Efficacy and Safety Study of Acoziborole (SCYX-7158) in Patients With Human African Trypanosomiasis (HAT) Due to Trypanosoma Brucei Gambiense: a Multicentre, Open-label, Prospective Study
Phase: PHASE2
Conditions: Trypanosomiasis, African, Gambiense Trypanosomiasis, Sleeping Sickness
Sponsor: Drugs for Neglected Diseases

Protocol DNDi-OXA-02-HAT Version 4.0
Acoziborole
Confidential
CLINICAL STUDY PROTOCOL
Efficacy and Safety Study of Acoziborole (SCYX-7158)
in Patients with Human African Trypanosomiasis due to
T.b. gambiense: a Multicentre, Open-label, Prospective Study
Registration number
NCT03087955
Version 4.0 – 11 August 2020

Protocol DNDi-OXA-02-HAT Version 4.0 11 August 2020 
Acoziborole 
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CLINICAL STUDY PROTOCOL 
Efficacy and Safety Study of Acoziborole (SCYX-7158) in 
Patients with Human African Trypanosomiasis due to T.b. 
gambiense: a Multicentre, Open-label, Prospective Study 
Short title 
OXA002 
Product name/code 
Acoziborole (SCYX-7158) 
Therapeutic class 
Antiprotozoal 
Phase 
II/III 
Indication 
Human African Trypanosomiasis (HAT) due to 
Trypanosoma brucei gambiense 
Protocol Number 
DNDi-OXA-02-HAT 
EudraCT Number 
Not applicable 
Sponsor 
Drugs for Neglected Diseases initiative (DNDi) 
15 chemin Louis Dunant, 1202 Geneva, Switzerland 
Telephone: +41 22 906 9230 
Principal Investigator 
 
 
 
 
 
 
Coordinating 
Investigator  
 
 
 
National Coordinator in 
Guinea 
 
 
 
 
 
DNDi 
Drugs for Neglected Diseases initiative 

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Protocol Version and 
Date 
Version 4.0 / 11 August 2020 
Protocol Amendment 
Number and Date 
Amendment 3 dated 11 August 2020 
The information contained in this document is confidential. It is intended solely for the 
investigators, potential investigators, consultants or applicable independent ethics 
committees. It is understood that this information will not be disclosed to others without 
prior written authorisation from DNDi, except where required by applicable local laws. 

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Signatures 
 
 
Head of HAT Clinical Programme 
 
Signature 
 
 
Date of signature 
(DD/MM/YYYY) 
 
Name  
 
Title 
 
Organisation 
 
Address 
 
 
 
Clinical Project Manager 
Signature 
 
 
Date of signature 
(DD/MM/YYYY) 
 
Name  
 
Title 
  
Organisation 
 
Address 
 
 
 
 
Statistician 
 
Signature 
 
 
Date of signature 
(DD/MM/YYYY) 
 
Name  
 
Title 
 
Organisation 
 
Address 
 
 
 
 
 

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Investigator Signature Page 
 
I have read this protocol and agree that it contains all of the information required to 
conduct the study. I will conduct the study in compliance with the protocol, with Good 
Clinical Practice (GCP) and with the regulations in effect in my country, and I will 
complete the study within the specified timeframe. 
I will provide copies of the protocol and all relevant information to all individuals 
participating in the study under my responsibility. I will ensure that they are given all of 
the necessary information on the study treatment and the procedures of the study. 
I will use only the informed consent form approved by the Sponsor or its representative, 
and I agree to submit all relevant documentation to the Independent Ethics Committee 
(IEC) responsible for the study. 
I also agree that the Sponsor or its representatives shall have access to all source 
documents from which data entered in the case report forms was generated. 
 
Principal Investigator and National Investigator for the DRC 
 
Signature of 
Investigator 
 
 
Date of signature 
(DD/MM/YYYY) 
 
Name  
 
Title 
 
Organisation 
 
 
 
Address 
 
 
 
 

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Investigator Signature Page 
 
I have read this protocol and agree that it contains all of the information required to 
conduct the study. I will conduct the study in compliance with the protocol, with Good 
Clinical Practice (GCP) and with the regulations in effect in my country, and I will 
complete the study within the specified timeframe. 
I will provide copies of the protocol and all relevant information to all individuals 
participating in the study under my responsibility. I will ensure that they are given all of 
the necessary information on the study treatment and the procedures of the study. 
I will use only the informed consent form approved by the Sponsor or its representative, 
and I agree to submit all relevant documentation to the Independent Ethics Committee 
(IEC) responsible for the study. 
I also agree that the Sponsor or its representatives shall have access to all source 
documents from which data entered in the case report forms was generated. 
 
Coordinating Investigator 
 
Signature of 
Investigator  
 
 
Date of signature 
(DD/MM/YYYY) 
 
Name  
 
Title 
  
Organisation 
 
Address 
 
  
 
 

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Investigator Signature Page 
 
I have read this protocol and agree that it contains all of the information required to 
conduct the study. I will conduct the study in compliance with the protocol, with Good 
Clinical Practice (GCP) and with the regulations in effect in my country, and I will 
complete the study within the specified timeframe. 
I will provide copies of the protocol and all relevant information to all individuals 
participating in the study under my responsibility. I will ensure that they are given all of 
the necessary information on the study treatment and the procedures of the study. 
I will use only the informed consent form approved by the Sponsor or its representative, 
and I agree to submit all relevant documentation to the Independent Ethics Committee 
(IEC) responsible for the study. 
I also agree that the Sponsor or its representatives shall have access to all source 
documents from which data entered in the case report forms was generated. 
 
Investigator 
 
Signature of 
Investigator 
 
 
Date of signature 
(DD/MM/YYYY) 
Name 
 
Title 
 
Organisation 
 
Address 
 
 
Investigator 
 
Signature of 
Investigator 
 
 
Date of signature 
(DD/MM/YYYY) 
Name 
 
Title 
 
Organisation 
 
Address 
 
 
 

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TABLE OF CONTENTS 
 
Abbreviations – Glossary of Terms .............................................................. 10 
Protocol Summary ......................................................................................... 12 
1. 
Background and Study Rationale ..................................................................20 
1.1. 
Epidemiology .............................................................................................20 
1.2. 
Clinical Presentation of HAT ......................................................................21 
1.3. 
Management of Patients in the Study ........................................................21 
1.4. 
Current Therapeutic Options for g-HAT .....................................................24 
1.5. 
Investigational Product and Preclinical Data ..............................................24 
1.6. 
Pharmacokinetics and Metabolism In Healthy Volunteers ..........................25 
1.7. 
Safety in Healthy Volunteers ......................................................................26 
1.8. 
Choice of the Dose and Dosing Regimen ..................................................26 
1.9. 
Rationale for the Study Design ..................................................................27 
1.10. 
Target Population ...................................................................................27 
2. 
Study Objectives and Endpoints ...................................................................27 
2.1. 
Objectives ..................................................................................................27 
2.1.1. 
General Objective ...............................................................................27 
2.1.2. 
Primary Objective ...............................................................................28 
2.1.3. 
Secondary Objectives .........................................................................28 
2.2. 
Endpoints ..................................................................................................28 
2.2.1. 
Primary Endpoint – Efficacy ................................................................28 
2.2.2. 
Secondary Endpoints - Efficacy ..........................................................29 
2.2.3. 
Secondary Endpoints - Safety ............................................................31 
2.2.4. 
Secondary Endpoints - Pharmacokinetics ...........................................31 
2.2.5. 
Secondary Endpoints - Electrocardiogram ..........................................31 
3. 
Study Design ...................................................................................................31 
4. 
Selection of Study Population .......................................................................31 
4.1. 
Enrolment and Inclusion Procedures .........................................................32 
4.2. 
Inclusion Criteria ........................................................................................32 
4.3. 
Exclusion Criteria .......................................................................................33 
5. 
Study Treatments ...........................................................................................34 
5.1. 
Investigational Product ..............................................................................34 
5.1.1. 
Treatment Allocation ...........................................................................34 
5.1.2. 
Labelling and Packaging of IP ............................................................34 
5.1.3. 
Accountability of IP .............................................................................35 
5.1.4. 
Storage of IP ......................................................................................35 
5.1.5. 
Blinding and Procedure for Unblinding ................................................35 
5.2. 
Concomitant Treatment .............................................................................36 
5.2.1. 
Malaria ...............................................................................................36 
5.2.2. 
Helminthiasis ......................................................................................36 
5.2.3. 
Contraception .....................................................................................36 
5.3. 
Other Medication .......................................................................................36 
5.4. 
Rescue Treatment .....................................................................................37 
6. 
Schedule of Study Procedures and Assessments .......................................39 
6.1. 
Timing of Assessments ..............................................................................39 
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6.2. 
Pre-screening, Screening and Baseline Assessment .................................40 
6.2.1. 
Diagnosis of HAT ................................................................................40 
6.2.2. 
Pre-screening and Screening .............................................................40 
6.2.3. 
Baseline Assessment .........................................................................41 
6.3. 
Assessments during Hospitalisation: D1 to D15 .........................................42 
6.3.1. 
Laboratory Tests .................................................................................42 
6.3.2. 
Digital ECG .........................................................................................42 
6.3.3. 
Pharmacokinetic Analyses ..................................................................43 
6.3.4. 
Assessments on Day 1 - Treatment Day.............................................44 
6.3.5. 
Assessments at the Visit on Day 5......................................................44 
6.3.6. 
Assessments at the Visit on Day 11 ....................................................44 
6.3.7. 
Assessments on Day 15 - End-of-Hospitalisation Visit ........................45 
6.4. 
Assessments at Out-patient Follow-up Visits .............................................45 
6.4.1. 
At the 3-month Follow-up Visit ............................................................45 
6.4.2. 
At the 6-month Follow-up Visit ............................................................46 
6.4.3. 
At the 12-month and 18-month Follow-up Visits..................................46 
6.4.4. 
At Unscheduled Visits .........................................................................47 
6.5. 
Safety Assessment, Definitions and Reporting of Adverse Events .............48 
6.5.1. 
Definition of Adverse Event.................................................................48 
6.5.2. 
Definition of Serious Adverse Event ....................................................49 
6.5.3. 
Collection of Information on AEs .........................................................50 
6.5.4. 
AE Collection Period ...........................................................................50 
6.5.5. 
Requirements for AE Reporting ..........................................................50 
6.5.6. 
Grading of AE Severity .......................................................................51 
6.5.7. 
Assessment of AE Causality ...............................................................51 
6.5.8. 
Exposure in utero ...............................................................................52 
6.5.9. 
Follow-up on AEs ...............................................................................52 
7. 
Study Duration ................................................................................................53 
8. 
Withdrawal Criteria .........................................................................................53 
8.1. 
Patient Withdrawal from the Study and Replacement of Patients...............53 
8.2. 
Patients Lost to Follow-up..........................................................................54 
9. 
Data Analysis and Statistical Methods ..........................................................54 
9.1. 
Sample Size Determination .......................................................................54 
9.2. 
Definition of Study Populations included in the Analyses ...........................54 
9.3. 
Patient Disposition .....................................................................................55 
9.4. 
Demographic and Baseline Data ...............................................................56 
9.5. 
Treatment Compliance ..............................................................................56 
9.6. 
Efficacy Analyses ......................................................................................56 
9.6.1. 
Primary Efficacy Analysis ...................................................................56 
9.6.2. 
Futility Analyses ..................................................................................57 
9.6.3. 
Secondary Analyses ...........................................................................58 
9.7. 
Safety Analyses .........................................................................................59 
9.8. 
Handling of Missing Data and Patients Lost to Follow-up ..........................59 
9.9. 
Handling of Centres ...................................................................................60 
9.10. 
Analyses of Other Endpoints ..................................................................60 
10. 
Data and Safety Monitoring Board .............................................................61 
11. 
Quality Assurance and Quality Control Procedures .................................61 
11.1. 
Investigator Site File ...............................................................................61 
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11.2. 
Case Report Forms ................................................................................61 
11.3. 
Source Documents .................................................................................62 
11.4. 
Retention of Documents .........................................................................62 
11.5. 
Monitoring ..............................................................................................63 
11.6. 
Audits and Inspections ...........................................................................63 
11.7. 
Data Management ..................................................................................64 
11.8. 
Confidentiality of Information, Study Documents and Patients’ Files ......64 
12. 
Protocol Amendments ................................................................................64 
13. 
Early Termination of the Study ..................................................................65 
14. 
Ethical Considerations ...............................................................................65 
14.1. 
Information of Communities ...................................................................66 
14.1.1. 
In the Democratic Republic of the Congo ........................................66 
14.1.2. 
In Guinea ........................................................................................68 
14.2. 
Informed Consent Process .....................................................................69 
14.2.1. 
General Process .............................................................................69 
14.2.2. 
Impartial Witness ............................................................................70 
14.2.3. 
Illiterate Patients .............................................................................71 
14.2.4. 
Patients Unable to Give Consent ....................................................71 
14.2.5. 
Patients Under Legal Age ...............................................................71 
14.2.6. 
Changes in the Benefit-to-Risk Assessment during the Study .........72 
14.3. 
Ethical Aspects of Study Treatment, Sampling for Laboratory Tests and 
Imaging  ...............................................................................................................72 
14.4. 
Costs for Patients ...................................................................................73 
15. 
Insurance and Liability ...............................................................................74 
16. 
Reports and Publication .............................................................................74 
17. 
References ...................................................................................................75 
Appendices ..................................................................................................... 77 
 
 
List of Tables 
 
Table 1 - Clinical Classification of Patients .................................................................. 38 
Table 2 - Theoretical Schedule of Visits and Acceptable Leeway ................................ 39 
Table 3 - Schedule of ECG Recordings ....................................................................... 43 
Table 4 - Schedule of PK Sample Collection ............................................................... 43 
Table 5 - Populations Used in the Analyses ................................................................ 55 
Table 6 - Schedule of Events ...................................................................................... 89 
 
List of Figures 
 
Figure 1. Number of New Cases Reported at End of 2017 ..........................................20 
Figure 2. Decision Tree for the Diagnosis of HAT in the Context of the Study .............22 
 
 
 
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Abbreviations – Glossary of Terms 
 
AE 
Adverse event 
ALP 
Alkaline phosphatase  
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransférase 
AUC 
Area under the curve 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CATT 
Card agglutination test for trypanosomiasis 
CERSAC 
Ethics Committee for Health Research in Central Africa (Comité 
d’Ethique pour la Recherche en Santé en Afrique Centrale) 
CRF 
Case report form 
CSF 
Cerebrospinal fluid 
CTCAE 
Common Toxicity Criteria for Adverse Events 
D 
Day 
DBS 
Dry blood spot 
DNDi 
Drugs for Neglected Diseases initiative 
DRC 
Democratic Republic of the Congo 
DSMB 
Data and Safety Monitoring Board 
e.g. 
For example 
ECG 
Electrocardiogram 
EoH 
End of Hospitalisation [visit] 
g-HAT 
Human African trypanosomiasis due to T.b. gambiense 
H 
Hour 
HAT 
Human African trypanosomiasis 
i.e. 
id est 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INRB 
Institut National de Recherche Biomédicale (Democratic Republic 
of the Congo) 
IV 
Intravenous 
M 
Month 
mAECT 
Mini-anion exchange column test 
mAECT-BC 
Mini-anion exchange column test - buffy coat 
mITT 
Modified Intention to treat (set) 
MSC 
Modified single centrifugation 
NCI 
National Cancer Institute 
NECT 
Nifurtimox-eflornithine combined therapy 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PNLTHA 
Programme National de Lutte contre la Trypanosomiase Humaine 
Africaine 

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QT 
QT interval on ECG (time interval between electrical depolarisation 
and repolarisation of the left and right cardiac ventricles) 
QTcF 
QT interval corrected by heart rate, according to the formula 
proposed by Fridericia 
RDT 
Rapid diagnostic test 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SMS 
Short message service 
T.b. 
Trypanosoma brucei 
T3 
Tri-iodothyronine 
T4 
Thyroxine 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal range 
WBC 
White blood cell / white blood cell count 
WHO 
World Health Organisation 
WHO-TDR 
Tropical Disease Research programme of the WHO 
Y 
Year 
 
 
 

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Protocol Summary 
 
Study Title 
 
Efficacy and safety study of acoziborole (SCYX-7158) in 
patients with human African trypanosomiasis (HAT) due to 
Trypanosoma brucei gambiense: a multicentre, open-label, 
prospective study 
Study Phase 
II/III 
Indication 
Human African Trypanosomiasis (HAT) due to Trypanosoma 
brucei gambiense 
Protocol Number DNDi-OXA-02-THA 
Short Number: OXA002 
Study Rationale 
Human African trypanosomiasis (HAT) is a neglected disease 
that is usually fatal. 
Few therapeutic options are currently available to treat HAT in 
the late (or meningoencephalitic) stage. Nifurtimox-eflornithine 
combination therapy (NECT), introduced in 2009, has 
demonstrated efficacy with a success rate between 94% and 
97%, and has been chosen as first-line treatment in all 
endemic countries where cases have been declared in the past 
10 years. The need for a hospital infrastructure to administer 
NECT (2-hour infusions, twice daily for 7 days for eflornithine) 
and logistical difficulties relating to supply, as well as difficulties 
relating to access to patients have prompted research into 
drugs that can be administered orally, including fexinidazole 
and acoziborole. 
Acoziborole is an orally active benzoxaborole-6-carboxamide 
that has been shown to have in vitro and in vivo activity against 
the two subspecies of parasites, T.b. rhodesiense and 
T.b. gambiense, responsible for HAT. 
Single oral doses of acoziborole ranging from 20 to 1200 mg 
have been administered to healthy volunteers with no major 
toxic effects (6). The dose of 960 mg was chosen as the 
therapeutic dose because it ensures exposure levels in the 
cerebrospinal 
fluid 
(CSF) 
1.5-fold 
higher 
than 
the 
pharmacologically active levels at which a 100% trypanocidal 
effect was obtained in infected animals. In healthy volunteers, 
plasma levels remained above the effective concentration up 
to 69 days after the administration of acoziborole. The 
objective of the study is to assess the efficacy and safety of 
acoziborole administered as a single oral dose in fasting 
patients with HAT due to T.b. gambiense. 
Study Objectives General Objective 
To assess the efficacy and safety of a single oral dose of 
acoziborole administered to patients in the fasting state with g-
HAT. 
Primary Objective 

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To estimate the success rate at 18 months of follow-up with 
acoziborole, administered as a single 960-mg oral dose to 
patients in the fasting state with late-stage g-HAT. 
An estimate of the success rate observed with NECT in 
patients with late-stage g-HAT, based on historical data, will be 
provided as a yardstick. 
Secondary Objectives 
▪ To estimate the success rate at 12 months in late-stage 
patients 
▪ To estimate the time course of the failure rate in patients 
with late-stage g-HAT. 
▪ To assess the safety profile of a single dose of acoziborole 
in patients with g-HAT using historical data on NECT as a 
yardstick. 
▪ To establish the relationship between, on the one hand, 
concentrations of acoziborole in the blood and the CSF and, 
on the other hand, the efficacy and safety of acoziborole. 
As part of the clinical package, a cohort of patients over 15 
years of age with early- or intermediate-stage g-HAT will be 
enrolled following the futility analysis, provided that it does not 
show futility and that the safety review shows no concerns. The 
general objective will be to assess the efficacy of acoziborole 
in this cohort and to enrich the safety database at the time of 
regulatory filing. 
▪ To estimate the success rate with acoziborole in this cohort, 
using pentamidine as a yardstick. 
▪ To assess the safety profile in this cohort and in the overall 
population. 
▪ To assess the safety of acoziborole in patients with early- 
and intermediate-stage HAT to determine whether its safety 
profile is comparable to the historical safety profile of 
pentamidine. 
Primary 
Endpoint 
 
Efficacy  
The rate of success, according to World Health Organisation 
(WHO) criteria (23), for patients with late-stage HAT 18 months 
after receiving acoziborole. 
Secondary 
Endpoints 
Efficacy  
▪ Treatment efficacy at each visit between the end of 
treatment and 18 months, estimated, on the one hand, 
based on criteria for success specific to each visit and, on 
the other hand, based on a calculation of the cumulative risk 
of failure over time. 
Safety 
▪ Occurrence of any adverse event during the observation 
period. Adverse events will be graded according to the 

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Common Toxicity Criteria for Adverse Events (CTCAE) of 
the National Cancer Institute (NCI), version 4.03. 
▪ Occurrence of any serious adverse event during the 
observation period and until the 18-month follow-up visit. 
Pharmacokinetics (PK) / Pharmacodynamics 
▪ PK parameters in the blood and CSF: acoziborole 
concentrations in whole blood and in the CSF; population 
PK parameters, i.e. clearance, area under the curve and 
half-life. 
Electrocardiogram 
▪ Categories of QT/QTcF interval and changes at various 
timepoints. 
Futility Analyses 
Futility analyses to assess the response rate are planned in 
order to stop exposure to the investigational product if efficacy 
is below an acceptable limit. 
Study Design 
This is a prospective, multicentre, open-label, non-randomised 
phase II/III study. 
Inclusion and 
Exclusion 
Criteria 
 
To be included in the study, the patient must fulfil all of the 
inclusion criteria and none of the exclusion criteria: 
Inclusion Criteria 
▪ Male or female 
▪ 15 years of age or older 
▪ Signed informed consent form (as well as assent from 
illiterate and under-age patients, and those unable to give 
consent) 
▪ Karnofsky Performance Status above 50 
▪ Able to ingest oral tablets 
▪ Having a permanent address or being traceable by other 
persons 
▪ Able to comply with the schedule of follow-up visits and 
requirements of the study 
▪ Agreement to be hospitalised in order to receive treatment 
For patients with late-stage HAT: 
▪ Confirmation of g-HAT by detection of the parasite in the 
blood and/or the lymph and/or the CSF, at the 
investigational centre 
▪ If trypanosomes are found in the blood or lymph, but not in 
the CSF, the CSF white blood cell count, measured at the 
investigational centre, must be above 20/µL for the patient 
to be included in the cohort of patients with late-stage HAT 
For patients with early- or intermediate-stage HAT: 
▪ Confirmation of g-HAT by detection of the parasite in the 
blood and/or the lymph, at the investigational centre 

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▪ Absence of parasites in the CSF 
▪ The CSF white blood cell count, measured at the 
investigational centre, must be between 6 and 20/µL for the 
patient to be included in the cohort of patients with 
intermediate-stage HAT and equal to or below 5/µL for the 
patient to be included in the cohort of patients with early-
stage HAT 
Exclusion Criteria 
▪ Severe malnourishment, as defined by a body-mass index 
below 16 
▪ Pregnancy or breastfeeding, (for women of child-bearing 
potential, confirmed pregnancy on a urine pregnancy test 
performed within 24 hours prior to administration of 
acoziborole) 
▪ Clinically significant medical condition that could, in the 
opinion of the Investigator, jeopardise the patient’s safety or 
interfere with participation in the study, including, but not 
limited to significant liver or cardiovascular disease, 
suspected or proven active infection, central nervous 
system trauma or seizure disorder, coma or consciousness 
disturbances 
▪ Severely 
deteriorated 
health 
status, 
e.g. 
due 
to 
cardiovascular shock, respiratory distress syndrome or end-
stage disease 
▪ Previously treated for HAT (except prior treatment with 
pentamidine) 
▪ Prior enrolment in the study 
▪ Foreseeable difficulty complying with follow-up, including 
migrant worker, refugee status, itinerant trader etc. 
▪ Current alcohol abuse or drug addiction 
▪ Not tested for malaria and/or not having received 
appropriate treatment for malaria 
▪ Not having received appropriate treatment for soil-
transmitted helminthiasis 
▪ Clinically significant abnormal laboratory value including: 
o AST and/or ALT more than 2 times the upper limit of 
normal (ULN), 
o Total bilirubin more than 1.5 ULN, 
o Severe leukopenia at less than 2000/mm3, 
o Potassium below 3.5 mmol/L, 
o Any other clinically significant abnormal laboratory 
value. 
Investigational 
Product 
The investigational product (IP) is acoziborole, in 320-mg 
tablets, administered by the oral route to patients in the fasting 
state according to the following dosing regimen: 
▪ 960 mg (3 tablets) in a single intake on Day 1. 

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Study Duration 
The duration of the enrolment period is estimated to be 
approximately 28 months. 
Each patient’s participation in the study will last approximately 
18 months and will include:  
▪ pre-treatment 
period 
(pre-screening 
and 
screening, 
treatment of concurrent diseases) up to 15 days; 
▪ a treatment period of 1 day; 
▪ an observation period in hospital of a total of 15 days, 
including the treatment day (Day 1); 
▪ an out-patient follow-up period of 18 months with visits at 3, 
6, 12 and 18 months. 
The total duration of the study is estimated to be 46 months. 
Study Schedule 
D-15 to D-1: pre-screening and screening 
 
• including the baseline assessment: D-4 to D-1 
D1: treatment day 
D1 to D15: observation period at hospital 
D11: initial assessment of treatment effect (lumbar puncture) 
D15: end-of-hospitalisation visit 
Out-patient follow-up visits at 3 months, 6 months, 12 months 
and 18 months 
Sample Size 
Calculation 
The sample size is based on the largest number of patients 
who can be enrolled within a reasonable timeframe. 
The sample size will be 155 late-stage patients. 
Patients lost to follow-up who fled the region due to armed 
conflict or natural disaster will be replaced. A provision of 5% 
(7 patients) is planned in order to allow for replacement of 
patients lost to follow-up. Thus, a total of 162 patients will be 
included. 
As a result of the reduction in the number of patients, it is 
estimated that approximately 50 early- or intermediate-stage 
patients may be enrolled in the study during the enrolment 
period. 
Statistical 
Analyses 
Analysis Sets 
The population of late-stage patients will be separated from the 
population of early- and intermediate-stage patients. 
The primary analysis will be performed on late-stage patients 
in the modified intention-to-treat (mITT) population and who 
received at least one tablet of acoziborole. Patients lost to 
follow-up who fled the region due to armed conflict or natural 
disaster will not be included in the mITT population and will be 
replaced by other patients. 
The analysis of the primary endpoint for early- and 
intermediate-stage patients, which is considered to be a 
secondary analysis, will be also performed on the mITT 
population. 
The sensitivity analyses will be performed by cohort, 
separating late-stage patients from early- and intermediate-

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stage patients. 
Primary Efficacy Analysis: Success Rate at 18 Months in 
Late-stage Patients 
The primary analysis is based on the mITT set, i.e. patients 
who received at least one tablet of acoziborole, and will consist 
in an estimate of the success rate at 18 months of follow-up. 
The 95% Jeffreys confidence interval of the estimate will be 
provided. 
Analysis of Surrogate Primary Endpoint for Late-stage 
Patients 
Amendment 2 dated 07/01/2020 deletes analysis of the 
surrogate primary endpoint at 12 months in patients with late-
stage g-HAT, as the data set required for early submission at 
12 months is not available in its entirety. 
Success Rate for the Yardstick 
The current standard of care for late-stage patients is NECT, 
and the success rate with NECT will be used as a yardstick. 
The success rates will be provided study-by-study along with 
the 95% Jeffreys confidence interval. Three studies will be 
taken into account: the study by Priotto et al. (18) involving 143 
patients exposed to NECT; the WHO-TDR study (13) involving 
55 patients exposed to NECT; and the DNDiHATFEX004 study 
involving approximately 130 patients exposed to NECT. Data 
from the NECT-Field study will not be used because it did not 
include the same population and the large number of missing 
lumbar punctures could drastically reduce the success rate, 
particularly at 12 months (20). 
Secondary Efficacy Analysis at 12 Months in Late-stage 
Patients 
The estimated success rate at 12 months in late-stage patients 
is a secondary analysis. The 95% Jeffreys confidence interval 
of the estimate will be provided. 
Efficacy Analysis in Early- and Intermediate-stage 
Patients 
The efficacy analysis for early- and intermediate-stage patients 
is a secondary analysis, similar to the primary analysis for late-
stage patients and concerns the success rate at 12 months and 
at 18 months in early- and intermediate-stage patients. The 
95% Jeffreys  confidence interval for the estimated rates will 
be provided. 
Other Secondary Analyses 
▪ The correlation between acoziborole concentrations in the 
blood and CSF and the success rate in late-stage patients 
will be determined using logistic regression with success or 
failure as the response (dependent variable) and two 
covariables (explanatory variables): blood and CSF 
concentrations. 
▪ The correlation between acoziborole concentrations in the 
blood and CSF and the occurrence of AEs in late-stage 
patients will be determined using logistic regression with the 
occurrence of AEs during hospitalisation as the response 

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(dependent variable) and two covariables (explanatory 
variables): blood and CSF concentrations.  
▪ Changes in the rate of favourable outcomes over time for 
late-stage patients on the one hand, and for early- and 
intermediate-stage patients on the other hand, will be 
studied using the mixed model for repeated measures 
(Glimmix). 
▪ Time to proven relapse will be analysed in each cohort using 
the Kaplan-Meier approach in order to estimate, at each 
follow-up visit, the cumulative rate of proven failures. 
Patients lost to follow-up will be censored at the last 
available visit, unless the outcome at that visit was failure. 
Safety Analyses 
All patients who received acoziborole will be included in the 
safety analyses. 
The percentage of patients who experienced a serious adverse 
event (SAE) will be described by system-organ class. 
The percentage of patients who experienced at least one 
adverse event will (AE) be described. Each SAE will be 
described in a narrative presenting all aspects of the medical 
event and the causality assessment. 
The incidence of AEs and of SAEs and their respective 95% 
confidence intervals will be presented by category and by 
frequency. In other cases, only descriptive statistics will be 
presented. 
Laboratory 
safety 
parameters, 
i.e. 
haematology 
and 
biochemistry, will be described individually, indicating the 
percentages of patients by the size of the increase in relation 
to the ULN and to baseline values, as well as changes in blood 
levels over time. Shift tables will be provided. A listing of 
patients with increases in laboratory parameters will be 
provided. 
Abnormalities on electrocardiogram (ECG) tracings will be 
described for each timepoint. 
Futility Analyses 
An independent Data and Safety Monitoring Board (DSMB) will 
be appointed, among other things, to supervise and review the 
futility and PK analyses, as well as the safety data. The DSMB 
will make recommendations on study continuation based on all 
available information. 
The first futility analysis will be performed once the first 20 late-
stage patients reach the 3-month visit. If the failure rate at Day 
11 is significantly higher than the failure rate for melarsoprol 
(19), the study should be stopped for futility and for ethical 
reasons. The failure rate for melarsoprol at the end of 
treatment was 5% (4.8% for N = 6840). If 4 patients out of 20 
are failures at Day 11 (p = 0.0159), then the DSMB should 
recommend stopping the study, unless the rate can be 
explained by exceptional circumstances. 
The second futility analysis will be performed once 70 late-
stage patients reach the 3-month visit. The recommendation to 

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stop the study should be made if 8 patients or more out of 70 
are failures at the end of hospitalisation (p = 0.023 one-sided). 
The last futility analysis will be performed once 70 late-stage 
patients reach the 6-month visit. The proven failure rate will be 
compared to the failure rate with melarsoprol at 6 months, 
which is 20%. If the failure rate is significantly higher than 20%, 
i.e.  22 out of 70 patients (p = 0.016, one-sided), the DSMB 
should recommend stopping the study. 
Additional futility analyses may be performed if deemed 
necessary during the course of the study. 
Rules for Success of the Study 
There are no objective rules for the success of the study. As 
recommended by the Scientific Advice Working Party, the 
observed success rate and lower bound of the 95% CI will be 
interpreted in light of those obtained in the literature and with 
the historical data, taking into account the obvious advantage 
of having a single oral dose for patients living in remote areas. 
 
 
 

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1. Background and Study Rationale 
 
1.1. 
Epidemiology 
Human African trypanosomiasis (HAT), or sleeping sickness, is a vector-borne 
parasitic disease that is present in sub-Saharan Africa. It is transmitted by the 
bite of the tsetse fly (genus Glossina) and, if left untreated, it invariably leads to 
the patient’s death. The parasites responsible for HAT are the protozoa, 
Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, which 
are found only in foci in regions of sub-Saharan Africa where the tsetse fly is 
endemic (2, 15, 22). Twenty-four countries are considered to be endemic for HAT 
due to T.b. gambiense (g-HAT), however, since 2005, cases have been reported 
in only 14 of these countries. Thirteen countries are considered to be endemic for 
HAT due to T.b. rhodesiense, however cases have been reported in only 6 of the 
countries. Uganda is the only country where both subspecies of parasite are 
found. In 2014, the WHO identified 3679 cases of g-HAT worldwide, 87% of which 
in the Democratic Republic of the Congo (DRC) alone (11, 24, 25). According to 
the same source, however, the actual number of cases may be as high as 20,000 
and as many as 65 million people may actually be exposed to the disease. The 
number of reported cases steadily declines each year, and the historically lowest 
level of 2110 cases was reached in 2016 (12). The most recent data presented 
by WHO in April 2018, i.e. 1420 cases in 2017, confirmed this trend, as shown in 
Figure 1. 
Figure 1. Number of New Cases Reported at End of 2017 
 
35000 ,-------------------~;::::======= 
----Cases report1?d I 
-
cases expected 

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1.2. 
Clinical Presentation of HAT 
There are two successive stages in the clinical course of HAT. In the first stage, 
called the haemolymphatic or early stage, trypanosomes are present only in the 
blood and lymphatic system. The clinical signs and symptoms are mild and non-
specific, including bouts of fever, headache, joint pain, itching and lymph node 
enlargement. The signs and symptoms are very similar to those of malaria, which 
explains why patients with early-stage HAT are often misdiagnosed with malaria. 
If HAT is not diagnosed and treated, patients progress to the next stage, called 
the meningoencephalitic stage or late stage, in which parasites invade the central 
nervous system. At this stage, patients display neurological signs including 
mental 
confusion, 
behavioural 
changes, 
sensory 
disturbances, 
sleep 
disturbances and, eventually, coma and death. There is also an intermediate 
stage in which no parasites are detected in the cerebrospinal fluid (CSF), 
however the white blood cell count (WBC) in the CSF is between 6 and 20/µL (2, 
15, 22, 27). 
 
1.3. 
Management of Patients in the Study 
HAT due to T.b. gambiense may be diagnosed either in the context of passive 
screening in patients who present spontaneously to the hospital or to one of the 
outlying healthcare centres or in the context of active screening by mobile teams 
working in the field. In Guinea, the study will be conducted in the HAT treatment 
centre in Dubreka, with two satellite centres, i.e. the HAT treatment centre in 
Forecariah and the prefectural hospital in Boffa, for screening and follow-up of 
patients. Whatever the context, the diagnostic process will consistently include 
the following three steps: screening for potential infection using clinical and 
serological assessments, detection of the parasite and staging of the disease 
(see Figure 2). 

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Figure 2. Decision Tree for the Diagnosis of HAT in the Context of the Study
Screening, which consists in investigation of potential infection, will be performed 
by assessing clinical signs, including the presence of swollen cervical lymph 
nodes, and by serological tests. In the community or at hospital, serological 
screening will be performed using a rapid diagnostic test (RDT) or the card 
agglutination test for trypanosomiasis (CATT) (9). 
For patients with a positive result on serological screening, tests to detect the 
parasite will be performed, preferably using one of the concentration methods 
that allow for microscopic detection of motile parasites in fresh centrifugated 
samples. The testing will be performed on lymph node aspirate collected by 
needle biopsy and in the blood, using the Woo test (capillary tube centrifugation) 
or the mini-anion exchange centrifugation test (mAECT) (3) or, if concentration 
methods are not available, by examination of a thin blood smear or stained thick 
blood smear. 
In the context of the study, the improved technique, called the “mini-anion 
exchange centrifugation test on buffy coats” (mAECT-BC) (4), will be used 
whenever possible in patients with positive serological tests and negative findings 
on the usual parasitological tests. 
Lymph node
palpation
CATT on whole blood
or
Rapid diagnostic test*
Lymph node
aspiration
Patient is HAT negative
Parasitological tests
on blood**
CATT
end-dilution titre ≥ 1/16
Lumbar puncture
Tryps Pos in CSF and/or
Tryps Pos outside CSF
and CSF WBC > 20/µl
Patient with early or 
intermediate-stage HAT
Patient with late-stage HAT
*Preferably CATT for active screening and RDT for passive screening
**Preferably in the following order: mAECT-BC (passive); mAECT (active); CTC/Woo test; Thick blood smear
CATT: Card Agglutination Test for Trypanosomiasis
Tryps: Trypanosomes  
CSF: Cerebrospinal Fluid 
WBC: White Blood Cell count
Pos: Positive
Neg: Negative
AND
+
+
+
All -
-
-
+
-
+
AND
Tryps Neg in CSF and
Tryps Pos outside CSF
and CSF WBC ≤ 20/µl

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Because the serological tests currently available are not 100% reliable, an 
individual may have negative serological tests, but still show clinical signs 
suggestive of HAT. In this case, the individual will undergo the parasitological 
tests described above. 
Current therapeutic options are not the same for early- and late-stage HAT and, 
as a result, before initiating treatment, it is necessary to determine the stage of 
the disease by analysing CSF collected on lumbar puncture. In usual practice, 
late-stage HAT is confirmed by the presence of parasites and/or of a CSF WBC 
above 5/µL. However, in clinical studies assessing treatments for late-stage HAT, 
the WHO recommends that a CSF WBC of 20/µL should be used as the threshold 
for determination of late-stage HAT (23). A CSF WBC of 20/µL will therefore be 
used as the threshold in this study. 
In current practice, when  early-stage HAT is diagnosed, patients can be treated 
in their village with intramuscular injections of pentamidine for 7 days. Patients 
diagnosed with late-stage HAT are hospitalised to receive treatment with 
Nifurtimox-eflornithine combination therapy (NECT) (see Section 1.4, Current 
Therapeutic Options for g-HAT; p24). In the present study, all patients will receive 
acoziborole. 
In the context of the study, patients diagnosed outside the investigational centre 
will undergo a second assessment based on the decision tree presented above. 
Lumbar puncture for disease staging will be performed only at the investigational 
centre. It is planned to perform lumbar puncture, whenever possible, using a local 
anaesthetic cream, i.e. Emla®, as well as an atraumatic needle. Parasitological 
tests will be performed after modified single centrifugation (MSC) of the CSF. 
Only patients in whom the presence of parasites is confirmed by at least two team 
members at the investigational centre and approved by the Investigator, will be 
included in the study, regardless of the findings reported by the mobile teams. 
For quality control purposes, it is planned to record digital images of the 
parasitological tests and CSF WBC counts at the time of the initial diagnosis, as 
well as during follow-up visits. 
In usual practice, cure is defined as the absence of parasites in any body fluid 
and by a CSF WBC below 20/µL at 18 months. As a result, lumbar punctures 
must be performed to confirm the cure in patients treated for HAT. In the past, 
the recommendations for HAT control programmes were to assess cure every 6 
months up to 24 months after the end of treatment (5, 26). However, with the use 
of highly effective anti-HAT treatments such as pentamidine for the early stage 
and NECT for the late stage, and given the difficulty of routine post-treatment 
follow-up, systematic follow-up with CSF examination to confirm cure is no longer 
recommended, and assessment should be based on clinical features. This 
recommendation does not apply to clinical studies intended to test new 
compounds for the treatment of HAT (27). Therefore, in the present study, 

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parasitological tests on the blood and lymph, as well as lumbar puncture, will be 
performed at the 6-, 12- and 18-month follow-up visits. 
 
1.4. 
Current Therapeutic Options for g-HAT  
Few therapeutic options are currently available to treat HAT at either stage (1, 
14). When early-stage HAT is diagnosed, patients can be treated in their villages 
with intramuscular injections of pentamidine for 7 days. In patients with late-stage 
HAT, NECT, a combination of oral nifurtimox for 10 days plus eflornithine, two 2-
hour intravenous (IV) infusions daily for 7 days, was found to provide similar cure 
rates to the standard regimen with eflornithine for 14 days, but with obvious 
practical advantages, including ease of administration and a shorter duration of 
treatment. 
In May 2009, the WHO Expert Committee added NECT to the 16th edition of the 
WHO List of Essential Medicines for adults, as an alternative to single-drug 
therapy with melarsoprol or eflornithine. 
In keeping with the WHO recommendation, almost all of the national HAT control 
programmes have already adopted NECT as first-line treatment for late-stage g-
HAT and, in 2014, NECT became the most widely used treatment for late-stage 
disease (21). 
NECT represents a significant improvement over current therapies, however it is 
far from ideal given the conditions under which patients with HAT generally live, 
i.e. in poor, remote areas with little or no healthcare infrastructures and problems 
with logistics. Thus, there is an urgent need to develop easier-to-use products for 
the treatment of this fatal disease, ideally a simplified, short-course treatment that 
can be administered orally at a primary healthcare facility or indeed on an out-
patient basis. 
 
1.5. 
Investigational Product and Preclinical Data 
Acoziborole (SCYX-7158) is an orally active benzoxaborole-6-carboxamide. 
Acoziborole, also referred to as 
, is the result of a collaboration between 
DNDi, 
 
 
. Preclinical 
studies have identified the concentrations of acoziborole that must be achieved 
in the plasma and brain in order to be effective against late-stage g-HAT. Indeed, 
reversible in vitro assays for acoziborole showed that it is necessary to know the 
exposure time and area under the curve (AUC) for the minimum inhibitory 
concentration in order to predict efficacy. 
Complete and irreversible inhibition of parasite growth was achieved with an 
unbound AUC of 5.81 µg•h/mL. This was confirmed in animal models considered 
to be predictive of HAT in humans in which a 100% trypanocidal effect was 
obtained with daily administration of 25 mg/kg for 7 days. On the first day of 

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treatment, plasma concentrations reached 4.98 µg•h/mL, which is close to the 
critical threshold of 5.81 µg•h/mL for the unbound AUC of the minimum inhibitory 
concentration. From the second to the seventh day, the threshold was exceeded, 
and concentrations reached 7.15 µg•h/mL (28). 
Preclinical pharmacokinetic (PK) studies showed that acoziborole is well 
absorbed by the oral route, that it is widely distributed throughout the body and 
that it crosses the blood-brain barrier. In all of the animal species studied, 
acoziborole was rapidly metabolised through oxidation, leading to the formation 
of at least one inactive metabolite, SCYX-3109 (10). Toxicological studies, 
including safety pharmacology and 4-week repeated-dose toxicity studies 
(including toxicokinetics) in the rat and dog, have shown that acoziborole is well 
tolerated up to 40 mg/kg/day in rats, with no major toxicities identified. In both 
species, 15 mg/kg/day was considered as the no observed adverse effect level 
in the 4-week repeated-dose studies. 
 
1.6. 
Pharmacokinetics and Metabolism In Healthy Volunteers 
A randomised, double-blind, placebo-controlled Phase-I study (6) was performed 
in healthy African male volunteers between 18 and 45 years of age in order to 
assess the safety, PK and pharmacodynamics (PD) of acoziborole after single 
ascending oral doses. A total of 128 subjects were included, 102 of whom 
received acoziborole, and 26 received placebo. The doses studied ranged from 
20 mg to 1200 mg. 
Acoziborole was rapidly absorbed in the healthy volunteers, and the plasma 
concentrations remained stable for at least 96 hours, indicating that the 
elimination half-life is relatively long. Analysis of the PK data showed that 
acoziborole undergoes extensive enterohepatic recycling. Activated charcoal 
was administered to subjects, generally starting on Day 5, in order to accelerate 
clearance of the product and shorten the follow-up period for the subjects. The 
therapeutic dose of 960 mg was also administered without activated charcoal to 
mimic the future conditions of administration to patients. Clearance of acoziborole 
from the body was very slow with a half-life of approximately 400 hours. This 
profile suggests that a single administration of acoziborole may be sufficient for 
the treatment of HAT. Inter-subject variability was low at approximately 20%. 
Contrary to what was observed in animals, metabolism of acoziborole was very 
limited, which may explain the very long half-life in humans. 
The unbound fraction was determined by ultrafiltration. The ultrafiltrate-to-plasma 
ratio was in the same range as that in the in-vitro study. The mean unbound 
fraction was 2.2% of the plasma concentration. 
In addition, concentrations of acoziborole were determined in the CSF of healthy 
volunteers. In the 240 and 320 mg dose-level groups, mean CSF concentrations 
corresponded to 2.2% of the plasma concentration with a range of 1.8% to 3.2%. 

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1.7. 
Safety in Healthy Volunteers 
The safety of acoziborole was assessed in the Phase-I study (6). 
The most frequently reported acoziborole-related adverse events (AEs) were 
gastrointestinal disorders, mainly consisting in abdominal pain, nausea, 
constipation, vomiting and, more rarely, reduced appetite. The AEs were 
observed at different doses of acoziborole and were also observed with placebo. 
It should be noted that the use of activated charcoal promoted the occurrence of 
some gastrointestinal disorders such as constipation or vomiting. Central nervous 
system disorders were also reported, mainly consisting in headache, but none 
were considered to be possibly related to acoziborole. No correlation was found 
between the dose and the number of AEs observed. 
No relevant abnormal findings were observed on clinical monitoring, i.e. physical 
examination, vital signs and electrocardiograms (ECG). Conversely, laboratory 
monitoring found a few clinically significant abnormalities with acoziborole, as 
well as with placebo, primarily consisting in elevated levels of creatine 
phosphokinase and of transaminases. In addition, thyroid function tests found 
irregular and incomplete, sub-clinical variations in TSH, free T3 and free T4, in 
the acoziborole group, as well as with placebo. One case of sub-clinical 
hyperthyroidism after administration of acoziborole at 240 mg was however 
reported as a serious adverse event (SAE). The case was mild in severity, sub-
clinical, transient and spontaneously resolutive, and was considered to be 
possibly related to acoziborole. The variations were observed in both the placebo 
and the acoziborole groups, regardless of the dose, however considerably fewer 
variations were observed in the higher dose-level groups, including the selected 
therapeutic dose. 
In subjects exposed to acoziborole, no abnormalities were observed in the 
following parameters: bilirubin, pancreatic function (blood glucose, lipase and 
amylase) lipid profile (triglycerides, total cholesterol, high-density lipoproteins - 
cholesterol, low-density lipoproteins - cholesterol), kidney function (creatinine, 
urea, 
electrolytes), 
haematology, 
coagulation 
tests 
(activated 
partial 
thromboplastin time, international normalised ratio), reticulocytes, haptoglobin, 
ferritin and Coombs test. 
 
1.8. 
Choice of the Dose and Dosing Regimen 
The dose of 960 mg was chosen as the therapeutic dose because it ensures 
exposure levels in the CSF 1.5-fold higher than the pharmacologically active 
levels at which a 100% trypanocidal effect was obtained in infected animals. In 
healthy volunteers, plasma levels remained above the effective concentration up 
to 69 days after the administration of acoziborole. 

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No safety signals were observed at 1200 mg, which was the highest dose tested 
in humans. This provides a safety margin approximately 1.5- to 3-fold higher than 
the no observed adverse effect level in animals. 
No studies have been performed on the effect of food on the bioavailability of 
acoziborole and, for this reason, the single dose of the investigational product 
must be taken in the fasting state. 
 
1.9. 
Rationale for the Study Design 
The principle of an open-label, non-randomised, prospective study was accepted 
by the European Medicines Agency, taking into account the difficulty of 
completing enrolment of late-stage HAT patients in a prospective, randomised, 
non-inferiority study within a reasonable timeframe. 
The European Agency recommended calculating the sample size in the present 
non-randomised study based on the maximum feasible enrolment within a 
reasonable timeframe. 
Given the drastic decline in prevalence, it was estimated that the sample size that 
is possibly feasible to attain within a reasonable timeframe, i.e. approximately 28 
months, is 155 patients with late-stage g-HAT, with a provision of 5% (7 patients) 
to allow for possible replacement of patients lost to follow-up who fled the region 
due to armed conflict or natural disaster, for a total of 162 late-stage patients. 
 
1.10. Target Population 
The target population will initially be limited to patients 15 years of age or older 
with late-stage HAT. After the first futility analysis, a second cohort of patients 
with early- or intermediate-stage HAT will be enrolled in order to enrich the safety 
database on acoziborole and to assess its efficacy in this population. 
As in the preceding studies on HAT, the inclusion of adolescent patients 15 years 
of age or older, in addition to adults, will facilitate the enrolment of patients with 
late-stage HAT. 
 
2. Study Objectives and Endpoints 
 
2.1. 
Objectives 
 
2.1.1. General Objective 
The aim of the study is to assess the efficacy and safety of a single oral dose of 
acoziborole administered to patients in the fasting state with g-HAT. 
 

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2.1.2. Primary Objective 
The primary objective is to estimate the success rate at 18 months of follow-up 
with acoziborole, administered as a single 960-mg oral dose to patients in the 
fasting state with late-stage g-HAT. 
An estimate of the success rate observed with NECT in patients with late-stage 
g-HAT, based on historical data, will be provided as a yardstick. 
 
2.1.3. Secondary Objectives 
▪ To estimate the success rate at 12 months in late-stage patients 
▪ To estimate the time course of the failure rate in patients with late-stage 
g-HAT. 
▪ To assess the safety profile of a single dose of acoziborole in patients 
with g-HAT using historical data on NECT as a yardstick. 
▪ To establish the relationship between, on the one hand, concentrations 
of acoziborole in the blood and the CSF and, on the other hand, the 
efficacy and safety of acoziborole. 
A cohort of patients 15 years of age or older with early- or intermediate-stage g-
HAT will be enrolled following the futility analysis, provided that the latter does 
not show futility and that the safety review shows no concerns. The overall 
objective will be to assess the efficacy of acoziborole in this cohort and to enrich 
the safety database at the time of regulatory filing. 
▪ To estimate the success rate with acoziborole in this cohort, using 
pentamidine as a yardstick, in order to verify the underlying hypothesis 
according to which, in HAT, a treatment able to clear the parasite from 
the CSF also clears it from the other compartments. 
▪ To assess the safety profile in this cohort and in the overall population. 
▪ To assess the safety of acoziborole in patients with early- and 
intermediate-stage HAT to determine whether its safety profile is 
comparable to the historical safety profile of pentamidine. 
 
2.2. 
Endpoints 
 
2.2.1. Primary Endpoint – Efficacy 
 
Primary Endpoint for Patients with Late-stage HAT 
 
A patient will be considered as a success, in accordance with the WHO criteria 
(23), if the patient is alive with no evidence of trypanosomes in any body fluid and 
a CSF WBC equal to or below 20/µl 18 months after receiving acoziborole. 

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A patient with no parasitological evidence of a relapse and a CSF WBC above 
20/µL or who, in the Investigator’s opinion, requires rescue treatment will be 
considered as a probable relapse. 
A patient who refuses the end-of-study lumbar puncture will be classified as a 
probable cure (success) in the absence of any clinical signs or symptoms 
suggestive of THA or with another obvious aetiology, provided that the outcome 
was favourable, i.e. a CSF WBC equal to or below 20/µl, at the last available 
assessment at 6 months or later. 
Death for any reason, patients lost to follow-up and not retrieved or patients who 
refuse a lumbar puncture at 18 months and who had an unfavourable outcome 
earlier (probable relapse) will be considered as failures, with the exception of 
patients who fled the region due to armed conflict or natural disaster. These 
patients will be replaced by patients from another centre in order to maintain the 
planned sample size. In order to allow for replacement of some patients lost to 
follow-up due to armed conflict and to maintain the planned sample size of 155 
evaluable patients, 7 additional patients will be enrolled in the study. 
 
Surrogate Primary Endpoint for Patients with Late-stage HAT 
Amendment 2 dated 07/01/2020 deletes analysis of the surrogate primary 
endpoint at 12 months in patients with late-stage g-HAT, as the data set required 
for early submission at 12 months is not available in its entirety. 
 
2.2.2. Secondary Endpoints - Efficacy 
Efficacy in Patients with Late-stage HAT 
A patient with late-stage HAT will be considered as a success at 6 months and at 
12 months if the CSF WBC is equal to or below 20/µL and in the absence of 
trypanosomes, rescue treatment and signs or symptoms suggesting a relapse at 
the visit in question or previously. 
If the patient does not have a lumbar puncture at 6 months, the outcome of the 
lumbar puncture at 12 months will be used. If the patient does not have a lumbar 
puncture at 12 months and if a lumbar puncture is performed at 18 months, the 
outcome at 18 months will be used. Otherwise, the outcome at 6 months will be 
used. If the patient has no post-treatment lumbar puncture, s/he will be 
considered as a failure. Patients lost to follow-up and deaths, regardless of the 
cause, will be considered as failures. 
 
Endpoints in Patients with Early- or Intermediate-stage HAT 
Two efficacy endpoints will be used for patients with early- and intermediate-
stage HAT: the outcome at 12 months and the outcome at 18 months after 
receiving treatment. A patient will be considered as a success at 12 months if the 
patient is alive with no evidence of trypanosomes in any body fluid and if the CSF 

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WBC is equal to or less than 20/µL. A patient with no parasitological evidence of 
relapse, but with a CSF WBC above 20/µL or who, in the Investigator’s opinion, 
requires rescue treatment, will be considered as a relapse. A patient who refuses 
the lumbar puncture at 12 months will be classified as a probable cure (success) 
in the absence of any clinical signs or symptoms suggestive of THA or with 
another obvious aetiology, provided that the outcome was favourable, i.e. a CSF 
WBC equal to or less than 5/µL, at 6 months. Death for any reason, patients lost 
to follow-up and not retrieved or patients with no post-treatment lumbar puncture 
will be considered as failures, with the exception of patients who fled the region 
due to armed conflict or natural disaster. For memory, patients who fled the region 
due to armed conflict or natural disaster will not be included in the mITT 
population and will therefore not be taken into account in the calculation of the 
success rate. A patient with early- or intermediate-stage HAT will be considered 
as a success at 18 months if the CSF WBC is equal to or below 20/µL and in the 
absence of trypanosomes, rescue treatment and signs or symptoms suggestive 
of a relapse. If the patient does not have a lumbar puncture at 18 months, the 
outcome at 6 months or at 12 months will be used. 
A patient with early- or intermediate-stage HAT will be considered as a success 
at 6 months and at 12 months if the CSF WBC is equal to or less than 20/µL and 
in the absence of trypanosomes, rescue treatment and signs or symptoms 
suggestive of a relapse. If the patient does not have a lumbar puncture at 6 
months, the outcome at 12 months and, if necessary, at 18 months will be used. 
If the patient does not have a lumbar puncture at 12 months, the outcome at 18 
months will be used and, if necessary, the outcome at 6 months will be used. If 
no post-treatment lumbar punctures were performed, the outcome will be 
considered as unfavourable. 
 
Time to Failure in Patients with Late-stage HAT 
The starting point is administration of acoziborole. The time to failure is the time 
up until the first objective evidence of failure is observed. The first evidence may 
be the presence of trypanosomes in any body fluid, a CSF WBC above 50/µL at 
6 months and above 20/µL at 12 and/or 18 months, clinical signs or symptoms 
suggestive of a relapse (see Table 1, Clinical Classification of Patients in Section 
5.4 Rescue Treatment; p38), the decision to use rescue treatment or death for 
any reason. Unlike the preceding endpoints, a patient cannot be a failure at a 
given timepoint and a success at a subsequent timepoint. Consequently, a patient 
with a CSF WBC above 20/µL at 12 months and below 20/µL at 18 months 
becomes a success at 6 months and 12 months in the time-to-failure analysis, 
but not in the time course of the success rate. A patient lost to follow-up is a 
patient censored at the last available visit if there is no evidence of failure up to 
the last available visit. A success at 18 months (last assessment) is a patient 
censored at 18 months, i.e. with no evidence of failure up to 18 months. 
 

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2.2.3. Secondary Endpoints - Safety 
The secondary endpoints concerning the safety of acoziborole are as follows: 
▪ Occurrence of any AE, including an abnormal laboratory test result, 
during the observation period. AEs will be graded according to the 
Common Toxicity Criteria for Adverse Events (CTCAE) of the National 
Cancer Institute (NCI), version 4.03 (16). 
▪ Occurrence of any SAE during the observation period and until the end 
of follow-up (18 months). 
 
2.2.4. Secondary Endpoints - Pharmacokinetics 
The following PK parameters will be measured in the blood and CSF: 
▪ Concentrations of acoziborole in whole blood and CSF, and population 
PK parameters, i.e. clearance, AUC and half-life (see also Section 6.3.3 
Pharmacokinetic Analyses; p43) 
 
2.2.5. Secondary Endpoints - Electrocardiogram 
ECG tracings will be recorded at various timepoints to assess the QT/QTcF 
interval and variations over time (see Section 6.3.2 Digital ECG; p42 and the 
Schedule of Procedures; p89). 
 
3. Study Design 
This is a multicentre, prospective, open-label, non-randomised, phase II/III study 
to assess the efficacy and safety of acoziborole in two cohorts of patients with 
g-HAT. The first cohort will be composed of patients with late-stage HAT, and the 
second cohort will be composed of patients with early- or intermediate-stage 
HAT. 
Early- and intermediate-stage patients will be enrolled in the same centres as 
late-stage patients, however enrolment of early- and intermediate-stage patients 
will begin approximately 6 months later, once the Data and Safety Monitoring 
Board (DSMB) has examined the PK and safety data at 3 months for the first 20 
patients with late-stage HAT and once it has been informed of the results of the 
first futility analysis. 
 
4. Selection of Study Population 
The patient must fulfil all of the inclusion criteria and none of the exclusion criteria. 
The inclusion and exclusion criteria are similar to those in the study published by 
Priotto et al. (18), and the study design is the same as that in the study conducted 
by WHO-TDR and in the DNDiHATFEX004 study, as these three studies 
constitute the basis for the use of NECT as a yardstick in this study. Once the 
patient has signed the informed consent form, s/he will be assigned a number 
comprising the 3-digit centre number starting with 7 (7XX- and a 3-digit patient 

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number, which the Investigator will assign in ascending order of inclusion of the 
patient in the study. 
 
4.1. 
Enrolment and Inclusion Procedures 
The study is to be conducted in hospitals located in endemic regions and having 
experience in treating patients with HAT. 
In Guinea, the clinical study will be conducted in the HAT treatment centre in 
Dubreka. The HAT treatment centre in Forecariah and the prefectural hospital in 
Boffa will be satellite centres whose role will be to screen patients and refer them 
to the centre in Dubreka. Follow-up visits may take place in the centres in 
Forecariah and Boffa with the National Investigator and her/his team, who will 
travel to the centres to ensure better patient follow-up and avoid patients lost to 
follow-up.  
Patients who meet pre-inclusion criteria that do not require any study-specific 
procedures will be invited to participate in the study, and they will then receive 
the information necessary to collect their informed consent. 
For the patient to be enrolled in the study, s/he must sign the informed consent 
form after having received explanations from the Investigator or a representative. 
The patient will then be considered as a “screened patient”. 
The enrolment and inclusion procedures are to be performed between 1 and 15 
days prior to the planned date of administration of acoziborole. The procedures 
are 
described 
in 
Section 
6, 
Schedule 
of 
Study 
Procedures 
and 
Assessments; p39. 
 
4.2. 
Inclusion Criteria 
To be included in the study, the patient must fulfil all of the following criteria: 
▪ Male or female 
▪ 15 years of age or older 
▪ Signed informed consent form (as well as assent from illiterate and 
under-age patients, and those unable to give consent) 
▪ Karnofsky Performance Status above 50 (see Appendix 2; p83) 
▪ Able to ingest oral tablets 
▪ Having a permanent address or being traceable by other persons 
▪ Able to comply with the schedule of follow-up visits and requirements of 
the study 
▪ Agreement to be hospitalised in order to receive treatment. 
For patients with late-stage HAT:  

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o 
Confirmation of g-HAT by detection of the parasite in the blood and/or 
the lymph and/or the CSF, at the investigational centre 
o 
If trypanosomes are found in the blood or lymph, but not in the CSF, 
the CSF WBC, measured at the investigational centre, must be 
above 20/µL for the patient to be included in the cohort of patients 
with late-stage HAT 
For patients with early- or intermediate-stage HAT: 
o 
Confirmation of g-HAT by detection of the parasite in the blood and/or 
the lymph, at the investigational centre 
o 
Absence of parasites in the CSF 
o 
The CSF WBC, measured at the investigational centre, must be 
between 6 and 20/µL for the patient to be included in the cohort of 
patients with intermediate-stage HAT and equal to or below 5/µL for 
the patient to be included in the cohort of patients with early-stage 
HAT. 
 
4.3. 
Exclusion Criteria 
To be included in the study, the patient must not fulfil any of the following 
exclusion criteria: 
▪ Severe malnourishment, defined as body-mass index (BMI) below 16 
▪ Pregnancy or breastfeeding (for women of child-bearing potential, 
confirmed pregnancy on a urine pregnancy test performed within 24 
hours prior to administration of acoziborole – see Section 5.2.3 
Contraception; p36) 
▪ Clinically significant medical condition that could, in the opinion of the 
Investigator, jeopardise the patient’s safety or interfere with participation 
in the study, including, but not limited to significant liver or cardiovascular 
disease, suspected or proven active infection, central nervous system 
trauma or seizure disorder, coma or consciousness disturbances 
▪ Severely deteriorated health status, e.g. due to cardiovascular shock, 
respiratory distress syndrome or end-stage disease 
▪ Previously treated for HAT (except prior treatment with pentamidine) 
▪ Prior enrolment in the study 
▪ Foreseeable difficulty complying with follow-up, including migrant worker, 
refugee status, itinerant trader etc. 
▪ Current alcohol abuse or drug addiction 
▪ Not tested for malaria and/or not having received appropriate treatment 
for malaria (see Section 5.2.1 Malaria; p36) 

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▪ Not having received appropriate treatment for soil-transmitted 
helminthiasis (see Section 5.2.2 Helminthiasis; p36) 
▪ Clinically significant abnormal laboratory values including: 
o 
AST and/or ALT more than 2 times the upper limit of normal (ULN) 
o 
Total bilirubin more than 1.5 ULN 
o 
Severe leukopenia at less than 2000/mm3 
o 
Potassium below 3.5 mmol/L 
o 
Any other clinically significant abnormal laboratory value. 
 
5. Study Treatments 
 
5.1. 
Investigational Product 
The investigational product (IP) is acoziborole, in 320-mg tablets, administered 
by the oral route to patients in the fasting state according to the following dosing 
regimen: 
• 960 mg (3 tablets) in a single intake on Day 1. 
Acoziborole will be provided by DNDi, 15 chemin Louis Dunant, 1202 Geneva, 
Switzerland. 
For the course of action in the event of vomiting, see the Investigator Manual. 
 
5.1.1. Treatment Allocation 
All patients who give their consent or assent to participate in the study and who 
fulfil the inclusion and exclusion criteria will be allocated to treatment with 
acoziborole. In addition, the treatment kits will be numbered, and the number will 
be recorded in the case report form (CRF). 
 
5.1.2. Labelling and Packaging of IP 
The tablets of acoziborole will be packaged in aluminium-aluminium blister packs. 
Each pack will contain the number of tablets required for one administration, i.e. 
3 tablets. The blister pack will be packaged in an individual treatment kit for each 
patient. 
The labelling on the treatment kit will display the following information items: 
• Name of Sponsor*, name and contact details for the Coordinating or 
Principal Investigator 
• Study number*  
• Name* and dosage strength* of the IP  
• Dosage form*, route of administration*, number of dosage units* 
• Instructions for use 
• Statements “For clinical study use only”* and “Keep out of reach of 
children” 

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• Batch number* and number of treatment kit* 
• Expiry date and storage conditions 
The information items marked with an asterisk (*) will also be displayed on the 
immediate packaging of the IP. 
Information on acoziborole will be provided in the Investigator Brochure attached 
to the protocol submitted to the National Authorities. 
 
5.1.3. Accountability of IP  
Study-specific forms must be used for accountability of acoziborole. Appropriate 
records concerning receipt, use, return, loss or any other disposition of 
acoziborole must be maintained by the Investigators at the investigational centre, 
or by their delegates, under the supervision of the Principal Investigator. In 
addition, the study monitors must check accountability of acoziborole during their 
on-site monitoring visits. 
In the investigational centres, acoziborole must be stored in a locked room, or a 
locked cabinet if no specific room is available, with access limited to the nurse in 
charge of the pharmacy or to authorised study personnel. 
The IP, acoziborole, must not be used for purposes other than the present 
protocol. The Investigator and the study personnel may not under any 
circumstances provide other investigators or healthcare services with the 
acoziborole attributed to their centre, or allow acoziborole to be used other than 
as described in this protocol without prior written approval from DNDi. 
 
5.1.4. Storage of IP 
The IP, acoziborole, must be transported and stored at a temperature not 
exceeding 30°C. It is recommended to store acoziborole at room temperature. 
Long-term stability studies showed that the 320-mg tablets of acoziborole, 
packaged in aluminium-aluminium blister packs, were stable for at least 24 
months at 30°C under very humid conditions (75%) and for 6 months at 40°C. 
The storage conditions, including the temperature, at the investigational centres 
must be monitored by the study personnel, and appropriate records must be 
available. 
 
5.1.5. Blinding and Procedure for Unblinding 
This is an open-label study. Thus, the patients and the Investigators will 
necessarily know which treatment is administered. 
 

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5.2. 
Concomitant Treatment 
5.2.1. Malaria 
All patients will undergo a test to detect malaria. All patients with a positive thick 
smear and/or rapid diagnostic test (RDT) will receive treatment. 
Prior to administration of acoziborole, malaria will be treated with Coartem® 
unless the patient has personal contraindications, such as severe malaria or 
hypersensitivity to one of the components, i.e. artemether or lumefantrine. All of 
the existing artemisinin-based combination therapies used against malaria have 
effects on the QT interval. Coartem® was chosen because its effects on QT-
interval prolongation are known to be moderate and well quantified (8). 
In patients with a contraindication to Coartem®, the Investigator can choose 
another antimalarial agent. The choice must be recorded in the CRF. 
Treatment will be followed by a recovery period of at least 3 days between the 
last dose of the antimalarial agent and the administration of acoziborole. 
 
5.2.2. Helminthiasis 
Treatment for helminthiasis, with mebendazole or albendazole, will be provided 
free of charge by the Sponsor. 
This prophylactic treatment will be given to all patients in the study and will be 
followed by a recovery period of at least 3 days between the last dose of the 
anthelminthic agent and the administration of acoziborole. 
 
5.2.3. Contraception 
Preclinical studies showed that acoziborole has no effect on fertility or on post-
natal development (cf. Investigator Brochure). However, because acoziborole 
has never been administered to women of child-bearing potential, women, as well 
as men, of reproductive age will be advised to have protected sexual relations 
during the observation period and up to the 3-month visit. Contraceptive methods, 
i.e. hormonal contraception and/or condoms, will be available to patients free of 
charge throughout the duration of their participation in the study. 
 
5.3. 
Other Medication 
If the patient requires treatment during the first 6 months after administration of 
acoziborole, the Investigator should be informed and approve the proposed 
medication. Any medication used after inclusion in the study and/or during the 
first 6 months of the follow-up period must be recorded in the CRF, specifying the 
reason for use. 
Any medication used to treat an SAE during the follow-up period must be 
recorded in the CRF (see Section 6.5 Safety Assessments, Definitions and 
Collection of Adverse Events; p48) and on the SAE reporting form. Any 

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medication used to treat other non-serious medical events will be recorded only 
in the patient’s medical file. 
Any essential medicine required during the 18-month follow-up period will be 
provided to the patient free of charge. The WHO List of Essential Medicines will 
be used as a reference guide for the treatment of any concomitant condition (see 
Investigator Manual). For any chronic condition, the study team will take all 
necessary measures to ensure that the patient is referred to the most appropriate 
healthcare facility in the region. 
 
5.4. 
Rescue Treatment 
In the event of a relapse and after discussion with the Principal Investigator, the 
patient will receive first-line rescue treatment with NECT or pentamidine, 
depending on the stage of the disease. 
Rescue treatment for HAT will be recorded as rescue treatment in the CRF on 
the end-of-study page. 
Probable relapse at the 6-month, 12-month or 18-month follow-up visit is defined 
as shown in Table 1. 
 
 
 

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Table 1 - Clinical Classification of Patients 
Visit 
Ideal 
timing of 
visit after 
end of 
treatmen
t 
Favourable outcome 
Uncertain outcome 
Probable relapse 
Proven relapse 
D11 
± 1 day 
• 
Patient alive with 
no evidence of 
trypanosomes in any 
body fluid (23) 
 
 
• Evidence of 
trypanosomes in 
any body fluid 
3 
months 
 
3 months  
± 1 week  
• 
Patient alive with 
no evidence of 
trypanosomes in any 
body fluid (no lumbar 
puncture at 3 months 
unless Investigator 
suspects a relapse) 
• Any reason 
prompting the 
Investigator to 
request an 
additional follow-up 
visit 
• Neurological signs 
or symptoms 
leading to use of 
rescue treatment 
• Evidence of 
trypanosomes in 
any body fluid 
6 
months  
 
 
 
 
 
6 months 
± 2 weeks 
• 
Patient alive with 
no evidence of 
trypanosomes in any 
body fluid and CSF 
WBC ≤ 20/µL 
• CSF WBC 
between 20 and 
50/µL and 
additional visit 
requested within 1-
3 months 
• Any reason 
prompting the 
Investigator to 
request an 
additional follow-up 
visit 
• CSF WBC ≥ 50/µL 
• Neurological signs 
or symptoms 
leading to use of 
rescue treatment 
• Evidence of 
trypanosomes in 
any body fluid 
12 
months 
12 months 
± 4 weeks 
• 
Patient alive with 
no evidence of 
trypanosomes in any 
body fluid and CSF 
WBC ≤ 20/µL 
• 
CSF WBC 
between 20 and 
50/µL, and lower as 
compared to prior 
value(s) 
• CSF WBC > 
20/µL and non-
significant increase 
from a clinical 
standpoint in 
relation to prior 
value(s) 
• Any reason 
prompting the 
Investigator to 
request an 
additional follow-up 
visit 
• CSF WBC > 20/µL 
and significant 
increase from a 
clinical standpoint in 
relation to prior 
value(s) 
• Neurological signs 
or symptoms 
leading to use of 
rescue treatment 
• Evidence of 
trypanosomes in 
any body fluid 
18 
months 
18 months 
± 4 weeks 
• 
Patient alive with 
no evidence of 
trypanosomes in any 
body fluid and CSF 
WBC ≤ 20/µL 
• 
Patient with no 
signs of HAT and who 
refuses to undergo 
lumbar puncture and 
who, in the opinion of 
the Investigator does 
not require rescue 
treatment or an 
additional follow-up 
visit 
• Any reason 
prompting the 
Investigator to 
request an 
additional follow-up 
visit 
• CSF WBC > 20/µL 
• Neurological signs 
or symptoms 
leading to use of 
rescue treatment 
• Evidence of 
trypanosomes in 
any body fluid 
 
Any discrepancy between the clinical features and laboratory findings may also 
be an uncertain outcome, or any situation that leads the Investigator or the study 
team to consider that an additional follow-up visit is required to decide whether 
or not to provide rescue treatment. 

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6. Schedule of Study Procedures and Assessments 
 
6.1. 
Timing of Assessments 
Study procedures will be performed in accordance with the following schedule: 
• D-15 to D-1: pre-screening, screening and baseline assessment 
• D1: treatment day 
• D1 to D15: observation period at hospital 
• D11: initial assessment of treatment effect (lumbar puncture) 
• D15: end-of-hospitalisation (EoH) visit 
• Out-patient follow-up visits at 3 months, 6 months, 12 months and 18 
months (see Table 2 – Theoretical Schedule of Visits and Acceptable 
Leeway). The timing of follow-up visits is calculated from D1. 
 
Table 2 - Theoretical Schedule of Visits and Acceptable Leeway 
 
Theoretical schedule of visits 
Ideal timing of visits 
Acceptable leeway* 
End-of-hospitalisation (EoH) visit 
Between D13 and D18 after D1 
D18 at the latest 
3 months 
3 months ± 1 week after D1 
2-4 months after D1 
6 months 
6 months ± 2 weeks after D1 
5-9 months after D1 
12 months 
12 months ± 4 weeks after D1 
10-16 months after D1 
18 months 
18 months ± 4 weeks after D1 
17-21 months after D1 
* The acceptable leeway for the visit starts on the first day of the period mentioned and ends on the last day of 
the period mentioned. 
 
Any additional unscheduled visits that may take place must be recorded in the 
CRF. 
In addition to this study, patients will be invited to participate in a prospective 
study, DiTECT-HAT-WP4, the aim of which is to assess tests to predict the 
efficacy of treatment of HAT. If the patient declines the invitation to participate in 
the DiTECT-HAT-WP4 study, this will have no effect on his/her participation in 
the study on acoziborole or on the care s/he receives. For patients who accept 
the invitation to participate in the DiTECT-HAT-WP4 study, and only for these 
patients, additional blood (+ 2.5 mL) and CSF (+ 2.5 mL) samples will be 
collected at the same time as samples are collected in the present study, i.e. at 

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baseline, on D11 and at the follow-up visits at 6 months, 12 months and 18 
months, to avoid subjecting the patient to additional invasive procedures.  
See also Table 6 - Schedule of Procedures (Appendix 4 p89). 
 
6.2. 
Pre-screening, Screening and Baseline Assessment 
 
6.2.1. Diagnosis of HAT 
▪ In the context of active screening, the mobiliser of the mobile team will 
inform the communities in the villages of the HAT screening activities, as 
is usually the case (see Section 14.1 Information of the Communities; 
p66). Specific information concerning the study will be provided to the 
community, i.e. a brief description of the aim of the study, explanation of 
the process for collecting informed consent, duration and importance of 
follow-up. 
▪ In the context of passive screening, specific information concerning the 
study will be provided by static healthcare structures located near the 
investigational centre in order to refer patients to the investigational 
centre. 
▪ Diagnosis of HAT and staging of the disease will be performed at the 
investigational centre. (see Section 4.1. Enrolment and Inclusion 
Procedures; p32). 
 
6.2.2. Pre-screening and Screening 
The following procedures will be carried out to confirm the diagnosis of HAT, to 
collect historical safety data and to check the inclusion and exclusion criteria. 
▪ Collection of informed consent / assent prior to administering any 
additional medication or to performing any non-routine assessment; 
▪ Review of inclusion and exclusion criteria; 
▪ Collection of blood and/or lymph samples for testing for parasites (see 
Sections 4.1 and 4.2 Enrolment and Inclusion Procedures; p32); 
▪ Collection of CSF sample for disease staging. Confirmation of the 
laboratory and parasitological diagnosis by a second technician at the 
investigational centre and, if necessary, by the local supervisor must be 
obtained in accordance with the operating method described in the 
Laboratory Manual. If possible, images of cell counts and/or videos 
(approximately 5 seconds) showing the presence of parasites will be 
used for the traceability of the microscopy diagnosis; 
▪ Collection of full medical history, with special attention to HAT, in 
particular severity and time since the start of symptoms; 
▪ Collection of demographic and geographical data; 

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▪ Karnofsky performance status; 
▪ Height, weight and BMI; 
▪ Vital signs: body temperature, blood pressure, heart rate, respiratory rate 
and general status; 
▪ Diagnosis of malaria using RDT and/or thick blood smear; 
▪ Treatment of helminthiasis and, if necessary, malaria; 
▪ Laboratory safety assessments – samples will be collected in the morning 
from patients in the fasting state: 
o Haemoglobin; 
o Haematology: WBC, platelet count; 
o Biochemistry: 
albumin, 
alkaline 
phosphatase 
(ALP), 
alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), blood 
urea nitrogen (BUN), chloride, creatinine, glucose, potassium, 
sodium, calcium, total bilirubin, bicarbonates and total protein; 
▪ Urine pregnancy test for women of child-bearing potential; 
▪ Collection of concomitant medication and adverse events. 
 
6.2.3. Baseline Assessment 
The baseline assessment will be performed between Day -4 and Day -1 to assess 
the patient’s baseline status just prior to administration of the IP. The patient’s 
eligibility to participate in the study will also be reconfirmed. The following 
procedures will be performed: 
▪ Review of informed consent/assent; 
▪ Review of Karnofsky performance status; 
▪ Review of inclusion/exclusion criteria; 
▪ Height, weight and BMI; 
▪ Vital signs: body temperature, blood pressure, heart rate, respiratory rate 
and general status; 
▪ Physical and neurological examinations; questionnaire on symptoms; 
▪ Collection of concomitant medication and adverse events; 
▪ Urine pregnancy test for women of child-bearing potential; 
▪ Thyroid function test: TSH, free T3, free T4; 
▪ Laboratory safety assessments, if the following tests were performed 
before D-4 during the Pre-screening / Screening period or if the tests 
found abnormalities requiring repeat tests – sampling will be performed 
in the morning on patients in the fasting state: 

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o Haemoglobin 
o Haematology: WBC, platelet count 
o Biochemistry: albumin, ALP, ALT, AST, BUN, chloride, creatinine, 
glucose, potassium, sodium, calcium, total bilirubin, bicarbonates and 
total protein. 
If the assessments were performed within 4 days prior to administration 
of the IP, those findings will be considered as baseline values and 
recorded in the CRF. 
 
6.3. 
Assessments during Hospitalisation: D1 to D15 
The following procedures will be performed every day throughout the 
hospitalisation period: 
▪ Collection of concomitant medication; 
▪ Collection of adverse events. 
 
6.3.1. Laboratory Tests 
Blood haematology and biochemistry assessments will be repeated on D5 and 
D11. Blood samples will be analysed in the laboratory in each centre using 
standard equipment specifically provided for the study by the Sponsor. The 
samples will be collected in the morning from patients in the fasting state. 
The samples for the thyroid function tests will be collected on D11 and will be 
analysed centrally at the 
 
. 
The urine pregnancy test will be repeated on D11. 
During hospitalisation, additional safety assessments, such as haematology, 
biochemistry or urinalysis may be performed at the Investigator’s discretion in 
order to monitor abnormal parameters. 
The volume and number of samples required for each patient are presented in 
Appendix 3 – Laboratory Tests (p84). 
 
6.3.2. Digital ECG 
Two ECG tracings will be recorded in duplicate prior to administration of 
acoziborole on D1. Triplicate ECG will be recorded after administration of 
acoziborole to assess QT interval, in accordance with the schedule of recordings 
in Table 3. The tracings will be recorded after a 20-minute rest interval and before 
collection of the blood samples for the PK analyses. 

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Table 3 - Schedule of ECG Recordings 
Ideal timing of ECG recordings 
(after 20-minute rest interval and before PK 
sampling) 
Acceptable 
leeway 
D1: before intake of IP 
1 hour -1 hour 30 
D1: 4 hours after intake of IP 
± 1 hour 
D1: 9 hours after intake of IP 
± 1 hour 
D2: 24 hours after intake of IP 
± 1 hour 
D3: 48 hours after intake of IP 
± 1 hour 
D4: 72 hours after intake of IP 
± 1 hour 
D5: 96 hours after intake of IP 
± 1 hour 
D11: 240 hours after intake of IP 
± 1 hour 
 
6.3.3. Pharmacokinetic Analyses 
PK analyses will be performed regularly on samples collected from the first 20 
patients in order to obtain information on exposure to acoziborole in the blood. 
Depending on the results, it may be decided not to perform PK analyses on the 
subsequent patients. 
The procedure for sampling and the assay method will be described in the 
corresponding laboratory manual. 
▪ Whole blood, approximately 300 µL per sample, will be collected and 
deposited on filter paper using the dry blood spot (DBS) technique in 
accordance with the following schedule of sample collection: 
Table 4 - Schedule of PK Sample Collection 
 
Ideal timing of PK sample collection 
Acceptable 
leeway 
D1: before intake of IP 
 
D1: 4 hours after intake of IP 
± 1 hour 
D1: 9 hours after intake of IP 
± 1 hour 
D2: 24 hours after intake of IP 
± 1 hour 
D3: 48 hours after intake of IP 
± 1 hour 
D4: 72 hours after intake of IP 
± 1 hour 
D5: 96 hours after intake of IP 
± 1 hour 
D11: 240 hours after intake of IP 
± 1 hour 
 
▪ The timepoints for sampling were chosen in order to best predict the 
concentrations of acoziborole during the absorption and elimination 
phases. 
Lumbar puncture will be performed on Day 11, 240 hours after the intake of 
acoziborole, and the CSF sample will be used for initial assessment of the 
treatment effect, based on WBC and screening for trypanosomes, as well as for 
assays of acoziborole. The samples will be destroyed at the latest once the final 

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study report has been validated and signed. The destruction procedure will be 
recorded in a certificate of destruction. 
The blood and CSF samples collected on filter paper will be stored at room 
temperature (see Laboratory Manual). 
 
6.3.4. Assessments on Day 1 - Treatment Day 
The following procedures will be performed on Day 1 (see also Table 6 - Schedule 
of Procedures; p89). 
▪ Collection of concomitant medication; 
▪ Collection of adverse events; 
▪ Two duplicate ECGs and blood sampling for PK analyses prior to 
administration of acoziborole (cf. Table 3 and Table 4); 
▪ Triplicate ECG and blood sampling for PK analyses after administration 
of acoziborole (cf. Table 3 and Table 4). 
 
6.3.5. Assessments at the Visit on Day 5 
The following procedures will be performed at the visit on Day 5. 
▪ Height, weight and BMI; 
▪ Vital signs: body temperature, blood pressure, heart rate, respiratory rate 
and general status; 
▪ Physical and neurological examinations; 
▪ Collection of concomitant medication and adverse events; 
▪ Laboratory safety assessments (see Appendix 3 – Laboratory Tests; p84) 
– samples will be collected in the morning from patients in the fasting 
state: 
o Haemoglobin 
o Haematology: WBC, platelet count; 
o Biochemistry: albumin, ALP, ALT, AST, BUN, chloride, creatinine, 
glucose, potassium, sodium, calcium, total bilirubin, bicarbonates and 
total protein; 
▪ Blood sampling for PK  analyses; 
▪ Triplicate digital ECG (CarTouch®) to assess QT interval. 
 
6.3.6. Assessments at the Visit on Day 11  
The following procedures will be performed at the visit on Day 11. 
▪ Height, weight and BMI; 
▪ Vital signs: body temperature, blood pressure, heart rate, respiratory rate 
and general status; 

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▪ Physical and neurological examinations; 
▪ Urine pregnancy test for women of child-bearing potential; 
▪ Sampling for testing for trypanosomes in the blood (Woo test/CTC, 
mAECT, mAECT-BC) and lymph (test on fresh lymph node aspirate, if 
swollen lymph nodes present, with microscopy examination); 
▪ CSF sampling for WBC and testing for trypanosomes; 
▪ Laboratory safety assessments (see Appendix 3 – Laboratory Tests; p84) 
– samples will be collected in the morning from patients in the fasting 
state: 
o Haemoglobin; 
o Haematology: WBC, platelet count; 
o Biochemistry: albumin, ALP, ALT, AST, BUN, chloride, creatinine, 
glucose, potassium, sodium, calcium, total bilirubin, bicarbonates and 
total protein; 
▪ Blood sampling for PK  analyses; 
▪ CSF sampling for PK  analyses (if possible on CSF sample collected to 
test for trypanosomes); 
▪ Thyroid function test: TSH, free T3, free T4; 
▪ Triplicate digital ECG (CarTouch®) to assess QT interval; 
▪ Collection of concomitant medication and adverse events. 
 
6.3.7. Assessments on Day 15 - End-of-Hospitalisation Visit 
The following procedures will be performed at the visit on Day 15: 
▪ Height, weight and BMI; 
▪ Vital signs: body temperature, blood pressure, heart rate, respiratory rate 
and general status; 
▪ Physical and neurological examinations; 
▪ Collection of concomitant medication and adverse events. 
 
6.4. 
Assessments at Out-patient Follow-up Visits 
 
6.4.1. At the 3-month Follow-up Visit 
The following procedures will be performed at the 3-month visit: 
▪ Karnofsky performance status; 
▪ Height, weight and BMI; 
▪ Vital signs: body temperature, blood pressure, heart rate, respiratory rate 
and general status; 
▪ Physical and neurological examinations; 

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▪ Collection of concomitant medication and adverse events; 
▪ Laboratory safety assessments (see Appendix 3 – Laboratory Tests; p84) 
– samples will be collected in the morning from patients in the fasting 
state: 
o Haemoglobin 
o Haematology: WBC, platelet count 
o Biochemistry: albumin, ALP, ALT, AST, BUN, chloride, creatinine, 
glucose, potassium, sodium, calcium, total bilirubin, bicarbonates and 
total protein; 
▪ Thyroid function test: TSH, free T3, free T4; 
▪ Urine pregnancy test for women of child-bearing potential; 
▪ Blood sampling for PK  analyses. 
 
6.4.2. At the 6-month Follow-up Visit 
The following procedures will be performed at the 6-month visit: 
▪ Karnofsky performance status; 
▪ Height, weight and BMI; 
▪ Vital signs: body temperature, blood pressure, heart rate, respiratory rate 
and general status; 
▪ Sampling for testing for trypanosomes in the blood (Woo test/CTC, 
mAECT, mAECT-BC) and lymph (test on fresh lymph node aspirate, if 
swollen lymph nodes present, with microscopy examination); 
▪ CSF sampling for WBC and testing for trypanosomes; 
▪ Physical and neurological examinations; 
▪ Collection of concomitant medication and adverse events; 
▪ Laboratory safety assessments (see Appendix 3 – Laboratory Tests; p84) 
– samples will be collected in the morning from patients in the fasting 
state: 
o Haemoglobin 
o Haematology: WBC, platelet count 
o Biochemistry: albumin, ALP, ALT, AST, BUN, chloride, creatinine, 
glucose, potassium, sodium, calcium, total bilirubin, bicarbonates and 
total protein; 
▪ Thyroid function test: TSH, free T3, free T4; 
▪ Urine pregnancy test for women of child-bearing potential; 
▪ Blood sampling for PK  analyses. 
 
6.4.3. At the 12-month and 18-month Follow-up Visits 
The following procedures will be performed at the 12-month and 18-month visits: 

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▪ Karnofsky performance status; 
▪ Height, weight and BMI; 
▪ Vital signs: body temperature, blood pressure, heart rate, respiratory rate 
and general status; 
▪ Sampling for testing for trypanosomes in the blood (Woo test/CTC, 
mAECT, mAECT-BC) and lymph (test on fresh lymph node aspirate, if 
swollen lymph nodes present, with microscopy examination); 
▪ CSF sampling for WBC and testing for trypanosomes; 
▪ Physical and neurological examinations; 
▪ Collection of serious adverse events; 
▪ Laboratory safety assessments (see Appendix 3 – Laboratory Tests; p84) 
– samples will be collected in the morning from patients in the fasting 
state: 
o Haemoglobin 
o Haematology: WBC, platelet count 
o Biochemistry: albumin, ALP, ALT, AST, BUN, chloride, creatinine, 
glucose, potassium, sodium, calcium, total bilirubin, bicarbonates and 
total protein; 
▪ Thyroid function test: TSH, free T3, free T4. 
 
6.4.4. At Unscheduled Visits 
If a relapse of HAT is suspected on the basis of physical examination findings or 
CSF WBC at any visit, the patient must attend a return visit within 1 to 3 months, 
at the discretion of the Investigator. 
The patient must also return to the investigational centre if s/he does not feel well, 
even if there is no apparent relationship with treatment or HAT. 
The following assessments will be performed: 
▪ Karnofsky performance status; 
▪ Height, weight and BMI; 
▪ Vital signs: body temperature, blood pressure, heart rate, respiratory rate 
and general status; 
▪ Physical and neurological examinations (including signs and symptoms 
of HAT since the previous visit); 
▪ Investigation of any concomitant condition that may have led to the visit; 
▪ Testing for T.b. gambiense in blood and lymph, if indicated; 
▪ CSF sampling, only if symptoms suggesting relapse are present; 
▪ Laboratory safety assessments at the discretion of the Investigator (see 
Appendix 3 – Laboratory Tests; p84) – if possible, samples will be 
collected in the morning from patients in the fasting state: 

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o Haemoglobin 
o Haematology: WBC, platelet count 
o Biochemistry: albumin, ALP, ALT, AST, BUN, chloride, creatinine, 
glucose, potassium, sodium, calcium, total bilirubin, bicarbonates and 
total protein; 
▪ Thyroid function test, if indicated: TSH, free T3, free T4; 
▪ Additional safety assessments, e.g. ECG or urine analysis, may be 
performed at the discretion of the Investigator; 
▪ Urine pregnancy test for women of child-bearing potential, at the 
discretion of the Investigator; 
▪ Collection of concomitant medication and adverse events. 
 
6.5. 
Safety Assessment, Definitions and Reporting of Adverse Events 
 
6.5.1. Definition of Adverse Event 
In accordance with current regulations (7), an AE is defined as any untoward 
medical occurrence in a patient or clinical trial subject and which does not 
necessarily have a causal relationship with the trial or the IP. 
An AE can therefore be any unfavourable and unintended sign (including a 
clinically significant abnormal ECG or laboratory test finding with accompanying 
clinical signs or symptoms, or aggravation of any pre-existing condition), 
symptom or disease temporally associated with the use of the IP, whether or not 
it is considered to be related to the IP. 
Any abnormality on a laboratory test, i.e. haematology or biochemistry, that is 
assessed as “clinically significant” must be reported as an AE if it appears or 
worsens after administration of the IP and if it is above CTCAE grade 1, unless it 
is associated with a previously reported clinical event. 
Laboratory abnormalities assessed as “clinically significant” must be reported as 
an AE if they correspond to any of the following situations: 
▪ The abnormality suggests a disease and/or organ toxicity and the 
abnormality was not present at the baseline assessment or is considered 
to have worsened since the baseline assessment; 
▪ The abnormality is considered to be an SAE (see Section 6.5.2 Definition 
of Serious Adverse Event; p49); 
▪ The abnormality leads to discontinuation of the IP; 
▪ The abnormality requires a medical procedure or treatment. 
When a laboratory abnormality is reported, whenever possible, a clinical 
diagnosis should be reported rather than simply an abnormal value, e.g. 
“anaemia” instead of “reduced red blood cell count”. 
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The Investigator or appropriate personnel at the investigational centre must 
examine any patient who experiences an AE as soon as possible. The 
Investigator will take whatever medical measures are necessary to ensure the 
patient’s safety and well-being. The patient will remain under observation up to 
the final day of the hospitalisation period (Day 15), or longer if medically indicated 
in the opinion of the Investigator. All AEs observed or reported after 
administration of the IP must be followed until they resolve or until the Investigator 
considers them to be “chronic” or “stable”, or until the end of the patient’s 
participation in the study, i.e. until the End-of-Study page in the CRF for the 
patient has been completed. 
All AEs must be recorded in the appropriate section of the CRF using concise 
medical terminology and avoiding vague, ambiguous or colloquial language. 
SAEs must be reported to the study monitor by telephone, short message service 
(SMS) or e-mail (see Section 6.5.5 Requirements for AE Reporting; p50). 
 
6.5.2. Definition of Serious Adverse Event 
An SAE is any event that: 
▪ results in death; 
▪ is life-threatening; 
▪ requires hospitalisation or prolongation of existing hospitalisation: 
o i.e. the AE requires admission for at least 24 hours or prolongs 
hospitalisation beyond the expected length of stay. Hospital 
admissions for surgery planned before study entry, for social 
reasons, for any elective surgery (e.g. plastic surgery) or for normal 
disease management (including treatment adjustment) will not to 
be considered as SAEs; 
▪ results in persistent or significant disability or incapacity; 
▪ is a congenital anomaly or birth defect; 
▪ is an important medical event in which the patient is not at risk of death 
or which does not directly result in death or hospitalisation, but which may 
jeopardise patient safety or may require an intervention to prevent one of 
the above-mentioned outcomes; 
▪ In this study, ALT or AST above 3 ULN accompanied by total bilirubin 
above 2 ULN will be considered as an SAE; 
▪ Any suspected transmission of an infectious agent via a medicinal 
product will also be considered as an SAE. 
Any other event defined as serious in this protocol or by the Regulatory 
Authorities in the countries where the study is being conducted will also be 
considered as an SAE. 
For the purposes of this study, hospitalisation for uncomplicated delivery will not 
be considered as an SAE. 

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Use of the Glasgow coma scale (Appendix 5 - Glasgow Coma Scale 
 
The scale was developed at the Institute of Neurological Sciences in Glasgow, 
Scotland in the early 1970s to assess the extent of a coma following a head injury 
and to monitor the course of the coma. It is now widely recognised by the 
international community. 
The patient’s level of consciousness is assessed based on three criteria: eye 
opening (E score), motor response (M score) and verbal response (V score). 
Eye Response (E) 
Motor Response (M) 
Verbal Response (V) 
Opens eyes spontaneously: 
4 
Obeys verbal commands: 6 
Orientated and clear: 4 
Opens eyes in response to 
speech: 3 
Localises painful stimuli: 5 
Confused: 3 
Opens eyes in response to 
painful stimuli: 2 
Withdraws from painful 
stimuli: 4 
Inappropriate: 3 
No response: 1 
Abnormal flexion to painful 
stimuli: 3 
Incomprehensible: 2 
 
Extension to painful stimuli: 
2 
No response: 1 
 
No response: 1 
 
 
The Glasgow score is obtained by adding the three scores. 
By definition: 
- if the Glasgow score is > 12, the patient is considered to have mild head 
injury; 
- if the score is between 9 and 12 inclusive, the patient is considered to have 
moderate head injury; 
- if the Glasgow score is  8, the patient is considered to have severe head 
injury.) is recommended in patients with coma. 
 
6.5.3. Collection of Information on AEs 
The Investigator must collect all AEs s/he observes directly, as well as all AEs 
spontaneously reported by the patient, using concise medical terminology. In 
addition, during the hospitalisation period (Day 1 to Day 15) and at subsequent 
follow-up visits, a physical examination will be performed to detect any potential 
AEs. 
 
6.5.4. AE Collection Period 
The periods for the collection of AEs that occur in the context of the study are 
defined as follows: 
▪ For any AE that is not considered to be an SAE: from the time of 

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administration of the IP on Day 1 until the 6-month follow-up visit; 
▪ For any SAE: from the time of enrolment of the patient in the study (after 
signature of informed consent form) and until the end of follow-up (18 
months). SAEs will be followed and analysed up to 18 months. 
AEs considered to be possibly related to study participation that occur during the 
screening period, i.e. after signature of the informed consent form and before 
administration of the IP, will also be collected by the medical personnel and 
recorded in the CRF. 
 
6.5.5. Requirements for AE Reporting 
Information on AEs must be assessed by a physician. The Investigator must 
determine whether the AE is considered to be serious or not, if necessary with 
the assistance of the Coordinating Investigator and the study monitor. This 
classification will determine the reporting procedure for the AE. 
All SAEs must be reported immediately, and no later than 24 hours after the 
Investigator becomes aware of the SAE, to the clinical study monitor, first by 
telephone and/or SMS, then by e-mail using the SAE reporting form. This report 
should include a description of the event, onset date and type, duration, severity, 
relationship to IP (assessed with the assistance of the Coordinating Investigator, 
as needed), measures taken and outcome, as well as any other relevant clinical 
or laboratory data. Any additional information, including responses to data 
queries concerning SAEs, must be sent on an SAE follow-up form as it becomes 
available. Follow-up reports should be submitted as soon as possible, and, if 
possible, within 5 working days after the new information becomes available. A 
close-out follow-up report must be sent after the final assessment of the case, 
specifying the outcome of the SAE as “recovery”, “recovery with sequelae”, 
“death” etc. 
SAEs must be reported using the AE reporting form in the CRF and the SAE 
reporting form. It should be noted that the SAE reporting form is not the same as 
the form in the AE section of the CRF. The two forms must be completed in a 
consistent manner, using the same medical terminology. 
All AEs must be recorded in the CRF. 
For the purposes of this study, the Coordinating Investigator will be responsible 
for reporting serious unexpected adverse events to the ethics committees in the 
countries where the study is being conducted and to the other appropriate 
governing bodies. DNDi will be responsible for reporting serious unexpected 
adverse events to the Regulatory Authorities in accordance with current 
regulations. 
 

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6.5.6. Grading of AE Severity 
The severity of the AE will be graded according to NCI CTCAE, version 4.03  (16). 
If the AE is not described in the CTCAE, version 4.03, the Investigator will use 
the terms “mild”, “moderate” or “severe” to describe the maximum severity, as 
defined below: 
Mild 
The patient is aware of the event or symptom, which is easily 
tolerated; the event does not lead to any reduction in the patient’s 
usual activities (easily tolerated). 
Moderate The patient feels discomfort such that it reduces or interferes with 
the patient’s usual activities. 
Severe  
Significant functional impairment: the patient is unable to carry out 
usual activities and/or the event is life threatening. 
Information on the severity of the AE must be recorded in the Adverse Events 
section of the CRF. 
It is important to distinguish between the severity and the seriousness of an AE: 
a severe AE is not necessarily a serious AE, since the criteria for seriousness 
(see Section 6.5.2 Definition of Serious Adverse Event; p49) are different from 
the criteria for severity. 
 
6.5.7. Assessment of AE Causality  
For each AE, the Investigator must assess the possible causal relationship 
between the IP and the AE, with the assistance of the Coordinating Investigator 
and study monitor if necessary, in order to determine whether there is a 
reasonable possibility that the IP caused or contributed to the AE. 
The causal relationship between the IP and the AE is assessed by the 
Investigator after a detailed analysis of the event in terms of the biological 
plausibility, taking into account possible unrelated causes, pre-existing medical 
conditions, concomitant medication, the temporal relationship between intake of 
the IP and onset or worsening of the AE, and the known patterns of response to 
acoziborole in general. 
The two types of causal relationships are defined as follows: 
▪ Not related: there is no reasonable possibility of a causal relationship.  
▪ Related: there is at least a reasonable possibility of a causal relationship 
between the IP and the AE. This means that there are facts (proof) or 
evidence to suggest a causal relationship. 
 
6.5.8. Exposure in utero 
At least five pregnancy tests are planned during the study: at the screening visit, 
at the baseline assessment (between Day -4 and Day -1), on Day 11 and at the 

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out-patient follow-up visits up to 6 months. Among women of child-bearing 
potential, only those who have a negative result on the pregnancy test at the 
baseline assessment will be eligible to participate in the study. 
Pregnancy is not considered to be an AE. 
The Investigator must report any pregnancy using the appropriate pregnancy 
reporting form (see Investigator Manual). The pregnancy must be reported 
whether or not an AE occurred. If known, the due date should be specified. 
The Investigator must monitor the patient until the full term of the pregnancy or 
preterm in the event of a miscarriage. The Investigator must provide information 
on the outcome of the pregnancy using the pregnancy follow-up reporting form. 
A physician, preferably a paediatrician, should examine the newborn at birth and 
submit a report using a Newborn Follow-up form. The Investigator will offer the 
parents follow-up on infants exposed to the IP in utero until they reach 24 months 
of age. As far as possible, stillborn infants should be examined by a physician to 
ascertain the cause of death. 
Any SAE that occurs in a pregnant patient (exposed to the IP or who is found to 
be pregnant any time up to the 6-month visit) and that concerns the pregnancy 
or the foetus, will be reported using the SAE reporting form in the same manner 
as any other SAE. Any non-serious AE concerning a pregnant patient will be 
collected using the AE form in the CRF. 
 
6.5.9. Follow-up on AEs 
All AEs and SAEs must be followed until they resolve completely or until the 
Investigator considers them to be “chronic” or “stable”, or until the end of the 
patient’s participation in the study, i.e. until the End-of-Study page in the CRF for 
the patient has been completed. 
In addition, all SAEs that the Investigator considers as having a reasonable 
causal relationship with the IP must be followed even after the end of the patient’s 
participation in the study. These events must be followed until they resolve 
completely or until the Investigator considers them to be “chronic” or “stable”. The 
outcome of the events must be recorded in the CRF up to the end of the patient’s 
participation in the study and, in addition, for SAEs, using the SAE reporting form. 
 
7. Study Duration 
The duration of the enrolment period is estimated to be approximately 28 months. 
Each patient’s participation in the study will last approximately 18 months and will 
include: 
▪ pre-treatment period (pre-screening and screening, treatment of 
concurrent diseases) up to 15 days; 
▪ a treatment period of 1 day; 

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▪ an observation period in hospital of a total of 15 days, including the 
treatment day (Day 1); 
▪ an out-patient follow-up period of 18 months with visits at 3, 6, 12 and 18 
months. 
The total duration of the study is estimated to be 46 months. 
 
8. Withdrawal Criteria 
 
8.1. 
Patient Withdrawal from the Study and Replacement of Patients 
A patient may be withdrawn from the study in the following cases: 
▪ withdrawal of consent by the patient or his/her legal representative; 
▪ study termination by the Sponsor. 
If the patient withdraws his/her consent, no further study assessments will be 
performed and no further data will be collected, with the exception of safety data 
and data on the patient’s clinical status, which must be collected whenever 
possible. 
If a patient decides to withdraw from the study, the reason must be recorded in 
the CRF. If a patient is withdrawn from the study due to an AE, all necessary 
measures must be taken to clearly document the outcome of the AE. 
Data collected prior to withdrawal of the patient will be taken into account in the 
PK, efficacy and safety analyses, except in the event of patient refusal. 
Patients withdrawn from the study will not be replaced. 
If a patient is lost to follow-up for reasons related to armed conflict or natural 
disaster, after several unsuccessful attempts have been made to contact him/her, 
and if no data are available after the treatment period, the patient will be removed 
from the primary analysis and another patient will be added in order to maintain 
the planned sample size, provided that the enrolment period is still on-going. 
 
8.2. 
Patients Lost to Follow-up 
In order to ensure adequate follow-up on patients, a schedule of patient follow-
up will be made available to the Investigator. If a patient does not attend a 
protocol-planned visit, all possible measures must be taken to contact him/her. In 
all cases, the Investigator must take all possible measures to document the 
course of the patient’s condition. 
 
9. Data Analysis and Statistical Methods 
An initial draft of the Statistical Analysis Plan (SAP) will be prepared and 
approved prior to database lock. It will provide a more detailed description of the 
statistical methods. The SAP will be reviewed and, if necessary, amended prior 

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to final database lock. The different approved versions will be dated and 
numbered. 
9.1. 
Sample Size Determination 
The sample size is based on the largest number of patients who can be enrolled 
within a reasonable timeframe. It is expected that 155 late-stage patients should 
be enrolled within approximately 2 years. A provision of 5% (7 patients) is planned 
in order to allow for replacement of patients lost to follow-up who fled the region 
due to armed conflict or natural disaster. Approximately 50 early- and 
intermediate-stage patients could be enrolled within this timeframe. As a 
reminder, enrolment of early- and intermediate-stage patients will begin 
approximately 6 months after the start of enrolment of late-stage patients and will 
end at the same time. 
If the observed success rate is around 89% (the same as the expected rate for 
fexinidazole and the observed rate with eflornithine) then the width of the 95% 
Jeffreys confidence interval will be 9.8% (83.4%–93.2%) for an 89% success rate. 
The width decreases with an increase in the success rate to reach 7.4% (89.7%–
97.1%) for a 94% success rate. In contrast, the precision is not highly sensitive 
to the sample size. With 200 patients, the width of the confidence interval is 8.7% 
(84.1%–92.8%) for an 89% success rate. Indeed, the sample size must increase 
by 50%, i.e. 300 patients instead of 200, to reduce the width of the lower arm of 
the 95% confidence interval by one percentage point. 
In early- and intermediate-stage patients, the expected success rate is around 
91%, i.e. the same as for pentamidine. The width of the confidence interval with 
50 patients will be of the order of 17%. 
9.2. 
Definition of Study Populations included in the Analyses 
Populations Used in the Analyses 
The population of late-stage patients will be separated from the population of 
early- and intermediate-stage patients. 
The primary analysis will be performed on late-stage patients in the modified 
intention-to-treat (mITT) population and who received at least one tablet of 
acoziborole. Patients lost to follow-up who fled the region due to armed conflict 
or natural disaster will not be included in the mITT population and will be replaced 
by other patients. 
The analysis of the primary endpoint for early- and intermediate-stage patients, 
which is considered to be a secondary analysis, will also be performed on the 
mITT population. 
The sensitivity analyses will also be performed by cohort, separating late-stage 
patients from early- and intermediate-stage patients (see Table 5 - Populations 
Used in the Analyses). 

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Table 5 - Populations Used in the Analyses 
Type 
Aim 
Definition 
Primary: 
modified intent-
to-treat (mITT) 
patients 
Primary analysis  
All patients who received at least one tablet of 
acoziborole, excluding patients who fled the 
region due to armed conflict or natural disaster, 
or due to force majeure, and for whom no post-
treatment data are available. These patients will 
be included in the population as failures for an 
“all-patient” sensitivity analysis. 
All patients 
Safety analyses and 
sensitivity analyses 
on efficacy 
All patients who received at least one tablet of 
acoziborole. There will be no exceptions to this 
rule. 
Secondary: 
evaluable 
patients  
Sensitivity analyses 
on efficacy 
Patients in the mITT population for whom at 
least one lumbar puncture is available (at 6, 12 
or 18 months), and excluding patients who died 
for reasons clearly unrelated to efficacy or 
safety, or who fled the region due to armed 
conflict or natural disaster. 
Secondary: 
per-protocol 
patients 
Sensitivity analyses 
on efficacy 
Patients in the mITT population with no major 
protocol violations. Major violations will be 
described by patient, and exclusion will be 
decided during the data review. 
 
9.3. 
Patient Disposition 
At the end of the study, patient disposition will be presented using the following 
categories: 
▪ Number of patients included, by cohort; 
▪ Number of patients included by cohort who received at least one tablet of 
acoziborole; 
▪ Number of patients included by cohort and who received at least one 
tablet of acoziborole, except those who died for reasons clearly unrelated 
to the IP (evaluable patients); 
▪ Number of patients included by cohort who had no major protocol 
violations (per-protocol patients); 
▪ Number of patients by cohort who received at least one tablet of 
acoziborole and who attended the end-of-hospitalisation visit. The same 
count for patients who attended the 6-month visit, the 12-month visit, the 
18-month visit and beyond the window of the 18-month visit; 
▪ Number of patients by cohort who received at least one tablet of 
acoziborole and who underwent lumbar puncture at the end-of-
hospitalisation visit, at the 3-month visit, the 6-month visit, the 12-month 
visit, the 18-month visit and beyond the window of the 18-month visit; 
▪ Number of patients by cohort who received at least one tablet of 
acoziborole and who withdrew from the study prematurely, listed by 
reason for withdrawal; 

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▪ Number of patients by cohort who received at least one tablet of 
acoziborole and who had at least one minor protocol violation; 
▪ Number of patients by cohort who received at least one tablet of 
acoziborole and who had at least one major protocol violation. 
 
9.4. 
Demographic and Baseline Data 
Summary descriptive statistics (N, mean, standard deviation, median, minimum, 
maximum) or frequencies and percentages will be presented for the following 
baseline characteristics for each of the study cohorts: 
▪ Demographic data 
▪ Medical history 
▪ Physical examination 
▪ Vital signs 
▪ Urine pregnancy test (for women of child-bearing potential) 
▪ Laboratory assessments 
▪ Karnofsky performance status 
▪ Neurological examination 
▪ Concomitant medication 
A summary table of baseline characteristics of patients in each study involving 
NECT will be provided. 
 
9.5. 
Treatment Compliance 
Administration of acoziborole will be recorded in the CRF. 
 
9.6. 
Efficacy Analyses 
 
9.6.1. Primary Efficacy Analysis 
Primary Efficacy Analysis: Success Rate at 18 Months in Late-stage 
Patients 
The primary analysis is based on the mITT set and will consist in an estimate of 
the success rate at 18 months of follow-up. 
The 95% Jeffreys confidence interval of the estimate will be provided. The 
Jeffreys confidence interval has a coverage probability that does not exceed 95% 
to any large extent and is equal tailed, i.e. the probability of the interval lying 
above or below the upper and lower bounds are both close to 2.5%, which is 
important when the lower bound of the 95% confidence interval is more 
meaningful from a clinical standpoint than the upper bound. 
Analysis of Surrogate Primary Endpoint for Late-stage Patients 
Amendment 2 dated 07/01/2020 deletes this analysis, as the data set required 
for early submission at 12 months is not available in its entirety.  

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Success Rate for the Yardstick 
The current standard of care for late-stage patients is NECT, and the success 
rate with NECT will be used as a yardstick. 
The success rates will be provided study-by-study along with the 95% Jeffreys 
confidence interval. Three studies will be taken into account: the study by Priotto 
et al. (18) involving 143 patients exposed to NECT; the WHO-TDR study (13) 
involving 55 patients exposed to NECT; and the DNDiHATFEX004 study 
involving approximately 130 patients exposed to NECT. Data from the NECT-
Field study will not be used because it did not include the same population and 
the large number of missing lumbar punctures could drastically reduce the 
success rate, particularly at 12 months (20). All of the results will be represented 
together in graphic format using a Forest plot. 
The method described in Section 2.2.1 Primary Endpoint - Efficacy concerning 
analysis of the primary endpoint will not be used directly on the historical data as 
no raw data are available. However, all deaths, regardless of the cause, will be 
considered as failures. For estimates in the literature, the classification method 
described in the publications will be applied to the data on acoziborole to ensure 
that successes are the same in nature. Differences in the definitions will be 
explicitly identified. In all cases, the mITT set of patients will be used. In all cases, 
the Jeffreys confidence interval will be used. 
 
9.6.2. Futility Analyses 
An independent DSMB (see Section 10 Data and Safety Monitoring Board; p61) 
will be appointed, among other things, to supervise and review the futility and PK 
analyses, as well as the safety data. The DSMB will make recommendations on 
study continuation based on all available information. 
The first futility analysis will be performed once the first 20 late-stage patients 
reach the 3-month visit. If the failure rate at Day 11 is significantly higher than the 
failure rate for melarsoprol, (19) the study should be stopped for futility and for 
ethical reasons. The failure rate for melarsoprol at the end of treatment was 5% 
(4.8% for N = 6840). If 4 patients out of 20 are failures at Day 11 (p = 0.0159), 
then the DSMB should recommend stopping the study, unless the rate can be 
explained by exceptional circumstances. 
The second futility analysis will be performed once 70 late-stage patients reach 
the 3-month visit. The recommendation to stop the study should be made if 8 
patients or more out of 70 are failures at the end of hospitalisation (p = 0.023 one-
sided). 
The last futility analysis will be performed once 70 late-stage patients reach the 
6-month visit. The proven failure rate will be compared to the failure rate with 
melarsoprol at 6 months, which is around 20%. If the rate is significantly higher 
than 20%, i.e.  22 out of 70 patients (p = 0.016, one-sided), the DSMB should 
recommend stopping the study. 

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Additional futility analyses may be performed if deemed necessary during the 
course of the study. 
Rules for Success of the Study 
There are no objective rules for the success of the study. As recommended by 
the Scientific Advice Working Party, the observed success rate and lower bound 
of the 95% CI will be interpreted in light of those obtained in the literature and 
with the historical data, taking into account the obvious advantage of having a 
single oral dose for patients living in remote areas. 
 
9.6.3. Secondary Analyses 
Efficacy Analysis at 12 Months in Late-stage Patients 
The estimated success rate at 12 months in late-stage patients is a secondary 
analysis. The 95% Jeffreys confidence interval for the estimated rate will be 
provided. 
Efficacy Analysis in Early- and Intermediate-stage Patients 
The efficacy analysis for early- and intermediate-stage patients is a secondary 
analysis, similar to the primary analysis for late-stage patients, and concerns the 
success rate at 12 months and at 18 months in early- and intermediate-stage 
patients. The 95% Jeffreys  confidence interval for the estimated rates will be 
provided. 
Other Secondary Analyses 
▪ The correlation between acoziborole concentrations in the blood and 
CSF and the success rate in late-stage patients will be determined using 
logistic regression with success or failure as the response (dependent 
variable) and two covariables (explanatory variables): blood and CSF 
concentrations. 
▪ The correlation between acoziborole concentrations in the blood and 
CSF and the occurrence of AEs in late-stage patients will be determined 
using logistic regression with the occurrence of AEs during hospitalisation 
as the response (dependent variable) and two covariables (explanatory 
variables): blood and CSF concentrations. 
▪ Changes in the rate of favourable outcomes over time for late-stage 
patients on the one hand, and for early- and intermediate-stage patients 
on the other hand, will be studied using the mixed model for repeated 
measures (Glimmix). 
▪ Time to proven relapse will be analysed in each cohort using the Kaplan-
Meier approach in order to estimate, at each follow-up visit, the 
cumulative rate of proven failures. Patients lost to follow-up will be 
censored at the last available visit, unless the outcome at that visit was 
failure. 

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9.7. 
Safety Analyses 
All patients who received at least one tablet of acoziborole will be included in the 
safety analyses. 
The percentage of patients who experienced an SAE will be described by system-
organ class using MedDRA terms and/or according to NCI CTCAE, version 4.03 
(16). 
The percentage of patients who experienced at least one AE will be described. 
Events described with the same term and that occur several times in the same 
patient will be counted only once. If a patient experiences several events 
described with the same term, the event with the maximal severity will be included 
in the analysis. In addition, each SAE will be described in a narrative presenting 
all aspects of the medical event and the causality assessment. 
The incidence of AEs and of SAEs and their respective 95% confidence intervals 
will be presented by category and by frequency. In other cases, only descriptive 
statistics will be presented. 
Laboratory safety parameters, i.e. haematology and biochemistry, will also be 
described individually, indicating the percentages of patients, the size of the 
increase in relation to the ULN and to baseline values, as well as changes in 
blood levels over time. Shift tables will be provided. A listing of patients with 
increases in laboratory parameters will be provided. 
Abnormalities on ECG tracings will be described for each timepoint. 
 
9.8. 
Handling of Missing Data and Patients Lost to Follow-up 
The primary endpoint is the outcome at 18 months. If outcome assessed at the 
final visit is missing, the primary imputation method will consist in imputing a 
probable success (considered as a success) to patients who attended the 18-
month visit, but who refused the lumbar puncture planned at the visit, who 
showed no signs or symptoms of HAT at 18 months, who did not subsequently 
report any symptoms of relapse and for whom the outcome was considered as 
favourable at the last available assessment (17). If these criteria are not fulfilled, 
the patients will be considered as treatment failures. The outcome for patients 
who did not attend the 18-month visit or later will also be considered as a failure, 
except for patients who fled the region due to armed conflict or natural disaster. 
Because the historical data may not allow for other imputation methods to be 
applied, only the primary imputation method will be used. The method will be 
described in detail in the SAP. Sensitivity analyses will be performed to assess 
the impact of missing data on acoziborole. The method will be described in detail 
in the SAP. 
 

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9.9. 
Handling of Centres 
The primary analysis will not be stratified by centre because the weight of each 
centre in the overall population is unknown. Nevertheless, the results by centre 
for each cohort will be presented and a test of homogeneity (a likelihood-ratio 
test) will be performed on the success rates. A centre effect is entirely possible. 
In this case, an estimate of the overall success rate will also be provided, giving 
equal weight to each centre rather than weighting the centres based on the 
number of patients. The estimate of the rate will be given by p =  Wh ph where 
Wh is the weight of each centre, i.e. the inverse of the number (k) of the centre (k-
1). The variance of the estimator will be equal to Var(Ph) =  Wh2. ph(1-ph) / nh 
where nh is the number of patients in centre h. In addition, a Forest plot will be 
presented to determine whether the heterogeneity is quantitative (dispersion 
around a central value) or qualitative (presence of entirely atypical centres). 
 
9.10. Analyses of Other Endpoints 
 
Pharmacokinetic Analyses 
 
• Concentrations of acoziborole in whole blood and CSF, and PK parameters 
derived from a population PK model. 
• All PK samples will be analysed centrally. A population PK model will be 
developed using Nonmem software. 
• The model will be used to estimate the population PK parameters. All of the 
analyses and the statistical methods, including the conventions relating to 
data handling, will be described in detail in a separate SAP, which will be 
finalised prior to database lock. 
• The correlations between the concentrations in the blood and in the CSF will 
be described based on the samples collected at the end-of-treatment visit. 
The correlations between, on the one hand, the blood and CSF concentrations 
and, on the other hand, the success rate and rate of AEs will be described. 
Based on analysis of the PK data from the study, it will be possible to confirm the 
data from the Phase-I study on a larger sample size, to analyse individual 
intolerance or treatment failures and to predict the dose for a future study on HAT 
in children. 
 
10. Data and Safety Monitoring Board 
A DSMB, composed of at least 3 members independent of the Investigators and 
the Sponsor, will be set up prior to the start of the study. The DSMB will monitor 
the study in order to minimise any risk of harm to the patients included in the 
study. At each of its meetings, the DSMB will examine safety data and all 
information related to SAEs, and will issue recommendations regarding the study 
if the benefit-to-risk ratio for patients seems to be in jeopardy. The data and the 

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intervals for review will be decided before, or shortly after the start of the study 
and will be recorded in the DSMB Charter. 
The results of the futility analyses will be presented to the DSMB, who will decide 
whether or not the study can continue and whether the enrolment period should 
be extended. 
The organisation of the DSMB will be described in the DSMB Charter, which will 
be prepared and approved prior to the first planned futility analysis. 
Additional ad hoc members may be invited to join the DSMB if any safety 
concerns emerge, in order to give additional support to the competencies already 
present. 
 
11. Quality Assurance and Quality Control Procedures 
 
11.1. Investigator Site File 
The Investigator must maintain appropriate accurate records to ensure that all 
aspects of study conduct are fully documented, and that study data can be 
verified at the end of the study. These documents include the Investigator Site 
File, the patients’ clinical source documents, screening/enrolment logs and other 
study-specific forms. 
The Investigator Site File must contain the protocol and protocol amendments, 
Independent Ethics Committee (IEC) and regulatory approval with all 
correspondence, a copy of the patient information and informed consent form, 
the Investigator Brochure, drug accountability records and curriculum vitae for 
study personnel, as well as authorisation forms and any other relevant documents 
or correspondence. 
 
11.2. Case Report Forms 
Data will be collected by laboratory technicians, physicians, nursing staff or care-
givers authorised by the Investigator. Data collection will be supervised by the 
Investigator. Study-specific information will be entered in a CRF in paper format. 
Data generated from this information must be consistent with the source 
documents and any discrepancies must be accounted for. All data that are 
recorded directly in the CRF must be rendered anonymous, i.e. such that they 
can only be traced back to the patient number. 
The Investigator must ensure the accuracy, completeness, legibility and timely 
entry of all data reported to the Sponsor via the CRF, as well as any additional 
information that may be requested. The Investigator is responsible for ensuring 
that all informed consent forms and screening forms for all patients are stored in 
a secure location. After each visit, data will be entered in the CRF, scanned and 
sent by Internet to the data manager for entry (double data entry for numerical 

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data and, for verbatims, single entry with review by another data entry operator) 
in the database. The CRF will be signed by the Investigator at each visit. 
 
11.3. Source Documents 
The data in the CRF must be verified by direct inspection of the source 
documents. The source documents are the patients’ medical files, the physicians’ 
and nursing staff’s notes, appointment books, originals of laboratory test results, 
ECG tracings, reports on specific assessments, signed informed consent forms, 
recorded images of microscopic examinations, data clarification forms and 
patient screening/enrolment logs. 
In the study, 100% source document verification will not be carried out. Instead, 
the focus will be on monitoring data consistency (cf. the monitoring plan). 
The Investigator must keep the source documents up to date, i.e. reports on 
laboratory tests and consultations, records of medical history and physical 
examination reports, so that they can be examined and/or audited by designated 
personnel and/or by the Regulatory Authorities, as required.  
 
11.4. Retention of Documents 
The Investigator must retain all essential documents for at least 2 years after 
approval of the last marketing authorisation is obtained, and until there are no on-
going or planned applications for marketing authorisation, or until at least 25 
years after the end of the study. However, study documents may need to be 
retained for a longer period of time if required by local regulations in effect or by 
agreement with DNDi. It is the responsibility of the Sponsor to inform the 
Investigator/institution as to when these documents no longer need to be 
retained. After that date, the documents may be destroyed with prior permission 
from DNDi, subject to local regulations. 
DNDi must be notified in advance if the Investigator plans to assign the study 
records to another party or move them to another location. 
 
11.5. Monitoring 
Clinical monitors will perform regular monitoring visits, in accordance with the 
monitoring plan, during which they will verify source data, informed consent 
forms, medical records, laboratory test results, imaging reports if present, CRFs, 
drug dispensing logs and protocol violations. The monitors will be given access 
to the corresponding source documents for each patient on condition that patient 
confidentiality is maintained in accordance with local regulations. Monitoring will 
be more intensive for the first patients included in the study. 
Monitoring visits at the investigational sites will be performed periodically by DNDi 
representatives or designated clinical monitors to ensure compliance with Good 
Clinical Practice and all aspects of the protocol. Source documents will be 

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reviewed for verification of consistency with the data in the CRFs (and any 
additional data provided on Data Clarification Forms concerning SAEs). The 
clinical monitor will be responsible for inspecting the CRFs at regular intervals. 
The Investigator will ensure that DNDi designated representatives have direct 
access to source documents. It is important that the Investigators and the 
personnel concerned are available during monitoring visits. The Investigator 
agrees to cooperate with the clinical monitor to ensure that any problems 
detected during monitoring visits are resolved. 
The monitoring visits provide DNDi with the opportunity to assess progress of the 
study, to verify the accuracy and completeness of the CRFs and to resolve any 
inconsistencies in the study records, as well as to ensure compliance with all 
protocol requirements, applicable regulations and Investigator obligations. 
Four types of visits are planned: a centre evaluation visit in centres where the 
Sponsor has no prior experience, an initiation visit, monitoring visits and a close-
out visit. 
In addition, data quality will be checked on a regular basis by DNDi 
representatives in the context of centralised monitoring in order to detect any 
missing data, inconsistencies, discrepancies and deviations, with analysis of the 
performance of the investigational centres in order to adapt and/or optimise the 
monitoring visits and the need for training, and to implement corrective and/or 
preventive actions, depending on the risks identified and/or deficiencies 
observed. 
 
11.6. Audits and Inspections 
The investigational centre may also be subject to quality assurance audits by 
DNDi or designated representatives, and/or to inspection by regulatory 
authorities or IEC members. 
The purpose of the audits and/or inspections is to verify protocol adherence and 
to ensure that the study is being conducted in accordance with Good Clinical 
Practice. It is important that the Investigators and the personnel concerned are 
available for any audits or inspections. 
 
11.7. Data Management 
A CRF must be completed for each patient who gives informed consent to 
participate in the study. A paper CRF will be used in the study. The study data 
will be stored in a computer database that ensures confidentiality of the data, in 
accordance with national legislation on data protection. 
All data are entered in the CRF under the responsibility of the Investigator or a 
designated qualified staff member. 
The clinical monitor will monitor the data continuously. Data queries will be 
generated, documented and resolved continuously throughout the study. 

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11.8. Confidentiality of Information, Study Documents and Patients’ 
Files 
The Investigator must ensure that the anonymity of patients is maintained and 
that their identity is protected from unauthorised third parties. Patients must not 
be identified by their names in the CRF or on any other documents or imaging 
submitted to the Sponsor. Only the patient number should appear. The 
Investigator must keep a patient enrolment log containing the number, name and 
address of patients. The Investigator must ensure the confidentiality of all 
documents submitted to the Sponsor’s authorised representatives, including the 
signed informed consent form. 
The findings of any assessments, including laboratory tests, will remain strictly 
confidential to the patient him/herself. This includes patients under legal age and 
vulnerable patients. Particular attention will be paid to the confidentiality of the 
results of pregnancy tests and tests related to concomitant diseases. 
 
12. Protocol Amendments 
The Investigators will ensure that the study is conducted in strict compliance with 
the protocol, and that all data are collected and recorded in the CRF. 
All protocol modifications must be documented in writing. A protocol amendment 
can be initiated by the Sponsor, by the DSMB or by any Investigator. The 
Investigator will provide the reasons for the proposed amendment in writing and 
will discuss it with the Sponsor and the Principal Investigator. 
Any protocol amendment must be approved and signed by the Sponsor and the 
Principal Investigator, and must be submitted to the appropriate IEC for 
information and approval in accordance with local requirements, and to regulatory 
agencies, if required. A favourable opinion must be received from the IEC, and 
the regulatory authorities, if applicable, before any changes can be implemented, 
with the exception of changes required to avert an immediate danger for study 
participants, or when the change involves only logistical or administrative aspects 
of the study, e.g. changes in telephone numbers. 
 
13. Early Termination of the Study 
Both the Sponsor and the Principal Investigator will have the right to terminate 
the study early, i.e. at any time prior to inclusion of the planned number of 
patients, however they may exercise this right only for valid scientific or 
administrative reasons. If necessary, after consultation, the two parties will define 
the procedures for terminating the study. The Sponsor and the Principal 
Investigator will ensure that early termination of the study takes place in such a 
way as to protect the patients’ interests. 

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Reasons for which the Sponsor may terminate the study include, but are not 
limited to:  
▪ Insufficient enrolment rate; 
▪ Protocol violations; 
▪ Inaccurate or incomplete data; 
▪ Dangerous or unethical practices; 
▪ Recommendation from the DSMB or IEC. 
 
Reasons for which the Investigator may terminate the study include, but are not 
limited to: 
▪ Insufficient time or resources to conduct the study; 
▪ Lack of eligible patients. 
 
If the study is terminated early by the Sponsor or the Investigator, the latter must: 
▪ Complete all CRFs to the fullest extent possible; 
▪ Return all study-related articles and equipment to the Sponsor who 
provided them; 
▪ Answer all queries from the Sponsor, or delegated representatives, 
related to data on patients enrolled by the centre prior to study 
termination; 
▪ Ensure that patients enrolled in the study who have not yet attended any 
follow-up visits receive all necessary medical care; 
▪ Provide the IEC, the regulatory authorities and, if appropriate, the 
Sponsor with a written explanation of the decision to terminate the study. 
 
14. Ethical Considerations 
The protocol for this study was prepared in accordance with the general ethical 
principles set out in the Declaration of Helsinki of the World Medical Association 
(see Appendix 1 – Declaration of Helsinki; p77) and ICH guidelines for Good 
Clinical Practice (ICH Harmonised Tripartite Guideline - Guideline For Good 
Clinical Practice E6(R1) - current Step 4 version, dated 10 June 1996). DNDi 
commits to respect all applicable laws for the protection of the rights and welfare 
of human subjects. 
The study was submitted to the Ethics Committee for Health Research in Central 
Africa (CERSAC), an independent institution common to several central African 
countries including Cameroon, the Republic of the Congo, Gabon, Equatorial 
Guinea, the Central African Republic and Chad. It is based in Yaoundé, 
Cameroon, at the Organisation for Coordination in the Fight against Endemic 
Diseases in Central Africa. 
The CERSAC is mandated to ensure that, prior to implementation and throughout 
their conduct, research projects involving human subjects comply with ethical 
principles. The projects involve research scientists, students and members of 
research organisations based in central African countries. A single, multinational 

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ethics committee provides adequate and appropriate ethical evaluation to ensure 
that clinical research conducted in the region reflects the values of African 
communities. 
 
 
. 
The minutes of the meeting, as well as the responses from the Sponsor, are 
presented in appendix to the dossier for submission of the protocol to the various 
national ethics committees. 
The protocol was submitted by the Principal Investigator for official approval  from 
the Ethics Committee of the Ministry of Health of the DRC and in Guinea. 
Specific approval must be obtained from each country before any study-specific 
procedures are performed on any patient in the countries concerned. 
Any changes made to the protocol after it has been approved by the IEC must be 
submitted in writing to the IEC by the Principal Investigator in accordance with 
local procedures and regulatory requirements in effect (see Section 12 Protocol 
Amendments; p64). 
The protocol must be submitted along with the appendices related to the 
information and safety of patients, including the Patient Information Sheet, the 
Informed Consent/Assent Form and the Investigator Brochure. 
 
14.1. Information of Communities 
14.1.1. In the Democratic Republic of the Congo 
The study will be conducted in collaboration with the National Programme for the 
Control of Human African Trypanosomiasis (PNLTHA). The programme is 
responsible for all prevention and treatment activities regarding HAT within the 
country, and in particular for the supervision and coordination of the mobile teams 
in charge of HAT screening activities. PNLTHA is fully involved in the design and 
implementation of the study on acoziborole. 
Information of the communities participating in the study will be provided at three 
different levels. 
Firstly, the study will be presented to the public health representatives of the 
provinces concerned, i.e. the Provincial Medical Inspectors (Médecins 
Inspecteurs Provinciaux) and District Medical Officers (Médecins Chefs de 
Zones), as well as the District Administrators prior to any study-related activity in 
their respective geographic area of responsibility. Information on the study will be 
provided by the Provincial Coordinators of the PNLTHA (Médecins 
Coordinateurs), if possible in conjunction with a DNDi representative. The 
information will be based on the study protocol summary, the patient information 
sheet and consent form, and a summary of the Investigator Brochure. 

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Secondly, and before starting screening activities for the study in a given area or 
health zone, an adequate, HAT-experienced person with good knowledge of the 
area and local culture and good communication skills, i.e. either a member of a 
mobile team or a community mobiliser, will visit the local authorities, and tribal or 
village chiefs a few days before arrival of the mobile team, and inform them about 
the study on acoziborole and the related activities. In agreement with the local 
chiefs, an additional information session for the local population should be held, 
possibly during the usual community information session, which routinely takes 
place just before the start of screening activities by mobile teams. HAT is endemic 
in the regions where the study is to be conducted, and therefore, individuals 
already have a basic knowledge of the disease. In addition, most of the 
community mobilisers and many mobile team members have received specific 
training in community communication and HAT and will also receive additional 
study-specific training. Their experience and knowledge will therefore be highly 
useful in promoting a good understanding of the study. 
The following information on the study will be disseminated at the community 
level: 
▪ Routine procedures for detection and diagnosis of HAT; 
▪ Primary objective of the study, i.e. to develop a safe oral drug to treat 
HAT that will be made available to the local population; 
▪ Information on the new drug, the availability of a rescue treatment and on 
concomitant treatments as needed; 
▪ Information on the duration of hospitalisation, number of follow-up visits 
up to 18 months as compared to routine treatment, importance of 
attending follow-up visits and possibility of visits by study staff at village 
level if the patient does not attend the follow-up visits at the centre; 
▪ Information on provision of food to all HAT patients, regardless of whether 
they are included in the study; 
▪ Information on organisation of transportation and/or reimbursement of 
transportation costs for patients included in the study;  
▪ Importance of the freedom of each individual to accept or to refuse to 
take part in the study, after full explanation of the study. Availability of 
treatment in either case; 
▪ Need for minors and patients with impaired cognitive capacities to come 
to the centre accompanied by a legal representative/guardian. 
 
The third level of information concerns the individual consent of each patient (see 
Section 14.2. Informed Consent Process; p69). 
At the end of the study, the community will receive information on the results 
using the same means of communication, i.e. community mobilisers. 
 

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14.1.2. In Guinea 
The study will be conducted in collaboration with the National HAT Control 
Programme (PNLTHA) in Guinea. The programme brings together all of the 
activities for prevention and treatment of HAT in that country and, in particular, 
supervision and coordination of the teams in charge of all HAT screening 
activities, including survey activities. The PNLTHA is fully involved in planning 
and implementing the study in Guinea. 
Information of the communities who will participate in the study will follow the 
procedures of the PNLTHA. 
The following information on the study will be disseminated at various levels 
within the communities: 
▪ Routine screening and diagnostic procedures for HAT; 
▪ Primary objective of the study, i.e. to have an oral drug that is safe to use 
in the treatment of HAT and that will be made available to the local 
population; 
▪ Information on the new treatment, on the rescue treatment and on 
concomitant treatments if necessary; 
▪ Information on the duration of hospitalisation and the number of follow-up 
visits up to 18 months, as compared to the usual treatment, on the 
importance of attending follow-up visits and the possibility of visits in the 
village by the study personnel if the patient does not attend follow-up visits 
at the investigational centre; 
▪ Information on the fact that food will be provided to all patients with HAT 
treated at the centre in Dubreka; 
▪ Information on the organisation of travel and/or reimbursement of travel 
costs from their village to the investigational centre for patients included in 
the study and the person accompanying them; 
▪ Information on the importance of free choice, expressed by each individual 
patient, to decide whether or not s/he wishes to participate in the study, 
after receiving full information on the study and on the possibility of 
receiving treatment in any case; 
▪ Information on the need for patients under legal age or those with impaired 
cognitive faculties to come to the centre accompanied by a guardian/legal 
representative. 
At the end of the study, the community will receive information on the results 
using the same means of communication, i.e. community mobilisers. 
 
14.2. Informed Consent Process  
 
14.2.1. General Process 
The patient will not be included in the study until after s/he has given informed 
consent in writing. It is the responsibility of the Investigator to obtain, for each 

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individual who participates in the study, voluntary written informed consent after 
having provided adequate explanation of the aims, methods, anticipated benefits 
and potential risks of the study. This task can be performed by a designee, 
referred to as a “facilitator”, who may be a study nurse. 
The written informed consent document will be translated into the local language 
or a language understood by the patients, and submitted to the IEC in each 
country for approval. The informed consent document will not be translated into 
the local language in Guinea because a version already exists in French, which 
is the official written language. The oral information provided to patients may 
however be delivered by the investigator in the local language. 
A written information sheet, more extensive than the patient information, will be 
used as a tool for the facilitator to provide oral explanations. The facilitator will be 
chosen within the team for her/his good knowledge of the patients’ preferred local 
language, and for her/his skills in interacting with patients. More than one 
facilitator may be chosen in each centre to cover all local languages and dialects. 
Visual aids, including photographs, drawings and samples, will also be made 
available to the facilitator, describing the activities performed during the study, 
e.g. lumbar puncture, finger pricks and ECG. 
The patient will be invited to attend the information session alone or together with 
family or friends if s/he wishes. The session will be held in a separate room in 
order to ensure patient confidentiality, with only one facilitator present. 
The patient will first be informed about the disease, i.e. HAT, with a clear 
description of the signs and symptoms. 
The information provided during the session will address the following topics: 
▪ Currently available treatments; 
▪ Study objective and need for scientific evaluation of a new treatment; 
▪ Information on the new drug from previous study (safety, PK/PD…); 
▪ Number of patients to be enrolled and the duration of the study; 
▪ Criteria to fulfil to be eligible for inclusion in the study; 
▪ Patients’ commitments during the study, i.e. time, compliance with study-
specific procedures and attendance at follow-up visits; 
▪ Samples to be collected for laboratory tests and purpose of tests; 
▪ Benefits and risks associated with study participation; 
▪ Compensation for travel costs and provision of food during 
hospitalisation; 
▪ Patients’ rights regarding withdrawal, rescue treatment, additional 
information, etc. 

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If the patient wishes, s/he will be given time to discuss the information received 
with members of his/her community or family before giving consent. Written 
consent will be given after the information session (or later) by signing the form, 
provided the facilitator is convinced that the patient has fully understood what was 
explained. 
The informed consent form has been translated into the local/national 
languages/lingua franca spoken in the areas where the study is being conducted. 
If the patient does not speak the national/local language/lingua franca and if pre-
specified and authorised staff with knowledge of the dialect/local language are 
present, an ad hoc oral translation may be acceptable. The oral translation will 
be supported by the use of the available visual aids. The document signed by the 
patient will be the form in the lingua franca of his/her country/region. The 
procedures for illiterate patients should apply. The oral translation should be 
documented on the signed consent form, i.e. the person who did the translation 
will indicate her/his name and the language/dialect used, and will sign the form. 
14.2.2. Impartial Witness 
The presence of an impartial witness is mandatory when illiterate patients are 
recruited and/or the legal representative is illiterate. Other situations may also 
require such a witness (see Section 14.2.3. Illiterate Patients; p71 and Section 
14.2.4. Patients Unable to Give Consent; p71). 
The witness should have no connection with the study team, and, whenever 
possible, should be chosen by the patient. The witness must be literate, i.e. able 
to read. If the patient does not know any appropriate witness, the team will 
propose someone from the hospital staff who is not working in the HAT clinical 
unit, or any literate person from the neighbourhood who is willing to act as a 
witness. The study team will take all necessary measures to prepare a list of 
possible witnesses before the start of the study and keep this list updated, in 
order to find a witness quickly, whenever necessary. 
The witness will sign the consent form to attest to the completeness of the 
information given to the patient, and its compliance with the written information in 
the patient information sheet. The witness must be present throughout the entire 
information session. 
The witness will confirm that the patient has freely given his/her informed consent 
to participate in the study. 
14.2.3. Illiterate Patients 
If the patient is illiterate, an impartial witness must be present throughout the 
information session. 
The facilitator will explain the information contained in the written document to the 
patient and ask whether s/he gives his/her consent to participate. The patient’s 

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consent will be documented with his/her fingerprint on the form, and the witness 
will sign the form. 
 
14.2.4. Patients Unable to Give Consent 
Some patients with late-stage HAT may already have impaired cognitive 
capacities or behavioural abnormalities that preclude them from giving free and 
informed consent. 
Considering the frequency of such symptoms in late-stage HAT, exclusion of 
these patients could jeopardise the capacity to complete the study. 
Consequently, for patients who present with symptoms of psychological or 
behavioural disturbances and/or with impaired mental status, such as memory or 
vigilance disorders, disorientation, etc., consent will be requested from an 
accompanying family member, acting as legal representative. It should be noted 
that patients with very advanced late-stage HAT will not be invited to participate 
in the study (see Section 4.3 Exclusion Criteria, item 3; p33). 
As is the case with minors, the eventual non-consent of the patient will prevail if 
s/he refuses to participate in the study. 
In addition, the consent process should be conducted in the presence of an 
impartial witness who will attest that the patient’s wishes and best interests have 
been respected. 
As soon as the patient has recovered his/her capacity to decide, s/he will be 
asked to confirm his/her desire to participate in the study, usually during the 
hospitalisation period, attested by the signature of an additional consent form. If 
the patient decides not to continue to participate in the study, no additional data 
concerning him/her will be collected, however data collected up to that time may 
be used in the analyses. 
 
14.2.5. Patients Under Legal Age 
For patients under legal age, i.e. between 15 and 18 years old, considered as 
adolescents/young adults, the consent of one of their parents or another culturally 
acceptable, legal representative will be required in addition to their own personal 
assent. During field visits by the mobile team, adolescents and young adult 
patients will be advised to come to the study centre accompanied by a legal 
representative. 
No specific patient information sheet or specific form will be used to collect assent 
from adolescents/young adults recruited to the study, since the data in the patient 
information sheet is considered to be understandable by both adolescents and 
adults. 
The form must be signed by both the adolescent/young adult and his/her legal 
representative. If the patient or the legal representative is illiterate, a fingerprint 

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should replace the signature. If the legal representative is illiterate, an impartial 
witness must attend the assent process and the consent process for the legal 
representative (see Section 14.2.2. Impartial Witness; p70). 
For young adults considered as emancipated because they are already married, 
the legal representative may be the spouse. If they are not married, but are living 
on their own, they may be included with their own consent, provided an impartial 
witness is present during the consent process to confirm their understanding of 
the study, to confirm the probability that they are indeed emancipated and to sign 
the consent form along with them. 
14.2.6. Changes in the Benefit-to-Risk Assessment during the 
Study 
If new safety information results in significant changes to the benefit-to-risk ratio, 
the patient information sheet and consent form will be reviewed and updated. 
Patients currently being treated will be informed of the new information, given a 
copy of the revised patient information and asked to renew their consent to 
continue the study. 
14.3. Ethical Aspects of Study Treatment, Sampling for Laboratory 
Tests and Imaging 
Experimental data suggest that acoziborole has significant potential for the 
treatment of T.b. gambiense infections. Phase-I studies in healthy volunteers who 
received acoziborole suggest that the benefit-to-risk ratio of the dose selected is 
acceptable. 
No screened patients will be left without treatment. Patients not eligible for the 
study will be offered alternative treatment. 
Sampling will be performed only for the purposes of safety assessments and PK 
analyses. The volume of blood collected will be reduced to a minimum. 
The PK analyses will be performed on a sufficient number of patients using a 
DBS assay method involving 2 µL of venous blood, i.e. about 20 µL in total 
throughout the study (see Section 6.3.1 Laboratory Tests; p42). 
CSF samples will be collected from a sufficient number of patients in order to 
assess exposure to acoziborole in the brain. The samples will be collected, 
whenever possible, using atraumatic needles and, if possible, using a local 
anaesthetic cream, i.e. Emla®, in order to reduce pain and limit the adverse 
effects related to sampling. This analysis will be performed on the sample used 
in the efficacy analyses, collected as per usual practice in the investigational 
centre. The PK analyses will require 40 µL of CSF. 
The samples collected on filter paper will be sent out of the country where the 
study is being conducted for centralised assessment of exposure to acoziborole. 

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The samples will only be identified by the study number and the patient number. 
Thus, no information identifying the patient personally will leave the country. 
In the DNDi-OXA-02-HAT study, none of the samples will be retained after the 
end of the study. All remaining biological material will be destroyed at the latest 
once the final study report has been validated and signed. The destruction 
procedure will be recorded in a certificate of destruction. 
 
 
Images of cell counts and/or detection of trypanosomes will be recorded for 
quality control purposes only and sent to the Sponsor. The images will be 
identified only by the study number and the patient number. Thus, no information 
identifying the patient personally will be sent to the Sponsor. 
14.4. Costs for Patients 
Patients will be reimbursed for their travel costs to and from the investigational 
centre, but will not receive any payment for participation in the study. During the 
in-patient treatment phase, food will be provided to the patients free of charge. 
Food may or may not be prepared for the patients, depending on usual practice 
in each investigational centre. If not, the family will prepare it. Enough food will 
be provided to cover the needs of the relatives accompanying the patient during 
hospitalisation. 
For follow-up visits, the patients’ travel costs will be covered by the Sponsor, 
based on centre-specific procedures, e.g. payment of taxi, use of study-specific 
vehicle, transport by mobile teams, reimbursement at flat rate. Food will be 
provided for the patient during his/her stay in hospital. Missed days of work due 
to travel for follow-up visits may be compensated, depending on requirements 
from local IECs. 
Any medication that is required during the study, i.e. at any time during the 18-
month follow-up period, will be provided to the patient free of charge. The WHO 
List of Essential Medicines and the guides entitled “Clinical Guidelines” and 
“Essential Medicines” (2013 edition), published by Doctors Without Borders, will 
be used as reference guides for the treatment of all concomitant conditions. For 
any chronic condition, the study team will take all necessary measures to ensure 
that the patient is referred to the most appropriate healthcare facility in the region. 
To ensure that participation in the study is voluntary, all patients diagnosed with 
HAT during the screening period at hospital/at the investigational centre will be 
treated at the hospital/investigational centre, in accordance with current 
guidelines for treating HAT, even if they are not included in the study, whether 
this is because they do not fulfil the inclusion criteria or because they do not wish 
to participate in the study. The patients may be hospitalised, if necessary, for 
treatment and will also receive food during this period. 

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15. Insurance and Liability
DNDi will take out an insurance policy to cover any claims arising from the study, 
with the exception of claims that arise from malpractice and/or negligence, in 
which case the Investigator or the institution will be held liable. In addition, DNDi 
will cover the costs of treating patients in the study in the event of study-related 
injuries, in accordance with applicable local regulatory requirements. 
16. Reports and Publication
The study will be registered with a recognised international registry of 
clinical trials, i.e. www.clinicaltrials.gov and in the Pan-African Clinical Trials 
Register, www.pactr.orgn. 
The results of the study may be published or presented at scientific meetings. If 
this is the case, the Investigator agrees to submit all manuscripts or abstracts to 
DNDi prior to publication. 
In accordance with standard editorial and ethical practices, the Sponsor will 
generally support publication of the results of multicentre studies only in their 
entirety and not as individual centre data. Any formal publication on the results of 
the study in which input from DNDi personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the Investigator and the 
appropriate DNDi personnel. Authorship will be decided by mutual agreement. 

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17. References
1. Astelbauer F, Walochnik J. Antiprotozoal compounds: state of the art and
new developments. Int J Antimicrob Agents. 2011;38(2):118-24. doi:
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2. Blum J, Schmid C, Burri C. Clinical aspects of 2541 patients with second
stage human African trypanosomiasis. Acta Trop 2006;97(1): 55-64
3. Büscher P, Mumba Ngoyi D, Kaboré J, Lejon V, Robays J, Jamonneau V,
Bebronne N, Van Der Veken W, Biéler S. Improved Models of Mini Anion
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4. Camara M, Camara O, Iboudo H, Sakande H, Kaboré J, N’Dri L, Jamonneau
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5. Checchi F, Chappuis F, Karunakara U, Priotto G, Chandramohan D.
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8. Falade C, Manyando C. Safety profile of Coartem®: the evidence base.
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9. Hasker E, Mitashi P, Baelmans R, Lutumba P, Jacquet D, Lejon V, Kande
V, Declercq J, Van der Veken W, Boelaert M. A new format of the CATT test
for the detection of Human African Trypanosomiasis, designed for use in
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10. Jacobs RT, Nare B, et al. SCYX-7158, an Orally-Active Benzoxaborole for
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13. Kansiime F, et al. A multicentre, randomised, non inferiority clinical trial
comparing a nifurtimox-eflornithine combination to standard eflornithine
monotherapy for late stage Trypanosoma brucei gambiense human African
trypanosomiasis in Uganda. Parasites and Vectors 2018; 11:105.
14. Lutje V, Seixas J, Kennedy A. Chemotherapy for second-stage Human
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15. Malvy D, Chappuis F. Sleeping sickness. Clin Microbiol Infect
2011;17(7):986-95. doi: 10.1111/j.1469-0691.2011.03536.x.
16. National Cancer Institute. Common Terminology Criteria for Adverse Events
(CTCAE) v4.0. Published 28 May 2009 (v4.03: 14 June 2010). Accessed on
13 January 2012 at http://evs.nci.nih.gov/ftp1/CTCAE/About.html

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17. Priotto G, Chappuis F, Bastard M, Flevaud L, Etard J-F (2012) Early 
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18. Priotto G, Kasparian S, Mutombo W, Ngouama D, Ghorashian S, Arnold U, 
Ghabri S, Baudin E, Buard V, Kazadi-Kyanza S, Ilunga M, Mutangala W, 
Pohlig G, Schmid C, Karunakara U, Torreele E, Kande V. Nifurtinox-
eflornithine combination therapy for second stage African Trypanosoma 
Brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, 
non-inferiority trial. Lancet 2009;374 (9683):56-64. doi:10.1016/S0140-
6736(09)61117-X 
 
19. Rodgers J, Jones A, Gibaud S, Bradley B, McCabe C, Barrett MP, Gettinby 
G, Kennedy PG. Melarsoprol Cyclodextrin Inclusion Complexes as 
Promising Oral Candidates for the Treatment of Human African 
Trypanosomiasis. PloS Negl Trop Dis 2011;5(9):e1308.. 
 
20. Schmid C, Kuemmerle A, Blum J, Ghabri S, Kande V, Mutombo W, Ilunga 
M, Lumpungu I,  Mutanda S, Nganzobo P, Tete D, Mubwa N, Kisala M, 
Blesson S, Valverde Mordt O In-Hospital Safety in Field Conditions of 
Nifurtimox Eflornithine Combination Therapy (NECT) for T. b. gambiense 
Sleeping Sickness, PloS Negl Trop Dis 2012,6(11):e1920. 
 
21. Simarro PP, Franco JR, Diarra A, Ruiz Postigo JA, Jannin J. Update on field 
use of the available drugs for the chemotherapy of human African 
trypanosomiasis. Parasitology 2012 Jun;139(7):842-6. 
 
22. Stich A, Abel PM, Krishna S. Human African trypanosomiasis. BMJ 
2002;325(7357):203–6. 
 
23. WHO (2007). Recommendations of the Informal Consultation on Issues for 
Clinical Product Development for Human African Trypanosomiasis. World 
Health Organisation. WHO/CDS/NTD/IDM/2007.1. 
 
24. WHO (2011). New cases of human African trypanosomiasis continue to 
drop. World Health Organisation. Consulted on January 30th, 2012, at 
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drop/en/index.html  
 
25. WHO (May 2015) Fact Sheet n° 259 Trypanosomiasis, human African 
(Sleeping Sickness). http://www.who.int/mediacentre/factsheets/fs259/en/ 
 
26. WHO (1995) Control and surveillance of human African trypanosomiasis. 
Report of a WHO Expert Committee (TRS n° 881) 
27. WHO (2013) Control and surveillance of human African trypanosomiasis. 
Report of a WHO Expert Committee (TRS n° 984) 
 
28. Wring S, et al. Pharmacokinetics and pharmacodynamics utilizing unbound 
target tissue exposure as part of a disposition-based rationale for lead 
optimization of benzoxaboroles in the treatment of Stage 2 Human African 
Trypanosomiasis. Parasitology 2014;141:104-118. 
 
 
 

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Appendices 
 
Appendix 1 – Declaration of Helsinki  
 
World Medical Association - Declaration of Helsinki 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, 
and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington, DC, USA, October 2002 
55th WMA General Assembly, Tokyo, Japan, October 2004 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013  
Preamble 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as 
a statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles. 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The 
health of my patient will be my first consideration,” and the International Code of Medical 
Ethics declares that, “A physician shall act in the patient’s best interest when providing 
medical care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights 
of patients, including those who are involved in medical research. The physician's 
knowledge and conscience are dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6. The primary purpose of medical research involving human subjects is to understand 
the causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 

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7. Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of 
personal information of research subjects. The responsibility for the protection of research 
subjects must always rest with the physician or other health care professionals and never 
with the research subjects, even though they have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration.  
11. Medical research should be conducted in a manner that minimises possible harm to 
the environment. 
12. Medical research involving human subjects must be conducted only by individuals 
with the appropriate ethics and scientific education, training and qualifications. Research 
on patients or healthy volunteers requires the supervision of a competent and 
appropriately qualified physician or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14. Physicians who combine medical research with medical care should involve their 
patients in research only to the extent that this is justified by its potential preventive, 
diagnostic or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the patients who 
serve as research subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens And Benefits 
16. In medical practice and in medical research, most interventions involve risks and 
burdens. 
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and groups involved in the 
research in comparison with foreseeable benefits to them and to other individuals or 
groups affected by the condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving human subjects unless 
they are confident that the risks have been adequately assessed and can be satisfactorily 
managed. 

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When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study. 
Vulnerable Groups And Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive 
to the health needs or priorities of this group and the research cannot be carried out in a 
non-vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research. 
Scientific Requirements And Research Protocols 
21. Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 
relevant sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
22. The design and performance of each research study involving human subjects must 
be clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, potential 
conflicts of interest, incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, 
the sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research 
is to be performed as well as applicable international norms and standards but these must 
not be allowed to reduce or eliminate any of the protections for research subjects set forth 
in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must 
provide monitoring information to the committee, especially information about any 
serious adverse events. No amendment to the protocol may be made without 
consideration and approval by the committee. After the end of the study, the researchers 
must submit a final report to the committee containing a summary of the study’s findings 
and conclusions. 
Privacy And Confidentiality 
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 

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Informed Consent 
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members 
or community leaders, no individual capable of giving informed consent may be enrolled 
in a research study unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, 
each potential subject must be adequately informed of the aims, methods, sources of 
funding, any possible conflicts of interest, institutional affiliations of the researcher, the 
anticipated benefits and potential risks of the study and the discomfort it may entail, post-
study provisions and any other relevant aspects of the study. The potential subject must 
be informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used to deliver 
the information. 
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-
given informed consent, preferably in writing. If the consent cannot be expressed in 
writing, the non-written consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 
27. When seeking informed consent for participation in a research study the physician 
must be particularly cautious if the potential subject is in a dependent relationship with 
the physician or may consent under duress. In such situations the informed consent must 
be sought by an appropriately qualified individual who is completely independent of this 
relationship. 
28. For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the potential 
subject, the research cannot instead be performed with persons capable of providing 
informed consent, and the research entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed 
consent is able to give assent to decisions about participation in research, the physician 
must seek that assent in addition to the consent of the legally authorised representative. 
The potential subject’s dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or mental 
condition that prevents giving informed consent is a necessary characteristic of the 
research group. 
In such circumstances the physician must seek informed consent from the legally 
authorised representative. If no such representative is available and if the research cannot 
be delayed, the study may proceed without informed consent provided that the specific 
reasons for involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been approved by a 
research ethics committee. Consent to remain in the research must be obtained as soon as 
possible from the subject or a legally authorised representative. 

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31. The physician must fully inform the patient which aspects of their care are related to 
the research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
Use Of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances: 
- Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or 
- Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention 
is necessary to determine the efficacy or safety of an intervention; and 
- When patients who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be subject to additional risks of serious or irreversible 
harm as a result of not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments 
should make provisions for post-trial access for all participants who still need an 
intervention identified as beneficial in the trial. This information must also be disclosed 
to participants during the informed consent process. 
Research Registration And Publication And Dissemination Of Results 
35. Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a 
duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should adhere 
to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive 
results must be published or otherwise made publicly available. Sources of funding, 
institutional affiliations and conflicts of interest must be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not 
be accepted for publication. 
Unproven Interventions In Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or 
other known interventions have been ineffective, the physician, after seeking expert 
advice, with informed consent from the patient or a legally authorised representative, may 
use an unproven intervention if in the physician's judgement it offers hope of saving life, 
re-establishing health or alleviating suffering. This intervention should subsequently be 

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made the object of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available. 
 
 
 

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Appendix 2 – Karnofsky Performance Scale 
 
Karnofsky Performance Status Scale  
Definitions of Rating Criteria (%) 
The Karnofsky Performance Status Scale allows patients to be classified in terms 
of their functional impairment. This can be used to compare the efficacy of 
different treatments and to assess the prognosis in individual patients. The lower 
the score, the greater the disability. 
Able to carry on normal activity and to work; no special 
care needed. 
 
100 
Normal no complaints; no evidence of 
disease. 
90 Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 Normal activity with effort; some signs or 
symptoms of disease.  
Unable to work; able to live at home and care for most 
personal needs; varying amount of assistance needed. 
70 Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is 
able to care for most of his personal 
needs. 
50 Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly. 
40 Disabled; requires special care and 
assistance. 
30 Severely disabled; hospital admission is 
indicated although death not imminent. 
20 Very sick; hospital admission necessary; 
active supportive treatment necessary. 
10 Moribund; fatal processes progressing 
rapidly. 
0 Dead. 
 
DI 
DI 
DI 
DI 
DI 
DI 
DI 
DI 
DI 
DI 
DI 

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Appendix 3 – Laboratory Tests  
 
 
Laboratory Tests and Methods 
 
All laboratory assessments will be described in a laboratory manual. Laboratory 
technicians have received specific training on these standard methods. 
 
Biochemical tests 
 
14 parameters will be analysed: 
Albumin 
Calcium 
Alkaline phosphatase  
Glucose 
Alanine aminotransferase 
Bicarbonates  
Aspartate aminotransferase 
Blood urea nitrogen 
Total bilirubin  
Sodium 
Total protein 
Chloride 
Creatinine 
Potassium 
 
Thyroid function tests: TSH, free T3 and free T4 
 
Haematological tests  
• 
Haemoglobin assay  
• 
White blood cells: count and differential count 
• 
Platelets: count 
• 
Microscope: full blood cell count (visual count) (see Investigator Manual) 
 
Urine pregnancy test 
CSF analysis (see Investigator Manual) 
• 
Modified Single Centrifugation (MSC): detection of parasite  
• 
Counting chamber: WBC count  
Blood parasitology tests (see Investigator Manual) 
• 
Thick/thin blood smears  
• 
Woo test /CTC  
• 
mAECT  
• 
mAECT-BC  
 
 

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Quantity of biological fluid required at each sampling timepoint 
 
Pre-screening and Screening Visit 
 
 
 
Type of test 
Specific test  
Number of 
samples 
Quantity per 
sample 
(approx.) 
Total 
quantity 
Blood 
Parasitology  
Woo/CTC 
1 
100 µL 
≤ 400 µL  
Thin/thick blood 
smear 
1 
≤ 300 µL 
mAECT (±BC)  
1 
5 mL 
5 mL 
Haematology 
Haemoglobin  
1 
20 µL 
Between 
170 µL 
(capillary 
blood1) 
and 9 mL 
(venous 
blood) 
WBC 
1 
20 µL 
Platelet count 
1 
10 µL 
Differential 
WBC 
1 
20 µL 
Biochemistry 
14 parameters 
1 
100 µL 
Thyroid function test 
TSH, free T3, 
freeT4 
1 
5 mL 
Lymph 
Parasitology 
If lymph nodes 
detectable 
 
 
 
CSF 
Parasitology 
Modified Single 
Centrifugation  
1 
4 mL 
4 mL 
Urine 
Pregnancy 
 
1 
5 mL 
5-10 mL 
 
 
 
1 All haematological and biochemical analyses can be performed using a single finger-prick with 
a Tenderlett® device or similar. 

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Hospitalisation (Baseline, D5 and D11) 
 
 
Type of test 
Specific test  
Number 
of 
samples 
Quantity per 
sample 
(approx.) 
Total 
quantity (3 
visits) 
Blood 
Parasitology  
Woo/CTC 
1 
100 µL 
≤ 400 µL 
Thin/thick blood 
smear 
1 
≤ 300 µL 
mAECT (±BC)  
1 
5 ml 
5 mL 
Haematology 
Haemoglobin  
3 
20 µL 
Between 
510 µL 
(capillary 
blood1) and 
22 mL 
(venous 
blood) 
WBC 
3 
20 µL 
Platelet count 
3 
10 µL 
Differential 
WBC 
3 
20 µL 
Biochemistry 
14 parameters 
3 
100 µL 
Thyroid function 
test 
TSH, free T3, 
freeT4 
2 
5 mL 
CSF 
Parasitology 
Modified Single 
Centrifugation  
1 
4 mL 
4 mL 
Urine 
Pregnancy 
 
1 
5 mL 
5-10 mL 
 
 
Follow-up visits (by visit) 
 
 
Type of test 
Specific test  
Number 
of 
samples 
Quantity per 
sample 
(approx.) 
Total volume 
per visit 
Blood 
Parasitology  
Woo/CTC 
1 
100 µL 
≤ 400 µL 
Thin/thick blood 
smear 
1 
≤ 300 µL 
mAECT (±BC)  
1 
5 mL 
5 mL  
Haematology 
(M3, M6, M12 
and M18) 
Haemoglobin  
4 
20 µL 
Between 
680 µL (sang 
capillary 
blood1) and 
36 mL 
(venous 
blood) 
WBC 
4 
20 µL 
Platelet count 
4 
10 µL 
Differential 
WBC 
4 
20 µL 
Biochemistry 
(M3, M6, M12 
and M18) 
14 parameters 
4 
100 µL 
Thyroid function 
test (M3, M6, 
M12 and M18) 
TSH, free T3, 
freeT4 
4 
5 mL 
Lymph 
Parasitology 
If lymph nodes 
detectable 
 
 
 
CSF 
Parasitology 
Modified Single 
Centrifugation  
1 
4 mL 
4 mL 
Urine* 
Pregnancy 
 
1 
5 mL 
5 mL 
* Only at visits at 3 months and 6 months. 

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Quantity of biological fluids required for PK analyses  
 
Entire study 
 
 
 
Type of test 
Number of 
samples 
Quantity per 
sample (approx.) 
Total volume  
Blood 
PK 
10 
2 mL 
20 mL 
CSF 
PK 
1 
Included in sample collected for detection of 
parasite (4x10µL) 
 

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Appendix 4 - Schedule of Events 
Table 6 - Schedule of Events 
Protocol procedures and 
forms to be completed 
Pre- 
screening 
and 
screening 
Baseline 
Observation Period until End of Hospitalisation Visit (EOH) 
 
Out-patient 
Follow-up 
Period 
 
Timing →
D-15 to 
D-1 
D-4 to D-1 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15 
(EoH) 
3, 6, 12 & 18 
months 
Unscheduled 
Visit1 
Diagnosis, i.e. detection of 
parasite in blood and/or lymph 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x (6, 12 & 18 
months only) 
x 
Lumbar puncture (parasite and 
WBC in CSF) 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x (6, 12 & 18 
months only) 
x 
Informed consent 
x 
Check 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-treatment of helminthiasis 
(+ 3-day recovery period) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rapid diagnostic test and/or thick 
blood smear for malaria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-treatment of malaria as 
needed (+3-day recovery period) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky index 
x 
Check 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Urinary pregnancy test (only for 
women) 
x 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x (up to 6 months) 
x  
Inclusion/exclusion criteria 
x 
Check 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Geographical data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, incl. symptoms, 
severity and time since start of 
disease 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, height and body-mass 
index 
x 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
Vital signs2 
x 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
Physical examination 
 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
Neurological examination 
 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
Haematology/biochemistry 
x 
x* 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
x  
x 
Thyroid function tests 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x  
x 
 
 

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Timing →
D-15 to 
D-1 
D-4 to D-1 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15 
(EoH) 
3, 6, 12 and 18 
months 
Unscheduled 
visit1 
ECG (2 duplicates)3 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG triplicate recording4 
 
 
x 
x 
x 
x 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
Administration of SCYX-7158 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of adverse events5 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Collection of concomitant 
medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x (up to 6 months) 
x 
Blood sampling for 
pharmacokinetic analyses6 
 
 
x 
x 
x 
x 
x 
 
 
 
 
 
x 
 
 
 
 
x (up to 6 months) 
 
CSF sampling for pharmacokinetic 
analyses7 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
* If the tests were performed prior to D-4 in the Pre-screening/Screening Period or if the findings included abnormalities requiring repeat tests. 
1 If relapse of the disease is suspected or if the patient does not feel well, s/he is to attend an unscheduled visit during which assessments, including additional safety assessments (at the Investigator’s discretion) will 
be performed, as well as investigation of concomitant disease. 
2 Body temperature, blood pressure, heart rate, respiratory rate and general status. 
3 Prior to administration of SCYX-7158, D1H0: 2 x 2 ECG. 
4 D1H4, D1H9, D1H24 (D2), D1H48 (D3), D1H72 (D4), D1H96 (D5), D1H264 (D11). 
5 Adverse events will be collected up to the 6-month visit. Serious adverse events will be collected up to the 18-month visit. 
6 D1H0, D1H4; D1H9; D1H24 (D2); D1H48 (D3); D1H72 (D4); D1H96 (D5); D1H264 (D11); D90 (M3); D180 (M6). 
7 Pharmacokinetic analyses performed on CSF sample collected for detection of parasites. 

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Appendix 5 - Glasgow Coma Scale 
The scale was developed at the Institute of Neurological Sciences in Glasgow, 
Scotland in the early 1970s to assess the extent of a coma following a head injury 
and to monitor the course of the coma. It is now widely recognised by the international 
community. 
The patient’s level of consciousness is assessed based on three criteria: eye opening 
(E score), motor response (M score) and verbal response (V score). 
Eye Response (E) 
Motor Response (M) 
Verbal Response (V) 
Opens eyes spontaneously: 4 
Obeys verbal commands: 6 
Orientated and clear: 4 
Opens eyes in response to 
speech: 3 
Localises painful stimuli: 5 
Confused: 3 
Opens eyes in response to 
painful stimuli: 2 
Withdraws from painful 
stimuli: 4 
Inappropriate: 3 
No response: 1 
Abnormal flexion to painful 
stimuli: 3 
Incomprehensible: 2 
Extension to painful stimuli: 2 
No response: 1 
No response: 1 
The Glasgow score is obtained by adding the three scores. 
By definition: 
- if the Glasgow score is > 12, the patient is considered to have mild head injury;
- if the score is between 9 and 12 inclusive, the patient is considered to have
moderate head injury;
- if the Glasgow score is  8, the patient is considered to have severe head injury.