 2, Cohort 9). 
Only supine measurements are required for subjects in Part 2, Cohort 10 (Table 5). 
Oral temperature will be measured only at screening and on Day -1. Additional 
collection times, or changes to collection times of blood pressure, heart rate and oral 
temperature will be permitted, as necessary, to ensure appropriate collection of 
safety data. 
Blood pressure and heart rate will be measured using oscillometric equipment.  
Seated blood pressure:  measurements will be measured using oscillometric 
equipment. For each specified timepoint, two measurements 2 minutes apart will be 
taken.  
Oral temperature will be measured using disposable thermometers. 


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Repeat vital signs measurements 
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 heart rate: 35–100 
beats/min 
Oral temperature: 
35.5–37.8°C  
If the result of the repeat measurement is still out of range, the investigator will 
decide on an appropriate course of action.  
8.19.4. 
Neurological and Physical Examination  
Physical examination: will be done by a physician. The following will be examined:  
general appearance; head, ears, eyes, nose and throat; thyroid; lymph nodes; back 
and neck; heart; chest; lungs; abdomen; skin; and extremities; and the following 
systems will be assessed:  musculoskeletal and neurological. Weight will also be 
measured (only at screening, and on Day -1). At certain timepoints, as detailed in 
Table 3, a short physical examination will be performed. 
Neurological examination: will be done by a physician, and will include 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); mood; and 
sleepiness. (Full details of the neurological exam will be in the Study Procedures 
Manual).  
8.19.5. 
Ophthalmology testing (Part 2, Cohort 10 only) 
In Cohort 10 only, subjects will undergo the following tests at a separate baseline 
screening visit (Screening Visit 2; within 1 week before dosing) and on ProfileDay 
(Day 0) approximately 2.5-3 h after dosing.   
Subjects will attend a specialist eye hospital for ophthalmology assessments to be 
performed by a Consultant Ophthalmologist (as shown below, and further described 
in the Study Procedures Manual).  
 Visual symptoms 
 Past ocular history 
 Auto-refraction 
 Best corrected distance Visual Acuity 
 Colour vision assessment 
 Amsler Grid assessment 
 Visual field to confrontation assessment 
 Ocular alignment and ocular motility assessment 


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 Slit lamp examination (anterior segment) 
 Intraocular pressure measurement (Goldmann Tonometry) 
 Post mydriatic ocular media (at Screening Visit 2 only) and retinal examination 
with slit lamp and lens 
 Optical Coherence scanning of optic nerve and macula 
Subjects will be informed that they will need to bring their distance glasses (if 
applicable, and their near vision will be blurred for approximately 2 hours (due to the 
use of mydriatic eye drops) following the eye-testing procedures at Screening Visit 2. 
Eye drops will not be used on the Profile-Day, so that any potential visual AEs are 
not obscured by the use of agents known to cause blurred vision.  
 
8.19.6. 
Laboratory Safety Assessments 
Blood volumes for these samples are shown in Table 8 (Part 1, Cohorts 1-8 and Part 
2, Cohort 9) and Table 5 (Part 2, Cohort 10).  
Collection of samples for laboratory safety tests:  Blood will be taken for 
haematology (EDTA), and biochemistry and serology (tubes with a gelatin plug). 
Blood will be taken for coagulation (in sodium citrate). Urine will be collected in 
Universal containers. Samples will then be transferred to the laboratory. 
Processing and analysis of samples for laboratory safety tests:  Processing of 
samples will be done by the HMR Analytical Laboratory in accordance with the 
laboratory’s‎standard‎operating‎procedures. 
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. 
9. Adverse Event Definition and Reporting 
9.1. Definitions of Adverse Events 
Adverse event 
Any untoward medical occurrence in a patient or clinical trial subject administered a 
medicinal product and which does not necessarily have a causal relationship with 
that treatment. It can therefore be any unfavourable and unintended sign (eg, an 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal 
product.  
Furthermore the definition of an AE includes worsening (in severity and frequency) of 
pre-existing conditions ("Medical history") before first Investigational Medicinal 
Product (IMP) administration and abnormalities of procedures (ie,, ECG, X-ray, 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 Investigator as 


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serious or non-serious. This classification will determine the reporting procedure for 
the event. 
Adverse drug reaction 
All untoward and unintended responses to an investigational medicinal product 
related to any dose administered. 
Note that, according to the ICH Guideline for Good Clinical Practice (ICH GCP), a 
causal relationship between the medicinal product and the adverse event is at least a 
reasonable possibility, ie a relationship cannot be ruled out. 
Unexpected adverse drug reaction 
An adverse reaction, the nature, severity or outcome of which is not consistent with 
the applicable product safety reference information (eg Investigator's Brochure for an 
unauthorised investigational product, or summary of product characteristics for an 
authorised product). 
Serious adverse event or serious adverse drug reaction 
An adverse event or adverse drug reaction that is: 
 fatal; 
 life-threatening;  
 requires or prolongs inpatient treatment;  
 results in persistent or significant disability or incapacity; or 
 is a congenital anomaly or birth defect; 
 Any suspected transmission via a medicinal product of an infectious agent; 
 An important medical event: 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. 
Note:  the term 'life-threatening' in the definition of 'serious' refers to an event or 
reaction in which the patient was at risk of death at the time of the event; it does not 
refer to an event or reaction which hypothetically might have caused death had it 
been more severe.  


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9.2. Procedures for Recording Adverse Events 
Subjects will be carefully monitored for all adverse events, which must be recorded in 
source documents and clinical trial AE CRF. The investigator or delegate will 
question the subjects about adverse events using a non-leading question, such as 
'How are you feeling?'. The investigator will also record adverse events reported 
spontaneously by the subjects.   
The investigator will use the following criteria when deciding whether to report an 
abnormal test result as an adverse event. 
1. 
The test result is associated with accompanying symptoms. 
2. 
Results of additional diagnostic tests cause concern or necessitate medical 
intervention. 
3. 
As a consequence of the test result, the dose administered to the subject is 
changed, the subject is withdrawn, or the subject is given concomitant 
treatment. 
4. 
The investigator considers the result to constitute an adverse event. 
A record will be kept in source documents and the CRF of all adverse events as 
reported, whether believed to be related or unrelated to the investigational treatment. 
The record will include the following. 
 Clinical symptoms: a simple, brief description. 
 Date and time of onset and end of clinical symptoms. 
 Frequency:  constant or intermittent. 
 Severity. The Investigator will use the terminology 'Mild, Moderate or Severe' 
to describe the maximum severity of the AE, as described below:  
Mild: 
The subject is aware of the event or symptom, but the event or 
symptom is easily tolerated (eg, no reduction in daily activities is 
required). 
Moderate: 
The subject experiences sufficient discomfort to interfere with or 
reduces his or her usual level of activity. 
Severe: 
Significant impairment of functioning: the subject is unable to carry out 
usual‎activities‎and/or‎the‎subject’s‎life‎is‎at‎risk‎from‎the‎event. 
It is to be noted the distinction between severity and seriousness of AEs. A severe 
AE is not necessarily a serious event. 
 Seriousness criteria (as defined in Section 9.1) 
 Causal relationship to treatment   


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The assessment of causal relationship of adverse events to the administration of 
investigational treatment is a clinical decision based on all available information at 
the time of the completion of the case report form.  
For both serious and non-serious AEs, the Investigator is required to assess the 
causal relationship between the onset of AE and the investigational treatment 
administration, ie, to determine whether there exists at least a reasonable possibility 
that the investigational treatment caused or contributed to the AE. 
The following categories will be used: 
 Related 
There is at least a reasonable possibility of a causal relationship between an 
adverse event and an investigational medicinal product. This means that there 
are facts (evidence) or arguments to suggest a causal relationship. 
 Not related 
There is no reasonable possibility of causal relationship. 
 Action taken 
None, drug treatment, subject withdrawn, other (specified). 
 Outcome 
Completely recovered; Recovered with  sequelae; Ongoing; Death; unknown 
9.3. Adverse Event Reporting Period 
AEs reporting period for this trial begins upon subject enrolment in the trial (after 
signature of informed consent) 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 related (ie, reasonable possibility of causal relationship) to 
the investigational medication should also be reported as an AE. 
9.4. Procedures for Dealing With Serious Adverse Events 
All SAEs are to be reported immediately (within 24 h of awareness of SAE by the 
Investigator) to the Sponsor Medical Expert and Sponsor Clinical Project Manager 
by telephone, and also using the serious adverse event (SAE) form sent to: 
pharmacovigilance@dndi.org (copy to the team members indicated in the Safety 
Management Plan). This includes a description of the event, onset date and 
seriousness criteria duration, severity, causal relationship to study drug, outcome, 
measures taken and all other relevant clinical and laboratory data.  


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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 of knowledge. 
SAE should also be reported on the clinical trial AE page of 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 the event of any SAE which, in the investigator's opinion, justifies termination or 
modification of the trial, dosing will be stopped and the Sponsor Medical Expert and 
Sponsor Clinical Project Manager will be informed immediately (within 24 h of the 
investigator becoming aware of the event) by telephone, and the SAE form sent to:  
pharmacovigilance@dndi.org (copy to the team members indicated in the Safety 
Management Plan.) 
In addition to immediately reporting SAEs to DNDi, the investigator will notify the 
main Research Ethics Committee (REC) of serious adverse events that occur during 
this trial, if applicable, in accordance with the standard operating procedures issued 
by the National Research Ethics Service (NRES). 
Expectedness: DNDi is responsible for determining the expectedness of the adverse 
event, using the reference safety information in the Investigator's Brochure. DNDi will 
notify the Medicines and Healthcare products Regulatory Agency (MHRA) and the 
European Medicines Agency (EMA) of all suspected unexpected serious adverse 
reactions (SUSARs), and will be responsible for ensuring that the main 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 days after DNDi becomes aware of the event.  
 Other SUSARs must be reported to the REC and MHRA within 15 days after 
DNDi becomes aware of the event.  
9.5. Procedures for Handling Withdrawals due to Adverse Events 
The investigator will assess the reason for study withdrawal as far as possible and 
will fully record the circumstances and medical details in the CRF.  
Provided that subjects give written informed consent, they will undergo the standard 
medical examination and laboratory tests at withdrawal from the trial which they 
would have undergone had they continued participation in the trial (see also 
Sections 8.13 and 15) 
9.6. Exposure in utero 
Not applicable 
9.7. Adverse Event Follow Up 
All AEs should be followed until they are resolved or the Investigator assesses them 
as chronic or stable or the subject participation in the trial ends (ie, until a final report 
is completed for that subject, in the case of SAEs).  


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In addition, all SAEs and those non-serious events assessed by the Investigator as 
related (i.e. reasonable possibility of causal relationship) to the investigational drug 
must continue to be followed even after the subject participation in the trial is over. 
Such events should be followed until they resolve or until the Investigator assesses 
them as "chronic" or "stable." Resolution of such events is to be documented in 
source documents and on the CRF. 
10. Data Analysis and Statistical Methods 
Detailed methodology for summary and statistical analyses of the data collected in 
this study will be documented in a Statistical Analysis Plan. This document may 
modify the plans outlined in the protocol; however, any major modifications of the 
primary endpoint definition and/or its analysis will also be reflected in a protocol 
amendment. Each part of the study (Part 1 and Part 2) will be reported separately. 
The Statistical Analysis Plan for each part will be prepared before database lock for 
that part. 
 
10.1. 
Sample Size Determination 
A sample size of up to 80 subjects (ie, up to 8 per cohort, Table 2) will be considered 
sufficient to examine the safety and tolerability of emodepside as well as the PK after 
single oral administration of the investigational drug.  
Assuming a screen failure rate of approximately 50%, a total of 144 subjects will 
need to be screened for inclusion into this study. 
For evaluation, a minimum number of 6 evaluable subjects per cohort is required. 
In each cohort of up to 8 subjects, 6 are randomised to emodepside and 2 are 
randomised to placebo. 
10.2. 
Definition of Study Populations Included in the Analysis 
The following population sets will be identified: 
 
Safety Population:  All subjects who received at least one dose of IMP. 
 
PK Concentration Population:  All subjects who received at least one dose of 
IMP and for whom a pharmacokinetic sample has been analyzed. 
 
PK Parameter Population:  All subjects in the PK Concentration Population for 
whom pharmacokinetic 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. 
Final definition of the study populations will be put in the statistical analysis plan 
(SAP). 
General considerations for data analyses:  The minimum set of summary statistics 
for numeric variables will be:  n, mean, standard deviation (or standard error), 


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median, minimum, and maximum. 95% confidence intervals will be presented where 
appropriate for data interpretation.  
Categorical data will be summarised in frequency tables with n and percentage. 
Summaries of a categorical variable will include all recorded values. 
The minimum and maximum values will be presented to the same number of decimal 
places as the raw data collected on the CRF (or to 3 significant figures for derived 
parameters). The mean, median and percentiles (eg, Q1, and Q3) will be presented 
to one additional decimal place. The standard deviation and standard error will be 
presented to 2 additional decimal places. 
In each part of the study, placebo subjects will be pooled across cohorts taking into 
account formulation and fed/fasted status. 
Out-of-range laboratory tests may be repeated. If a test is out of-range at baseline 
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. 
10.3. 
Subject Disposition  
The disposition of all subjects in the safety population will be summarized including:  
number of subjects randomized; number completing the study, by treatment; and 
number discontinued from the study. The number of subject in each analysis 
population will be summarized by treatment 
All subjects who withdraw or are withdrawn from the study will be listed, by treatment, 
with the reason for withdrawal. 
10.4. 
Efficacy Analysis 
Not Applicable 
10.5. 
Analysis of Human Pharmacokinetics of Emodepside  
PK concentration data will be summarised using the PK Concentration population. 
PK parameters will be summarised using the PK Parameter population.  
For log-transformed parameters, the primary measure of central tendency will be the 
geometric mean; for untransformed parameters, it will be the arithmetic mean or 
median.14 
For all variables, N (number of subjects in receiving the treatment/formulation in the 
population), n (number of observations), arithmetic mean, median, minimum, 
maximum, SD, %CV, and the 95% confidence interval of the arithmetic mean will be 
derived. For log transformed variables, all of the above plus the geometric mean, its 
95% confidence interval, and the SD of the log-transformed variables, will be 
provided. 
Plasma concentrations and PK parameters of emodepside and metabolites will be 
listed and summarised, by treatment, using descriptive statistics. Individual and mean 
plasma concentration–time profiles will be presented graphically. 


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The average relative bioavailability (Frel) of the IR tablet will be calculated using both 
of the following: 
 
 
To assess the effect of food, analysis of variance (ANOVA) models will be fitted to 
the fed (Part 2, Cohort 9) and relevant fasted (Part 1, Cohort 5) data with the 
logarithm of the pharmacokinetic parameters Cmax and AUC0- as the dependent 
variable, and fed/fasted as a fixed effect. The estimated least square means and 
residual variance from the model will be used to construct 90% CIs for the difference 
in means on the log scale for the comparison of fed versus fasted. 
Concentrations of emodepside and possibly its metabolites in urine will be 
determined, and the amount of emodepside excreted in the urine will be estimated. 
10.6. 
Pharmacodynamic Analysis 
Pharmacodynamic variables at each planned assessment, and change in 
pharmacodynamic variables from baseline at each planned post baseline 
assessment, will be summarised by actual treatment. 
10.7. 
Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics (eg physical examination, vital signs, 
weight and ECGs) will be summarised.  
Subjects who take concomitant medication will be listed.  
10.8. Safety Analysis 
Safety and tolerability data will be summarized using the following parameters:  
 Vital signs; 
 12-lead ECG; 
 Hematology; 
 Clinical chemistry; 
 Urinalysis; 
 Physical and neurological examination; 
 AEs. 
 Ophthalmology assessments (Part 2, Cohort 10) 
No formal hypothesis testing of these parameters will be carried out. 
10.8.1. Vital Signs and 12-Lead ECG Safety Parameters 
Vital signs at each planned assessment, and change in vital signs from baseline at 
each planned post baseline assessment will be summarised by actual treatment.  
sol 
IR 
rel 
eanAUC 
GeometricM eanAUC 
GeometricM 
F 
,
,



sol
IR
rel
eanAUC
GeometricM 
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GeometricM
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,
,

 
 



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Vital signs of potential clinical importance will be listed separately.  
QT interval will be corrected using Bazett's (QTcB) and Fridericia's (QTcF) formulae. 
Triplicate ECG measurements will be made at some timepoints on Day -1 and Day 0, 
the mean of the three measurements for each subject will be used at each timepoint.  
ECG variables will be summarised by treatment and time point. Differences from 
baseline will be summarised by treatment and time point.  
QTcB or QTcF > 450 msec  and increases in QTcB or QTcF from baseline of > 30 
msec will be considered to be potentially clinically important. The number of subjects 
with a potentially clinically important QTcB or QTcF will be summarised by actual 
treatment and time point, giving the numbers of subjects with QTcB or QTcF > 450 
msec, > 480 msec and > 500 msec, and the numbers of subjects with increases in 
QTcB or QTcF from baseline of > 30 msec and >60 msec.7 A supporting listing of all 
subjects with an ECG value of potential clinical importance, and a separate listing of 
ECG findings classified as abnormal by the investigator, will also be provided. 
10.8.2. Extracted 12-lead ECG for Central Evaluation 
When PK data is available for the cohorts who had continuous ECG recording, the 
sponsor in consultation with the investigator, will assess whether emodepside 
exposure has been sufficient to warrant analysis of the 12-lead ECG continuous 
monitoring data. Any such analysis will be carried out by iCardiac Ltd (or an 
alternative provider).  
At each protocol-specified timepoint, 10 ECG replicates will be extracted from a 5 
minute “ECG‎window”‎(typically,‎the‎last‎5‎minutes‎of‎the‎15-minute period when the 
subject is maintained in a supine or semi-recumbent quiet position). High-precision 
QT analysis will be performed on all analyzable (non-artifact) beats in the 10 ECG 
replicates. The final QC assessment is performed by a cardiologist. The median QT, 
QTc, and RR value from each extracted replicate is calculated, and then the mean of 
all‎available‎medians‎from‎a‎nominal‎timepoint‎is‎used‎as‎the‎subject’s‎reportable‎
value at that timepoint. 
Categorical T-wave morphology analysis and the measurement of PR and QRS 
intervals will be performed manually in 3 of the 10 ECG replicates at each timepoint. 
In addition to the T-wave categorical analysis, the presence of abnormal U-waves is 
noted. 
10.8.3. Hematology and Clinical Chemistry Parameters 
Data from haematology and clinical chemistry will be summarised by treatment.  
Any laboratory value outside the reference interval for that variable will be flagged 
with‎an‎‘H’‎if‎it‎is‎higher‎than‎the‎reference‎interval,‎and‎with‎an‎‘L’‎if‎it‎is‎lower.‎
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 
value‎will‎receive‎a‎flag‎‘I’‎if‎increased,‎or‎‘D’‎if‎decreased.‎Therefore,‎if‎a‎value‎both‎
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. 


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All laboratory values of potential clinical importance will be listed. In a separate 
listing, laboratory values of potential clinical importance will be listed with all related 
laboratory results (ie haematology or clinical chemistry). Frequencies of laboratory 
values of potential clinical importance will be summarised. 
10.8.4. Urinalysis Parameters 
These parameters will be individually listed and summarized. 
10.8.5. Physical and Neurological Examination 
An individual data listing of abnormal physical and neurological examination findings 
will be provided. 
10.8.6. 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 9. 
Adverse events will be coded using the version of the Medical Dictionary for 
Regulatory Activities (MedDRA) current at the time of database lock.  
All adverse events will be listed. 
An AE will be considered as treatment emergent if it appeared after the first dosing, 
or if appeared before dosing and worsened after dosing. In case of missing onset 
date of AE or missing onset time of AE when it appeared the first dosing day, the AE 
will be considered as treatment emergent (TEAE). 
The number of subjects with at least one TEAE will be tabulated by actual treatment 
and MedDRA system organ class and preferred term.  
For each of the following, the number of subjects for which adverse events occurred 
will be displayed in summary tables 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 highest severity 
or causal relationship, for each system organ class and preferred term. Adverse 
events with missing severity and/or causality will be treated as severe and related, 
respectively. 
Adverse events leading to withdrawal, deaths and serious adverse events will be 
listed separately (fatal events will be listed separately from non-fatal events). 


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11. Safety Review Meetings 
Safety will be reviewed throughout the study in Safety Review Meetings. Participants 
in the Safety Review Meeting (‘the‎Safety‎Review‎Group’)‎will be at a minimum the 
Principal Investigator or his/her deputy and at least one Sponsor's representative 
(medically qualified). As an option, independent advisor(s) will be appointed, who will 
have access to unblinded data to advise if required (eg, on dose escalation 
decisions).  
The data from the first two subjects dosed in Cohort 1 (Sentinel Dosing) will be 
reviewed by the Sponsor and Investigator before dosing the remaining subjects in the 
cohort (see Section 7.2).  
12. Quality Assurance and Quality Control Procedures 
12.1. 
Investigator’s File 
The investigator must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified. 
These‎documents‎include‎Investigator’s‎Site File, subject clinical source documents 
and screening / enrolment logs. The‎Investigator’s‎Site File will contain the 
protocol/protocol amendments, CRF and query forms, IEC 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’s‎Site File and other study documentation in a secure location. 
12.2. 
Case Report Forms (CRFs) 
Data will be collected by authorized staff at the clinical site. It will be supervised by 
the investigator and signed by the investigator or by an authorized staff member. 
After informed consent, data for all screened subjects will be recorded in either the 
panel screening case report form (CRF) or the screening section of the study-specific 
CRF and additional source documents.  The CRF is the source document for the 
majority of recorded data.  Source documents other than the CRF will be predefined 
in the Source Data Agreement. 
For subjects who are subsequently randomized, study-specific information will be 
entered into the CRF. All CRF data should be anonymized, ie, identified by study 
subject number only.   
The investigator at each trial site should ensure the accuracy, completeness, 
legibility, and timeliness of all data reported to the sponsor in the CRFs and any other 
additional information that is required. The investigator is responsible for keeping all 
consent forms, screening forms, CRF and the completed subject identification code 
list in a secure location. 
Data from subjects who are screening failures, or from enrolled subjects who leave 
the study before randomization will be recorded in the CRF but not entered in to the 
Database. 


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12.3. 
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 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, 
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 for possible review and/or audit by 
DNDi and/or Regulatory Authorities. The Investigator / designee will record the date 
of each subject’s‎visit together with a summary of their status and progress in the 
study. 
12.4. 
Record Retention 
The investigator must keep all study documents on file for at least 15 years, or as it 
may be required by the applicable laws, regulations and guidelines, 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. 
Storage conditions must be secure, and adequate to protect study records from 
damage or deterioration due extremes of temperature, humidity, vermin, or any other 
environmental factors. 
Should the investigator wish to assign the study records to another party or move 
them to another location, DNDi must be notified in advance. 
12.5. 
Monitoring 
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. The investigator will ensure direct access to source documents for 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 review 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 accord with local regulations. The reviews 
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, 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. 
Visits will take place before the study, during the study, and at study end, and will be 
detailed in the Monitoring Plan. Visits may also be performed by regulatory 
authorities. 


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It will be the clinical monitor’s‎responsibility‎to‎inspect‎the‎CRF‎at‎regular‎intervals‎
throughout the study, to verify the adherence to the protocol and the completeness, 
consistency and accuracy of the data being entered on them. The investigator agrees 
to cooperate with the clinical monitor to ensure that any problems detected in the 
course of these monitoring visits are resolved. 
12.6. 
Audits and Inspections 
The trial site may also be subject to quality assurance audits by DNDi or designated 
representatives and/or to inspection by regulatory authorities or Independent Ethics 
Committees (IEC). 
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. 
It is important that the investigators and their relevant personnel are available for 
possible audits or inspections. 
12.7. 
Data Management  
Only data from Randomised subjects will be entered in to the database.  
The data will be securely stored within HMR. 
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. 
Data 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. 
12.8. 
Confidentiality of Trial Documents and Subjects Records 
The investigator must assure that‎subjects’‎anonymity‎will‎be‎maintained‎and‎that‎
their identities are protected from unauthorized parties. On CRFs or other documents 
submitted to the sponsor, subjects should not be identified by their names, but 
exclusively by an identification code. The investigator should keep a subject 
enrolment list showing codes, names, and addresses. The investigator should 
maintain documents for submission to the sponsor’s authorized representative, and 
subject’s‎signed written consent forms, in strict confidence.  
13.  
Protocol Deviations and Amendments 
The Principal investigator will ensure that the study protocol is strictly adhered to 
throughout, and that all data are collected and recorded correctly on the CRF. 
After the protocol has been approved by the main REC and the Regulatory Authority 
(MHRA), no changes may be made without the agreement of both the investigator 
and the sponsor. 
The MHRA and main EC do not need to approve any substantial change to the 
protocol that needs to be implemented urgently to avoid an immediate hazard to trial 


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subjects. The sponsor will ensure that the MHRA and main REC are informed of 
urgent amendments in accordance with the detailed guidance to EU Directive 
2001/20/EC and the standard operating procedures issued by NRES for NHS RECs. 
Any substantial protocol amendment will be recorded on a written agreement which 
must be approved and signed by the sponsor and the Principal investigator and is to 
be submitted to the appropriate IEC and/or the MHRA for information and approval in 
accordance with local requirements. Approval by the RECand/or MHRA must be 
awaited before any changes can be implemented, except for changes necessary to 
eliminate an immediate hazard to trial subjects, or when the change involves only 
logistical or administrative aspects of the trial [eg, change in clinical monitor[s], 
change of telephone number[s]. 
The protocol amendment can be initiated by either sponsor or by the Principal 
investigator.  
The investigator will provide in writing the reasons for the proposed amendment and 
will discuss with the Sponsor’s‎Medical‎Expert.  
The standard text in the information and consent form template explains that the 
planned doses may change during the trial, and that subjects may be given any dose 
that has been approved by the MHRA and main REC for the trial. However, if it is 
considered desirable to reduce the planned dose, HMR consider it essential to fully 
inform the subject of the reasons, because a reduction in dose might be due to poor 
tolerability,‎and‎that‎might‎affect‎the‎subject’s‎decision‎to‎remain‎in‎the‎trial. 
Wherever possible, HMR will obtain prior approval from the main REC for the 
information and consent form that will be given to subjects before the dose is 
reduced. But, owing to the nature of trials on healthy subjects, sometimes an urgent 
amendment to lower the planned dose will have to be implemented, to avoid 
immediate hazard to the subjects. In that case, subjects will be fully informed of the 
reason for reducing the dose, and HMR will notify the main REC and MHRA promptly 
of the urgent amendment, in accordance with statutory requirements.   
14. Early Termination of the Study 
Premature termination of this study may occur because of a regulatory authority 
decision, change in opinion of the IRB/IEC, or drug safety problems. 
Furthermore, both the sponsor and the investigator reserve the right to terminate the 
study at any time should serious or severe adverse events or any other safety issue 
occur during the study, prior to inclusion of the intended number of subjects, but they 
intend to exercise this right only for valid scientific or administrative reasons. Should 
this 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’s‎interest. 


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Reasons for early termination by the sponsor(s) may include but arenot be limited to:  
 Too low enrolment rate. 
 Protocol violations. 
 Inaccurate or incomplete data. 
 Unsafe or unethical practices. 
 Questionable safety of the test article. 
 Following the recommendation of the participants in the Safety Review 
Meetings or 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 early terminated either by the sponsor or by the 
investigator, the investigator has to: 
 Complete all CRFs to the greater extent possible. 
 Return all test articles, CRF, and related study materials to the sponsor who 
provided them. 
 Answer all questions of the sponsors or their representatives related to data of 
subjects enrolled at the site prior to study termination. 
 Ensure that subjects enrolled in the study who had not yet reached a follow up 
time point are followed up with the necessary medical care. 
 Provide in writing the reasons for his decision to the IEC and MHRA and the 
sponsor. 
 
15. Ethical and regulatory requirements 
The trial proposal will be reviewed by a recognised IEC, and by the MHRA. The trial 
will not proceed unless the sponsor obtains from the MHRA a clinical trial 
authorisation (CTA), and the main IEC approves the trial.  
The trial will be done at HMR, in compliance with EU Directives 2001/20/EC and 
2005/28/EC, The Medicines for Human Use (Clinical Trials) Regulations 2004 
No. 1031 and current amendments, the Declaration of Helsinki (Brazil Revision, 
2013), GMP20, the standard operating procedures issued by NRES for RECs in the 
UK24, and ICH Good Clinical Practice.  
All subjects must give written consent to participate in this trial. Consent for screening 
evaluations may be obtained using the information and consent form for the HMR 
healthy volunteer panel, which has been approved by London – Brent Research 
Ethics Committee. The trial-specific information and consent form will be signed by 
the subject either before any screening evaluation or after the investigator confirms 
the eligibility of the subject for the trial and before the subject is randomized to 
receive the first administration of IMP. Before giving consent, subjects must read the 


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information sheet about the trial. They must also read the consent form. They will 
then discuss the trial with the investigator or his deputy and be given the opportunity 
to ask questions. The trial-specific information sheet and the consent form must be 
approved by the main REC. 
Each subject is free to withdraw from the trial at any time, without giving a reason. If a 
subject withdraws, the investigator will ask the subject to consent to a follow-up 
examination. For withdrawn subjects, the investigator will use a special information 
and consent form which has been approved by London – Brent Research Ethics 
Committee and by the Phase 1 Advert Review Committee. 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,‎the‎investigator‎will‎comply‎with‎the‎subject’s‎requests. 
The sponsor or investigator will ensure that the MHRA and the main IEC, are 
informed promptly of SUSARs (see Section 9.4), 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 main IEC, if applicable. The sponsor will provide the 
investigator, the main IEC and the MHRA with annual safety reports of each IMP 
under investigation, and listings of all suspected serious adverse reaction (SSAR) 
reports. 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 main IEC of 
any serious adverse event that occurs during this trial (see Section 9.4). The 
investigator will provide the main IEC with annual progress reports of the trial, if the 
trial lasts longer than a year.  
The investigator will report to the main IEC any protocol deviation that is, in his 
opinion, of clinical significance. The investigator will also inform the main IEC 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 main IEC of any serious breach of GCP (for example, the investigator puts 
subjects’‎safety‎at‎risk,‎falsifies‎data,‎or‎persistently‎fails‎to‎comply‎with‎this‎protocol‎
or good clinical practice).  
Within 90 days after the end of the trial, the sponsor will ensure that the main IEC 
and the MHRA are notified that the trial has finished. 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 report of the clinical trial to the MHRA and main 
IEC within 1 year after the end of the trial.  
Trial procedures at HMR will be subject to audits by the HMR QA Department, to 
ensure compliance with the protocol and applicable regulatory requirements. 
15.1. Informed Consent Process 
Inclusion in the study will occur only if the subject gives written informed consent. It is 
the responsibility of the investigator / designee to obtain written informed consent 
from each individual participating in this study, after adequate presentation of aims, 
methods, anticipated benefits, and potential hazards of the study. If needed, the 


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person will be given time to discuss the information received with members of the 
community or family before deciding to consent. The subject will be asked to provide 
written and signed consent. 
If new safety information results in significant changes in the risk/benefit assessment, 
the consent form should be reviewed and updated if necessary. All subjects 
(including those already being treated) should be informed of the new information, 
given a copy of the revised form and give their consent to continue in the study.  
15.2. Subject Recruitment 
Advertisements approved by ethics committees and investigator databases may be 
used as recruitment procedures.  
15.3. Compensation of volunteers 
The sponsor agrees to abide by the Association of the British Pharmaceutical Industry 
Guidelines for medical experiments in non-patient human volunteers (2012 edition),2 
and undertakes to compensate the subjects for injuries which are considered, on the 
balance of probabilities, to have arisen as a result of their participation in the trial.  
15.4. Insurance and Liability 
The Sponsor has taken out a liability insurance as required by local regulatory 
requirements. 
15.5. Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP 
In the event of any prohibition or restriction imposed by an applicable Competent 
Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, DNDi should be informed immediately.  
In addition, the investigator will inform DNDi immediately of any urgent safety 
measures taken by the investigator to protect the study subjects against any 
immediate hazard, and of any serious breaches of this protocol or of ICH GCP that 
the investigator becomes aware of. 
DNDi is responsible for reporting any serious breaches of the protocol or of ICH GCP 
to the UK Regulatory Authorities. 
16. 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. 
If the data merit, 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. Alonso LM, M.M., Jofre-Bonet M,, 2009. Psycho-social and economic evaluation of 
onchocerciasis :‎a‎literature review Soc. Med. 4, 8-31. 
2. Association of the British Pharmaceutical Industry. Guideline for Phase 1 Clinical Trials 
(2012).  http://www.abpi.org.uk/our-
work/library/guidelines/Documents/guidelines_phase1_clinical_trials.pdf 
3. Bain O, Casiraghi M, Martin C, Uni S. The mematoda filarioidea: critical analysis linking 
molecular and traditional approaches. Parasite (2008) 15, 342-348 
4. Boussinesq M, G.J., Gardon-Wendel N, Kamgno J, Ngoumou P, and Chippaux JP, 1998. 
Three probable cases of LOA loa encephalopathy following ivermectin treatment for 
onchocerciasis. Am. J. Trop. Med. Hyg. 58, 461-469. 
5. Boussinesq M, Gardon J, Kamgno J, Pion SD, Chippaux JP: Relationships between the 
prevalence and intensity of Loa loa infection in the Central province of Cameroon. Ann 
Trop Med Parasitol (2001) 95, 495-507. 
6. Chippaux, J.P., Boussinesq, M., Gardon, J., Gardon-Wendel, N., Ernould, J.C., 1996. 
Severe adverse reaction risks during mass treatment with ivermectin in loiasis-endemic 
areas. Parasitology today 12, 448-450. 
7. Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for  Non-
Antiarrhythmic Drugs. ICH Guidance for Industry  E14, 2005. 
8. Committee for Human Medicinal Products (CHMP) Guideline on the investigation of drug 
interactions. CPMP/EWP/560/95/Rev. 1 Corr. 2.  European Union 2012. 
9. Duke, B.O., 1993. The population dynamics of Onchocerca volvulus in the human host. 
Tropical medicine and parasitology: official organ of Deutsche Tropenmedizinische 
Gesellschaft and of Deutsche Gesellschaft fur Technische Zusammenarbeit 44, 61-68. 
10. Etya'ale D. and Taylor H. R. Duane's Ophthalmology, Lippincott Williams & Wilkins, 
Onchocerciasis, (2006) Chapter 62. 
http://www.oculist.net/downaton502/prof/ebook/duanes/pages/v5/v5c062.htmL 
11. Guidance for Industry.  Food-effect bioavailability and fed bioequivalence studies. 
December 2002.  US Food and Drug Administration. Available from:  
http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126833.pdf 
12. Hotez, P.J., Kamath, A., 2009. Neglected tropical diseases in sub-saharan Africa: review 
of their prevalence, distribution, and disease burden. PLoS neglected tropical diseases 3, 
e412. 
13. Ishihara, S. (1936). Series of plates designed as tests for colour-blindness. 
14. Julious,‎SA‎&‎Debarnot,‎CAM‎(2000)‎“Why‎are‎Pharmacokinetic‎Data‎Summarised‎by‎
Arithmetic‎Means?”,‎Journal‎of‎Biopharmaceutical‎Statistics,‎10(1):‎55-71. 
15. Murdoch ME, 2010. Onchodermatitis. Curr. Opin. Infect. Dis 23, 124-131. 
16. Osei-Atweneboana MY, E.J., Boakye D, Gyapong JO, and Prichard RK,, 2007. 
Prevalence and intensity of Onchocerca volvulus infection and efficacy of ivermectin in 
endemic communities in Ghana: a two-phase epidemiological study. Lancet 369, 2021-
2029. 
17. Takougang, I., Meremikwu, M., Wandji, S., Yenshu, E.V., Aripko, B., LamLenn, S.B., Eka, 
B.L., Enyong, P., Meli, J., Kale, O., Remme, J.H., 2002. Rapid assessment method for 
prevalence and intensity of Loa loa infection. Bulletin of the World Health Organization 
80, 852-858. 
18. The Mectizan Expert Committe and the Technical Consultative Committee, 2004. 
Recommendations for the treatment of Onchocerciasis with Mectizan ® in areas co-
endemic for Onchocerciasis and Loiasis The Mectizan ® Expert Committee. Bull. World 
Health Organ., 1-12. 
19. WHO, 1995. Onchocerciasis and its control. 


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20. WHO, 2007. Weekly epidemiological record Relevé épidémiologique hebdomadaire 
Meeting of for Disease Eradication. 197-208. 
21. WHO, 2010. Working to overcome the global impact of neglected tropical diseases: first 
WHO report on neglected tropical diseases. 
22. WHO, 2012. Global Burden of Disease. 
http://www.who.int/entity/healthinfo/global_burden_disease/GHE_DALY_WHOReg6_200
0_2012.xls. 
23. WHO, 2014a. Africa Programme for Onchocerciasis Control: progress report, 2013-2014. 
Wkly. Epidemiol. Rec. 49, 545-560. 
24. WHO, 2014b. Weekly epidemiological record Relevé épidémiologique hebdomadaire., 
409-420. 
25. WHO, 2014c. Weekly epidemiological record Relevé épidémiologique hebdomadaire., 
53-60. 
 

SAP_001.pdf: 
HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 1 of 73 
Statistical Analysis Plan 
Clinical trial protocol title:  
A phase 1, blinded, randomised, placebo-controlled, 
parallel-group, single-dose, dose-escalation study to 
investigate safety, tolerability, and pharmacokinetics of 
Emodepside (BAY 44-4400) after oral dosing in healthy 
male subjects 
HMR code: 
15-020 Part 2 
Sponsor code: 
DNDI-EMO-001 Part 2 
EudraCT no: 
2015-003592-29 
CRO details: 
Hammersmith Medicines Research 
Cumberland Avenue 
London NW10 7EW 
Sponsor details: 
DNDi, Chemin Louis Dunant 15, 1202 Geneva  
Switzerland 
Issued:  
10 March 2017 
Version:  
1 
Based on: 
Protocol version 5, Final, 18 January 2017 
Number of pages:  
73 
Prepared by:  
Stephen Sah 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 1 of 73 
Statistical Analysis Plan 
Clinical trial protocol title:  
A phase 1, blinded, randomised, placebo-controlled, 
parallel-group, single-dose, dose-escalation study to 
investigate safety, tolerability, and pharmacokinetics of 
Emodepside (BAY 44-4400) after oral dosing in healthy 
male subjects 
HMR code: 
15-020 Part 2 
Sponsor code: 
DNDI-EMO-001 Part 2 
EudraCT no: 
2015-003592-29 
CRO details: 
Hammersmith Medicines Research 
Cumberland Avenue 
London NW10 7EW 
Sponsor details: 
DNDi, Chemin Louis Dunant 15, 1202 Geneva  
Switzerland 
Issued:  
10 March 2017 
Version:  
1 
Based on: 
Protocol version 5, Final, 18 January 2017 
Number of pages:  
73 
Prepared by:  
Stephen Sah 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
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Page 2 of 73 
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(s) .......................................................................................... 8 
4.1.2 
Secondary Objective(s) ...................................................................................... 9 
4.2 
Study Endpoint(s) ......................................................................................9 
4.2.1 
Safety and Tolerability Variables: ...................................................................... 9 
4.2.2 
Pharmacokinetic Variables: .............................................................................. 10 
4.2.3 
Pharmacodynamic Variables: ........................................................................... 10 
4.3 
Statistical Hypotheses ..............................................................................10 
5 
STUDY DESIGN ................................................................................................10 
6 
PLANNED ANALYSES ....................................................................................17 
6.1 
Interim Analyses ......................................................................................17 
6.1.1 
Persons responsible for analysis ....................................................................... 17 
6.2 
Final Analysis ..........................................................................................17 
6.2.1 
Persons responsible for analysis ....................................................................... 17 
7 
SAMPLE SIZE CONSIDERATIONS .............................................................17 
7.1 
Sample Size Assumptions .......................................................................17 
8 
ANALYSIS POPULATIONS ...........................................................................18 
8.1 
Analysis Datasets .....................................................................................18 
9 
TREATMENT COMPARISONS .....................................................................18 
9.1 
Data Display Treatment and Other Subgroup Descriptors ......................18 
9.1.1 
Conventions for Summary Statistics and Data Displays .................................. 19 
10 
DATA HANDLING CONVENTIONS ............................................................19 
10.1 
Premature Withdrawal and Missing Data ................................................19 
10.2 
Derived and Transformed Data ...............................................................20 
10.3 
Assessment Windows ..............................................................................20 
10.4 
Values of Potential Clinical Importance ..................................................20 
11 
STUDY POPULATION ....................................................................................21 
11.1 
Disposition of Subjects ............................................................................21 
11.2 
Protocol Deviations .................................................................................21 
11.3 
Demographic and Baseline Characteristics .............................................22 


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11.4 
Treatment Compliance ............................................................................22 
12 
SAFETY ANALYSES .......................................................................................22 
12.1 
Extent of Exposure ..................................................................................22 
12.2 
Adverse Events ........................................................................................22 
12.3 
Deaths and Serious Adverse Events ........................................................23 
12.4 
Adverse Events Leading to Withdrawal from the Study .........................23 
12.5 
Clinical Laboratory Evaluations ..............................................................23 
12.6 
Other Safety Measures .............................................................................24 
12.6.1 Vital signs ......................................................................................................... 24 
12.6.2 ECG .................................................................................................................. 24 
12.6.3 Neurological examination ................................................................................ 24 
12.6.4 Physical examination ........................................................................................ 24 
12.6.5 Ophthalmology assessments ............................................................................. 24 
13 
PHARMACOKINETIC ANALYSES ..............................................................25 
13.1 
Plasma PK ................................................................................................25 
13.1.1 Pharmacokinetic Concentration Data ............................................................... 25 
13.1.2 Pharmacokinetic Parameters ............................................................................ 26 
13.2 
Urinary PK ...............................................................................................26 
14 
PHARMACODYNAMIC ANALYSES ...........................................................26 
15 
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSIS
 
27 
16 
REFERENCES ...................................................................................................27 
17 
ATTACHMENTS ..............................................................................................29 
17.1 
Table of Contents for Data Display Specifications .................................29 
17.2 
Data Display Specifications .....................................................................36 
17.2.1 Table Outlines .................................................................................................. 36 
17.2.2 Figure Outlines ................................................................................................. 50 
17.2.3 Listing Outlines ................................................................................................ 55 
APPENDIX A: LABORATORY RANGES ................................................................65 
APPENDIX B: PHARMACOKINETIC ANALYSIS ................................................67 
1 
CALCULATION METHODS ..........................................................................67 
1.1 
Data Handling Conventions .....................................................................67 
1.1.1 
Actual v Planned Times.................................................................................... 67 
1.1.2 
Missing and BQL Concentrations .................................................................... 67 
1.2 
AUC Calculations ....................................................................................67 
1.3 
Lambda-z Calculations ............................................................................68 
1.4 
Observed v Predicted Values ...................................................................68 


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2 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS .........................69 
2.1 
Derived and transformed data ..................................................................69 
2.2 
Summary data ..........................................................................................69 
3 
PARAMETER DEFINITIONS ........................................................................70 
3.1 
Plasma Parameters ...................................................................................70 
3.1.1 
Emodepside ...................................................................................................... 70 
APPENDIX C: SAMPLE PAGE LAYOUT ...............................................................73 
 


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1 
List of abbreviations 
λz 
Terminal rate constant 
AE 
Adverse Event 
ANOVA 
Analysis of variance 
ALT 
Alanine aminotransferase 
AP 
Alkaline phosphatase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under concentration-time curve 
AUC(0-24) 
Area under the plasma concentration-time curve from time zero to 24h 
AUC(0-24)/D 
Dose-normalised AUC from time zero to 24h 
AUC(0-24),norm 
Area under the concentration-time curve from time zero to 24h 
corrected by dose and body weight 
AUCt 
AUC from time zero to time t 
AUCt-∞ 
AUC from time t to infinity 
AUCt, norm 
AUC from time zero (pre-dose) to the time of last quantifiable 
concentration corrected by dose and body weight 
AUC∞ 
Area under the plasma drug concentration vs. time from zero to infinity 
AUC∞/D 
The area under the plasma drug concentration vs. time curve from time 
zero to infinity, corrected for dose. 
AUC∞, norm 
The area under the concentration-time curve from time zero to infinity 
corrected by dose and body weight 
BMI 
Body Mass Index 
BP 
Blood pressure 
BQL 
Below the limit of quantification 
CI 
Confidence Interval 
CK 
Creatine kinase 
CL/F 
Apparent Total body clearance 
Cmax 
Maximum Plasma Concentration 
Cmax/D 
Cmax corrected by dose 
Cmax,norm 
Cmax corrected by dose and body weight 
CRF 
Case Report Form 
CTR 
Clinical Trial Report 
CV 
Coefficient of Variation 
CVb 
Between subject CV 
            ECG 
Electrocardiogram 
GLDH 
Glutamate dehydrogenase 
GGT 
Gamma-glutamyl transpeptidase 
HbA1C 
Glycated haemoglobin 
HDL 
High-density lipoprotein 
HMR 
Hammersmith Medicines Research 
HR 
Heart Rate 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
IR 
Immediate release 
LDH 
Lactate dehydrogemnase 
LDL 
Low-density lipoprotein  
LSF 
Liquid Service Formulation 


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MCH 
Hemoglobin amount per red blood cell 
MCHC 
The amount of hemoglobin relative to the size of the cell (hemoglobin 
concentration) per red blood cell 
MCV 
Average red blood cell size 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean residence time 
N 
Number of subjects 
n 
Number of observations used in analysis 
PC 
Personal Computer 
PCI 
Potential clinical importance 
PD 
Pharmacodynamic(s) 
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. 
PT 
Prothrombin time 
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 
RBC 
Red blood cells 
RR 
 
Portion of the ECG between consecutive R waves, representing the 
ventricular rate 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
t1/2 
Terminal elimination half-life 
t1/2,dom 
Dominant half-life 
TEAE 
Treatment-Emergent Adverse Event 
Tmax 
Time to maximum plasma concentration 
TSH 
Thyroid-stimulating hormone 
Vz/F 
Apparent volume of distribution  
WBC 
White blood cells 
WHO 
World Health Organisation 
            
 
 




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3 
Introduction 
This Statistical Analysis Plan (SAP) is based on the current trial protocol (version 5, Final 18 
January 2017).  Where statistical methods differ substantially between this SAP and the 
protocol, the differences will be identified in the SAP. 
This SAP describes the datasets and the statistical methods to be used for the reporting and 
analysis of all data collected in Part 2 (cohorts 9 and 10), except for the 12-lead ECG 
continuous monitoring data which will be analysed by iCardiac Ltd (or an alternative 
provider), if applicable.   
The randomisation code will not be broken before this SAP is finalised and signed.  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 
trial report (CTR).  Any deviations from this SAP will be documented in the CTR. 
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 v6.3 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(s) 
• 
To investigate the safety and tolerability of emodepside (BAY 44-4400) after single oral 
doses administered as solution or immediate release (IR) tablets in healthy male subjects. 
 


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4.1.2 Secondary Objective(s) 
• 
To investigate the pharmacokinetics (PK) of emodepside (BAY 44-4400), after 
administration as oral solution, and IR tablet (optional) 
• 
To conduct an exploratory investigation of the relative bioavailability of the 5 mg and 20 
mg IR tablet formulation using data generated in this study (optional) 
• 
Possibility to determine the effect of food on the bioavailability of emodepside 
(BAY 44-4400) after single oral doses administered as solution or IR tablets. 
 
 
4.2 
Study Endpoint(s) 
4.2.1 Safety and Tolerability Variables: 
• Adverse Events (AEs). 
• Physical and Neurological examination findings (including assessments of 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; and gait and postural stability (Pull test); mood; and sleepiness.). 
• Vital signs: heart rate (HR), systolic and diastolic blood pressure (BP) in supine and 
sitting position (Cohort 10 only in supine), weight, body mass index (BMI; height at 
screening only), oral temperature. 
• 12-lead ECG (HR, PR, QRS, QTcF), and for selected cohorts 12-lead ECG continuous 
recording (for emodepside exposure response analysis - HR, PR, QRS and QTcF). 
• Clinical laboratory parameters: 
Hematology: hemoglobin, hematocrit, MCV, MCH, MCHC, platelets, reticulocytes, 
white blood cells (WBC) differential, red blood cells (RBC), glycated haemoglobin 
(HbA1C) (at screening);  
Coagulation: activated partial thromboplastin time (aPTT), prothrombin time (PT); 
• Biochemistry: aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
alkaline phosphatase (AP), glutamate dehydrogenase (GLDH), gamma-glutamyl 
transpeptidase (GGT), LDH, CK, amylase, lipase, free T4 and T3, thyroid-stimulating 
hormone (TSH), glucose, cholesterol (high-density lipoprotein [HDL], and low-density 
lipoprotein [LDL], total), triglycerides, creatinine, urea, uric acid, bilirubin (total and 
conjugated), total protein, sodium, potassium, calcium, chloride and magnesium in 
serum; 


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• Urinalysis: by dipstick - glucose, ketone bodies, specific gravity, occult blood, pH, 
proteins, leucocytes, bilirubin, urobilinogen, nitrites. 
 
• Ophthalmological assessments (Cohort 10 only) 
 
 
4.2.2 Pharmacokinetic Variables: 
Based on the plasma concentration time data , the following PK parameters  of emodepside 
will be calculated. 
• 
Main PK parameters: AUC∞, AUC∞/D, Cmax, Cmax/D, of emodepside (BAY 44-4400) 
• 
Exploratory PK parameters: Cmax,norm, Tmax, t½, MRT, CL/F, AUC∞,norm, AUCt, AUCt,norm, 
Vz/F of emodepside (BAY 44-4400) 
• 
Other parameters: λz, AUCt-∞, points terminal 
 
The following PK parameters of metabolites of emodepside may be calculated: 
AUC∞, AUC∞/D, Cmax, Cmax/D, Cmax,norm, Tmax, T½, AUC∞,norm, AUCt, AUCt,norm 
 
In urine, the amount and concentration of emodepside and possibly its metabolites will be 
measured. The appropriate specific PK parameters to be calculated will be decided according 
to the concentration. 
 
4.2.3 Pharmacodynamic Variables: 
• Profiles of glucose and insulin, glucagon and cortisol (Cohort 9 only), only on Pre-Day 
(Day -1), Profile Day (Day 0), and Day 1. 
• Single samples of prolactin and leptin, only on Pre-Day (Day -1), Profile Day (Day 0), 
and Day 1(Cohort 9 only). 
 
4.3 
Statistical Hypotheses 
No formal statistical testing will be done.  
5 
Study Design 
This is a single-center, blinded, randomised, placebo-controlled, parallel-group, single-dose, 
2-cohort, dose-escalation, comparison study investigating safety, tolerability, and PK of 


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emodepside, after administration as an oral liquid service formulation (LSF) solution in 
healthy male subjects. Within each cohort, subjects will be randomised to receive either 
emodepside or placebo (n=8 per cohort; 6 assigned to emodepside and 2 assigned to placebo).  
Subjects in Cohort 9 will receive 10mg solution of emodepside or matching placebo in a fed 
state and subjects in Cohort 10 will receive 40mg solution of emodepside in fasted state. 
 


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Table 1: Time and Events Table (Part 2, Cohort 9) 
 
Study Procedure 
Screen 
 
In-Patient Phasea 
See Table b 
Follow-
Up 
Visit 
 
Pre-Day 
Profile-Day 
Evaluation 
Day 
± allowable deviation -28 to -2 -2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
 
 
 
 
7 
+3 
Subject information and 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including 
demographics and previous / 
concomitant medications) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Neurological examinationd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Ward Admission 
(approx.16h) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drugs of abuse and 
alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hours a (pre/post drug) 
 
-36 -24* -23.5 -23 -22.5 -22 -21 -20 -18 -16 -12 
0* 0.5 
1 
1.5 
2 
2.5 
3 
4 
5 
6 
8 
12 
24 36 48 72 96 120 144 168 
 
 
 
 
 
Glucose, Insulin, Glucagon, 
and Cortisol profiles 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Samples for Prolactin & 
Leptin  
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of 
emodepsidee 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead safety ECGf 
X 
 
Xf 
X 
X 
X 
X 
X 
X 
 
X 
X 
Xf 
X 
X 
X 
X 
 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
ECGs extracted from 
continuous recordingsg 
 
 
 
 
 
 
 
 
 
 
 
 
Xg Xg Xg Xg Xg Xg Xg Xg 
 
Xg 
Xg 
Xg 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsh 
X 
 
Xh 
X 
X 
X 
Xh 
X 
Xh 
X 
X 
Xh 
Xh 
X 
X 
X 
Xh 
 
X 
Xh 
 
X 
X 
Xh 
Xh X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
Adverse event monitoringi 
X 
X 
X 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
PK and metabolitesj in 
plasma 
 
 
 
 
 
 
 
 
 
 
 
 
Xj 
X 
Xj 
X 
Xj 
X 
X 
Xj 
 
X 
Xj 
Xj 
Xj 
X 
Xj X 
X 
X 
X 
X 
 
 
 
 
X 
PK in urinek 
 
 
 
 
 
 
 
 
 
 
 
 
0–4k 
4–8k 
8–12k 12–24k 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Safetyl,m 
X m 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
Neurologicald examination 
and short physical 
examinationc 
 
 
Xc 
 
 
 
X 
 
X 
 
 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
*: In fasted subjects, all assessments at Hour –24 on Day –1 and Hour 0 on Day 0 are immediately before the administration of study drug (emodepside). In fed subjects, all assessments at 
Hour –24 on Day –1 and at Hour 0 on Day 0 are before the FDA breakfast.  The only exception is the 12-lead ECG continuous recording (see footnote g).  
a: Including a 10-minute supine phase before supine BP, HR, body temperature, ECG; and for 5 minutes after each nominal timepoint for ECGs extracted from continuous recording (see 
footnote); and also recommended before drawing blood samples. Before sitting BP assessments minimum 3-minute sitting period. 
b: If mean half-life of emodepside in any cohort is longer than predicted, there are options to extend in-house period, or out-patient ambulatory visits up to Day 14 if necessary, from Cohort 5 
onwards and in subsequent cohorts. Refer to Option 1, Option 2, and Option 3 as outlined in Table .    


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c: 
Height at screening only, for calculation of BMI. Weight at screening for calculation of BMI, also at -24h (Day -1) for PK calculations. 
d: Neurological examination designed for the study, see Protocol Section 8.19.4  and Study Procedures Manual 
e:  Administration of study drug while fasting or after a high-calorie, high-fat breakfast     
f: 
To include 3 repeat ECGs at these timepoints, with a time difference of about 1 minute, and single recordings at other timepoints 
g: For selected cohorts in Part 1 (see Protocol Section 8.19.2 continuous 12-lead ECG recording will be started 1 hour before dosing and continue for 24 hours post-dosing. ECGs will be 
extracted at predose, at three timepoints (-60, -45, and -30 minutes for fasted subjects or -90, -75, and -60 minutes for fed subjects) and at the timepoints at which PK blood samples are 
drawn. Subjects will be supine for 10 minutes prior to and 5 minutes after each nominal timepoint. When ECG extraction coincide with safety ECGs, vital signs and blood draws, 
procedures will be performed in said order. 
h: Vital signs to include BP (supine;  plus sitting BP at the indicated timepoints‘h’) and HR. Oral temperature only at screening and -24h. 
i: 
Adverse Event (AE) monitoring will be throughout the study (spontaneous and solicited) to include questioning for tolerability and safety, however at these indicated timepoints will be 
specific questioning about AEs. 
j: 
In addition to the PK sample, metabolite samples are collected only for the indicated time points ‘j’. As an option, at the sponsor’s discretion, an additional sample of no more than 1mL may 
be taken at each PK timepoint from all subjects in up to 2 cohorts. 
k: 
Start and end of urine collection for each bottle are indicated as hours post drug.. 
l: 
Hematology, Coagulation, Chemistry; Urinalysis by dip stick.  
m: At Screening only: HIV 1, 2, Hepatitis B, C, HbA1C,   in additional to hematology, coagulation, urinalysis, and chemistry. 
 
 


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Table 2. Follow-Up after Day 7 – Schedule Options 1, 2, or 3 Depending on Emodepside Plasma Concentrations at Day 7 in Previous 
Cohort(s) (from Cohort 5 onwards), Respectively. 
For Screening and Days -2 through Day 8 see Table 1 
OPTION 1 
 
Out-Patient Phase 
Day 
 
 
 
 
 
Follow-Up Visit  
at 3 weeks (+3 days) post-dose 
 
Discharge on Day 7  
Physical Examination 
 
 
 
 
 
(see Table 1) 
Neurological Examination 
 
 
 
 
 
(see Table 1) 
12-lead ECG 
 
 
 
 
 
(see Table 1) 
Vital signsh 
 
 
 
 
 
(see Table 1) 
Adverse event monitoringi 
 
 
 
 
 
(see Table 1) 
PK in plasma 
 
 
 
 
 
(see Table 1) 
Laboratory Safetyl,m 
 
 
 
 
 
(see Table 1) 
OPTION 2 
 
Out-Patient Phase 
Day 
Up to 4 visits during the period from Day 8–21 inclusive (as needed) 
Follow-Up Visit  
at 3 weeks (+3 days) post-dose 
 
Ambulatory Evaluation Visits, Scheduled As Needed 
Physical Examination 
 
 
 
 
 
(see Table 1) 
Neurological Examination 
 
 
 
 
 
(see Table 1) 
12-lead ECG 
 
 
 
 
 
(see Table 1) 
Vital signsh 
 
 
 
 
 
(see Table 1) 
Adverse event monitoringi 
X 
 
X 
X 
X 
(see Table 1) 
PK in plasma 
X 
 
X 
X 
X 
(see Table 1) 
Laboratory Safetyl,m 
X 
 
X 
X 
X 
(see Table 1) 
OPTION 3 
 
Discharge from Ward on Day X 
 
Day 
8 (±1) 
(as needed) 
 
10 (±1) 
(as needed) 
12 (±2) 
(as needed) 
14 (±2) 
(max.) 
Follow-Up Visit  
at 3 weeks (+3 days) post-dose 
 
Prolonged In-House Evaluation Phase  
with Discharge from Ward on Day X (8-14) 
Physical Examination 
 
 
 
 
 
(see Table 1) 
Neurological Examination 
 
 
 
 
 
(see Table 1) 
12-lead ECG 
 
 
 
 
 
(see Table 1) 
Vital signsh 
 
 
 
 
 
(see Table 1) 
Adverse event monitoringi 
X 
 
X 
X 
X 
(see Table 1) 
PK in plasma 
X 
 
X 
X 
X 
(see Table 1) 
Laboratory Safetyl,m 
X 
 
X 
X 
X 
(see Table 1) 
 
 


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Table 3. Schedule of Events (Part 2, Cohort 10) 
Study Procedure 
Screening
Visits  
 
In-Patient Phasea 
Out-patient 
phase 
Follo
w-Up 
1 
2 
 
Pre-Day 
Profile-Day 
Evaluation 
Day 
± allowable deviation 
-28 to 
-2 
-7 to 
−1 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
10 
±1 
14 
±2 
18 
±2 
21 
+3 
Subject information 
and Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
(including 
demographics, 
previous/concomitant 
medications) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Neurological 
examinationc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Colour blindness testd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmology exame 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ward Admission 
(approx.16h) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drugs of abuse 
and alcohol breath test 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hoursa (pre/post 
drug) 
 
 
-36 -24* -23.5 -23 -22.5 -22 -21 -20 -18 -16 
-12 
0* 0.5 
1 
1.5 
2 
2.5 
3 
4 
5 
6 
8 
12 
24 36 48 72 96 120 144 168 
 
 
 
 
Glucose and Insulin 
profiles 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Administration of 
emodepsidef 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead safety ECG 
X 
 
 
Xg 
 
X 
 
 
 
 
 
 
X 
Xg 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Vital signsh 
X 
 
 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Adverse event 
monitoringi 
X 
 
X 
X 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK in plasmaj 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
(X) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Safetyk,l 
Xl 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurologicalc 
examination and short 
physical examinationb 
 
 
 
Xb 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Travel and stay at 
ophthalmology clinic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmology examm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* All assessments at Hour 0 on Day 0 are immediately before the administration of study drug (emodepside), and assessments at Hour –24 on Day –1 will be time-matched to Profile Day 


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(dosing Day) 
a Including a 10-minute supine phase before supine BP, HR, body temperature, ECG; and also recommended before drawing blood samples. 
b Height at screening only, for calculation of BMI. Weight at screening for calculation of BMI, also at -24h (Day -1) for PK calculations. 
c Neurological examination designed for the study, see Protocol Section 8.19.4 and Study Procedures Manual. 
d Colour blindness to be determined at Screening visit 1. 
e If subjects are eligible for study entry based on Screening visit 1 assessments, they will be asked to undergo an ophthalmology exam (Screening visit 2) within a week before Profile Day 
or on Pre−Day at the latest. All assessments for Screening Visit 1 will be performed prior to Screening Visit 2, but visits can be combined if necessary.  
f Administration of study drug is in the fasted-state only. 
g To include 3 repeat ECGs at these timepoints, with a time difference of about 1 minute, and single recordings at other timepoints. 
h Vital signs to include supine BP and HR. Oral temperature only at screening and -24h. 
i Adverse Event (AE) monitoring will be throughout the study (spontaneous and solicited) to include questioning for tolerability and safety, however at these indicated timepoints will be 
specific questioning about AEs. 
j Timepoint shown as (X) indicates sample will be taken off-site whilst at the ophthalmology clinic. As an option, at the sponsor’s discretion, an additional sample of no more than 1 mL may 
be taken at each PK timepoint from all subjects in up to 3 cohorts. 
k Hematology, Coagulation, Chemistry; Urinalysis by dip stick. 
l At Screening only: HIV 1, 2, Hepatitis B, C, HbA1C, in additional to hematology, coagulation, urinalysis, and chemistry. 
m Ophthalmology exams will be performed on Profile-Day (Day 0) approximately 2-2.5 h post-dose. If deemed necessary by the ophthalmologist additional ophthalmology follow-up visit(s) 
may be scheduled for eye-related AEs. 


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6 
Planned Analyses 
6.1 
Interim Analyses 
No interim analyses are planned. However, the blinded safety and PK data will be reviewed 
after Cohort 9.  
 
6.1.1 Persons responsible for analysis 
Toni Mitchell (HMR) 
Statistician 
Nick Jackson (HMR) 
SAS Programmer 
6.2 
Final Analysis 
The database will be locked once all subjects have completed the study, data have been 
entered and all queries resolved.  The final analysis will be carried out following database 
lock and unblinding. 
6.2.1 Persons responsible for analysis 
Stephen Sah (HMR) 
Statistician 
Nick Jackson (HMR) 
SAS Programmer 
Bhavini Ladwa (HMR) 
Data Manager 
 
7 
Sample Size Considerations 
7.1 
Sample Size Assumptions 
No formal sample size calculations have been performed as this is an exploratory study. A 
sample size of 8 per cohort will be considered sufficient to examine the safety and tolerability 
of emodepside as well as the PK after single oral administration of the investigational drug.  
For evaluation, a minimum number of 6 evaluable subjects per cohort is required. 
 
 
 


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8 
Analysis Populations 
The following population sets will be identified: 
Safety Population: 
All subjects who received at least one dose of IMP. 
PK Concentration Population: All subjects who received at least one dose of IMP and for 
whom a pharmacokinetic sample has been analysed. 
PK Parameter Population: 
All subjects in the PK Concentration Population for whom 
pharmacokinetic parameters can be derived. 
 
In all populations, treatment will be assigned based upon the treatment subjects actually 
received, regardless of the treatment to which they were randomised. 
 
The primary endpoint will be analysed using the safety population. 
 
 
8.1 
Analysis Datasets 
All analysis datasets will be based on observed data, except as outlined in Section 10.2.  
9 
Treatment Comparisons 
The treatment comparison of interest is active (emodepside) versus placebo. 
9.1 
Data Display Treatment and Other Subgroup Descriptors 
The sort order for treatment groups will be placebo, then study treatment in ascending dose 
order.  
Listings of data will be sorted and displayed by treatment group, subject number, and also by 
date and time if applicable. 
All subjects in cohorts 9 and 10 receiving the same formulation of placebo will be combined 
to form a pooled placebo group.  
 
The treatment descriptions to be used on all tables and listings are:  
Treatment Groups  
 
Short Description 
Placebo [solution](Fed) 
PLA [sol](Fed) 
Placebo [solution](Fasted) 
PLA [sol](Fasted) 
Emodepside (xx mg) [solution](Fed) 
xx mg [sol](Fed) 
Emodepside (xx mg) [solution](Fasted) 
xx mg [sol](Fasting) 


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9.1.1 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). 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.  
Placebo subjects will be pooled across cohorts 9 and 10 taking into account formulation and 
fed/fasted status. 
 
10 
Data Handling Conventions 
10.1 Premature Withdrawal and Missing Data 
All subjects who withdraw prematurely from the study or 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 10.2.   
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.  


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Conventions for handling missing plasma concentrations are given in Appendix B. 
10.2 Derived and Transformed Data 
For ECGs, vital signs, glucose, insulin, glucagon, cortisol and neurological examinations 
recorded on Day -1 the baseline will be the -24 h value and for Day 0 the baseline will be the 
pre-dose value on Day 0.  The AUC0-24 for change from baseline in glucose, insulin, glucagon 
and cortisol will be calculated on Day -1 and Day 0, using the linear-linear trapezoidal 
method.  For prolactin and leptin the baseline will be pre-dose on Day 0. 
Laboratory data will be reported in standard units.  The baseline will be the latest value 
recorded pre-dosing on Day 0.  Out-of-range laboratory tests may be repeated.  If a test is 
out-of-range at a baseline timepoint 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 measurements will be made at some timepoints on Day -1 and Day 0, the 
mean of the three measurements for each subject will be used at each timepoint.    
The pharmacokinetic parameters to be derived are given in Appendix B 
10.3 Assessment Windows 
No assessment windows are defined for this report. 
10.4 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) 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: 


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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 
40–100 beats/min 
Respiration rate 
8–20 per min 
Oral temperature 
35.5–37.8°C 
 
QTcB or QTcF > 450 msec and increases in QTcB or QTcF from baseline of > 30 msec will 
be considered to be potentially clinically important.   
11 
Study Population 
11.1 Disposition of Subjects 
The disposition of all subjects in the safety population will be summarised including: number 
of subjects randomised; number completing the study (i.e. not withdrawn), by treatment; and 
number discontinued (withdrawn) from the study. The number of subjects in each analysis 
population will be summarised by treatment. 
 
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. 
 
11.2 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 and time. 


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• Had their treatment assignment unblinded. 
In addition, subjects with minor time deviations (measurements taken outside the allowable 
windows given in the protocol) will be identified. 
 
11.3 Demographic and Baseline Characteristics 
Demographic and baseline characteristics (e.g. physical examination, neurological 
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 version September 2016 of the WHO Drug dictionary. 
11.4 Treatment Compliance 
Dates and times of dosing will be listed.  
12 
Safety Analyses 
Summaries and listings of safety data will use the safety population.  
12.1 Extent of Exposure 
The dates and times of treatment dosing will be listed to indicate exposure to the study 
medication. 
12.2 Adverse Events 
Adverse events will be coded using the version  of the Medical Dictionary for Regulatory 
Activities (MedDRA) (version 20.0).   
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 and preferred term.  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 subjects with adverse events will be summarised by 
actual treatment: 


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• TEAEs by system organ class and preferred term 
• 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 
causal relationship, for each 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. 
 
12.3 Deaths and Serious Adverse Events 
Adverse events leading to deaths and serious adverse events will be listed separately (fatal 
events will be listed separately from non-fatal events). 
 
12.4 Adverse Events Leading to Withdrawal from the Study 
Adverse events leading to withdrawal will be listed separately.   
12.5 Clinical Laboratory Evaluations 
Haematology, clinical chemistry and urinalysis evaluation at each planned assessment, and 
change from baseline at each planned post-baseline assessment, will be summarised by actual 
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. 


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12.6 Other Safety Measures 
12.6.1 Vital signs 
Vital signs evaluation at each planned assessment, and change in vital signs baseline at each 
planned post-baseline assessment, will be summarised by actual treatment. Individual subject 
profiles will be plotted for each vital sign parameter (Blood Pressure and Heart Rate). 
Vital signs data of potential clinical importance will be listed separately.  
12.6.2 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 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. 
12.6.3 Neurological examination 
Neurological examination results will be summarised and normal and abnormal neurological 
examination findings will be listed in detail according to the CRF.  Total scores from 
neurological questionnaires at each planned assessment, and change from baseline at each 
planned post-baseline assessment, will be summarised by actual treatment.  
Total scores from neurological questionnaires will also be listed. 
 
12.6.4 Physical examination 
Physical examination results will be summarised and abnormal physical examination findings 
will be listed. 
 
12.6.5 Ophthalmology assessments 
Ophthalmology assessments results will be summarised and listed by time point. 


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13 
Pharmacokinetic Analyses 
Analytical Services International Ltd, London, U.K. will measure the plasma and urine 
concentrations of emodepside.  The pharmacokinetic analysis will be done by Statistics and 
Data Management Department at HMR.  Pharmacokinetic parameters will be calculated using 
WinNonlin, version 6.3.   
In addition, the plasma and urine concentration of emodepside metabolite(s) may be 
measured. If and when these data become available a SAP amendment will be written to 
specify their reporting (if applicable).   
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 transformed parameters, the primary measure of central tendency will be the 
geometric mean4; for untransformed 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 
13.1 Plasma PK 
13.1.1 Pharmacokinetic Concentration Data 
The plasma concentrations of emodepside and metabolites (if applicable) will be listed and 
summarised by treatment. Means at any time will only be calculated if at least 2/3rds of the 
individual data points are above the lower limit of quantification.   


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Individual and mean plasma concentration–time profiles will be presented graphically.  
13.1.2 Pharmacokinetic Parameters 
The pharmacokinetic parameters of emodepside and metabolites (if applicable) will be listed 
and summarised by treatment.  
To assess the effect of food, analysis of variance (ANOVA) models will be fitted to the fed 
(Part 2, Cohort 9) solution and relevant fasted (Part 1, Cohort 5) solution data with the 
logarithm of the pharmacokinetic parameters AUC0-24 as the dependent variable, and 
formulation as a fixed effect. The estimated least square means and residual variance from the 
model will be used to construct 90% CIs for the difference in means on the log scale for the 
comparison of fed versus fasted solutions. 
13.2 Urinary PK 
If concentrations of emodespide in urine are determined, the amount of emodespide excreted 
in the urine will be estimated.  The data will be listed and summarised by treatment.  
14 
Pharmacodynamic Analyses 
Summaries and listings will use the safety population. 
Pharmacodynamic variables (glucose, insulin, glucagon, cortisol, prolactin and leptin) at each 
planned assessment, and change from baseline at each planned post-baseline assessment, will 
be summarised by actual treatment.  
In addition, for glucose and insulin (Cohorts 9 and 10), glucagon and cortisol (Cohort 9): 
• Individual subject profiles will be plotted 
• 
The difference between change from baseline on Day 0 and Day -1 will be 
summarised at each planned post-baseline assessment by actual treatment 
• 
The AUC0-24 of change from baseline will be summarised for each day and treatment 
 
Individual Insulin and PK Concentration Plots, including Related Significantly Important AE 
Durations will be produced. 
For calculation of pharmacodynamics parameters, summary statistics and individual profile 
plots, values below the quantifiable limit of the assay will be substituted by one half of the 
lower limit of quantification. 


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15 
Changes from the Protocol Specified Statistical Analysis 
After the study was submitted to the MHRA and ethics committee the following changes were 
made to the analyses: 
1) The definition of treatment-emergent adverse event has been updated from “an AE 
will be considered as treatment emergent if it appeared after the first dosing, or if 
appeared before dosing and worsened after dosing” to: 
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.  
2) The AUC0-24 of change from baseline for glucose, insulin, glucagon and cortisol will 
be summarised for each day and treatment 
 
3) The following emodepside parameters have been added to those mentioned in the 
protocol: 
Main PK parameters: AUC0-24 and AUC0-24/D 
Exploratory PK parameters: AUC0-24,norm ,t1/2,dom 
4) The following analyses have been added for glucose, insulin, glucagon and cortisol: 
 
The difference between change from baseline on Day 0 and Day -1 will be 
summarised at each planned post-baseline assessment by actual treatment 
 
The AUC0-24 of change from baseline will be summarised for each day and 
treatment 
 
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. 


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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. 
5. FL140 HMR Laboratory alert and delta ranges ver 3 (HMR Lab form). 
 
 


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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 B for Part 2, e.g., 14.1B 
The numbering in the tables below will take precedence over the numbering in the shells.


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The following tables and figures will be produced (templates provided in Sections 17.2.1 and 17.2.2): 
  
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 
 
 
 
14.2.1.1 
Summary of Emodepside Plasma Pharmacokinetic 
Concentration-Time Data (ng/mL) 
PK 
16.2.6.1.1 
T_PK1 
14.2.1.2 
Summary of Derived Emodepside Plasma Pharmacokinetic 
Parameters  
PK 
16.2.6.1.2 
T_PK3 
14.2.1.3 
Summary of Log-Transformed Derived Emodepside Plasma 
Pharmacokinetic Parameters 
PK 
16.2.6.1.2 
T_PK4 
14.2.1.4 
Assessment of the Effect of Food on the PK of Emodepside 
PK 
16.2.6.1.2 
T_PK7 
14.2.2 
Summary of Derived Emodepside Urine Pharmacokinetic 
Parameters 
PK 
16.2.6.2 
T_PK3 
14.2.3.1 
Summary of Glucose 
Safety 
16.2.6.3 
T_PD1 
14.2.3.2 
Summary of Difference Between Day -1 and Day 0 in 
Glucose 
Safety 
16.2.6.3 
T_PD2 
14.2.3.3 
Summary of AUC0-24 for Change from Baseline in Glucose 
Safety 
16.2.6.4 
T_PD3 
14.2.4.1 
Summary of Insulin 
Safety 
16.2.6.3 
T_PD1 
14.2.4.2 
Summary of Difference Between Day -1 and Day 0 in Insulin 
Safety 
16.2.6.3 
T_PD2 
14.2.4.3 
Summary of AUC0-24 for Change from Baseline in Insulin 
Safety 
16.2.6.3 
T_PD3 
14.2.5.1 
Summary of Glucagon 
Safety 
16.2.6.3 
T_PD1 
14.2.5.2 
Summary of Difference Between Day -1 and Day 0 in 
Glucagon 
Safety 
16.2.6.3 
T_PD2 
14.2.5.3 
Summary of AUC0-24 for Change from Baseline in Glucagon 
Safety 
16.2.6.3 
T_PD3 


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Table 
Description 
Population 
Source 
Listing 
Template 
(Shells below) 
14.2.6.1 
Summary of Cortisol 
Safety 
16.2.6.3 
T_PD1 
14.2.6.2 
Summary of Difference Between Day -1 and Day 0 in 
Cortisol 
Safety 
16.2.6.3 
T_PD2 
14.2.6.3 
Summary of AUC0-24 for Change from Baseline in Cortisol 
Safety 
16.2.6.3 
T_PD3 
14.2.7 
Summary of Prolactin 
Safety 
16.2.6.3 
T_PD1 
14.2.8 
Summary of Leptin 
Safety 
16.2.6.3 
T_PD1 
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 Drug-Related Treatment-Emergent Adverse 
Events 
Safety 
16.2.7.1 
T_AE1 
14.3.1.3 
Summary of Treatment-Emergent Adverse Events by Severity 
Grade 
Safety 
16.2.7.1 
T_AE1 
14.3.1.4 
Summary of Drug Related Treatment-Emergent Adverse 
Events by Severity Grade 
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 Urinalysis Dipstick Results 
Safety 
16.2.8.5 
T_UR1 
14.3.6.1 
Summary of Vital Signs  
Safety 
16.4 
T_VS1 
14.3.6.2 
Summary of AUC0-24 for Change from Baseline in Supine 
Diastolic Blood Pressure (h*mmHg) 
Safety 
16.4 
T_VS2 
14.3.6.3 
Summary of AUC0-24 for Change from Baseline in Supine 
Systolic Blood Pressure (h*mmHg) 
Safety 
16.4 
T_VS2 
14.3.6.4 
Summary of AUC0-24 for Change from Baseline in Supine 
Safety 
16.4 
T_VS2 


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Table 
Description 
Population 
Source 
Listing 
Template 
(Shells below) 
Heart Rate (h*beats/min) 
14.3.7.1 
Summary of ECG values 
Safety 
16.4 
T_EG2 
14.3.7.2 
Summary of ECG Values and Changes in ECG Values of 
Potential Clinical Importance  
Safety 
16.4 
T_EG3 
14.3.8.1 
Summary of Neurological Examination Data 
Safety  
16.2.9.5 
T_NE1 
14.3.8.2 
Summary of Neurological Examination Questionnaire Data 
Safety  
16.2.9.6 
T_LB2 
14.3.9 
Summary of Physical Examination Data 
Safety 
16.2.9.4 
T_PE1 
14.3.10 
Summary of Ophthalmological Examination  Data 
Safety 
16.2.9.7 
T_NE1 
 
 


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Figure 
Description 
Population 
Source Listing 
Template 
(Shells below) 
14.2  
PHARMACOKINETIC AND PHARMACODYNAMIC 
DATA 
 
 
 
14.2.1.1 
Individual Emodepside Plasma Concentration-Time Plots 
(Linear and Semi-log) 
PK  
16.2.6.1.1 
F_PK1 
14.2.1.2 
Geometric mean (+/- SD) Emodepside Plasma 
Concentration-Time Plots (Linear and Semi-log) 
PK 
16.2.6.1.1 
F_PK2 
14.2.2.1 
Individual Glucose-Time Plots 
PD 
16.2.6.3 
F_PD1 
14.2.2.2 
Individual Glucose and PK Concentration Plots - 
Including Related Significantly Important AE Durations 
PD 
16.2.6.3, 
16.2.6.1.1, 
16.2.7.1 
F_PD2 
14.2.3.1 
Individual Insulin-Time Plots 
PD 
16.2.6.3 
F_PD1 
14.2.3.2 
Individual Insulin-Time Plots 0-12h 
PD 
16.2.6.3 
F_PD1 
14.2.3.3 
Individual Insulin and PK Concentration Plots - 
Including Related Significantly Important AE Durations 
PD 
16.2.6.3, 
16.2.6.1.1, 
16.2.7.1 
F_PD2 
14.2.4 
Individual Glucagon-Time Plots 
PD 
16.2.6.3 
F_PD1 
14.2.5 
Individual Cortisol-Time Plots 
PD 
16.2.6.3 
F_PD1 
14.3 
SAFETY DATA 
 
 
 
14.3.1.1 
Individual Systolic Blood Pressure-Time Plots 
Safety 
16.2.9.1 
F_PD1 
14.3.1.2 
Individual Diastolic Blood Pressure-Time Plots 
Safety 
16.2.9.1 
F_PD1 
14.3.2 
Individual Heart Rate-Time Plots 
Safety 
16.2.9.1 
F_PD1 
 
 
 


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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 
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 
16.2.6.1.1 
Listing of Emodepside Plasma Pharmacokinetic Concentration-Time 
Data  
L_PK1_PG 
16.2.6.1.2 
Listing of Derived Emodepside  Plasma Pharmacokinetic Parameters  
L_PK4_PG 
16.2.6.1.3 
Individual Emodepside Plasma Concentration-Time Plots (log scale) for 
Estimation of λz, with Regression Line 
F_PK10 
16.2.6.2 
Listing of Emodepside Urine Excretion Rate Data 
L_PK3_PG 
16.2.6.3 
Listing of PD concentration-Time Data 
L_PK1_PG 
16.2.6.4 
Listing of Derived AUC0-24 PD Concentration-Time Data 
L_PK1_PG 
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 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 35 of 73 
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 
16.2.9  
 Vital signs, ECG variables, neurological, physical findings and 
Ophthalmological Assessment 
 
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  
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  Neurological Examination Findings 
      L_NE1_PG 
16.2.9.6 
Listing of Neurological Questionnaire Findings 
L_NE2_PG 
16.2.9.7 
Listing of Ophthalmological Examination Data 
L_NE1_PG 
 
Complete listings of all data collected in this study will also be produced. 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 36 of 73 
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 
Safety Population 
Randomised 
 
 
 
 
 
Completed 
 
 
 
 
 
Withdrawn 
 
 
 
 
 
Death 
 
 
 
 
Adverse Events 
 
 
 
 
Withdrawal by subject 
 
 
 
 
Physician decision 
 
 
 
 
Protocol violation 
 
 
 
 
Study terminated by 
Sponsor 
 
 
 
 
Lost to follow-up 
 
 
 
 
 
 
Other 
 
 
 
 
PK Concentration 
Included 
 
 
 
 
 
PK Parameter 
Included 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatment groups and column for “All emodepside”   
                              This table will contain one column for placebo, each dose/formulation, all active and all subjects. 
 
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 37 of 73 
 
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 
 
 
 
 
Min 
 
 
 
 
Median 
 
 
 
 
Max 
 
 
 
 
Sex 
N 
 
 
 
 
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 
 
 
 
 
Min 
 
 
 
 
Median 
 
 
 
 
Max 
 
 
 
 
Weight (kg) 
n 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 38 of 73 
Variable 
Statistics 
Treatment 1 
(N=xx) 
Treatment 2 
(N=xx) 
Etc 
All Subjects (N=xx) 
Min 
 
 
 
 
Median 
 
 
 
 
Max 
 
 
 
 
BMI (kg/m2) 
n 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Min 
 
 
 
 
Median 
 
 
 
 
Max 
 
 
 
 
Cigarettes* 
(daily) 
n 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Min 
 
 
 
 
Median 
 
 
 
 
Max 
 
 
 
 
Alcohol* 
(units/week) 
n 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Min 
 
 
 
 
Median 
 
 
 
 
Max 
 
 
 
 
 
*includes only those subjects who drink alcohol or smoke 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatment groups and additional demographic characteristics 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 39 of 73 
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 
 
 
 
 
 
 
Gastrointestinal disorders 
Total number of subjects 
 
 
 
 
 
 
Abdominal discomfort 
 
 
 
 
 
 
Abdominal pain 
 
 
 
 
 
 
↓ 
 
 
 
 
 
Nervous system disorders 
Total number of subjects 
 
 
 
 
 
 
Dizziness 
 
 
 
 
 
 
Headache 
 
 
 
 
 
 
↓ 
 
 
 
 
 
↓ 
↓ 
 
 
 
 
 
 
*Subjects with ≥1 adverse event are counted only once per system organ class and preferred term.  
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.  
 
For tables by severity a sub-heading will be added to each table page 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 40 of 73 
 
Template T_LB1 
Table  14.3.4.xx 
Summary of Laboratory Values of Potential Clinical Importance 
 
 
Planned Relative 
 
Double Flags 
Lab Test 
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 
 
 
Template T_LB2 
Table  14.3.3.2 
Summary of Chemistry Laboratory Values 
 
 
 
 
 
 
 
 
 
 
Change from Baseline 
Laboratory Test (units) 
Treatment 
Planned 
Relative Time 
n 
Mean 
95% CI 
SD 
Median Min 
Max 
n 
Mean 
SD 
Median 
Min 
Max 
 
Treatment 1  (N=xx) 
-20h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Note: Baseline on Day -1 is -24h value, baseline on Day 0 is Day 0, pre-dose 
 
Programming notes: 
Continued with all treatments and time points.   
For the summary of neurological questionnaires the first column will be headed “Questionnaire (Total Score)” and the footnote will be removed 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 41 of 73 
Template T_UR1 
Table  14.3.3.4 
Summary of Urinalysis Dipstick Results 
Planned Relative 
Time 
Result 
Treatment 1 (N=xx) 
Treatment 2 (N=xx) 
n 
% 
n 
% 
Time 1 
Positive 
 
 
 
 
 
Negative 
 
 
 
 
 
No Result 
 
 
 
 
 
Not Done 
 
 
 
 
Time 2 
Positive 
 
 
 
 
 
Negative 
 
 
 
 
 
No Result 
 
 
 
 
 
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 
 
Template T_VS1 
Table  14.3.4 
Summary of Vital Signs 
 
 
 
 
 
Change from Baseline 
 
Treatment 
Planned 
Relative Time 
n 
Mean 
SD 
Median 
Min 
Max 
n 
Mean 
SD 
Median Min 
Max 
Systolic BP (mmHg) 
Treatment 1  (N=xx) 
-20h 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Note: Baseline on Day -1 is -24h value, baseline on Day 0 is Day 0, pre-dose 
 
Programming notes: 
Continued with all variables, treatments and time points.   
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 42 of 73 
Template T_VS2 
Table  14.3.4 
Summary of AUC0-24 for Change from Baseline in Supine Diastolic Blood Pressure (h*mmHg) 
 
Day -1 
Day 0 
Day 0 - Day -1 
Treatment 
n 
Mean 
SD 
Min 
Max 
n 
Mean 
SD 
Min 
Max 
N 
Mean 
SD 
95% CI (Lower, Upper) 
Treatment 1  (N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Difference is change from mean baseline 
 
Programming notes: 
Continued with all treatments 
 
 
Template T_EG2 
Table  14.3.5.1 
Summary of ECG Values 
 
 
 
 
Change from Baseline 
Variable 
Treatment 
Planned Relative 
Time 
n 
Mean 
SD 
Median 
Min 
Max 
n 
Mean 
SD 
Median 
Min 
Max 
Heart Rate  (bpm) 
Treatment 1 (N=xx) -20h 
 
 
 
 
 
 
 
 
 
 
 
 
-21h 
 
 
 
 
 
 
 
 
 
 
 
 
-23h 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 2 (N=xx) -20h 
 
 
 
 
 
 
 
 
 
 
 
 
-21h 
 
 
 
 
 
 
 
 
 
 
 
 
-23h 
 
 
 
 
 
 
 
 
 
 
 
 
PR Interval  (msec) 
Treatment 1 (N=xx) -20h 
 
 
 
 
 
 
 
 
 
 
 
 
-21h 
 
 
 
 
 
 
 
 
 
 
 
 
-23h 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 2 (N=xx) -20h 
 
 
 
 
 
 
 
 
 
 
 
 
-21h 
 
 
 
 
 
 
 
 
 
 
 
 
-23h 
 
 
 
 
 
 
 
 
 
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 43 of 73 
 
Source: Listing 16.2.xx 
 
Note: Baseline on Day -1 is -24h value, baseline on Day 0 is Day 0, pre-dose 
 
Programming notes: 
Continued with all treatment groups and time points.  Do not summarise RR or QRS axis 
 
 
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 
31-60 msec 
Increase 
>60 msec  
Increase 
n 
% 
n 
n 
n 
% 
n 
% 
n 
% 
QT interval 
Treatment 1 
(N=xx) 
1h 
 
 
 
 
 
 
 
 
 
 
2h 
 
 
 
 
 
 
 
 
 
 
3h 
 
 
 
 
 
 
 
 
 
 
Treatment 2 
(N=xx) 
1h 
 
 
 
 
 
 
 
 
 
 
2h 
 
 
 
 
 
 
 
 
 
 
3h 
 
 
 
 
 
 
 
 
 
 
QTcB interval 
 
Treatment 1 
(N=xx) 
1h 
 
 
 
 
 
 
 
 
 
 
2h 
 
 
 
 
 
 
 
 
 
 
3h 
 
 
 
 
 
 
 
 
 
 
Treatment 2 
(N=xx) 
1h 
 
 
 
 
 
 
 
 
 
 
2h 
 
 
 
 
 
 
 
 
 
 
3h 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Note: Baseline on Day -1 is -24h value, baseline on Day 0 is Day 0, pre-dose 
 
Programming notes: 
Continued with all treatments, variables and time points.  
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 44 of 73 
Template T_PE1 
Table  14.3.8.xx 
Summary of  Physical Examination Data 
Body System  
Planned 
Relative 
Time 
Result 
Treatment 1 
(N=xx) 
Treatment 2 
(N=xx) 
General Appearance 
Time 1 
Normal 
n (%) 
 
Abnormal NCS x (xx) 
 
Abnormal CS 
 
 
Time 2 
Normal 
 
 
Abnormal NCS  
 
Abnormal CS 
 
 
HEENT 
Time 1 
Normal 
 
 
Abnormal NCS  
 
Abnormal CS 
 
 
Time 2 
Normal 
 
 
Abnormal NCS  
 
Abnormal CS 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all body system, treatments and time points. Include rows for each outcome in CRF 
                                             If results are missing “missing” row will be added. Percentages calculated using the number of available results as denominator. 
 
 
 
 
 
 
 
 
 
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 45 of 73 
Template T_NE1 
Table  14.3.8.xx 
Summary of  Neurological Examination Data 
Mental Status 
Body System  
Planned 
Relative 
Time 
Result 
Treatment 1 
(N=xx) 
Treatment 2 
(N=xx) 
 
 
 
n (%) 
n (%) 
Alertness 
Time 1 
Normal 
x (xx) 
 
Abnormal NCS x (xx) 
 
Abnormal CS 
 
 
Time 2 
Normal 
 
 
Abnormal NCS  
 
Abnormal CS 
 
 
Speech 
Time 1 
Normal 
 
 
Abnormal NCS  
 
Abnormal CS 
 
 
Time 2 
Normal 
 
 
Abnormal NCS  
 
Abnormal CS 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all examinations/test, treatments and time points. Include rows for each outcome in CRF 
 
For Ophthalmological assessment, replace body system with Test 
 
                                         If results are missing “missing” row will be added. Percentages calculated using the number of available results as denominator. 
                                         Use PESCAT as subheading (not for Ophthalmological Assessment). 
                                             
 
 
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 46 of 73 
 
Template T_PK1 
Table   14..2.xx 
Summary of Emodepside Plasma Pharmacokinetic Concentration-Time Data [units]  
 
 
Treatment 
 
 
N 
Planned  
Relative 
Time 
 
 
n 
 
No. 
Imputed 
 
 
Mean 
 
 
95% CI 
 
 
SD 
%CV 
 
 
Median 
 
 
Min 
 
 
Max 
Dose 1 
Dose 2 
 
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 
 
 
n 
 
 
 Mean 
 
 
95% CI 
 
 
SD 
%CV 
 
 
Median 
 
 
Min 
 
 
Max 
AUClast (units) 
Cmax (units) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
Programming notes: 
Continued with all dose levels and parameters 
 
 
 
 
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 47 of 73 
 
 
Template T_PK4 
Table   14..2.xx 
Summary of Log-Transformed Derived Emodepside Plasma Pharmacokinetic Parameters 
 
Parameter 
 
 
Treatment 
 
 
N 
 
 
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_PK7 
Table   14.2.xx 
Assessment of the Effects of Food on the PK of Emodepside 
 
 
 
 
LS Means 
 
 
Parameter 
Treatment 
Fed 
Fasted 
Ratio 
(Fed/Fasted) 
90% CI 
Cmax (Units) 
 
xxxx.xx 
xxxx.xx 
xxxx.xx 
(xxxx.xx, xxxx.xx) 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with  AUCinf, 
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 48 of 73 
Template T_PD1 
Table  14…xx 
Summary of Glucose 
 
 
 
 
 
 
 
 
 
Change from Baseline 
Treatment 
Planned 
Relative Time 
n 
Mean 
95% CI SD 
Median Min 
Max 
n 
Mean 
SD 
Median 
Min 
Max 
Treatment 1  (N=xx) 
-24h 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
-20h 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Note: Baseline on Day -1 is -24h value, baseline on Day 0 is Day 0, pre-dose 
 
Programming notes: 
Continued with all PD parameters, treatments and timepoints 
                                                    Change from baseline calculated from ”pre-dose” on each day 
 
 
 
Template T_PD2 
Table  14…xx 
Summary of Difference Between Day -1 and Day 0 in Glucose 
 
Planned Relative Time 
Day -1 – Day 0 
Treatment 
n 
Mean 
SD 
95% CI 
Treatment 1  (N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Difference is change from baseline 
 
Programming notes: 
Continued with time points and treatments 
                                                      
                                                     
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 49 of 73 
Template T_PD3 
Table  14…xx 
Summary of AUC0-24 for change from baseline in Glucose (units) 
 
Day -1 
Day 0 
Day -1 – Day 0 
Treatment 
n 
Mean 
SD 
Min 
Max 
n 
Mean 
SD 
Min 
Max 
n 
Mean 
SD 
95% CI 
Treatment 1  (N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Difference is change from baseline 
 
Programming notes: 
Continued with all treatments  
 
 
 
 
 
 
 
 
 
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 50 of 73 
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
BAY 40-4400 concentration (ng/mL) 
Scheduled Time (h) 
Treatment x   
1
10
100
0
4
8
12
16
20
24
BAY 40-4400 concentration (ng/mL) 
Scheduled Time (h) 
Treatment x   


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 51 of 73 
Template F_PK2 
 Figure 16.2.4.xx 
Geometric mean (+ SD) of Emodepside Plasma Concentration-Time Plots (Linear and Semi-log) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming note: The SD is the geometric standard deviations 
 
 
 
 
 
0
2
4
6
8
10
12
14
16
18
20
22
24
0
4
8
12
16
20
24
Mean(SD) Emodepside Concentration (ng/mL) 
Time (hour) 
Linear Plot 
Emodepside (10 mg) Solution
Emodepside (10 mg) Tablet
1
10
100
0
4
8
12
16
20
24
Mean(SD)Emodepside Concentration (Units) 
Time (hour) 
Semi-Log Plot 
Emodepside (10 mg) Tablet
Emodepside (10 mg) Solution


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 52 of 73 
 
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


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 53 of 73 
Template F_PD1 
Figure  16.2.xx 
Individual Glucose-Time Plots  
 
Programming note: Continue with Insulin, Glucagon and Cortisol land normal rages as reference lines.  
                                   For Blood pressure and Heart Rate, include PCI limits as reference lines. 
                                   Plot will include all subjects for a given treatment group 
                                  4 plots per page 
 
 
 
 
 
 
 
80
90
100
110
120
130
140
150
160
170
180
-24
0
24
Parameter (units) 
Time (hours) 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 54 of 73 
 
Template F_PD2 
Figure  16.2.xx 
Individual Glucose and PK Concentration Plots - Including Related Significantly Important AE Durations 
 
 
 
Cohorts with at least 1 related significant AE displayed 
 
Programming note: Continue with Insulin 
                                  2 plots per page 
 
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 55 of 73 
17.2.3 Listing Outlines 
Template L_SD1_PG 
Listing 16.2.x.xx 
Listing of Study Dates 
Treatment 
Subject 
Screening 
Day -1 
Day 0 
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 
 
Template L_DV1_PG 
Listing 16.2.x.xx 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
Treatment 
Subject 
Type 
Criterion 
 
 
Inclusion 
 
 
 
Exclusion 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 56 of 73 
Template L_TD1_PG 
Listing 16.2.x.xx 
Listing of Subjects with Time Deviations 
Treatment 
Subject 
Timepoint 
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 16.2.2.3 
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 
PK concentration  
 
Programming notes: 
continue for all populations 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 57 of 73 
Template L_DM1_PG 
Listing 16.2.x.xx 
Listing of Demographic Characteristics 
 
 
 
 
 
 
Template L_CM1_PG 
Listing 16.2.x.xx 
Listing of Concomitant Medications 
Treatment 
Subject 
Drug Name/ 
Indication 
Dose/ 
Units/ Freq/ 
Route 
Date/time Started/ 
Date Stopped 
Time Since Last 
Dose 
Started 
Pre- 
Trial? 
Ongoing 
Medication? 
 
 
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 
 
 
 
Treatment  
Subject 
Date of visit 
Date of birth 
Age (y) 
Gender 
Race 
Ethnicity 
Height 
(cm) 
Weight 
(kg) 
BMI (kg/m2) 
Alcohol 
Consumption 
(units/week) 
Cigarettes 
(daily)  
Treatment 1 
 
 
 
 
 
 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
 
 
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 58 of 73 
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 
 


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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 
Normal Range 
NR 
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 
 
 
 
 
 
 
 
 
 
 
 
 
NR for Normal Range 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 
NR 
BL 
Result 
NR 
BL 
Result 
NR 
BL 
Result 
NR 
BL 
 
Treatment 
Subject 
Planned 
Relative 
Time 
Date/Time 
 
Chloride (MMOL/L) 
Glucose (MMOL/L) 
Potassium (MMOL/L) 
Sodium (MMOL/L) 
Result 
NR 
BL 
Result 
NR 
BL 
Result 
NR 
BL 
Result 
NR 
BL 
 
Treatment 
Subject 
Planned 
Relative 
Time 
Date/Time 
 
Calcium (MMOL/L) 
Creatinine (UMOL/L) 
Etc. 
Result 
NR 
BL 
Result 
NR 
BL 
Result 
NR 
BL 
 
NR for Normal Range  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 
Listing 16.2.x.xx 
Listing of Urinalysis Data 
Treatment 
Subject 
Planned 
Relative 
Time 
Date/Time 
Specific Gravity 
pH 
Protein 
Glucose 
Result 
NR 
Result 
NR 
Result 
NR 
Result 
NR 
 
 
NR for Reference interval flag, H = Above reference interval, L = Below reference interval 
 
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 
 
 
Pre-dose (1) 
26SEP2012:09:57 
63 
148 
78 
50 
390 
32.7 * 
399 
-27.7 
419 
-11 
 
 
Pre-dose (2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-dose (3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean Pre-dose  
 
 
 
 
 
 
 
 
 
 
 
 
24 H 
 
 
 
 
 
 
 
 
 
 
 
 
* 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 NCS’ or ‘Abnormal CS’ 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  Neurological Examination Findings 
Treatment 
Subject 
Planned 
Relative Time 
Date/Time 
Type 
Assessment 
Details 
 
Programming Notes:  
Type = (Mental Status, Mood, Cranial Nerves etc. 
List all findings 
If subjects have multiple abnormal assessment at a given time, create a separate row for each assessment. 
For Ophthalmological assessment, the columns will be Treatment, Subject, Planned relative Time, Date/Time, Test and Details 
 
 
Template L_NE2_PG 
Listing 16.2.x.xx  
Listing of Neurological Questionnaire Findings 
Mental Status 
 
 
 
 
Total Score 
Treatment 
Subject 
Planned Relative 
Time 
Date/Time 
Hamilton 
Depression 
Rating Scale 
Epworth 
Sleepiness 
Score 
BDI-II 


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Template L_PK1_PG 
Listing  16.2.4.xx 
Listing of Emodepside Plasma Pharmacokinetic Con centration-Time Data 
 
Treatment 
Subject 
 
{Add. 
time 
var.} 
 
 
Date 
 
 
Study Day 
Planned 
Relative Time 
 
Actual time 
Time Deviation 
(units) 
Actual Relative 
Time 
 
Concentration (units) 
 
 
 
 
 
 
 
 
 
 
 
BLQ  = Below Limit of Quantification 
 
Programming notes: 
Values below LLOQ are shown as BLQ 
 
For PD:  BLQ values are imputed to half LLOQ 
 
For the listings of derived AUC0-24 PD concentrations, the columns will be Treatment, Subject, Planned Relative Time,  Concentrations (units) 
 
 
Template L_PK3_PG 
Listing  16.2.4 xx 
Listing of Emodepside Urine Excretion Rate Data  
Treatment 
Subject 
Planned 
Relative 
Time 
 
 
Start Date/Time 
 
 
Stop Date/Time 
Urine Conc. 
(units) 
Total Sample Volume (mL) 
Amount excreted (units) 
 
 
 
 
 
 
 
 
 
 
 
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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Page 65 of 73 
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 
− 7.5 
+ 7.5 
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 
- 
+ 0.3 
Bilirubin conjugated 
DBIL 
µmol/L 
Both 
- 
+ 4.0 
Bilirubin total 
TBIL 
µmol/L 
F 
− 20 
+ 10.0 
Bilirubin total 
TBIL 
µmol/L 
M 
− 20 
+ 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 
- 
+ 0.5 
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 
+ 15 
Gamma glutamyl transferase 
GGT 
IU/L 
F 
- 
+ 40 
Gamma glutamyl transferase 
GGT 
IU/L 
M 
- 
+ 40 
Globulin 
GLOB 
g/L 
Both 
− 7.5 
- 
Glucose 
GLU 
mmol/L Both 
− 1.5 
+ 2.5 
Haematocrit 
HCT 
L/L 
Both 
− 0.05 
- 
Haemoglobin 
HB 
g/L 
Both 
− 20 
- 
High density lipoprotein 
HDL 
mmol/L Both 
− 1.5 
+ 1.5 
International normalised ratio 
INRR 
ratio 
Both 
- 
- 
Lactate dehydrogenase 
LDH 
IU/L 
Both 
- 
+ 150 
Lymphocytes 
LYMP 
109/L 
Both 
− 1.5 
+ 1.5 
Magnesium 
MG 
mmol/L Both 
- 
- 
Mean cell haemoglobin 
MCH 
pg 
Both 
− 2 
+ 2 
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 
+ 0.5 
Neutrophils 
NEUT 
109/L 
Both 
− 2 
+ 8 
Phosphate 
PHOS 
mmol/L Both 
− 1 
+ 1 
Platelets 
PLT 
109/L 
Both 
− 100 
+ 100 
Platelets (citrate tube) 
PLTC 
109/L 
Both 
− 100 
+ 100 
Potassium 
K 
mmol/L Both 
− 0.75 
+ 0.75 
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 
+ 3 
Total protein 
TP 
g/L 
Both 
− 15 
- 
Triglycerides 
TG 
mmol/L Both 
- 
+ 1.5 
Urea 
UREA 
mmol/L Both 
− 5 
+ 2 
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 
+ 8 
 
 


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Page 67 of 73 
Appendix B: Pharmacokinetic Analysis 
1 
Calculation Methods 
1.1 
Data Handling Conventions  
1.1.1 Actual v 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 will be substituted by one half of the lower limit of quantification for 
calculation of plasma concentration summary statistics . The  number of imputed 
values will be included in the summary table. 
For urine concentrations reported as BQL it is not possible to impute a value.  The 
amount excreted will be set to zero when concentration is BQL. 
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 
AUC(0-∞) values with <20% of this area extrapolated will be reported.   


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It is acceptable to include data from profiles with >20% extrapolated as long as at least 
80% of the profiles in the study have <20% of the AUC(0-∞) as extrapolated area.  In 
this instance, individual plasma concentration-time profiles for which the extrapolated 
areas are >20% of AUC(0-∞) will be identified.  
It is unacceptable to use AUC(0-∞) data if >40% of the AUC has been extrapolated, 
except in specific situations which should be carefully justified in the study report. 
1.3 
Lambda-z Calculations 
The apparent terminal phase rate-constant (λz) will be estimated by linear regression 
of logarithmically transformed concentration versus time data.  Only those data points 
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 
t
Cˆ  (the predicted value of the 
concentration at time tn); whilst the ‘observed’ parameters use the last observed 
concentration.  


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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, CL/F, Vz/F 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/D 
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 
λz 
Terminal rate constant 
The apparent terminal phase rate-constant 
(λz) will be estimated by linear regression of 
logarithmically transformed concentration 
versus time data. 
1/h 
Y 
Lambda_z 
LAMZ 
λz 
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 
Terminal half-life 
The terminal half-life calculated from the 
terminal slope of the log concentration-time 
curve, as follows: 
𝑡½ = log𝑒2
λ𝑧
 
h 
Y 
HL_Lambda_z 
LAMZHL 
t1/2 
t½,0-24 
Dominant half-life 
The half-life calculated from the terminal 
slope of the log concentration-time (0-24h) 
curve, as follows: 
𝑡½ = log𝑒2
λ𝑧
 
h 
Y 
HL_Lambda_z 
TBC 
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 
AUCt 
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 
AUClast 
AUCLST 
AUClast 
AUCt,norm 
Area under the 
concentration-time curve 
from time zero (pre-dose) to 
the time of last quantifiable 
concentration corrected by 
dose and body weight 
The AUC normalised by dose and body 
weight will be calculated as  
AUCt/(Dose administered*body weight) 
(h*ng/mL)/(mg*kg) 
Y 
N/A 
AUCLSTWD 
AUClast,norm 
AUCt-∞ 
Area under the exponential 
curve from tlast to infinity 
The area under the exponential curve from 
tlast to infinity, calculated as follows: 
z
t
t
C
AUC
λ
ˆ
=
∞
−
 where 
t
Cˆ is the 
predicted value of the concentration at tlast.   
h*ng/mL 
N/A 
N/A 
AUCIFO 
AUCt-inf 
AUC∞ 
Area under the plasma 
concentration-time curve 
from time zero to infinity 
The area under the concentration-time curve 
will be calculated using the (specified) 
trapezoidal method for the interval 0 to tlast 
(time tlast is the time at which the last non-
zero level was recorded), plus AUCt-∞.   
h*ng/mL 
Y 
AUCINF_pred 
AUCIFP 
AUCinf 
AUC∞/Dose 
Dose-normalised AUC to 
infinity 
The dose-normalised AUC to infinity will be 
calculated as AUC∞/Dose administered 
(h*ng/mL)/mg 
Y 
AUCINF_D_pred 
AUCIFPD 
AUCinf/D 
AUC∞,norm 
Area under the 
concentration-time curve 
from time zero to infinity 
corrected by dose and body 
weight 
The AUC normalised by dose and body 
weight will be calculated as  
AUC∞/(Dose administered*body weight) 
(h*ng/mL)/(mg*kg) 
Y 
N/A 
AUCIFPWD 
AUCinf,norm 
%AUCextrap 
Percentage of AUC∞ 
extrapolated from from tlast 
to infinity 
∞
∞
−
×
=
AUC
AUC
AUC
t
extrap
100
%
 
% 
N 
AUC_%EXTRAP
_pred 
AUCPEP 
%AUCextrap 


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Text Symbol 
Definition 
Calculation 
Typical Units 
Log 
Transform 
WNL 
CDISC 
Controlled 
Terminology 
TFL 
Symbol 
AUC0-24 
Area under the plasma 
concentration-time curve 
from time zero to 24h 
The area under the concentration-time curve 
from zero time (pre-dose) to 24h will be 
calculated using the (specified) trapezoidal 
method.  
 
If λz is not estimable, a partial AUC is not 
calculated (when tlast<t). 
h*ng/mL 
Y 
User specified 
area 
AUCINT 
AUC24 
AUC0-24/D 
Dose-normalised AUC from 
time zero to 24h 
The dose-normalised AUC from time zero to 
24h will be calculated as AUC0-24/Dose 
administered 
(h*ng/mL)/mg 
Y 
N/A 
AUCINTD 
AUC24/D 
AUC0-24,norm 
Area under the 
concentration-time curve 
from time zero to 24h 
corrected by dose and body 
weight 
The AUC from time zero to 24h normalised 
by dose and body weight will be calculated as  
AUC0-24/(Dose administered*body weight) 
(h*ng/mL)/(mg*kg) 
Y 
N/A 
AUCINTWD 
AUClast,norm 
Clearance, volume of distribution and mean residence time 
CL/F 
Apparent total clearance 
from plasma after oral 
administration 
Apparent total clearance from plasma will be 
calculated using the following formula: 
∞
=
AUC
Dose
F
CL /
 
L/h 
Y 
Cl_pred 
(actually derives 
Cl_F_pred for oral 
dose) 
CLFP 
CL/F 
Vz/F 
Apparent volume of 
distribution during terminal 
phase after non-intravenous 
administration 
Apparent volume of distribution will be 
calculated using the following formula: 
∞
•
=
AUC
Dose
F
V
z
z
λ
/
 
L 
Y 
Vz_pred 
(actually derives 
Vz_F_pred for 
oral dose) 
VZFP 
Vz/F 
MRT 
Mean Residence Time 
The mean residence time will be calculated 
using: 
∞
=
AUC
AUMC
MRT
 
h 
Y 
MRTINF_pred 
MRTIFP 
MRT 
AUMC 
Area under the first moment 
of the plasma concentration-
time curve from time zero to 
infinity 
The area under the first moment of the 
concentration-time curve from zero time (pre-
dose) extrapolated to infinite time will using 
the (specified) trapezoidal method, as for 
AUC.  
h2*ng/mL 
- 
AUMCINF_pred 
AUMCIFP 
AUMC 
 


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Page 73 of 73 
Appendix C: Sample Page Layout 
DNDi :  DNDI-EMO-001 
Page x of y* 
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 15-020 Part 2 
 
*y = last page of individual output 
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HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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10 March 2017  
Page 2 of 73 
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(s) .......................................................................................... 8
4.1.2 
Secondary Objective(s) ...................................................................................... 9
4.2 
Study Endpoint(s) ......................................................................................9
4.2.1 
Safety and Tolerability Variables: ...................................................................... 9
4.2.2 
Pharmacokinetic Variables: .............................................................................. 10
4.2.3 
Pharmacodynamic Variables: ........................................................................... 10
4.3 
Statistical Hypotheses ..............................................................................10
5 
STUDY DESIGN ................................................................................................10
6 
PLANNED ANALYSES ....................................................................................17
6.1 
Interim Analyses ......................................................................................17
6.1.1 
Persons responsible for analysis ....................................................................... 17
6.2 
Final Analysis ..........................................................................................17
6.2.1 
Persons responsible for analysis ....................................................................... 17
7 
SAMPLE SIZE CONSIDERATIONS .............................................................17
7.1 
Sample Size Assumptions .......................................................................17
8 
ANALYSIS POPULATIONS ...........................................................................18
8.1 
Analysis Datasets .....................................................................................18
9 
TREATMENT COMPARISONS .....................................................................18
9.1 
Data Display Treatment and Other Subgroup Descriptors ......................18
9.1.1 
Conventions for Summary Statistics and Data Displays .................................. 19
10 
DATA HANDLING CONVENTIONS ............................................................19
10.1 
Premature Withdrawal and Missing Data ................................................19
10.2 
Derived and Transformed Data ...............................................................20
10.3 
Assessment Windows ..............................................................................20
10.4 
Values of Potential Clinical Importance ..................................................20
11 
STUDY POPULATION ....................................................................................21
11.1 
Disposition of Subjects ............................................................................21
11.2 
Protocol Deviations .................................................................................21
11.3 
Demographic and Baseline Characteristics .............................................22


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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11.4 
Treatment Compliance ............................................................................22
12 
SAFETY ANALYSES .......................................................................................22
12.1 
Extent of Exposure ..................................................................................22
12.2 
Adverse Events ........................................................................................22
12.3 
Deaths and Serious Adverse Events ........................................................23
12.4 
Adverse Events Leading to Withdrawal from the Study .........................23
12.5 
Clinical Laboratory Evaluations ..............................................................23
12.6 
Other Safety Measures .............................................................................24
12.6.1 Vital signs ......................................................................................................... 24
12.6.2 ECG .................................................................................................................. 24
12.6.3
Neurological examination ................................................................................24
12.6.4 Physical examination ........................................................................................ 24
12.6.5 Ophthalmology assessments ............................................................................. 24
13 
PHARMACOKINETIC ANALYSES ..............................................................25
13.1 
Plasma PK ................................................................................................25
13.1.1 Pharmacokinetic Concentration Data ............................................................... 25
13.1.2 Pharmacokinetic Parameters ............................................................................ 26
13.2 
Urinary PK ...............................................................................................26
14 
PHARMACODYNAMIC ANALYSES ...........................................................26
15 
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSIS
 
27 
16 
REFERENCES ...................................................................................................27
17
ATTACHMENTS ..............................................................................................29
17.1 
Table of Contents for Data Display Specifications .................................29
17.2 
Data Display Specifications .....................................................................36
17.2.1 Table Outlines .................................................................................................. 36
17.2.2 Figure Outlines ................................................................................................. 50
17.2.3 Listing Outlines ................................................................................................ 55
APPENDIX A: LABORATORY RANGES ................................................................65
APPENDIX B: PHARMACOKINETIC ANALYSIS ................................................67
1 
CALCULATION METHODS ..........................................................................67
1.1
Data Handling Conventions .....................................................................67
1.1.1
Actual v Planned Times....................................................................................67
1.1.2 
Missing and BQL Concentrations .................................................................... 67
1.2 
AUC Calculations ....................................................................................67
1.3 
Lambda-z Calculations ............................................................................68
1.4 
Observed v Predicted Values ...................................................................68


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
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2 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS .........................69
2.1 
Derived and transformed data ..................................................................69
2.2 
Summary data ..........................................................................................69
3
PARAMETER DEFINITIONS ........................................................................70
3.1 
Plasma Parameters ...................................................................................70
3.1.1 
Emodepside ...................................................................................................... 70
APPENDIX C: SAMPLE PAGE LAYOUT ...............................................................73
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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1 
List of abbreviations 
λz 
Terminal rate constant 
AE 
Adverse Event 
ANOVA 
Analysis of variance 
ALT 
Alanine aminotransferase 
AP 
Alkaline phosphatase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under concentration-time curve 
AUC(0-24) 
Area under the plasma concentration-time curve from time zero to 24h 
AUC(0-24)/D 
Dose-normalised AUC from time zero to 24h 
AUC(0-24),norm 
Area under the concentration-time curve from time zero to 24h 
corrected by dose and body weight 
AUCt 
AUC from time zero to time t 
AUCt-∞ 
AUC from time t to infinity 
AUCt, norm 
AUC from time zero (pre-dose) to the time of last quantifiable 
concentration corrected by dose and body weight 
AUC∞ 
Area under the plasma drug concentration vs. time from zero to infinity 
AUC∞/D 
The area under the plasma drug concentration vs. time curve from time 
zero to infinity, corrected for dose. 
AUC∞, norm 
The area under the concentration-time curve from time zero to infinity 
corrected by dose and body weight 
BMI 
Body Mass Index 
BP 
Blood pressure 
BQL 
Below the limit of quantification 
CI 
Confidence Interval 
CK 
Creatine kinase 
CL/F 
Apparent Total body clearance 
Cmax 
Maximum Plasma Concentration 
Cmax/D 
Cmax corrected by dose
Cmax,norm 
Cmax corrected by dose and body weight 
CRF 
Case Report Form 
CTR 
Clinical Trial Report 
CV 
Coefficient of Variation 
CVb 
Between subject CV 
            ECG 
Electrocardiogram 
GLDH 
Glutamate dehydrogenase 
GGT 
Gamma-glutamyl transpeptidase 
HbA1C 
Glycated haemoglobin 
HDL 
High-density lipoprotein 
HMR 
Hammersmith Medicines Research 
HR 
Heart Rate 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
IR 
Immediate release 
LDH 
Lactate dehydrogemnase 
LDL 
Low-density lipoprotein  
LSF 
Liquid Service Formulation 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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MCH 
Hemoglobin amount per red blood cell
MCHC 
The amount of hemoglobin relative to the size of the cell (hemoglobin 
concentration) per red blood cell
MCV 
Average red blood cell size 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean residence time 
N 
Number of subjects 
n 
Number of observations used in analysis 
PC 
Personal Computer 
PCI 
Potential clinical importance 
PD 
Pharmacodynamic(s) 
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. 
PT 
Prothrombin time 
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
RBC 
Red blood cells 
RR 
 
Portion of the ECG between consecutive R waves, representing the 
ventricular rate 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
t1/2 
Terminal elimination half-life 
t1/2,dom 
Dominant half-life 
TEAE 
Treatment-Emergent Adverse Event 
Tmax 
Time to maximum plasma concentration 
TSH 
Thyroid-stimulating hormone 
Vz/F 
Apparent volume of distribution  
WBC 
White blood cells 
WHO 
World Health Organisation 
            
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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3 
Introduction 
This Statistical Analysis Plan (SAP) is based on the current trial protocol (version 5, Final 18 
January 2017).  Where statistical methods differ substantially between this SAP and the 
protocol, the differences will be identified in the SAP. 
This SAP describes the datasets and the statistical methods to be used for the reporting and 
analysis of all data collected in Part 2 (cohorts 9 and 10), except for the 12-lead ECG 
continuous monitoring data which will be analysed by iCardiac Ltd (or an alternative 
provider), if applicable.   
The randomisation code will not be broken before this SAP is finalised and signed.  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 
trial report (CTR).  Any deviations from this SAP will be documented in the CTR. 
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 v6.3 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(s) 
• 
To investigate the safety and tolerability of emodepside (BAY 44-4400) after single oral 
doses administered as solution or immediate release (IR) tablets in healthy male subjects. 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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10 March 2017  
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4.1.2 Secondary Objective(s) 
• 
To investigate the pharmacokinetics (PK) of emodepside (BAY 44-4400), after 
administration as oral solution, and IR tablet (optional) 
• 
To conduct an exploratory investigation of the relative bioavailability of the 5 mg and 20 
mg IR tablet formulation using data generated in this study (optional) 
• 
Possibility to determine the effect of food on the bioavailability of emodepside 
(BAY 44-4400) after single oral doses administered as solution or IR tablets. 
 
4.2 
Study Endpoint(s) 
4.2.1 Safety and Tolerability Variables: 
• Adverse Events (AEs). 
• Physical and Neurological examination findings (including assessments of 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; and gait and postural stability (Pull test); mood; and sleepiness.). 
• Vital signs: heart rate (HR), systolic and diastolic blood pressure (BP) in supine and 
sitting position (Cohort 10 only in supine), weight, body mass index (BMI; height at 
screening only), oral temperature. 
• 12-lead ECG (HR, PR, QRS, QTcF), and for selected cohorts 12-lead ECG continuous 
recording (for emodepside exposure response analysis - HR, PR, QRS and QTcF). 
• Clinical laboratory parameters: 
Hematology: hemoglobin, hematocrit, MCV, MCH, MCHC, platelets, reticulocytes, 
white blood cells (WBC) differential, red blood cells (RBC), glycated haemoglobin 
(HbA1C) (at screening);  
Coagulation: activated partial thromboplastin time (aPTT), prothrombin time (PT); 
• Biochemistry: aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
alkaline phosphatase (AP), glutamate dehydrogenase (GLDH), gamma-glutamyl 
transpeptidase (GGT), LDH, CK, amylase, lipase, free T4 and T3, thyroid-stimulating 
hormone (TSH), glucose, cholesterol (high-density lipoprotein [HDL], and low-density 
lipoprotein [LDL], total), triglycerides, creatinine, urea, uric acid, bilirubin (total and 
conjugated), total protein, sodium, potassium, calcium, chloride and magnesium in 
serum; 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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• Urinalysis: by dipstick - glucose, ketone bodies, specific gravity, occult blood, pH, 
proteins, leucocytes, bilirubin, urobilinogen, nitrites. 
 
• Ophthalmological assessments (Cohort 10 only) 
 
 
4.2.2 Pharmacokinetic Variables: 
Based on the plasma concentration time data , the following PK parameters  of emodepside 
will be calculated. 
•
Main PK parameters: AUC∞, AUC∞/D, Cmax, Cmax/D, of emodepside (BAY 44-4400) 
• 
Exploratory PK parameters: Cmax,norm, Tmax, t½, MRT, CL/F, AUC∞,norm, AUCt, AUCt,norm, 
Vz/F of emodepside (BAY 44-4400) 
• 
Other parameters: λz, AUCt-∞, points terminal 
 
The following PK parameters of metabolites of emodepside may be calculated: 
AUC∞, AUC∞/D, Cmax, Cmax/D, Cmax,norm, Tmax, T½, AUC∞,norm, AUCt, AUCt,norm 
 
In urine, the amount and concentration of emodepside and possibly its metabolites will be 
measured. The appropriate specific PK parameters to be calculated will be decided according 
to the concentration. 
 
4.2.3 Pharmacodynamic Variables: 
• Profiles of glucose and insulin, glucagon and cortisol (Cohort 9 only), only on Pre-Day 
(Day -1), Profile Day (Day 0), and Day 1. 
• Single samples of prolactin and leptin, only on Pre-Day (Day -1), Profile Day (Day 0), 
and Day 1(Cohort 9 only). 
 
4.3 
Statistical Hypotheses 
No formal statistical testing will be done.  
5 
Study Design 
This is a single-center, blinded, randomised, placebo-controlled, parallel-group, single-dose, 
2-cohort, dose-escalation, comparison study investigating safety, tolerability, and PK of 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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emodepside, after administration as an oral liquid service formulation (LSF) solution in 
healthy male subjects. Within each cohort, subjects will be randomised to receive either 
emodepside or placebo (n=8 per cohort; 6 assigned to emodepside and 2 assigned to placebo).  
Subjects in Cohort 9 will receive 10mg solution of emodepside or matching placebo in a fed 
state and subjects in Cohort 10 will receive 40mg solution of emodepside in fasted state. 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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10 March 2017  
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Table 1: Time and Events Table (Part 2, Cohort 9) 
 
Study Procedure 
Screen 
 
In-Patient Phasea 
See Table b 
Follow-
Up 
Visit 
 
Pre-Day 
Profile-Day 
Evaluation 
Day 
± allowable deviation -28 to -2 -2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
 
 
 
 
7 
+3 
Subject information and 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including 
demographics and previous / 
concomitant medications) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Neurological examinationd 
X
X
Ward Admission 
(approx.16h) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drugs of abuse and 
alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hours a (pre/post drug) 
 
-36 -24* -23.5 -23 -22.5 -22 -21 -20 -18 -16 -12 
0* 0.5 
1 
1.5 
2 
2.5 
3 
4 
5 
6 
8 
12 
24 36 48 72 96 120 144 168 
 
 
 
 
 
Glucose, Insulin, Glucagon, 
and Cortisol profiles 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Samples for Prolactin &
Leptin  
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of 
emodepsidee 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead safety ECGf 
X 
 
Xf 
X 
X 
X 
X 
X 
X
 
X 
X 
Xf 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
ECGs extracted from 
continuous recordingsg 
 
 
 
 
 
 
 
 
 
 
 
 
Xg Xg Xg Xg Xg Xg Xg Xg 
 
Xg 
Xg 
Xg 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsh 
X 
 
Xh 
X 
X 
X 
Xh 
X 
Xh 
X 
X 
Xh
Xh 
X 
X 
X 
Xh 
X 
Xh 
 
X 
X 
Xh 
Xh X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Adverse event monitoringi 
X 
X 
X 
 
 
 
X 
 
X
 
 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
PK and metabolitesj in 
plasma 
 
 
 
 
 
 
 
 
 
 
 
 
Xj 
X 
Xj 
X 
Xj 
X 
X 
Xj 
 
X 
Xj 
Xj 
Xj 
X 
Xj X 
X 
X 
X 
X 
 
 
 
 
X 
PK in urinek
 
 
 
 
 
 
 
 
 
 
 
 
0–4k 
4–8k
8–12k 12–24k 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Safetyl,m 
X m 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Neurologicald examination 
and short physical 
examinationc 
 
 
Xc 
 
 
 
X 
 
X 
 
 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
*: In fasted subjects, all assessments at Hour –24 on Day –1 and Hour 0 on Day 0 are immediately before the administration of study drug (emodepside). In fed subjects, all assessments at 
Hour –24 on Day –1 and at Hour 0 on Day 0 are before the FDA breakfast.  The only exception is the 12-lead ECG continuous recording (see footnote g).  
a: Including a 10-minute supine phase before supine BP, HR, body temperature, ECG; and for 5 minutes after each nominal timepoint for ECGs extracted from continuous recording (see 
footnote); and also recommended before drawing blood samples. Before sitting BP assessments minimum 3-minute sitting period. 
b: If mean half-life of emodepside in any cohort is longer than predicted, there are options to extend in-house period, or out-patient ambulatory visits up to Day 14 if necessary, from Cohort 5 
onwards and in subsequent cohorts. Refer to Option 1, Option 2, and Option 3 as outlined in Table .    


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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10 March 2017  
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c: 
Height at screening only, for calculation of BMI. Weight at screening for calculation of BMI, also at -24h (Day -1) for PK calculations. 
d: Neurological examination designed for the study, see Protocol Section 8.19.4  and Study Procedures Manual 
e:  Administration of study drug while fasting or after a high-calorie, high-fat breakfast     
f: 
To include 3 repeat ECGs at these timepoints, with a time difference of about 1 minute, and single recordings at other timepoints 
g: For selected cohorts in Part 1 (see Protocol Section 8.19.2 continuous 12-lead ECG recording will be started 1 hour before dosing and continue for 24 hours post-dosing. ECGs will be 
extracted at predose, at three timepoints (-60, -45, and -30 minutes for fasted subjects or -90, -75, and -60 minutes for fed subjects) and at the timepoints at which PK blood samples are 
drawn. Subjects will be supine for 10 minutes prior to and 5 minutes after each nominal timepoint. When ECG extraction coincide with safety ECGs, vital signs and blood draws, 
procedures will be performed in said order. 
h: Vital signs to include BP (supine;  plus sitting BP at the indicated timepoints‘h’) and HR. Oral temperature only at screening and -24h. 
i: 
Adverse Event (AE) monitoring will be throughout the study (spontaneous and solicited) to include questioning for tolerability and safety, however at these indicated timepoints will be 
specific questioning about AEs. 
j: 
In addition to the PK sample, metabolite samples are collected only for the indicated time points ‘j’. As an option, at the sponsor’s discretion, an additional sample of no more than 1mL may 
be taken at each PK timepoint from all subjects in up to 2 cohorts. 
k: 
Start and end of urine collection for each bottle are indicated as hours post drug.. 
l: 
Hematology, Coagulation, Chemistry; Urinalysis by dip stick.  
m: At Screening only: HIV 1, 2, Hepatitis B, C, HbA1C,   in additional to hematology, coagulation, urinalysis, and chemistry. 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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Table 2. Follow-Up after Day 7 – Schedule Options 1, 2, or 3 Depending on Emodepside Plasma Concentrations at Day 7 in Previous 
Cohort(s) (from Cohort 5 onwards), Respectively. 
For Screening and Days -2 through Day 8 see Table 1 
OPTION 1 
 
Out-Patient Phase 
Day 
 
 
 
 
 
Follow-Up Visit  
at 3 weeks (+3 days) post-dose 
 
Discharge on Day 7  
Physical Examination 
 
 
 
 
 
(see Table 1) 
Neurological Examination 
(see Table 1)
12-lead ECG 
 
 
 
 
 
(see Table 1) 
Vital signsh 
 
 
 
 
 
(see Table 1) 
Adverse event monitoringi 
 
 
 
 
 
(see Table 1) 
PK in plasma 
 
 
 
 
 
(see Table 1) 
Laboratory Safetyl,m 
 
 
 
 
 
(see Table 1) 
OPTION 2 
 
Out-Patient Phase 
Day 
Up to 4 visits during the period from Day 8–21 inclusive (as needed) 
Follow-Up Visit 
at 3 weeks (+3 days) post-dose 
 
Ambulatory Evaluation Visits, Scheduled As Needed 
Physical Examination 
 
 
 
 
 
(see Table 1) 
Neurological Examination 
 
 
 
 
 
(see Table 1) 
12-lead ECG 
 
 
 
 
 
(see Table 1) 
Vital signsh 
 
 
 
 
 
(see Table 1) 
Adverse event monitoringi 
X 
 
X 
X
X 
(see Table 1) 
PK in plasma 
X 
 
X 
X
X 
(see Table 1) 
Laboratory Safetyl,m 
X 
 
X 
X
X 
(see Table 1) 
OPTION 3 
 
Discharge from Ward on Day X 
 
Day 
8 (±1) 
(as needed) 
 
10 (±1) 
(as needed) 
12 (±2) 
(as needed) 
14 (±2) 
(max.) 
Follow-Up Visit  
at 3 weeks (+3 days) post-dose 
 
Prolonged In-House Evaluation Phase  
with Discharge from Ward on Day X (8-14) 
Physical Examination 
 
 
 
 
 
(see Table 1) 
Neurological Examination 
 
 
 
 
 
(see Table 1) 
12-lead ECG 
 
 
 
 
 
(see Table 1) 
Vital signsh 
 
 
 
 
 
(see Table 1) 
Adverse event monitoringi 
X 
 
X 
X
X 
(see Table 1) 
PK in plasma 
X 
 
X 
X
X 
(see Table 1) 
Laboratory Safetyl,m 
X 
 
X 
X
X 
(see Table 1) 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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Table 3. Schedule of Events (Part 2, Cohort 10) 
Study Procedure
Screening
Visits  
 
In-Patient Phasea
Out-patient 
phase 
Follo
w-Up 
1 
2 
 
Pre-Day 
Profile-Day 
Evaluation 
Day 
± allowable deviation 
-28 to 
-2 
-7 to 
−1 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
10 
±1 
14 
±2 
18 
±2 
21 
+3 
Subject information 
and Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
(including 
demographics, 
previous/concomitant 
medications) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Neurological 
examinationc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Colour blindness testd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmology exame 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ward Admission 
(approx.16h) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drugs of abuse 
and alcohol breath test 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hoursa (pre/post 
drug) 
 
 
-36 -24* -23.5 -23 -22.5 -22 -21 -20 -18 -16 
-12 
0* 0.5 
1 
1.5 
2 
2.5 
3 
4 
5 
6 
8 
12 
24 36 48 72 96 120 144 168 
 
 
 
 
Glucose and Insulin 
profiles 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Administration of 
emodepsidef 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead safety ECG 
X 
 
 
Xg 
 
X 
 
 
 
 
 
X 
Xg 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Vital signsh 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse event 
monitoringi 
X 
 
X 
X 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK in plasmaj
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
(X) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Safetyk,l 
Xl 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurologicalc 
examination and short 
physical examinationb 
 
 
 
Xb 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Travel and stay at 
ophthalmology clinic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmology examm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* All assessments at Hour 0 on Day 0 are immediately before the administration of study drug (emodepside), and assessments at Hour –24 on Day –1 will be time-matched to Profile Day 


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(dosing Day) 
a Including a 10-minute supine phase before supine BP, HR, body temperature, ECG; and also recommended before drawing blood samples. 
b Height at screening only, for calculation of BMI. Weight at screening for calculation of BMI, also at -24h (Day -1) for PK calculations. 
c Neurological examination designed for the study, see Protocol Section 8.19.4 and Study Procedures Manual. 
d Colour blindness to be determined at Screening visit 1. 
e If subjects are eligible for study entry based on Screening visit 1 assessments, they will be asked to undergo an ophthalmology exam (Screening visit 2) within a week before Profile Day 
or on Pre−Day at the latest. All assessments for Screening Visit 1 will be performed prior to Screening Visit 2, but visits can be combined if necessary.  
f Administration of study drug is in the fasted-state only. 
g To include 3 repeat ECGs at these timepoints, with a time difference of about 1 minute, and single recordings at other timepoints. 
h Vital signs to include supine BP and HR. Oral temperature only at screening and -24h. 
i Adverse Event (AE) monitoring will be throughout the study (spontaneous and solicited) to include questioning for tolerability and safety, however at these indicated timepoints will be 
specific questioning about AEs. 
j Timepoint shown as (X) indicates sample will be taken off-site whilst at the ophthalmology clinic. As an option, at the sponsor’s discretion, an additional sample of no more than 1 mL may 
be taken at each PK timepoint from all subjects in up to 3 cohorts. 
k Hematology, Coagulation, Chemistry; Urinalysis by dip stick. 
l At Screening only: HIV 1, 2, Hepatitis B, C, HbA1C, in additional to hematology, coagulation, urinalysis, and chemistry. 
m Ophthalmology exams will be performed on Profile-Day (Day 0) approximately 2-2.5 h post-dose. If deemed necessary by the ophthalmologist additional ophthalmology follow-up visit(s) 
may be scheduled for eye-related AEs.


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6 
Planned Analyses 
6.1 
Interim Analyses 
No interim analyses are planned. However, the blinded safety and PK data will be reviewed 
after Cohort 9.  
 
6.1.1 Persons responsible for analysis 
Toni Mitchell (HMR) 
Statistician 
Nick Jackson (HMR) 
SAS Programmer 
6.2 
Final Analysis 
The database will be locked once all subjects have completed the study, data have been 
entered and all queries resolved.  The final analysis will be carried out following database 
lock and unblinding. 
6.2.1 Persons responsible for analysis 
Stephen Sah (HMR) 
Statistician 
Nick Jackson (HMR) 
SAS Programmer 
Bhavini Ladwa (HMR) 
Data Manager 
 
7 
Sample Size Considerations 
7.1 
Sample Size Assumptions 
No formal sample size calculations have been performed as this is an exploratory study. A 
sample size of 8 per cohort will be considered sufficient to examine the safety and tolerability 
of emodepside as well as the PK after single oral administration of the investigational drug.  
For evaluation, a minimum number of 6 evaluable subjects per cohort is required. 
 
 
 


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8 
Analysis Populations 
The following population sets will be identified: 
Safety Population: 
All subjects who received at least one dose of IMP. 
PK Concentration Population: All subjects who received at least one dose of IMP and for 
whom a pharmacokinetic sample has been analysed. 
PK Parameter Population: 
All subjects in the PK Concentration Population for whom 
pharmacokinetic parameters can be derived. 
 
In all populations, treatment will be assigned based upon the treatment subjects actually 
received, regardless of the treatment to which they were randomised. 
 
The primary endpoint will be analysed using the safety population. 
 
 
8.1 
Analysis Datasets 
All analysis datasets will be based on observed data, except as outlined in Section 10.2. 
9 
Treatment Comparisons 
The treatment comparison of interest is active (emodepside) versus placebo. 
9.1 
Data Display Treatment and Other Subgroup Descriptors 
The sort order for treatment groups will be placebo, then study treatment in ascending dose 
order.  
Listings of data will be sorted and displayed by treatment group, subject number, and also by 
date and time if applicable. 
All subjects in cohorts 9 and 10 receiving the same formulation of placebo will be combined 
to form a pooled placebo group.  
 
The treatment descriptions to be used on all tables and listings are:  
Treatment Groups 
Short Description
Placebo [solution](Fed) 
PLA [sol](Fed) 
Placebo [solution](Fasted) 
PLA [sol](Fasted) 
Emodepside (xx mg) [solution](Fed) 
xx mg [sol](Fed) 
Emodepside (xx mg) [solution](Fasted) 
xx mg [sol](Fasting) 


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9.1.1 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). 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.  
Placebo subjects will be pooled across cohorts 9 and 10 taking into account formulation and 
fed/fasted status. 
 
10 
Data Handling Conventions 
10.1 Premature Withdrawal and Missing Data 
All subjects who withdraw prematurely from the study or 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 10.2.   
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.  


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Conventions for handling missing plasma concentrations are given in Appendix B. 
10.2 Derived and Transformed Data 
For ECGs, vital signs, glucose, insulin, glucagon, cortisol and neurological examinations 
recorded on Day -1 the baseline will be the -24 h value and for Day 0 the baseline will be the 
pre-dose value on Day 0.  The AUC0-24 for change from baseline in glucose, insulin, glucagon 
and cortisol will be calculated on Day -1 and Day 0, using the linear-linear trapezoidal 
method.  For prolactin and leptin the baseline will be pre-dose on Day 0. 
Laboratory data will be reported in standard units.  The baseline will be the latest value 
recorded pre-dosing on Day 0.  Out-of-range laboratory tests may be repeated.  If a test is 
out-of-range at a baseline timepoint 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 measurements will be made at some timepoints on Day -1 and Day 0, the 
mean of the three measurements for each subject will be used at each timepoint.    
The pharmacokinetic parameters to be derived are given in Appendix B 
10.3 Assessment Windows 
No assessment windows are defined for this report. 
10.4 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) 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: 


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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 
40–100 beats/min 
Respiration rate 
8–20 per min 
Oral temperature 
35.5–37.8°C 
 
QTcB or QTcF > 450 msec and increases in QTcB or QTcF from baseline of > 30 msec will 
be considered to be potentially clinically important.   
11 
Study Population 
11.1 Disposition of Subjects 
The disposition of all subjects in the safety population will be summarised including: number 
of subjects randomised; number completing the study (i.e. not withdrawn), by treatment; and 
number discontinued (withdrawn) from the study. The number of subjects in each analysis 
population will be summarised by treatment. 
 
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. 
 
11.2 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 and time. 


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• Had their treatment assignment unblinded. 
In addition, subjects with minor time deviations (measurements taken outside the allowable 
windows given in the protocol) will be identified. 
 
11.3 Demographic and Baseline Characteristics 
Demographic and baseline characteristics (e.g. physical examination, neurological 
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 version September 2016 of the WHO Drug dictionary. 
11.4 Treatment Compliance 
Dates and times of dosing will be listed.  
12 
Safety Analyses 
Summaries and listings of safety data will use the safety population.  
12.1 Extent of Exposure 
The dates and times of treatment dosing will be listed to indicate exposure to the study 
medication. 
12.2 Adverse Events 
Adverse events will be coded using the version  of the Medical Dictionary for Regulatory 
Activities (MedDRA) (version 20.0).   
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 and preferred term.  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 subjects with adverse events will be summarised by 
actual treatment: 


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• TEAEs by system organ class and preferred term 
• 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 
causal relationship, for each 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. 
 
12.3 Deaths and Serious Adverse Events 
Adverse events leading to deaths and serious adverse events will be listed separately (fatal 
events will be listed separately from non-fatal events). 
 
12.4 Adverse Events Leading to Withdrawal from the Study 
Adverse events leading to withdrawal will be listed separately.   
12.5 Clinical Laboratory Evaluations 
Haematology, clinical chemistry and urinalysis evaluation at each planned assessment, and 
change from baseline at each planned post-baseline assessment, will be summarised by actual 
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. 


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12.6 Other Safety Measures 
12.6.1 Vital signs 
Vital signs evaluation at each planned assessment, and change in vital signs baseline at each 
planned post-baseline assessment, will be summarised by actual treatment. Individual subject 
profiles will be plotted for each vital sign parameter (Blood Pressure and Heart Rate). 
Vital signs data of potential clinical importance will be listed separately.  
12.6.2 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 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. 
12.6.3 Neurological examination 
Neurological examination results will be summarised and normal and abnormal neurological 
examination findings will be listed in detail according to the CRF.  Total scores from 
neurological questionnaires at each planned assessment, and change from baseline at each 
planned post-baseline assessment, will be summarised by actual treatment.  
Total scores from neurological questionnaires will also be listed. 
 
12.6.4 Physical examination 
Physical examination results will be summarised and abnormal physical examination findings 
will be listed. 
 
12.6.5 Ophthalmology assessments 
Ophthalmology assessments results will be summarised and listed by time point. 


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13 
Pharmacokinetic Analyses 
Analytical Services International Ltd, London, U.K. will measure the plasma and urine 
concentrations of emodepside.  The pharmacokinetic analysis will be done by Statistics and 
Data Management Department at HMR.  Pharmacokinetic parameters will be calculated using 
WinNonlin, version 6.3.   
In addition, the plasma and urine concentration of emodepside metabolite(s) may be 
measured. If and when these data become available a SAP amendment will be written to 
specify their reporting (if applicable).   
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 transformed parameters, the primary measure of central tendency will be the 
geometric mean4; for untransformed 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 
13.1 Plasma PK 
13.1.1 Pharmacokinetic Concentration Data 
The plasma concentrations of emodepside and metabolites (if applicable) will be listed and 
summarised by treatment. Means at any time will only be calculated if at least 2/3rds of the 
individual data points are above the lower limit of quantification.   


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Individual and mean plasma concentration–time profiles will be presented graphically.  
13.1.2 Pharmacokinetic Parameters 
The pharmacokinetic parameters of emodepside and metabolites (if applicable) will be listed 
and summarised by treatment.  
To assess the effect of food, analysis of variance (ANOVA) models will be fitted to the fed 
(Part 2, Cohort 9) solution and relevant fasted (Part 1, Cohort 5) solution data with the 
logarithm of the pharmacokinetic parameters AUC0-24 as the dependent variable, and 
formulation as a fixed effect. The estimated least square means and residual variance from the 
model will be used to construct 90% CIs for the difference in means on the log scale for the 
comparison of fed versus fasted solutions. 
13.2 Urinary PK 
If concentrations of emodespide in urine are determined, the amount of emodespide excreted 
in the urine will be estimated.  The data will be listed and summarised by treatment.  
14 
Pharmacodynamic Analyses 
Summaries and listings will use the safety population.
Pharmacodynamic variables (glucose, insulin, glucagon, cortisol, prolactin and leptin) at each 
planned assessment, and change from baseline at each planned post-baseline assessment, will 
be summarised by actual treatment.  
In addition, for glucose and insulin (Cohorts 9 and 10), glucagon and cortisol (Cohort 9): 
• Individual subject profiles will be plotted 
• 
The difference between change from baseline on Day 0 and Day -1 will be 
summarised at each planned post-baseline assessment by actual treatment 
• 
The AUC0-24 of change from baseline will be summarised for each day and treatment 
 
Individual Insulin and PK Concentration Plots, including Related Significantly Important AE 
Durations will be produced. 
For calculation of pharmacodynamics parameters, summary statistics and individual profile 
plots, values below the quantifiable limit of the assay will be substituted by one half of the 
lower limit of quantification. 


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15 
Changes from the Protocol Specified Statistical Analysis 
After the study was submitted to the MHRA and ethics committee the following changes were 
made to the analyses: 
1) The definition of treatment-emergent adverse event has been updated from “an AE 
will be considered as treatment emergent if it appeared after the first dosing, or if 
appeared before dosing and worsened after dosing” to: 
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.  
2) The AUC0-24 of change from baseline for glucose, insulin, glucagon and cortisol will 
be summarised for each day and treatment 
 
3) The following emodepside parameters have been added to those mentioned in the 
protocol: 
Main PK parameters: AUC0-24 and AUC0-24/D 
Exploratory PK parameters: AUC0-24,norm ,t1/2,dom 
4) The following analyses have been added for glucose, insulin, glucagon and cortisol: 
 
The difference between change from baseline on Day 0 and Day -1 will be 
summarised at each planned post-baseline assessment by actual treatment 
 
The AUC0-24 of change from baseline will be summarised for each day and 
treatment 
 
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. 


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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. 
5. FL140 HMR Laboratory alert and delta ranges ver 3 (HMR Lab form). 
 
 


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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 B for Part 2, e.g., 14.1B 
The numbering in the tables below will take precedence over the numbering in the shells.


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The following tables and figures will be produced (templates provided in Sections 17.2.1 and 17.2.2): 
  
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 
 
 
 
14.2.1.1 
Summary of Emodepside Plasma Pharmacokinetic 
Concentration-Time Data (ng/mL)
PK 
16.2.6.1.1 
T_PK1
14.2.1.2 
Summary of Derived Emodepside Plasma Pharmacokinetic 
Parameters  
PK 
16.2.6.1.2 
T_PK3
14.2.1.3 
Summary of Log-Transformed Derived Emodepside Plasma 
Pharmacokinetic Parameters 
PK 
16.2.6.1.2 
T_PK4
14.2.1.4
Assessment of the Effect of Food on the PK of Emodepside
PK
16.2.6.1.2
T_PK7
14.2.2 
Summary of Derived Emodepside Urine Pharmacokinetic 
Parameters 
PK 
16.2.6.2 
T_PK3
14.2.3.1 
Summary of Glucose 
Safety 
16.2.6.3 
T_PD1
14.2.3.2 
Summary of Difference Between Day -1 and Day 0 in 
Glucose
Safety 
16.2.6.3 
T_PD2
14.2.3.3 
Summary of AUC0-24 for Change from Baseline in Glucose 
Safety 
16.2.6.4 
T_PD3
14.2.4.1 
Summary of Insulin 
Safety 
16.2.6.3 
T_PD1
14.2.4.2 
Summary of Difference Between Day -1 and Day 0 in Insulin 
Safety 
16.2.6.3 
T_PD2
14.2.4.3 
Summary of AUC0-24 for Change from Baseline in Insulin 
Safety 
16.2.6.3 
T_PD3
14.2.5.1
Summary of Glucagon
Safety
16.2.6.3
T_PD1
14.2.5.2 
Summary of Difference Between Day -1 and Day 0 in 
Glucagon 
Safety 
16.2.6.3 
T_PD2
14.2.5.3 
Summary of AUC0-24 for Change from Baseline in Glucagon 
Safety 
16.2.6.3 
T_PD3


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Table 
Description 
Population 
Source 
Listing
Template 
(Shells below)
14.2.6.1 
Summary of Cortisol 
Safety 
16.2.6.3 
T_PD1
14.2.6.2 
Summary of Difference Between Day -1 and Day 0 in 
Cortisol 
Safety 
16.2.6.3 
T_PD2
14.2.6.3 
Summary of AUC0-24 for Change from Baseline in Cortisol 
Safety 
16.2.6.3 
T_PD3
14.2.7 
Summary of Prolactin 
Safety 
16.2.6.3 
T_PD1
14.2.8 
Summary of Leptin 
Safety 
16.2.6.3 
T_PD1
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 Drug-Related Treatment-Emergent Adverse 
Events 
Safety 
16.2.7.1 
T_AE1 
14.3.1.3
Summary of Treatment-Emergent Adverse Events by Severity 
Grade 
Safety
16.2.7.1
T_AE1
14.3.1.4 
Summary of Drug Related Treatment-Emergent Adverse 
Events by Severity Grade 
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 Urinalysis Dipstick Results 
Safety 
16.2.8.5 
T_UR1 
14.3.6.1 
Summary of Vital Signs  
Safety 
16.4 
T_VS1
14.3.6.2 
Summary of AUC0-24 for Change from Baseline in Supine 
Diastolic Blood Pressure (h*mmHg)
Safety 
16.4 
T_VS2
14.3.6.3 
Summary of AUC0-24 for Change from Baseline in Supine 
Systolic Blood Pressure (h*mmHg) 
Safety 
16.4 
T_VS2
14.3.6.4 
Summary of AUC0-24 for Change from Baseline in Supine 
Safety 
16.4 
T_VS2


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Table 
Description 
Population 
Source 
Listing
Template 
(Shells below)
Heart Rate (h*beats/min) 
14.3.7.1 
Summary of ECG values 
Safety 
16.4 
T_EG2 
14.3.7.2 
Summary of ECG Values and Changes in ECG Values of 
Potential Clinical Importance  
Safety 
16.4 
T_EG3 
14.3.8.1 
Summary of Neurological Examination Data 
Safety  
16.2.9.5 
T_NE1 
14.3.8.2 
Summary of Neurological Examination Questionnaire Data 
Safety  
16.2.9.6 
T_LB2
14.3.9 
Summary of Physical Examination Data 
Safety 
16.2.9.4 
T_PE1 
14.3.10 
Summary of Ophthalmological Examination  Data 
Safety 
16.2.9.7 
T_NE1 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 33 of 73 
 
Figure 
Description 
Population 
Source Listing 
Template 
(Shells below) 
14.2  
PHARMACOKINETIC AND PHARMACODYNAMIC 
DATA 
 
 
 
14.2.1.1 
Individual Emodepside Plasma Concentration-Time Plots 
(Linear and Semi-log) 
PK  
16.2.6.1.1 
F_PK1 
14.2.1.2 
Geometric mean (+/- SD) Emodepside Plasma 
Concentration-Time Plots (Linear and Semi-log) 
PK 
16.2.6.1.1 
F_PK2 
14.2.2.1 
Individual Glucose-Time Plots 
PD 
16.2.6.3 
F_PD1 
14.2.2.2 
Individual Glucose and PK Concentration Plots - 
Including Related Significantly Important AE Durations 
PD 
16.2.6.3, 
16.2.6.1.1, 
16.2.7.1 
F_PD2 
14.2.3.1 
Individual Insulin-Time Plots 
PD 
16.2.6.3 
F_PD1 
14.2.3.2 
Individual Insulin-Time Plots 0-12h
PD 
16.2.6.3 
F_PD1 
14.2.3.3 
Individual Insulin and PK Concentration Plots - 
Including Related Significantly Important AE Durations 
PD 
16.2.6.3, 
16.2.6.1.1, 
16.2.7.1 
F_PD2 
14.2.4 
Individual Glucagon-Time Plots 
PD 
16.2.6.3 
F_PD1 
14.2.5 
Individual Cortisol-Time Plots 
PD 
16.2.6.3 
F_PD1 
14.3 
SAFETY DATA 
 
 
 
14.3.1.1 
Individual Systolic Blood Pressure-Time Plots 
Safety 
16.2.9.1 
F_PD1 
14.3.1.2 
Individual Diastolic Blood Pressure-Time Plots 
Safety 
16.2.9.1 
F_PD1 
14.3.2 
Individual Heart Rate-Time Plots 
Safety 
16.2.9.1 
F_PD1 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 34 of 73 
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 
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 
16.2.6.1.1 
Listing of Emodepside Plasma Pharmacokinetic Concentration-Time 
Data  
L_PK1_PG 
16.2.6.1.2 
Listing of Derived Emodepside  Plasma Pharmacokinetic Parameters  
L_PK4_PG 
16.2.6.1.3 
Individual Emodepside Plasma Concentration-Time Plots (log scale) for 
Estimation of λz, with Regression Line 
F_PK10 
16.2.6.2 
Listing of Emodepside Urine Excretion Rate Data 
L_PK3_PG 
16.2.6.3 
Listing of PD concentration-Time Data 
L_PK1_PG 
16.2.6.4 
Listing of Derived AUC0-24 PD Concentration-Time Data 
L_PK1_PG 
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 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 35 of 73 
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 
16.2.9  
 Vital signs, ECG variables, neurological, physical findings and 
Ophthalmological Assessment 
 
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  
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  Neurological Examination Findings 
      L_NE1_PG 
16.2.9.6 
Listing of Neurological Questionnaire Findings 
L_NE2_PG 
16.2.9.7 
Listing of Ophthalmological Examination Data 
L_NE1_PG 
 
Complete listings of all data collected in this study will also be produced. 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 36 of 73 
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 
Safety Population 
Randomised 
 
 
 
 
 
Completed 
 
 
 
 
 
Withdrawn 
 
 
 
 
 
Death 
 
 
 
 
Adverse Events 
 
 
 
 
Withdrawal by subject 
 
 
 
 
Physician decision 
 
 
 
 
Protocol violation 
 
 
 
 
Study terminated by 
Sponsor 
 
 
 
 
Lost to follow-up 
 
 
 
 
 
 
Other 
 
 
 
 
PK Concentration 
Included 
 
 
 
 
 
PK Parameter 
Included 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatment groups and column for “All emodepside”   
                              This table will contain one column for placebo, each dose/formulation, all active and all subjects. 
 
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 37 of 73 
 
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 
 
 
 
Min 
 
 
 
Median 
 
 
 
Max 
 
 
 
Sex 
N 
 
 
 
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 
 
 
 
Min 
 
 
 
Median 
 
 
 
Max 
 
 
 
Weight (kg) 
n 
 
 
 
Mean 
 
 
 
SD 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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10 March 2017  
Page 38 of 73 
Variable 
Statistics 
Treatment 1 
(N=xx) 
Treatment 2 
(N=xx) 
Etc
All Subjects (N=xx) 
Min 
 
 
 
Median 
 
 
 
Max 
 
 
 
BMI (kg/m2) 
n 
 
 
 
Mean 
 
 
 
SD 
 
 
 
Min 
 
 
 
Median 
 
 
 
Max 
 
 
 
Cigarettes* 
(daily) 
n 
 
 
 
Mean 
 
 
 
SD 
 
 
 
Min 
 
 
 
Median 
 
 
 
Max 
 
 
 
Alcohol* 
(units/week) 
n 
 
 
 
Mean 
 
 
 
SD 
 
 
 
Min 
 
 
 
Median 
 
 
 
Max 
 
 
 
 
*includes only those subjects who drink alcohol or smoke 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatment groups and additional demographic characteristics 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 39 of 73 
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 
 
 
 
 
 
Gastrointestinal disorders 
Total number of subjects 
 
 
 
 
 
Abdominal discomfort 
 
 
 
 
 
Abdominal pain 
 
 
 
 
 
↓ 
 
 
 
 
Nervous system disorders 
Total number of subjects 
 
 
 
 
 
Dizziness 
 
 
 
 
 
Headache 
 
 
 
 
 
↓ 
 
 
 
 
↓ 
↓ 
 
 
 
 
 
*Subjects with ≥1 adverse event are counted only once per system organ class and preferred term.  
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.  
 
For tables by severity a sub-heading will be added to each table page 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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10 March 2017  
Page 40 of 73 
 
Template T_LB1 
Table  14.3.4.xx 
Summary of Laboratory Values of Potential Clinical Importance 
 
 
Planned Relative 
 
Double Flags 
Lab Test 
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 
 
 
Template T_LB2 
Table  14.3.3.2 
Summary of Chemistry Laboratory Values 
 
 
 
 
 
 
 
 
 
Change from Baseline 
Laboratory Test (units) 
Treatment 
Planned 
Relative Time 
n 
Mean 
95% CI 
SD 
Median Min 
Max 
n 
Mean 
SD 
Median 
Min 
Max 
 
Treatment 1  (N=xx)
-20h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Note: Baseline on Day -1 is -24h value, baseline on Day 0 is Day 0, pre-dose
 
Programming notes: 
Continued with all treatments and time points.   
For the summary of neurological questionnaires the first column will be headed “Questionnaire (Total Score)” and the footnote will be removed 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 41 of 73 
Template T_UR1 
Table  14.3.3.4 
Summary of Urinalysis Dipstick Results 
Planned Relative 
Time 
Result 
Treatment 1 (N=xx) 
Treatment 2 (N=xx) 
n 
% 
n 
% 
Time 1 
Positive 
 
 
 
 
Negative 
 
 
 
 
No Result 
 
 
 
 
Not Done 
 
 
 
 
Time 2 
Positive 
 
 
 
 
Negative 
 
 
 
 
No Result 
 
 
 
 
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 
 
Template T_VS1 
Table  14.3.4 
Summary of Vital Signs 
 
 
 
Change from Baseline 
Treatment 
Planned 
Relative Time 
n 
Mean 
SD 
Median 
Min 
Max 
n 
Mean 
SD 
Median Min 
Max 
Systolic BP (mmHg) 
Treatment 1  (N=xx) 
-20h 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Note: Baseline on Day -1 is -24h value, baseline on Day 0 is Day 0, pre-dose 
 
Programming notes: 
Continued with all variables, treatments and time points.   
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 42 of 73 
Template T_VS2 
Table  14.3.4 
Summary of AUC0-24 for Change from Baseline in Supine Diastolic Blood Pressure (h*mmHg) 
 
Day -1 
Day 0 
Day 0 - Day -1 
Treatment 
n 
Mean 
SD 
Min 
Max 
n 
Mean 
SD 
Min 
Max 
N 
Mean 
SD
95% CI (Lower, Upper) 
Treatment 1  (N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Difference is change from mean baseline 
 
Programming notes: 
Continued with all treatments 
 
 
Template T_EG2 
Table  14.3.5.1 
Summary of ECG Values 
 
 
 
 
Change from Baseline
Variable 
Treatment 
Planned Relative 
Time 
n 
Mean 
SD 
Median 
Min 
Max 
n
Mean 
SD 
Median 
Min 
Max 
Heart Rate  (bpm) 
Treatment 1 (N=xx) -20h 
 
 
 
 
 
 
 
 
 
 
 
-21h 
 
 
 
 
 
 
 
 
 
 
 
 
-23h 
 
 
 
 
 
 
 
 
 
 
 
Treatment 2 (N=xx) -20h 
 
 
 
 
 
 
 
 
 
 
 
-21h 
 
 
 
 
 
 
 
 
 
 
 
-23h 
 
 
 
 
 
 
 
 
 
 
 
PR Interval  (msec) 
Treatment 1 (N=xx) -20h 
 
 
 
 
 
 
 
 
 
 
 
-21h 
 
 
 
 
 
 
 
 
 
 
 
-23h 
 
 
 
 
 
 
 
 
 
 
 
Treatment 2 (N=xx) -20h 
 
 
 
 
 
 
 
 
 
 
 
-21h 
 
 
 
 
 
 
 
 
 
 
 
-23h 
 
 
 
 
 
 
 
 
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 43 of 73 
 
Source: Listing 16.2.xx 
 
Note: Baseline on Day -1 is -24h value, baseline on Day 0 is Day 0, pre-dose 
 
Programming notes: 
Continued with all treatment groups and time points.  Do not summarise RR or QRS axis 
 
 
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 
31-60 msec 
Increase 
>60 msec  
Increase 
n 
% 
n 
n 
n 
% 
n 
% 
n 
% 
QT interval 
Treatment 1 
(N=xx) 
1h 
 
 
 
 
 
 
 
 
 
2h 
 
 
 
 
 
 
 
 
 
3h 
 
 
 
 
 
 
 
 
 
 
Treatment 2 
(N=xx) 
1h 
 
 
 
 
 
 
 
 
 
2h 
 
 
 
 
 
 
 
 
 
3h 
 
 
 
 
 
 
 
 
 
QTcB interval 
 
Treatment 1 
(N=xx) 
1h 
 
 
 
 
 
 
 
 
 
2h 
 
 
 
 
 
 
 
 
 
3h 
 
 
 
 
 
 
 
 
 
Treatment 2 
(N=xx) 
1h 
 
 
 
 
 
 
 
 
 
2h 
 
 
 
 
 
 
 
 
 
3h 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Note: Baseline on Day -1 is -24h value, baseline on Day 0 is Day 0, pre-dose 
 
Programming notes: 
Continued with all treatments, variables and time points.  
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 44 of 73 
Template T_PE1 
Table  14.3.8.xx 
Summary of  Physical Examination Data 
Body System  
Planned 
Relative 
Time
Result 
Treatment 1 
(N=xx) 
Treatment 2 
(N=xx) 
General Appearance 
Time 1 
Normal 
n (%) 
 
Abnormal NCS x (xx) 
 
Abnormal CS 
 
 
Time 2 
Normal 
 
 
Abnormal NCS  
 
Abnormal CS 
 
 
HEENT 
Time 1 
Normal 
 
 
Abnormal NCS  
 
Abnormal CS 
 
 
Time 2 
Normal 
 
 
Abnormal NCS  
 
Abnormal CS 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all body system, treatments and time points. Include rows for each outcome in CRF 
                                             If results are missing “missing” row will be added. Percentages calculated using the number of available results as denominator. 
 
 
 
 
 
 
 
 
 
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 45 of 73 
Template T_NE1 
Table  14.3.8.xx 
Summary of  Neurological Examination Data 
Mental Status 
Body System  
Planned 
Relative 
Time
Result 
Treatment 1 
(N=xx) 
Treatment 2 
(N=xx) 
 
 
 
n (%) 
n (%) 
Alertness 
Time 1 
Normal 
x (xx) 
 
Abnormal NCS x (xx) 
 
Abnormal CS 
 
 
Time 2 
Normal 
 
 
Abnormal NCS  
 
Abnormal CS 
 
 
Speech 
Time 1 
Normal 
 
 
Abnormal NCS  
 
Abnormal CS 
 
 
Time 2 
Normal 
 
 
Abnormal NCS  
 
Abnormal CS 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all examinations/test, treatments and time points. Include rows for each outcome in CRF 
 
For Ophthalmological assessment, replace body system with Test 
 
                                         If results are missing “missing” row will be added. Percentages calculated using the number of available results as denominator. 
                                         Use PESCAT as subheading (not for Ophthalmological Assessment). 
                                             
 
 
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 46 of 73 
 
Template T_PK1 
Table   14..2.xx 
Summary of Emodepside Plasma Pharmacokinetic Concentration-Time Data [units]  
 
 
Treatment
 
 
N 
Planned  
Relative 
Time 
 
 
n 
 
No. 
Imputed 
 
 
Mean 
 
 
95% CI 
 
 
SD 
%CV 
 
 
Median 
 
 
Min 
 
 
Max 
Dose 1 
Dose 2 
 
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 
 
 
n 
 
 
 Mean
 
 
95% CI 
 
 
SD 
%CV 
 
 
Median 
 
 
Min 
 
 
Max 
AUClast (units) 
Cmax (units)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
Programming notes: 
Continued with all dose levels and parameters 
 
 
 
 
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 47 of 73 
 
 
Template T_PK4 
Table   14..2.xx 
Summary of Log-Transformed Derived Emodepside Plasma Pharmacokinetic Parameters 
 
Parameter 
 
 
Treatment 
 
 
N 
 
 
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_PK7 
Table   14.2.xx 
Assessment of the Effects of Food on the PK of Emodepside 
 
 
 
 
LS Means 
 
 
Parameter 
Treatment 
Fed 
Fasted 
Ratio 
(Fed/Fasted) 
90% CI 
Cmax (Units) 
 
xxxx.xx 
xxxx.xx 
xxxx.xx 
(xxxx.xx, xxxx.xx) 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with  AUCinf, 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 48 of 73 
Template T_PD1 
Table  14…xx 
Summary of Glucose 
 
 
 
 
 
 
 
 
 
Change from Baseline 
Treatment 
Planned 
Relative Time 
n 
Mean 
95% CI SD 
Median Min 
Max
n 
Mean 
SD 
Median 
Min 
Max 
Treatment 1  (N=xx) 
-24h 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
-20h 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Note: Baseline on Day -1 is -24h value, baseline on Day 0 is Day 0, pre-dose 
 
Programming notes: 
Continued with all PD parameters, treatments and timepoints 
                                                    Change from baseline calculated from ”pre-dose” on each day 
 
 
 
Template T_PD2 
Table  14…xx 
Summary of Difference Between Day -1 and Day 0 in Glucose 
 
Planned Relative Time 
Day -1 – Day 0 
Treatment 
n 
Mean 
SD 
95% CI 
Treatment 1  (N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Difference is change from baseline 
 
Programming notes: 
Continued with time points and treatments 
                                                      
                                                     
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 49 of 73 
Template T_PD3 
Table  14…xx 
Summary of AUC0-24 for change from baseline in Glucose (units) 
 
Day -1 
Day 0 
Day -1 – Day 0
Treatment 
n 
Mean 
SD
Min 
Max 
n 
Mean 
SD 
Min 
Max 
n 
Mean 
SD 
95% CI 
Treatment 1  (N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Difference is change from baseline 
 
Programming notes: 
Continued with all treatments  
 
 
 
 
 
 
 
 
 
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 50 of 73 
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
BAY 40-4400 concentration (ng/mL) 
Scheduled Time (h) 
Treatment x   
1
10
100
0
4
8
12
16
20
24
BAY 40-4400 concentration (ng/mL) 
Scheduled Time (h) 
Treatment x   


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
Hammersmith Medicines Research  
10 March 2017  
Page 51 of 73 
Template F_PK2 
 Figure 16.2.4.xx 
Geometric mean (+ SD) of Emodepside Plasma Concentration-Time Plots (Linear and Semi-log) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming note: The SD is the geometric standard deviations 
 
 
 
 
 
0
2
4
6
8
10
12
14
16
18
20
22
24
0
4
8
12
16
20
24
Mean(SD) Emodepside Concentration (ng/mL) 
Time (hour) 
Linear Plot 
Emodepside (10 mg) Solution
Emodepside (10 mg) Tablet
1
10
100
0
4
8
12
16
20
24
Mean(SD)Emodepside Concentration (Units) 
Time (hour) 
Semi-Log Plot 
Emodepside (10 mg) Tablet
Emodepside (10 mg) Solution


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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10 March 2017  
Page 52 of 73 
 
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


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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10 March 2017  
Page 53 of 73 
Template F_PD1 
Figure  16.2.xx 
Individual Glucose-Time Plots  
 
Programming note: Continue with Insulin, Glucagon and Cortisol land normal rages as reference lines.  
                                   For Blood pressure and Heart Rate, include PCI limits as reference lines. 
                                   Plot will include all subjects for a given treatment group 
                                  4 plots per page 
 
 
 
 
 
 
 
80
90
100
110
120
130
140
150
160
170
180
-24
0
24
Parameter (units) 
Time (hours) 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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10 March 2017  
Page 54 of 73 
 
Template F_PD2
Figure  16.2.xx 
Individual Glucose and PK Concentration Plots - Including Related Significantly Important AE Durations 
 
 
 
Cohorts with at least 1 related significant AE displayed 
 
Programming note: Continue with Insulin
                                  2 plots per page 
 
 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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10 March 2017  
Page 55 of 73 
17.2.3 Listing Outlines 
Template L_SD1_PG
Listing 16.2.x.xx 
Listing of Study Dates 
Treatment 
Subject 
Screening
Day -1 
Day 0 
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 
 
Template L_DV1_PG 
Listing 16.2.x.xx 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
Treatment 
Subject 
Type 
Criterion 
 
 
Inclusion 
 
 
 
Exclusion 
 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
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10 March 2017  
Page 56 of 73 
Template L_TD1_PG 
Listing 16.2.x.xx 
Listing of Subjects with Time Deviations 
Treatment 
Subject 
Timepoint 
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 16.2.2.3 
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
PK concentration  
 
Programming notes: 
continue for all populations 
 
 
 


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Template L_DM1_PG 
Listing 16.2.x.xx 
Listing of Demographic Characteristics 
 
 
 
 
 
 
Template L_CM1_PG 
Listing 16.2.x.xx 
Listing of Concomitant Medications 
Treatment 
Subject 
Drug Name/ 
Indication 
Dose/ 
Units/ Freq/ 
Route 
Date/time Started/ 
Date Stopped 
Time Since Last 
Dose 
Started 
Pre- 
Trial? 
Ongoing 
Medication? 
 
 
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 
 
 
 
Treatment  
Subject 
Date of visit 
Date of birth 
Age (y) 
Gender 
Race 
Ethnicity 
Height 
(cm) 
Weight 
(kg) 
BMI (kg/m2) 
Alcohol 
Consumption 
(units/week) 
Cigarettes 
(daily)  
Treatment 1 
 
 
 
 
 
 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
 
 
 
 
 
 


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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 
 


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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 
Normal Range 
NR 
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 
 
 
 
 
 
 
 
 
 
 
 
 
NR for Normal Range 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 
NR 
BL 
Result 
NR 
BL 
Result 
NR 
BL 
Result 
NR 
BL 
 
Treatment 
Subject 
Planned 
Relative 
Time 
Date/Time 
 
Chloride (MMOL/L) 
Glucose (MMOL/L) 
Potassium (MMOL/L) 
Sodium (MMOL/L) 
Result 
NR 
BL 
Result 
NR 
BL 
Result 
NR 
BL 
Result 
NR 
BL 
 
Treatment
Subject 
Planned 
Relative 
Time 
Date/Time 
 
Calcium (MMOL/L)
Creatinine (UMOL/L) 
Etc. 
Result 
NR 
BL 
Result 
NR 
BL 
Result 
NR 
BL 
 
NR for Normal Range  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 
Listing 16.2.x.xx 
Listing of Urinalysis Data 
Treatment 
Subject 
Planned 
Relative 
Time 
Date/Time 
Specific Gravity 
pH 
Protein 
Glucose 
Result 
NR 
Result 
NR 
Result 
NR 
Result 
NR 
 
 
NR for Reference interval flag, H = Above reference interval, L = Below reference interval 
 
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 
 
 
Pre-dose (1) 
26SEP2012:09:57 
63 
148 
78 
50 
390 
32.7 * 
399 
-27.7 
419 
-11 
 
 
Pre-dose (2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-dose (3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean Pre-dose  
 
 
 
 
 
 
 
 
 
 
 
 
24 H 
 
 
 
 
 
 
 
 
 
 
 
 
* 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 NCS’ or ‘Abnormal CS’ 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  Neurological Examination Findings 
Treatment 
Subject 
Planned 
Relative Time 
Date/Time 
Type 
Assessment 
Details
 
Programming Notes:  
Type = (Mental Status, Mood, Cranial Nerves etc. 
List all findings 
If subjects have multiple abnormal assessment at a given time, create a separate row for each assessment. 
For Ophthalmological assessment, the columns will be Treatment, Subject, Planned relative Time, Date/Time, Test and Details 
 
 
Template L_NE2_PG 
Listing 16.2.x.xx  
Listing of Neurological Questionnaire Findings 
Mental Status 
 
 
 
 
Total Score 
Treatment 
Subject 
Planned Relative 
Time 
Date/Time 
Hamilton 
Depression 
Rating Scale 
Epworth 
Sleepiness 
Score 
BDI-II 


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Template L_PK1_PG 
Listing  16.2.4.xx 
Listing of Emodepside Plasma Pharmacokinetic Con centration-Time Data 
 
Treatment 
Subject 
 
{Add. 
time 
var.} 
 
 
Date 
 
 
Study Day 
Planned 
Relative Time 
 
Actual time 
Time Deviation 
(units) 
Actual Relative 
Time 
 
Concentration (units) 
 
 
 
 
 
 
 
 
 
 
 
BLQ  = Below Limit of Quantification 
 
Programming notes: 
Values below LLOQ are shown as BLQ 
 
For PD:  BLQ values are imputed to half LLOQ 
 
For the listings of derived AUC0-24 PD concentrations, the columns will be Treatment, Subject, Planned Relative Time,  Concentrations (units) 
 
 
Template L_PK3_PG 
Listing  16.2.4 xx 
Listing of Emodepside Urine Excretion Rate Data  
Treatment 
Subject 
Planned
Relative 
Time 
 
 
Start Date/Time 
 
 
Stop Date/Time 
Urine Conc. 
(units) 
Total Sample Volume (mL) 
Amount excreted (units) 
 
 
 
 
 
 
 
 
 
 
 
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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Page 65 of 73 
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 
− 7.5 
+ 7.5 
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 
- 
+ 0.3 
Bilirubin conjugated 
DBIL 
µmol/L 
Both 
- 
+ 4.0 
Bilirubin total 
TBIL
µmol/L 
F 
− 20 
+ 10.0 
Bilirubin total 
TBIL
µmol/L 
M 
− 20 
+ 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 
- 
+ 0.5 
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 
+ 15 
Gamma glutamyl transferase 
GGT 
IU/L
F 
- 
+ 40 
Gamma glutamyl transferase 
GGT 
IU/L
M 
- 
+ 40 
Globulin 
GLOB 
g/L 
Both 
− 7.5 
- 
Glucose 
GLU 
mmol/L Both 
− 1.5 
+ 2.5 
Haematocrit 
HCT 
L/L 
Both 
− 0.05 
- 
Haemoglobin 
HB 
g/L 
Both 
− 20 
- 
High density lipoprotein 
HDL 
mmol/L Both 
− 1.5 
+ 1.5 
International normalised ratio 
INRR 
ratio 
Both 
- 
- 
Lactate dehydrogenase 
LDH 
IU/L
Both 
- 
+ 150 
Lymphocytes 
LYMP 
109/L 
Both 
− 1.5 
+ 1.5 
Magnesium 
MG 
mmol/L Both 
- 
- 
Mean cell haemoglobin 
MCH 
pg 
Both 
− 2 
+ 2 
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 
+ 0.5 
Neutrophils 
NEUT 
109/L 
Both 
− 2 
+ 8 
Phosphate 
PHOS 
mmol/L Both 
− 1 
+ 1 
Platelets 
PLT 
109/L 
Both 
− 100 
+ 100 
Platelets (citrate tube) 
PLTC 
109/L 
Both 
− 100 
+ 100 
Potassium 
K
mmol/L Both 
− 0.75 
+ 0.75 
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 
+ 3 
Total protein 
TP 
g/L 
Both 
− 15 
- 
Triglycerides 
TG 
mmol/L Both 
- 
+ 1.5 
Urea 
UREA 
mmol/L Both 
− 5 
+ 2 
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 
+ 8 
 
 


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Page 67 of 73 
Appendix B: Pharmacokinetic Analysis 
1 
Calculation Methods 
1.1 
Data Handling Conventions  
1.1.1 Actual v 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 will be substituted by one half of the lower limit of quantification for 
calculation of plasma concentration summary statistics . The  number of imputed 
values will be included in the summary table. 
For urine concentrations reported as BQL it is not possible to impute a value.  The 
amount excreted will be set to zero when concentration is BQL. 
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 
AUC(0-∞) values with <20% of this area extrapolated will be reported.   


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It is acceptable to include data from profiles with >20% extrapolated as long as at least 
80% of the profiles in the study have <20% of the AUC(0-∞) as extrapolated area.  In 
this instance, individual plasma concentration-time profiles for which the extrapolated 
areas are >20% of AUC(0-∞) will be identified.  
It is unacceptable to use AUC(0-∞) data if >40% of the AUC has been extrapolated, 
except in specific situations which should be carefully justified in the study report. 
1.3 
Lambda-z Calculations 
The apparent terminal phase rate-constant (λz) will be estimated by linear regression 
of logarithmically transformed concentration versus time data.  Only those data points 
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 
t
Cˆ  (the predicted value of the 
concentration at time tn); whilst the ‘observed’ parameters use the last observed 
concentration.  


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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, CL/F, Vz/F 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/D 
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 
λz
Terminal rate constant 
The apparent terminal phase rate-constant 
(λz) will be estimated by linear regression of 
logarithmically transformed concentration 
versus time data. 
1/h 
Y 
Lambda_z 
LAMZ 
λz 
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 
Terminal half-life 
The terminal half-life calculated from the 
terminal slope of the log concentration-time 
curve, as follows: 
𝑡½ = log𝑒2
λ𝑧
 
h 
Y 
HL_Lambda_z 
LAMZHL 
t1/2 
t½,0-24
Dominant half-life 
The half-life calculated from the terminal 
slope of the log concentration-time (0-24h) 
curve, as follows:
𝑡½ = log𝑒2
λ𝑧
 
h 
Y 
HL_Lambda_z 
TBC
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 
AUCt 
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 
AUClast 
AUCLST 
AUClast 
AUCt,norm 
Area under the 
concentration-time curve 
from time zero (pre-dose) to 
the time of last quantifiable 
concentration corrected by 
dose and body weight 
The AUC normalised by dose and body 
weight will be calculated as  
AUCt/(Dose administered*body weight) 
(h*ng/mL)/(mg*kg) 
Y 
N/A 
AUCLSTWD 
AUClast,norm 
AUCt-∞ 
Area under the exponential 
curve from tlast to infinity 
The area under the exponential curve from 
tlast to infinity, calculated as follows: 
z
t
t
C
AUC
λ
ˆ
=
∞
−
 where 
t
Cˆ is the 
predicted value of the concentration at tlast.   
h*ng/mL 
N/A 
N/A 
AUCIFO 
AUCt-inf 
AUC∞ 
Area under the plasma 
concentration-time curve 
from time zero to infinity 
The area under the concentration-time curve 
will be calculated using the (specified) 
trapezoidal method for the interval 0 to tlast 
(time tlast is the time at which the last non-
zero level was recorded), plus AUCt-∞.  
h*ng/mL 
Y 
AUCINF_pred 
AUCIFP 
AUCinf 
AUC∞/Dose 
Dose-normalised AUC to 
infinity 
The dose-normalised AUC to infinity will be 
calculated as AUC∞/Dose administered 
(h*ng/mL)/mg 
Y 
AUCINF_D_pred 
AUCIFPD 
AUCinf/D 
AUC∞,norm 
Area under the 
concentration-time curve 
from time zero to infinity 
corrected by dose and body 
weight 
The AUC normalised by dose and body 
weight will be calculated as  
AUC∞/(Dose administered*body weight) 
(h*ng/mL)/(mg*kg) 
Y 
N/A 
AUCIFPWD 
AUCinf,norm 
%AUCextrap 
Percentage of AUC∞ 
extrapolated from from tlast 
to infinity
∞
∞
−
×
=
AUC
AUC
AUC
t
extrap
100
%
% 
N 
AUC_%EXTRAP
_pred 
AUCPEP 
%AUCextrap 


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Text Symbol 
Definition 
Calculation 
Typical Units 
Log 
Transform 
WNL 
CDISC 
Controlled 
Terminology 
TFL 
Symbol 
AUC0-24 
Area under the plasma 
concentration-time curve 
from time zero to 24h 
The area under the concentration-time curve 
from zero time (pre-dose) to 24h will be 
calculated using the (specified) trapezoidal 
method.  
 
If λz is not estimable, a partial AUC is not 
calculated (when tlast<t). 
h*ng/mL 
Y 
User specified 
area 
AUCINT 
AUC24 
AUC0-24/D 
Dose-normalised AUC from 
time zero to 24h
The dose-normalised AUC from time zero to 
24h will be calculated as AUC0-24/Dose 
administered 
(h*ng/mL)/mg 
Y 
N/A 
AUCINTD 
AUC24/D 
AUC0-24,norm 
Area under the 
concentration-time curve 
from time zero to 24h 
corrected by dose and body 
weight
The AUC from time zero to 24h normalised 
by dose and body weight will be calculated as  
AUC0-24/(Dose administered*body weight) 
(h*ng/mL)/(mg*kg) 
Y 
N/A 
AUCINTWD 
AUClast,norm 
Clearance, volume of distribution and mean residence time 
CL/F 
Apparent total clearance 
from plasma after oral 
administration 
Apparent total clearance from plasma will be 
calculated using the following formula: 
∞
=
AUC
Dose
F
CL /
 
L/h 
Y 
Cl_pred 
(actually derives 
Cl_F_pred for oral 
dose) 
CLFP 
CL/F 
Vz/F 
Apparent volume of 
distribution during terminal 
phase after non-intravenous 
administration 
Apparent volume of distribution will be 
calculated using the following formula: 
∞
•
=
AUC
Dose
F
V
z
z
λ
/
 
L 
Y 
Vz_pred 
(actually derives 
Vz_F_pred for 
oral dose) 
VZFP 
Vz/F 
MRT
Mean Residence Time 
The mean residence time will be calculated 
using:
∞
=
AUC
AUMC
MRT
 
h 
Y 
MRTINF_pred 
MRTIFP 
MRT 
AUMC 
Area under the first moment 
of the plasma concentration-
time curve from time zero to 
infinity 
The area under the first moment of the 
concentration-time curve from zero time (pre-
dose) extrapolated to infinite time will using 
the (specified) trapezoidal method, as for 
AUC.  
h2*ng/mL 
- 
AUMCINF_pred 
AUMCIFP 
AUMC 
 


HMR code:  15-020 Part 2  
Sponsor code:  DNDI-EMO-001 Part 2 
 
 
Hammersmith Medicines Research 
10 March 2017 
Page 73 of 73 
Appendix C: Sample Page Layout 
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HMR 15-020 Part 2 
 
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