Clinical trial NCT03974178
Conditions: Trypanosomiasis, African Sleeping Sickness Trypanosoma Brucei Rhodesiense; Infection
Keywords: Trypanosoma Brucei (T. b.) rhodesiense HAT Neglected Tropical Disease
Sponsor: Drugs for Neglected Diseases
Start date: 2019-09-29; Completion date: 2022-10-12
Enrollment: 45 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The ultimate goal of this study is to show that fexinidazole offers an alternative over the existing treatments of Human African trypanosomiasis due to Trypanosoma brucei rhodesiense (r-HAT): melarsoprol in patients with stage 2 r-HAT and suramin in patients with stage 1 r-HAT. The main questions it aims to answer are:

* Is the short-term fatality rate and failure rate associated with fexinidazole lower than those of melarsoprol in patients with stage 2 r-HAT?
* Is the long-term failure rate associated with fexinidazole lower than that of melarsoprol in patients with stage 2 r-HAT?
* Can fexinidazole in patients with stage 1 r-HAT replace the treatment with suramin?
* Is fexinidazole treatment safe in patient with r-HAT, regardless of stage?

Participants will receive fexinidazole oral treatment for 10 days. Regular blood draws and lumbar punctures will be performed over 12 months to confirm the cure of the disease. Other assessments will include the recording of adverse events, signs and symptoms of the disease, laboratory tests, vital signs, electrocardiograms.

Detailed description:

Arms: arm 1: Patients with stage 1 r-HAT were patients without trypanosomes in the cerebrospinal fluid (CSF) but with trypanosomes in the blood and/or lymph and CSF white blood cells (WBC) ≤5 cells/µL. Patients were to receive fexinidazole orally for 10 days. arm 2: Patients with stage 2 r-HAT were patients with trypanosomes in the CSF (and/or in blood/lymph) and/or CSF WBC \>5 cells/µL. Patients were to receive fexinidazole orally for 10 days.
Interventions: intervention 1: Fexinidazole
Intervention descriptions: intervention 1: Tablets of 600 mg; Participants with a weight between 20 and 34 kg received 1200 mg (2 tablets) for 4 days, then 600 mg (1 tablet) for 6 days (with food); Participants with a weight of 35 kg and above received 1800 mg (3 tablets) for 4 days, then 1200 mg (2 tablets) for 6 days (with food)

Protocol documents:
Prot_000.pdf: 
Protocol DNDi-FEX-07-HAT Version 6.0 
 
Fexinidazole  
 
Confidential  
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
Efficacy and safety of fexinidazole in patients  
with Human African Trypanosomiasis (HAT) due to 
Trypanosoma brucei rhodesiense:  
a multicentre, open-label clinical trial 
 
 
 
 
 
 
Registration number 
NCT03974178 
 
 
Version 6.0 – 19 August 2022 
 
 


DNDi-FEX-07-HAT 
 
Fexinidazole 
Protocol version 6.0_19 Aug 2022 
 
Confidential  
Page 1 of 83 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
Efficacy and safety of fexinidazole in patients with Human African Trypanosomiasis 
(HAT) due to Trypanosoma brucei rhodesiense:  
a multicentre, open-label clinical trial  
Short title 
FEX007 
Name of product(s) 
Fexinidazole 
Drug Class 
Antiprotozoal 
Phase 
II-III 
Indication 
Trypanosoma brucei rhodesiense (T.b.rhodesiense) Human 
African Trypanosomiasis (HAT) 
Clinical Trial Protocol Number 
DNDi-FEX-07-HAT 
EudraCT Number 
NA 
Sponsor 
Drugs for Neglected Diseases initiative (DNDi)  
15 Chemin Camille-Vidart  
1202 Geneva, Switzerland 
Phone: +41 22 906 92 30 
Principal 
Investigator 
and 
Global/National 
Coordinating 
Investigator  
 
Principal Investigator:  
Prof. Enock Matovu 
Makerere University, College of Veterinary Medicine, Animal 
Resources and Biosecurity- Main Campus 
P.O. Box 7062, Kampala, Uganda 
Coordinating Investigators: 
Coordinating Investigator for Uganda: 
 
 
 
Coordinating Investigator for Malawi: 
 
 
Clinical Trial Protocol Version / Date 
6.0_19 Aug 2022 
Protocol Amendment Number / Date 
4.0_19 Aug 2022 
 
The information contained in this document is confidential. It is to be used by investigators, potential 
investigators, consultants, or applicable independent ethics committees. It is understood that this information 
will not be disclosed to others without written authorisation from DNDi, except where required by applicable 
local laws. 
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DNDi 
Drugs for Neglected Diseases initiative 


DNDi-FEX-07-HAT
Fexinidazole
Protocol version 6.0_19 Aug 2022 
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Clinical Trial Protocol template_Version 1.2_02 June 2014 
Site Principal Investigator’s Signature Page 
x 
I have read this protocol and agree that it contains all necessary details for carrying 
out this trial.  
x 
I will conduct the trial according to the protocol, any subsequent approved protocol 
amendments, International Council for Harmonization (ICH) for Good Clinical 
Practice (GCP) and all applicable regulatory authority requirements and national 
laws.  
x 
I will not deviate from the protocol without prior written permission from the Sponsor 
and 
prior 
review 
and 
written 
approval 
from 
the 
Institutional 
Review 
Board/Independent Ethics Committee (IRB/IEC), except where necessary to prevent 
any immediate danger to the patient.  
x 
I have sufficient time to properly conduct and complete the trial within the time 
designated and I have available an adequate number of qualified staff and adequate 
facilities for the foreseen duration of the trial to conduct it properly and safely. 
x 
I have read and understand fully the Investigator Brochure (IB) for fexinidazole, and 
I am familiar with the Investigational Medicinal Product(s) and its/their use according 
to this protocol. 
x 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this trial. I will discuss this material 
with them to ensure they are fully informed regarding the drug and the conduct of the 
trial. 
x 
I will use only the informed consent form approved by the sponsor or its 
representative and will fulfill all responsibilities for submitting pertinent information to 
the IRB/IEC responsible for this trial if required by national law. 
x 
I agree that the sponsor or its representatives shall have access to any source 
documents from which case report form information may have been generated. 
Principal Investigator at each trial site 
Investigator 
Signature 
Date 
of 
Signature 
(DD/MMM/YY) 
Name  
Title 
Institution 
Address 
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Clinical Trial Protocol template_Version 1.2_02 June 2014 
TABLE OF CONTENTS  
ABBREVIATIONS – GLOSSARY OF TERMS ............................................................. 11 
PROTOCOL SYNOPSIS ............................................................................................... 14 
1 
BACKGROUND AND TRIAL RATIONALE ....................................................... 25 
2 
TRIAL OBJECTIVES AND ENDPOINTS ........................................................... 27 
2.1 
Objectives ................................................................................................................................ 27 
2.1.1 
Ultimate Objective ............................................................................................................ 27 
2.1.2 
Primary Objective ............................................................................................................. 27 
2.1.3 
Secondary Objectives ...................................................................................................... 27 
2.1.4 
Exploratory Objectives ..................................................................................................... 28 
2.2 
Trial Endpoints ........................................................................................................................ 28 
2.2.1 
Primary Endpoint .............................................................................................................. 28 
2.2.2 
Secondary Endpoint(s) ..................................................................................................... 28 
2.2.3 
Exploratory Endpoints ...................................................................................................... 28 
3 
TRIAL DESIGN AND TRIAL DESIGN RATIONALE .......................................... 29 
3.1 
Trial design .............................................................................................................................. 29 
3.2 
Trial duration and duration of patient participation ............................................................ 29 
3.3 
Definition of the end of trial ................................................................................................... 29 
3.4 
Rationale of trial design ......................................................................................................... 29 
4 
SELECTION OF PATIENTS ............................................................................... 30 
4.1 
Inclusion criteria ..................................................................................................................... 30 
4.2 
Exclusion criteria .................................................................................................................... 30 
5 
SCHEDULE OF EVENTS ................................................................................... 31 
6 
ENROLMENT PROCEDURES ........................................................................... 31 
7 
TRIAL TREATMENTS ........................................................................................ 33 
7.1 
DNDi trial treatment ................................................................................................................ 33 
7.2 
Comparator trial treatment ..................................................................................................... 33 
7.3 
Non-IMP(s) ............................................................................................................................... 33 
7.4 
Doses and treatment regimens ............................................................................................. 33 
7.5 
Trial treatments labelling, packaging .................................................................................... 34 
7.6 
Accountability ......................................................................................................................... 34 
7.7 
Compliance .............................................................................................................................. 35 
7.8 
Storage ..................................................................................................................................... 35 
7.9 
Blinding and procedures for unblinding .............................................................................. 35 
7.10 
Concomitant treatments ......................................................................................................... 35 
7.10.1 
Concomitant Medications/measures ............................................................................ 35 
7.10.2 
Prohibited treatments ................................................................................................... 36 
7.10.3 
Contraception Methods ................................................................................................ 37 
7.11 
Rescue treatment .................................................................................................................... 38 
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8 
TRIAL ASSESSMENTS ..................................................................................... 38 
8.1 
Timing of Assessments .......................................................................................................... 38 
8.1.1 
Diagnosis of HAT .............................................................................................................. 38 
8.1.2 
Screening and Baseline Assessments ............................................................................. 39 
8.1.3 
Treatment period assessments ........................................................................................ 40 
8.1.4 
Post-treatment period assessments ................................................................................. 40 
8.1.5 
Follow-up period assessments ......................................................................................... 41 
8.1.6 
Unscheduled visits............................................................................................................ 42 
8.2 
Assessment of efficacy .......................................................................................................... 42 
8.2.1 
HAT diagnosis and staging .............................................................................................. 42 
8.2.2 
Medical History with emphasis on HAT signs and symptoms questionnaire ................... 43 
8.2.3 
Karnofsky Index ................................................................................................................ 43 
8.2.4 
Physical and Neurological Examinations ......................................................................... 43 
8.3 
Other assessments ................................................................................................................. 44 
8.3.1 
PK sampling ..................................................................................................................... 44 
8.3.2 
qPCR to detect trypanosome nucleic acids in patient blood ............................................ 44 
8.4 
Assessment of Safety ............................................................................................................. 44 
8.4.1 
Vital Signs ......................................................................................................................... 44 
8.4.2 
Laboratory examinations .................................................................................................. 45 
8.4.3 
Pregnancy test .................................................................................................................. 45 
8.4.4 
ECG .................................................................................................................................. 45 
8.5 
Adverse event definitions and reporting .............................................................................. 46 
8.5.1 
Adverse Event definition ................................................................................................... 46 
8.5.2 
Assessment of Laboratory/Procedures Abnormalities ..................................................... 46 
8.5.3 
Serious Adverse Event (SAE) .......................................................................................... 47 
8.5.4 
Adverse Event of Special Interest (AESI): ....................................................................... 48 
8.5.5 
Eliciting Adverse Event information .................................................................................. 49 
8.5.6 
Adverse Event reporting period ........................................................................................ 49 
8.5.7 
Grading of Adverse Event severity ................................................................................... 50 
8.5.8 
Adverse Event causality assessment ............................................................................... 50 
8.5.9 
Adverse Event reporting requirements ............................................................................. 51 
8.5.10 
Exposure in utero ......................................................................................................... 52 
8.5.11 
Exposure during breastfeeding .................................................................................... 52 
8.5.12 
Adverse event follow-up ............................................................................................... 53 
9 
WITHDRAWAL CRITERIA ................................................................................. 53 
9.1 
Rules for temporary interrupting the trial treatment ........................................................... 53 
9.2 
Rules for permanently interrupting trial treatment .............................................................. 54 
9.3 
Patient withdrawal from the trial and patient replacement ................................................. 54 
9.3.1 
Rules in case of withdrawal from trial ............................................................................... 54 
9.3.2 
Patient replacement:......................................................................................................... 55 
10 
DATA ANALYSIS AND STATISTICAL METHODS ........................................... 55 
10.1 
Sample size determination ..................................................................................................... 55 
10.2 
Definition of trial populations included in the analysis ...................................................... 56 
10.3 
Analyses................................................................................................................................... 57 
10.3.1 
Primary analysis ........................................................................................................... 57 
10.3.2 
Secondary analysis ...................................................................................................... 57 
10.4 
Safety Analysis ........................................................................................................................ 57 
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Clinical Trial Protocol template_Version 1.2_02 June 2014 
10.5 
Analysis of other endpoints ................................................................................................... 58 
10.5.1 
PK analyses ................................................................................................................. 58 
10.5.2 
ECG analysis ............................................................................................................... 58 
10.5.3 
Trypanosome nucleid acids detection analysis. .......................................................... 59 
10.6 
Futility analysis ....................................................................................................................... 59 
11 
DATA SAFETY MONITORING BOARD ............................................................ 59 
12 
QUALITY ASSURANCE AND QUALITY CONTROL PROCEDURES .............. 60 
12.1 
Investigator’s file ..................................................................................................................... 60 
12.2 
Case report forms (CRFs) ...................................................................................................... 60 
12.3 
Source documents .................................................................................................................. 60 
12.4 
Record Retention .................................................................................................................... 60 
12.5 
Monitoring, audits and inspections ...................................................................................... 61 
12.6 
Audits and inspections ........................................................................................................... 61 
12.7 
Data Management ................................................................................................................... 61 
12.8 
Confidentiality of trial documents and patients’ records ................................................... 62 
13 
PROTOCOL AMENDMENTS ............................................................................. 62 
14 
EARLY TERMINATION OF THE TRIAL ............................................................ 63 
15 
ETHICS ............................................................................................................... 63 
15.1 
Informed consent process ..................................................................................................... 64 
15.1.1 
Impartial Witness .......................................................................................................... 65 
15.1.2 
Illiterate Patients ........................................................................................................... 65 
15.1.3 
Patients Unable to Give Consent ................................................................................. 65 
15.1.4 
Collection of Assent from Children (patients below 18 years old) ............................... 66 
15.2 
Ethical aspects of patient inclusion and trial procedures .................................................. 66 
15.3 
Patient costs ............................................................................................................................ 67 
15.4 
Insurance and Liability ........................................................................................................... 67 
16 
REPORTING AND PUBLICATION OF TRIAL RESULTS ................................. 67 
17 
REFERENCES ................................................................................................... 68 
18 
APPENDICES .................................................................................................... 70 
Appendix 1 – Declaration of Helsinki ................................................................................................ 70 
Appendix 2 – Evaluation criteria of efficacy endpoints .................................................................. 75 
Appendix 3 – Karnofsky Index ........................................................................................................... 76 
Appendix 4 – modified CTCAE 5.0 .................................................................................................... 77 
Appendix 5 – Schedule of events ...................................................................................................... 82 
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TABLE OF FIGURES 
Figure 1- Overall trial design .......................................................................................... 30 
Figure 2 – Diagnostic tree ............................................................................................. 32 
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Abbreviations – Glossary of terms 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALB 
Albumin 
ALT 
Alanine aminotransferase (SGPT) 
AP 
Alkaline Phosphatase 
AST 
Aspartate aminotransferase (SGOT) 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
Ca2+ 
cDNA 
Calcium 
Complementary DNA 
CIOMS 
Council for International Organizations of Medical Sciences 
Cl- 
Chloride 
CLN 
Cervical Lymph Node 
CNS 
Central nervous system 
CRE 
Creatinine 
CRF 
Case Report Form 
CSF 
Cerebrospinal Fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome 
D 
Day 
DBS 
Dry-Blood-Spot 
DNA 
Deoxyribonucleic acid 
DNDi 
Drugs for Neglected Diseases initiative 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
e.g. 
EMA 
Exempli gratia, “for example” 
European Medicines Agency 
EoH 
End of Hospitalization 
EoT 
End of Treatment 
EoS 
End of Study 
g-HAT 
GCP 
Gambiense Human African Trypanosomiasis 
Good Clinical Practice 
GLU 
Glucose 
GMP 
H 
Good Manufacturing Practice 
Hour 
HAT 
Human African Trypanosomiasis 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
i.e. 
id est, “that is to say” 
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Clinical Trial Protocol template_Version 1.2_02 June 2014 
IEC 
Independent Ethics Committee 
 
 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intent to treat 
IV 
Intravenous 
K+ 
Potassium 
LMP 
Last Menstrual Period 
LP 
Lumbar Puncture 
M 
Month 
M1 
Sulfoxide Metabolite of fexinidazole 
M2 
mITT 
Sulfone Metabolite of fexinidazole 
Modified intention to treat 
mAECT 
Mini Anion Exchange Centrifugation Technique 
mAECT-BC 
Mini Anion Exchange Centrifugation Technique on Buffy Coat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHCT 
Microhematocrit centrifugation test 
Microhematocrit centrifugation test 
mRNA 
Messenger RNA 
MSF 
Médecins Sans Frontières 
Na+ 
Sodium 
NCI 
NDA 
National Cancer Institute 
National Drug Authority 
qPCR 
Quantitative Polymerase Chain Reaction 
PK 
Pharmacokinetics 
PV 
Pharmacovigilance 
QT 
QT Interval on the ECG (time interval between electrical depolarization 
and repolarization of the left and right heart ventricles) 
QTcF 
QT Interval Corrected for Heart Rate by the Fridericia’s formula 
r-HAT 
Rhodesiense Human African Trypanosomiasis 
RDT 
Rapid Diagnostic Test 
RNA 
Ribonucleic Acid  
RR 
Respiratory Rate 
RT 
Reverse Transcription 
SAC 
Scientific Advisory Committee 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SSL 
Secure Sockets Layer 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T.b. 
Trypanosoma brucei 
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T.b.r. 
Trypanosoma brucei rhodesiense 
TBIL 
Total Bilirubin 
tCO2 
Total CO2 - bicarbonate 
TEAE 
Treatment-Emergent Adverse Event 
ToC 
Test of Cure 
TP 
Tryps 
Total Protein 
Trypanosomes 
ULN 
Upper limit of normal 
vs. 
versus 
W 
Week 
WBC 
White blood cell 
WHO 
y.o. 
World Health Organization 
Years old 
 
 
 
 
 
 
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Clinical Trial Protocol template_Version 1.2_02 June 2014 
PROTOCOL SYNOPSIS 
Background 
Information and 
Trial Rationale 
Rhodesiense human African trypanosomiasis (r-HAT) is the zoonotic, 
acute form of sleeping sickness in Eastern Africa. The disease is 
rapidly lethal if untreated and has caused large epidemics in the past 
century. Over the past 15 years, efforts by the national HAT control 
programmes in all disease-endemic countries and key stakeholders 
have brought down the patient number to less than 100 per year. Even 
though these numbers are encouraging, approximately 1.5 million 
people live in areas still with moderate to high risk of contracting r-
HAT1,2. East Africa is affected by sleeping sickness in different foci, 
which tend to remain spatially stable over time, although the 
transmission intensity waxes and wanes over the years3. To date, 
Uganda and Malawi reported the highest number of cases worldwide. 
Latest WHO available data for the 6 years between 2012 and 2017 
showed 235 cases in Uganda (50% of all) and 157 in Malawi (34%)4. 
Disease severity appears to be very different across East African 
countries. In a cohort of patients treated in Lwala, Uganda between 
2004-12; 42.8% were identified as 1st stage (306/715)5  
In Zambia, T.b. rhodesiense infection has shown two different patterns 
of progression (acute and chronic)6, whereas an acute disease with 
rapid progression to late-stage infection is observed in Uganda and 
more chronic seems to be prevalent in Malawi7. Variation in HAT 
disease severity could be explained by a genetic variation in 
trypanosome virulence and/or differences in host response to 
trypanosomes infection8. Indeed, two genetically distinct strains of 
parasite (T.b.r. busoga and T.b.r. zambezi) have been associated with 
separate geographical locations: the strain group busoga appears to 
be associated with infections in northern areas, while the zambezi 
group is associated with the southern semi-acute form of the disease9. 
To date, only one drug, melarsoprol, is available for late-stage 
(meningoencephalitic stage) r-HAT. The use of this arsenic-based drug 
is associated with severe adverse drug reactions, the most important 
being an encephalopathic syndrome, which occurs in an average 8.0% 
of T.b. rhodesiense patients, with a case fatality rate of 57%10. Patients 
treated with melarsoprol need to be hospitalized. Furthermore, 
melarsoprol-monotherapy could be prone to the development  of 
parasite resistance to the drug in the long term, as already observed in 
the T. b. gambiense endemic region of northwestern Uganda11. 
Suramin, a sulphated naphtylamide, remains the treatment of choice 
for early haemolymphatic stage of Tb rhodesiense infection as it does 
not penetrate the CSF. Its half-life in Plasma can be between 44-54 
days.  Its relapse levels have been described between 6.9 -31% of 1st 
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stage Tb rhodesiense patients, increasing up to 64% in patients with 
borderline CSF anomalies (WBC count between 7-10/L). It has 
sometimes been recommended as pre-treatment before giving 
melarsoprol, but its effect in improving the outcome has not been 
demonstrated10 
In a declaration for the elimination of HAT due to T.b. rhodesiense, 
WHO stakeholders urged for a safe, effective and preferably oral 
treatment2. Fexinidazole was identified by DNDi out of hundreds of 
nitroimidazole compounds as a promising anti-protozoal drug 
candidate for the treatment of sleeping sickness. The ultimate goal of 
this study is to provide evidence for the safety and efficacy of 
fexinidazole for Tb rhodesiense HAT. 
Fexinidazole is a 2-substituted 5-nitroimidazole, formulated for oral 
administration. It has been shown to possess in vitro and in vivo activity 
against both T.b. rhodesiense and T.b. gambiense parasites12. 
Fexinidazole was shown to be safe in healthy volunteers given single 
or repeated doses for 14 days. Study participants administered with 
fexinidazole have shown mild to moderate headache, vomiting and/or 
other gastrointestinal symptoms. Some reversible elevations in liver 
enzymes and plasma creatinine levels have been observed in few 
volunteers after receiving fexinidazole. Changes in ECG parameters 
consisting of an increased heart rate and prolongation of the QT 
interval have been observed across several dose levels, with no clear 
dose effect seen. None of these changes are considered clinically 
relevant. Predicted CSF concentrations reached target levels after 
repeated dosing13.  
Fexinidazole efficacy and safety in patients with early- and late-stage 
HAT due to T.b. gambiense has been tested in three clinical trials 
(DNDiFEX00414, 
DNDiHATFEX005, 
DNDiHATFEX006). 
Overall 
tolerance in all three studies is similar to healthy volunteers’ studies 
(see section IB for Phase I clinical data). Patients presented 
nausea/vomiting, CNS/psychiatric AEs (dizziness, headache, tremor, 
anxiety, depression including suicidal ideation or insomnia), decreased 
appetite and asthenia. The majority of AEs were mild or moderate in 
severity and only two led to permanent treatment discontinuation. Also, 
a mild and reversible increase in creatinine levels was observed in 
some patients without any clinical consequence. Variations in ECG 
parameters 
were 
observed 
within 
normal 
ranges 
including 
asymptomatic QTc prolongation (see IB section for Phase II/III and 
cohort studies in HAT). The trial DNDi-FEX-09-HAT testing 
fexinidazole for Tb gambiense has been recently completed in 
additional population groups, including pregnant and breastfeeding 
women, as well as outpatients taking the treatment at home. Preclinical 
testing has shown that fexinidazole has no genotoxicity in mammalian 
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DNDi-FEX-07-HAT 
 
Fexinidazole 
Protocol version 6.0_19 Aug 2022 
 
Confidential  
Page 16 of 83 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
cells. It is present in breast milk, in similar concentration as in blood, 
but no relevant toxicity has been predicted for breastfed children15 
Efficacy and safety of fexinidazole as a treatment in other kinetoplastid 
diseases has been tested. The dose finding, 7-arm placebo-controlled 
trial for American trypanosomiasis (Chagas disease) DNDi-CH-FEXI-
001 was interrupted for safety and tolerability after including 47 
patients, using higher dosages than the one used for HAT. The key 
safety events are described in the IB (section DNDi-CH-FEXI-001 
study results). This led to a second clinical trial DNDi-FEX-12-CH, a 
proof-of-concept evaluation of low doses (600 and 1200 mg) and short 
treatment duration (at 3, 7 and 10 days) to determine the minimal 
efficacious and safe dose for the treatment of adult patients with 
chronic indeterminate Chagas disease. This trial is ongoing. 
The proof-of-concept trial DNDiFEXIVL001 for visceral leishmaniasis, 
which used the same dose as for HAT, was suspended for lack of 
efficacy. Overall, fexinidazole was well tolerated by the 14 visceral 
leishmaniasis patients enrolled in the trial. No SAEs have been 
reported during this clinical trial. Refer to IB for details in section 
possible risks, adverse drug reactions and contraindications 
Risks and 
benefits of 
study 
intervention 
First-in-man studies showed that fexinidazole is safe and well tolerated 
when given in the same doses used in this study13. The drug is well 
absorbed when administered in tablet form and its bioavailability 
depends on concomitant food intake. Drug-related adverse events are 
generally mild to moderate, and include headaches, nausea, vomiting, 
reversible rise in markers of the liver function and psychological 
problems (anxiety) with high doses13. Data in patients with HAT due to 
T.b. gambiense confirmed that fexinidazole is overall well tolerated14. 
Higher doses studied in Chagas disease patients showed transient 
neutropenia and raised transaminases. 
This trial will be conducted in hospitals experienced in the treatment of 
HAT patients, where qualified staff, equipment and other agents will be 
available in case of severe adverse reactions to fexinidazole or lack of 
efficacy. Patients will be followed up to 12 months after hospital 
discharge to detect potential relapses. 
If proven to be safe and effective, fexinidazole could replace the toxic 
melarsoprol for late-stage and suramin for early-stage HAT caused by 
T.b rhodesiense. Furthermore, fexinidazole could be used even in 
community health centres because it is easy to administer. 
If proven to be safe and effective in both stages of HAT, fexinidazole 
could then overcome the need for staging the disease. This would not 
only save patients from a painful lumbar puncture but also reduce the 
overall costs of equipment, infrastructure and trained personnel. 
If an early failure is observed, the DSMB may propose to continue the 
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DNDi-FEX-07-HAT 
 
Fexinidazole 
Protocol version 6.0_19 Aug 2022 
 
Confidential  
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Clinical Trial Protocol template_Version 1.2_02 June 2014 
study until 34 stage-2 patients or until further decision whichever 
comes first, assuming that no statistical conclusion will be drawn. 
Fexinidazole has received a positive opinion from the European 
Medicines Agency (EMA) on 15th November 2018 and has been 
registered in Democratic Republic of the Congo on 24th December 
2018 for the use in HAT due to T.b gambiense. It has been submitted 
for registration in Uganda and is currently under review by the National 
Drug Authority (NDA).  
Trial Objectives Ultimate Objective  
To show that fexinidazole offers an alternative over melarsoprol in 
stage-2 r-HAT patients and over suramin in stage-1 r-HAT patients 
Primary objective 
To show that the fatality rate (r-HAT or treatment related death) at the 
end of hospitalisation in stage-2 patients treated with fexinidazole is 
smaller than a threshold of unacceptable rate of 8.5% 
Rationale: The major issue with melarsoprol is not the cure rate if the 
patient survives at EoH, but the fatality rate due to toxicity 
Secondary Objectives 
1. To show that the failure rate (r-HAT or treatment related death 
according to DSMB or presence of trypanosomes) at the end 
of hospitalisation in stage-2 patients treated with fexinidazole 
is smaller than a threshold of an unacceptable rate of 9% 
Rationale: A new compound can show low mortality rate but still 
be not efficacious.   
2. To show that the proven failure rate (r-HAT related death 
according to DSMB or relapse) at 12 months (or before) in 
stage-2 patients treated with fexinidazole is below an 
unacceptable rate of 12% 
Rationale: A new compound can be non-toxic and initially 
efficacious (trypanosomes no longer observed at EoH), but the 
sustainability of effect can be poor (i.e. no complete elimination 
of trypanosomes or persistence of high WBC in CSF during 
follow-up).     
3. To estimate the failure rate at EoH and at 12 months in stage-
1 r-HAT patients treated with fexinidazole and to verify whether 
the estimates are smaller than that of suramin 
4. To estimate the fatality rate and success rate at 12 months in 
the overall population (late- and early-stage r-HAT patients) 
treated with fexinidazole 
Rationale: 1) It is the same parasite; the same population of 
patients and the ultimate objective is to yield one treatment 
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DNDi-FEX-07-HAT 
 
Fexinidazole 
Protocol version 6.0_19 Aug 2022 
 
Confidential  
Page 18 of 83 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
regardless of the stage of advancement of the disease. 2) 
Stage-1 patients are rare hence the estimates for stage 1 alone 
will not be very informative.   
5. To evaluate the safety profile of fexinidazole in late- and early-
stage r-HAT patients and to compare it to the one of 
melarsoprol and suramin as reported in the literature16. 
Exploratory Objective 
1. To estimate the time course of relapse of fexinidazole from EoT 
to 12 months after the end of treatment 
2. To assess the PK of fexinidazole and its main metabolites in the 
blood 
3. To assess the reduction in the number of trypanosomes in the 
blood until the end of study visit 
Trial Endpoints Primary Endpoint 
Possibly Related fatality rate at the end of hospitalisation in stage 2 r-
HAT patients treated with fexinidazole (death possibly related to r-HAT 
or treatment according to DSMB; since at the study sites 
anatomopathological techniques are not available, the completion of 
the WHO verbal autopsy questionnaire will be requested in case of 
death)   
Secondary endpoints  
1. Success rate at the end of treatment in stage 1 and stage 2 r-
HAT patients, where success is defined as: no trypanosomes at 
EoT and patient alive at EoH. Failure is defined as presence of 
trypanosomes in any body fluid at EoT or death at EoH. Deaths 
to be considered are defined as possibly related to r-HAT or 
treatment according to DSMB. Unrelated deaths are neither 
success nor failure.   
2. Success and failure outcomes at the test-of-cure (ToC) visit 12 
months after the end of treatment (EOT). A modification of the 
WHO recommendations [15] is used to determine success and 
failure for stage-1 and stage-2 r-HAT patients (Appendix 2 - 
Evaluation criteria of efficacy endpoints) 
3. Occurrence of adverse events, including abnormal laboratory 
or ECG findings, during the observation period (until the end of 
hospitalisation scheduled up to 7 days after EOT) and those 
considered as possibly related to r-HAT or treatment, among 
those detected until the end of the follow-up period (12-month 
visit). All serious adverse events (SAE) whether they are 
considered as possibly related to r-HAT treatment or not. 
4. Unsatisfactory clinical and parasitological response, defined as 
the compound analysis of the evolution of signs and symptoms 
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DNDi-FEX-07-HAT
Fexinidazole
Protocol version 6.0_19 Aug 2022
Confidential 
Page 19 of 83
Clinical Trial Protocol template_Version 1.2_02 June 2014
as well as laboratory tests during the observation period and at 
the end of treatment visit. 
Exploratory Endpoints
5. Earliest time to detect a relapse from EOT to 12 months after 
the end of treatment
6. PK parameters for fexinidazole and its metabolites in whole 
blood
7. Semi quantification of trypanosomes in blood until end of study and 
trypanosomes genetic analysis until EoT
Trial Design
Multicentre, open-label, non-randomized, clinical trial of patients with 
r-HAT on efficacy/ tolerability of fexinidazole
From 2012 to 2017, the annual number of patients treated for Tb 
rhodesiense in all endemic countries was decreasing almost every 
year: 110, 86, 118, 71, 54 and 274. This rare occurrence/incidence of 
disease raises the issue of the best use of available patients. A positive 
control randomized trial is not applicable because a randomized study 
based on the failure rate at EoH requires 124 patients per arm to get a 
power of 80%. A randomized study based on fatality rate at EoH would 
require a similar number of patients. With 20 patients per group and 
using the same expectations (failure rate of 9% and mortality rate of 
1%), the exact power is equal to 2.39% This is actually equal to the 
type I error. In this case, the working hypothesis (smaller fatality rate 
with fexinidazole) cannot be validated through a frequentist statistical 
test. In order to retain a null hypothesis that can be rejected by data 
with a small and realistic sample size, a benchmark study comparing 
the observed fatality rate to an unacceptable rate (that of melarsoprol 
in the recent years) was designed. Moreover, a non-inferiority trial is 
not applicable because the non-inferiority margin is a possible 
difference in fatality rate in favour of the positive control (melarsoprol) 
and the goal of the trial is to verify whether fexinidazole could decrease 
the mortality rate at EOH. For this reason, this trial was designed as a 
single-arm trial treating patients with fexinidazole only.       
Initiation 
DSMB : Futility 
Analysis
Follow-up visits at EOH, M1, 
W9, M6, EoS
End FU M12
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DNDi-FEX-07-HAT 
 
Fexinidazole 
Protocol version 6.0_19 Aug 2022 
 
Confidential  
Page 20 of 83 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
Main Entry 
Criteria 
Inclusion/Exclusi
on 
Patients must meet all the inclusion criteria and none of the exclusion 
criteria. 
Inclusion criteria 
x Signed Informed Consent Form (plus assent for children) 
x  6 years old 
x  20 kg body weight 
x Ability to ingest at least one complete meal per day (or at least 
one Plumpy’Nut® sachet) 
x Karnofsky index  40 
x Parasitological confirmed of T.b. rhodesiense infection 
x Having a permanent address or being traceable by others and 
willing and able to comply with follow-up visit schedule 
x Agreement to be hospitalised for a minimum of 13ays and to 
receive the study treatment 
Exclusion criteria 
x Active clinically relevant medical conditions other than HAT that 
may jeopardize subject safety or at the investigator discretion 
may interfere with participation in the study (e.g. Patients at risk 
of QT interval prolongations, cf. details listed in IB section 
Possible Risk), 
x Compromised general health or severely deteriorated general 
condition, such as severe malnutrition, cardiovascular shock, 
respiratory distress, or terminal illness 
x Known hypersensitivity to fexinidazole, to any nitroimidazole 
drugs (e.g. metronidazole, tinidazole) or to any of the excipients 
x Patients previously enrolled in the study or having already 
received fexinidazole 
x Patients with severe hepatic impairment (ex: clinical signs of 
cirrhosis or jaundice) 
Study Duration The entire study should last about 36 months.  
The enrolment period should be at least 24 months. The participation 
of each patient will last 12-13 months, and will include: 
x Hospitalisation period: 
o Pre-treatment: up to 7 days 
o Treatment: 10 days 
o Observation: 2 to 8 days 
x Follow-up period: 12 months after the first dose of treatment. 
If the recruitment of 34 evaluable stage-2 patients is shorter than 2 
years, the duration of the study can be shortened.  
Study 
Fexinidazole, 600 mg tablets, given orally, once daily for 10 days, right 
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DNDi-FEX-07-HAT 
 
Fexinidazole 
Protocol version 6.0_19 Aug 2022 
 
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Clinical Trial Protocol template_Version 1.2_02 June 2014 
Treatments 
after the main meal and preferably at the same time every day and only 
during hospitalisation. 
The daily doses are adjusted based on body weight and day of 
treatment, as follows: 
x Patients with a body weight  35 kg: 
 
 1800 mg (3 tablets) from day 1 to 4 
 
 1200 mg (2 tablets) from day 5 to 10 
x Patients with a body weight  20 and < 35 kg: 
 
 1200 mg (2 tablets) from day 1 to 4 
 
 600 mg (1 tablet) from day 5 to 10 
Allocation of treatment 
All consenting individuals will be assigned to treatment with 
fexinidazole. 
Sample size 
A scientific hypothesis is a hypothesis that can be rejected in an 
experimentation through a statistical test or a given observed fact. If 
the sample size is too small, the null hypothesis is not rejected even if 
no deaths are observed (whatever the observed death rate, H0 is not 
rejected). The minimal sample size to get a possible rejection of H0 
(fatality rate at EOH = 8.5% or more) in favour of H1 (fatality rate < 
8.5%) is 34 evaluable stage-2 patients for alpha = 0.05 one-sided. In 
that case if no patients died during treatment the exact one-sided test 
becomes significant (p = 0.0488). 
Consequently, the sample size is not set according a minimal power of 
80%, but according to the possible rejection of the null hypothesis. The 
second consequence of such an approach is: as soon as one death is 
observed at EOH, the study may be stopped for futility and failure 
(inconclusive result). To accept one failure and get a rejection of the 
null hypothesis once one failure is observed, the minimal sample size 
becomes 53 patients (p = 0.04967, for 1/53 deaths). Because this 
sample size cannot be reached within two years, the study is 
unfeasible if this hypothesis is applied.  
 
Even if the minimal sample size (n= 34) was retained to get a working 
hypothesis that can be rejected statistically, the power of the study 
remains quite reasonable.  Fexinidazole was administered to 361 
stage 2 patients suffering from HAT T.b gambiense. Two deaths were 
observed before the end of hospitalisation, considered unrelated to the 
treatment or disease. The fatality rate for any cause was therefore 
equal to 0.554%. These deaths were probably not due to treatment but 
considering the case of deaths regardless the cause, the power of the 
study in patients infected by T.b gambiense would be 82.79%. Using 
MSF data 17, the fatality rate in r-HAT stage 2 patients treated with 
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DNDi-FEX-07-HAT 
 
Fexinidazole 
Protocol version 6.0_19 Aug 2022 
 
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Clinical Trial Protocol template_Version 1.2_02 June 2014 
melarsoprol was twice (exactly 1.98) larger in T.b rhodesiense than in 
T.b gambiense stage 2 patients. If we consider it is due to the fragility 
of patients infected by rhodesiense trypanosomes, then the expected 
fatality rate for any cause with fexinidazole could reach 1.097%. Using 
the corrected estimate (1.097%) as true then the exact power of the 
study is 68.73 %. Considering deaths possibly related to treatment or 
disease, the power should be larger than 70% that is a reasonable 
power in a rare and neglected disease.             
 
If one death attributable to the treatment or disease may occur, the 
DSMB will rule whether or not the use of fexinidazole shall continue 
until the sample size of 34 patients is reached but no statistical 
inference will be made with regards to the unacceptable limit of 8.5%. 
 
N.B. In case of non-evaluable patients, the sample size will be 
increased to reach 34 evaluable patients that are required to get a 
testable hypothesis in the primary analysis (see primary analysis).  
 
The recruitment will be stopped once 34 evaluable stage-2 patients are 
recruited  
Statistics 
Randomization 
Planned 
Analyses 
Unacceptable Thresholds: 
Unacceptable fatality rate at end of hospitalisation 
Annual fatality rates reported in the four most endemic countries 
together (Malawi, Uganda, Zambia and Zimbabwe) for stage-2 patients 
treated with melarsoprol are the following: 12.5% (12/96) in 2010, 
12.4% (11/89) in 2011, 20% (14/70) in 2012, 12.1% (8/66) in 2013, 
10.4% (10/96) in 2014 and 14.3% (6/42) in 2015. On average, the 
fatality rate in these 6 years in those 4 countries was 13.3% (61/459). 
The average (13%) cannot be retained as a threshold because the 
fatality rate is clearly dependent upon the site and the rate is probably 
lower in clinical studies. For example, in 2014, the observed fatality 
rate was 23.3% at the Rumphi site (Malawi) and 6.7% at the Lwala site 
(Uganda). Moreover, in the Impamel III clinical study the observed 
death rate was 8.4% (9/107)16. The retained threshold for the 
unacceptable fatality rate is therefore 8.5%. 
Unacceptable failure rate at end of hospitalisation  
The rate of failure at the end of hospitalisation due to presence of 
trypanosome is quite infrequent. In the Impamel III study, all failures at 
end of hospitalisation were due to death.  
The unacceptable rate of failure (death or presence of trypanosomes) 
at the end of hospitalisation for stage-2 patients is therefore set at 9%. 
This threshold was proposed by HAT experts and WHO 
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DNDi-FEX-07-HAT 
 
Fexinidazole 
Protocol version 6.0_19 Aug 2022 
 
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Clinical Trial Protocol template_Version 1.2_02 June 2014 
representatives in a meeting held in December 201618.   
Unacceptable failure rate at 12 months follow-up 
The rate of failure at 12 months in the IMPAMEL III study for stage-2 
patients was 10.3% (9 deaths at EOH + 1 death and 1 relapse during 
FU). The unacceptable rate of failure set by HAT experts and WHO 
representatives in December 2016 was 12% and this threshold was 
retained in this study18. The slightly higher failure rate is justified by the 
fact that a relapse with a new drug can be treated with melarsoprol as 
a rescue medication 
Populations 
The population of evaluable patients is composed of patients who took 
at least one dose of fexinidazole excluding those whose death (if any) 
is documented and clearly attributable to other causes than r-HAT or 
treatment according to the DSMB and those who escape from the 
hospital and were not retrieved later to know their status on the primary 
outcome. This is the primary population. The choice of this set as the 
primary one is justified by the fact that the study is inconclusive if only 
one death occurred. If a death is, according to the DSMB, clearly 
unrelated to r-HAT or treatment such as poisoning, it is not reasonable 
to stop the trial for failure due to such an unrelated event. The 
secondary population is the modified intent to treat (mITT) set of 
patients consisting of all patients who took at least one dose of the 
study drug. This set will also be the safety set of patients. 
The intent to treat population (ITT set of patients: all recruited patients 
who signed the inform consent and were eligible for treatment) will be 
used to describe the disposition of patient.  
The fexinidazole treatment completer set of patients will consist of all 
patients who terminate the 10 days of treatment with fexinidazole.     
 Primary analysis 
The primary population is the evaluable set of stage-2 patients. 
The primary outcome is survival (alive or dead) at EoH. 
The primary parameter of interest is death rate at the EoH. 
In case of escape of a patient from the hospital and if the patient is not 
retrieved, the patient will be excluded from the population of evaluable 
patients and will be considered as a failure, but not a proven death.  
A one-sided exact test with respect to 8.5% (unacceptable fatality rate 
under H0) will be performed (alpha = 0.05 one-sided). 
The one-sided test is justified by the very small number of available 
patients.  
Sensitivity analyses 
The same analysis will be performed on the mITT set of patients and 
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Fexinidazole 
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Clinical Trial Protocol template_Version 1.2_02 June 2014 
on the set of treatment completers if at least 34 patients belong to these 
sets. 
Sample size 
Recruitment of both stages will stop once 34 evaluable stage-2 patients 
are reached.  
Futility analysis 
Because it is a one arm design and because only one death will lead 
to a failure of the trial (inconclusive results), the DSMB will meet as 
soon as one death occurs and the study can be stopped depending on 
the DSMB recommendations (the DSMB can recommend continuing 
the trial for exploratory purposes). 
Presence of trypanosomes or persistence of high WBC in CSF at any 
time from the end of hospitalisation until the end of follow up will also 
be considered as failure and could also help the DSMB in their 
recommendation to stop the trial.   
In case of unsatisfactory clinical and/or parasitological response during 
the treatment period and if the patient’s survival is at risk for an 
assumed lack of efficacy of the study treatment, the investigator may 
introduce rescue treatment with suramin for stage 1 and melarsoprol 
for stage 2 patients. These cases may also be taken into consideration 
by the DSMB in their recommendation. 
Secondary analyses 
The first secondary analysis will consist of calculating the failure rate 
at end of hospitalisation in stage-2 patients and to compare it with the 
threshold of unacceptable failure rate 9%) through a one-sided exact 
test (alpha = 0.05 one-sided). 
The second secondary analysis will consist of estimating the failure 
rate at 12 months in stage-2 patients and comparing it with the 
unacceptable threshold of 12%. A one-sided exact test of comparison 
will be performed if the observed rate is below 12%.  
The fatality rate at EOH, failure rate at EOH and failure rate at 12 
months will be estimated. Because the sample size will be very small, 
no null hypotheses will be testable. 
The estimate of fatality rate at EOH, failure rate at EOH and failure rate 
at 12 months for stage-1 and stage-2 combined will be calculated and 
tested against the unacceptable limit of 8.5%, 9% and 12%, 
respectively.    
Stopping rules 
The study can be stopped prematurely after recommendation by the 
DSMB if the DSMB considers that the tolerance to treatment or efficacy 
is insufficient.  
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Clinical Trial Protocol template_Version 1.2_02 June 2014 
1 Background and Trial Rationale 
Rhodesiense human African trypanosomiasis (r-HAT) is the zoonotic, acute form of 
sleeping sickness in Eastern Africa. The disease is rapidly lethal if untreated and has 
caused large epidemics in the past century. Over the past 15 years, efforts by the national 
HAT control programmes in all disease-endemic countries and key stakeholders have 
brought down the patient number to less than 100 per year. Even though these numbers 
are encouraging, approximately 1.5 million people live in areas still with moderate to high 
risk of contracting r-HAT1,2. East Africa is affected by sleeping sickness in different foci, 
which tend to remain spatially stable over time, although the transmission intensity waxes 
and wanes over the years3. To date, Uganda and Malawi reported the highest number of 
cases worldwide. Latest WHO available data for the 6 years between 2012 and 2017 
showed 235 cases in Uganda (50% of all) and 157 in Malawi (34%)4. Disease severity 
appears to be very different across East African countries. In a cohort of patients treated 
in Lwala, Uganda between 2004-12; 42.8% were identified as 1st stage (306/715)5  
In Zambia, T.b. rhodesiense infection has shown two different patterns of progression 
(acute and chronic)6, whereas an acute disease with rapid progression to late-stage 
infection is observed in Uganda and more chronic seems to be prevalent in Malawi7. 
Variation in HAT disease severity could be explained by a genetic variation in 
trypanosome virulence and/or differences in host response to trypanosomes infection8. 
Indeed, two genetically distinct strains of parasite (T.b.r. busoga and T.b.r. zambezi) have 
been associated with separate geographical locations: the strain group busoga rather 
appears to be associated with infections in northern areas, while the zambezi group is 
associated with the southern semi-acute form of the disease9. 
To date, only one drug, melarsoprol, is available for late-stage (meningoencephalitic 
stage) r-HAT. The use of this arsenic-based drug is associated with severe adverse drug 
reactions, the most important being an encephalopathic syndrome, which occurs in an 
average 8.0% of T.b. rhodesiense patients, with a case fatality rate of 57%10. Patients 
treated with melarsoprol need to be hospitalized. Furthermore, melarsoprol-monotherapy 
could be prone to the development  of parasite resistance to the drug in the long term, as 
already observed in the T. b. gambiense endemic region of north-western Uganda11.  
Suramin, a sulphated naphtylamide, remains the treatment of choice for early 
haemolymphatic stage of Tb rhodesiense infection as it does not penetrate the CSF. Its 
half-life in Plasma can be between 44-54 days10.  Its relapse levels have been described 
between 6.9 -31% of 1sts stage Tb rhodesiense patients, increasing up to 64% in patients 
with borderline CSF anomalies (WBC count between 7-10/L). It has sometimes been 
recommended as pre-treatment before giving melarsoprol, but its effect in improving the 
outcome has not been demonstrated10. 
In a declaration for the elimination of HAT due to T.b. rhodesiense, World Health 
Organization (WHO) stakeholders urged for a safe, effective and preferably oral 
treatment2. Fexinidazole was identified by DNDi out of hundreds of nitroimidazole 
compounds as a promising anti-protozoal drug candidate for the treatment of sleeping 
sickness. The ultimate goal of this study is to provide evidence for the safety and efficacy 
of fexinidazole for Tb rhodesiense HAT. 
Fexinidazole is a 2-substituted 5-nitroimidazole, formulated for oral administration. It has 
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Clinical Trial Protocol template_Version 1.2_02 June 2014 
been shown to possess in vitro and in vivo activity against both T.b. rhodesiense and 
T.b. gambiense parasites12. 
Fexinidazole was shown to be safe in healthy volunteers given single or repeated doses 
for 14 days. Study participants administered with fexinidazole have shown mild to 
moderate headache, vomiting and/or other gastrointestinal symptoms. Some reversible 
elevations in liver enzymes and plasma creatinine levels have been observed in few 
volunteers after receiving fexinidazole. Changes in ECG (Electrocardiogram) parameters 
consisting of an increased heart rate and prolongation of the QT interval have been 
observed across several dose levels, with no clear dose effect seen. None of these 
changes are considered clinically relevant. Predicted CSF (Cerebrospinal Fluid) 
concentrations reached target levels after repeated dosing13.  
Fexinidazole efficacy and safety in patients with early- and late-stage HAT due to T.b. 
gambiense has been tested in three clinical trials (DNDiFEX00414, DNDiHATFEX005, 
DNDiHATFEX006). Overall tolerance in all three studies is similar to healthy volunteers’ 
studies (see IB section for Phase I clinical data). Patients presented nausea/vomiting, 
CNS (Central Nervous System)/psychiatric AEs (dizziness, headache, tremor, anxiety 
depression including suicidal ideation or insomnia), decreased appetite and asthenia. The 
majority of AEs were mild or moderate in severity and only two led to permanent treatment 
discontinuation. Also, a mild and reversible increase in creatinine levels was observed in 
some patients without any clinical consequence. Variations in ECG parameters were 
observed within normal ranges including asymptomatic QTc prolongation (see IB section 
for Phase II/III and cohort studies in HAT). The trial DNDi-FEX-09-HAT testing 
fexinidazole for T.b. gambiense has been recently completed in additional population 
groups, including pregnant and breastfeeding women, as well as outpatients taking the 
treatment at home without new safety issues. 
Preclinical testing has shown that fexinidazole has no genotoxicity in mammalian cells. It 
is present in breast milk, in similar concentration as in blood, but no relevant toxicity has 
been predicted for breastfed children15.   
Efficacy and safety of fexinidazole as a treatment in other kinetoplastid diseases has been 
tested. The dose finding, 7-arm placebo-controlled trial for American trypanosomiasis 
(Chagas disease) DNDi-CH-FEXI-001 was interrupted for safety and tolerability after 
including 47 patients, using higher dosages than the one used for HAT. The key safety 
events are described in the IB (section DNDi-CH-FEXI-001 study results). This led to a 
second clinical trial DNDi-FEX-12-CH, a proof-of-concept evaluation of low doses (600 
and 1200 mg) and short treatment duration (at 3, 7 and 10 days) to determine the minimal 
efficacious and safe dose for the treatment of adult patients with chronic indeterminate 
Chagas Disease. This trial is ongoing. 
The proof-of-concept trial DNDiFEXIVL001 for visceral leishmaniasis, which used the 
same dose as for HAT, was suspended for lack of efficacy. Overall, fexinidazole was well 
tolerated by the 14 visceral leishmaniasis patients enrolled in the trial. No SAEs have 
been reported during this clinical trial. 
Refer to IB section for details on possible risks, adverse drug reactions and 
contraindications.  
Fexinidazole has received a positive opinion from the European Medicines Agency (EMA) 
on 15th November 2018 and has been registered in Democratic Republic of the Congo 
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on 24th December 2018 for the use in HAT due to T.b gambiense. It has been submitted 
for registration in Uganda and is currently under review by the National Drug Authority 
(NDA). 
2 Trial Objectives and Endpoints 
2.1 Objectives 
2.1.1 Ultimate Objective 
To show that fexinidazole offers an alternative over melarsoprol in stage-2 r-HAT patients 
and over suramin in stage-1 r-HAT patients 
2.1.2 Primary Objective 
To show that the fatality rate (r-HAT or treatment related death) at the end of 
hospitalisation in stage-2 patients treated with fexinidazole is smaller than a threshold of 
unacceptable rate of 8.5% 
Rationale: The major issue with melarsoprol is not the cure rate if the patient survives at 
EoH, but the fatality rate due to toxicity. 
2.1.3 Secondary Objectives 
1. To show that the failure rate (r-HAT or treatment related death according to DSMB
(Data Safety Monitoring Board) or presence of trypanosomes) at the end of
hospitalisation in stage-2 patients treated with fexinidazole is smaller than a
threshold of an unacceptable rate of 9%
Rationale: A new compound can show low mortality rate but still be not efficacious.
2. To show that the proven failure rate (r-HAT or treatment related death according
to DSMB or relapse) at 12 months (or before) in stage-2 patients treated with
fexinidazole is below an unacceptable rate of 12%
Rationale: A new compound can be non-toxic and initially efficacious
(trypanosomes no longer observed at EoH (End of Hospitalisation)), but the
sustainability of effect can be poor (i.e. no complete elimination of trypanosomes
or persistence of high WBC in CSF during follow up).
3. To estimate the failure rate at EoH and at 12 months in stage-1 r-HAT patients
treated with fexinidazole and to verify whether the estimates are smaller than that
of suramin
4. To estimate the fatality rate and success rate at 12 months in the overall population
(late- and early-stage r-HAT patients) treated with fexinidazole
Rationale: 1) It is the same parasite; the same population of patients and the
ultimate objective is to yield one treatment regardless of the stage of advancement
of the disease. 2) Stage-1 patients are rare hence the estimates for stage 1 alone
will not be very informative.
5. To evaluate the safety profile of fexinidazole in late- and early-stage r-HAT patients
and to compare it to the one of melarsoprol and suramin as reported in the
literature16.
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2.1.4 Exploratory Objectives 
1. To estimate the time course of relapse of fexinidazole from EoT to 12 months after
the end of treatment
2. To assess the PK (pharmacokinetics) of fexinidazole and its main metabolites in
the blood
3. To assess the reduction in the number of trypanosomes in the blood until the end
of study visit
2.2 Trial Endpoints 
2.2.1 Primary Endpoint 
Possibly related fatality rate at the end of hospitalisation in stage 2 r-HAT patients treated 
with fexinidazole (death possibly related to r-HAT or treatment according to DSMB; since 
at the study sites anatomopathological techniques are not available, the completion of 
the WHO verbal autopsy questionnaire will be requested in case of death).   
2.2.2 Secondary Endpoint(s) 
1. Success rate at the end of treatment in stage 1 and stage 2 r-HAT patients, where
success is defined as: no trypanosomes at EoT and patient alive at EoH. Failure
is defined as: presence of trypanosomes in any body fluid at EoT or death at EoH.
Deaths to be considered are defined as possibly related to r-HAT or treatment
according to DSMB. Unrelated deaths are neither success nor failure.
2. Success and failure outcomes at the test-of-cure (ToC) visit 12 months after the
start of treatment. A modification of the WHO recommendations [15] is used to
determine success and failure for stage-1 and stage-2 r-HAT patients (Appendix 2
- Evaluation criteria of efficacy endpoints)
3. Occurrence of adverse events, including abnormal laboratory or ECG findings,
during the observation period (until the EoH scheduled up to 7 days after EoT) and
those considered as possibly related to r-HAT or treatment among those detected
until the end of the follow-up period (12-month visit). All serious adverse events
(SAE) whether they are considered as possibly related to r-HAT treatment or not.
4. Unsatisfactory clinical and parasitological response, defined as the analysis of the
evolution of signs and symptoms as well as laboratory tests during the observation
period and at the end of treatment visit.
2.2.3 Exploratory Endpoints 
1. Earliest time to detect a relapse from EoT to 12 months after the end of treatment
2. PK parameters for fexinidazole and its metabolites in whole blood
3. Semi quantification of trypanosomes in blood and trypanosome nucleid acids
detection until end of study
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3 Trial design and Trial design rationale 
3.1 Trial design 
This is a multicentre, phase II/III, open-label, non-randomized clinical trial of r-HAT 
patients on efficacy and safety of fexinidazole. 
3.2 Trial duration and duration of patient participation 
The entire study should last about 36 months. 
x Hospitalisation period: 
o
Pre-treatment: up to 7 days
o
Treatment: 10 days
o
Observation: 2 to 8 days
x Follow-up period: 12 months after the first dose of treatment 
If the recruitment of 34 evaluable stage-2 patients is shorter than 2 years, the duration of 
the study can be shortened. 
Patients will be hospitalized from their arrival at the hospital/study centre until D18. They 
will be able to leave the hospital starting from D12 if their clinical status allows it. 
Additional unscheduled visits could occur and will be recorded as such in the Case Report 
Form (CRF). 
3.3 Definition of the end of trial 
The end of the trial is defined as the last visit of the last patient undergoing the trial (Last 
Patient Last Visit (LPLV)).  
3.4 Rationale of trial design  
From 2012 to 2017, the annual number of patients treated for T.b rhodesiense in all 
endemic countries was decreasing almost every year: 110, 86, 118, 71, 54 and 274. This 
rare occurrence/incidence of disease raises the issue of the best use of available patients. 
A positive control randomized trial is not applicable because a randomized study based 
on the failure rate at EoH requires 124 patients per arm to get a power of 80%. A 
randomized study based on fatality rate at EoH would require a similar number of patients. 
With 20 patients per group and using the same expectations (failure rate of 9% and 
mortality rate of 1%) the exact power is equal to 2.39%. This is actually equal to the type 
I error. In this case the working hypothesis (smaller fatality rate with fexinidazole) cannot 
be validated through a frequentist statistical test. In order to retain a null hypothesis that 
can be rejected by data with a small and realistic sample size, a benchmark study 
comparing the observed fatality rate to an unacceptable rate (that of melarsoprol in the 
recent years) was designed18. Moreover, a non-inferiority trial is not applicable because 
the non-inferiority margin is a possible difference in fatality rate in favour of the positive 
control (melarsoprol) and the goal of the trial is to verify whether fexinidazole could 
decrease the mortality rate at EoH. For this reason, this trial was designed as a single-
arm trial treating patients with fexinidazole only.       
The overall trial design is presented in the Figure 1- Overall trial design below: 
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Figure 1- Overall trial design  
4 Selection of Patients
34 stage-2 patients have to be enrolled and the recruitment of both stages will stop once 
34 evaluable stage-2 patients are reached. 
The following eligibility criteria were designed to select patients for whom the protocol 
treatment is considered appropriate. All relevant medical and non-medical conditions 
should be taken into consideration when deciding whether this protocol is suitable for a 
particular patient. Any questions regarding a patient’s eligibility should be discussed with 
DNDi Medical responsible personprior to patient’s enrolment.No waiver will beallowed
to include a patient who do not fulfil all eligibility criteria.
4.1 Inclusion criteria
Patients must meet all the following inclusion criteria to be eligible for enrollment into the 
trial: 
x
Signed Informed Consent Form (plus assent for children)
x
 6 years old
x
 20 kg body weight
x
Ability to ingest at least one complete meal per day (or at least one Plumpy’Nut®
sachet)
x
Karnofsky index  40
x
Parasitological confirmed T.b. rhodesiense infection
x
Having a permanent address or being traceable by others and willing and able to 
comply with follow-up visit schedule
x
Agreement to be hospitalised for a minimum of 13 days and to receive the study 
treatment

4.2 Exclusion criteria
The presence of any of the following will exclude a patientfrom trialenrolment:
x
Active clinically relevant medical conditions other than HAT that may jeopardize 
subject safety or at the investigator discretion may interfere with participation in 
the study (e.g. Patients at risk of QT interval prolongations, cf details listed in IB 
section Possible Risk).
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D-7to D-1 
D1 toDl0: 
Treatment period 
Screening 
and Baseline 
• 
• 
Inclusion 
D11 toD18: 
Observation period 
EoT 
• • 
EoH 
EoHtoM12: 
Follow-up period 
Ml (home) 
W9 
M6 
• • • 
• 
M12 
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x Compromised general health or severely deteriorated general condition, such as 
severe malnutrition, cardiovascular shock, respiratory distress, or terminal illness 
x Patients with severe hepatic impairment (ex. Clinical signs of cirrhosis or jaundice)  
x Known hypersensitivity to fexinidazole, to any nitroimidazole drugs (e.g. 
metronidazole, tinidazole) or to any of the excipients 
x Patients previously enrolled in the study or having already received fexinidazole 
5 Schedule of events  
Cf Appendix 5 – Schedule of events 
6 Enrolment procedures  
This clinical trial will be conducted in 2 centres in Uganda (Lwala Hospital) and Malawi 
(Rumphi District Hospital). Eligible HAT patients from other hospitals and centres in 
Kaberamaido/Dokolo Districts (Uganda) and Rumphi/Mzimba North Districts (Malawi) 
and possibly from Chama province in Zambia will be referred to Lwala and Rumphi 
Hospitals, respectively, for treatment.  
 
According to the standard medical procedures for HAT, patients presenting at the study 
site will undergo blood sampling and/or lymph node aspirate collection, followed by 
microscopic examination, to detect trypanosomes. In case of a positive result, a 
diagnostic lumbar puncture will be performed to evaluate the disease stage (Figure 2 – 
Diagnostic tree) 
Prior to any clinical trial specific procedures and evaluations, written signed informed 
consent must be obtained (as per ICF process detailed in Section 0). A patient number 
will be assigned to the patient.  
 
After signing the Informed Consent Form, HAT patients will be subjected to further 
evaluations/tests, including complete medical history, physical and neurological 
examination, haematology and biochemistry to assess their eligibility to the study (see 
Section 8.1.2). All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular patient based 
on inclusion and exclusion criteria (refer to section 4).  
Patients who are not eligible or who decide not to participate in the trial for any reason 
will be treated with melarsoprol or suramin according to the National guidelines. 
 
 
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Figure 2 – Diagnostic tree  
 
  
 
If mAECT is not available, Woo test, also named micro Haematocrit Centrifugation Technique (mHCT) to 
be done or thin/thick blood smear (only for initial diagnosis at screening) 
mAECT = Mini Anion Exchange Centrifugation Technique 
Tryps= Trypanosomes 
WBC = White Blood Cells 
 
The clinical sites should complete a Patient Screening/Enrolment Log to reflect patient 
number, enrolment status, date of enrolment, study enrolment number, date of non-
enrolment, and reason for not enrolling. Subjects older than 6 years old who fulfil the 
inclusion / exclusion criteria will be included in the study and will receive study medication. 
There is no randomization in this study. 
A note describing how the ICF (Informed Consent Form) was presented and the signature 
obtained, and a confirmation of eligibility to treat the patient will also be made in the 
patient's file.  
HAT clinical signs 
and symptoms 
lymph node 
palpation
mAECT
lymph node 
aspiration
Lumbar Puncture
Tryps Neg in CSF  
AND WBC ч 5/ђl
Tryps Pos in CSF 
AND/OR WBC > 5/ђl 
HAT Stage 1 patient
HAT stage 2 patient
+
+
+
+
-
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7 Trial treatments 
7.1 DNDi trial treatment  
Fexinidazole, a 2-substituted 5-nitroimidazole drug, is presented as pale yellow, round 
biconvex tablets packaged into aluminium/aluminium foil blisters. Each blister will contain 
one fexinidazole 600 mg tablet and the number of blisters per strip will be determined by 
the clinical trial protocol. The Investigational Medicinal Product (IMP) will be manufactured 
and packaged by 
. 
7.2 Comparator trial treatment 
Not applicable 
7.3 Non-IMP(s) 
Not applicable 
7.4 Doses and treatment regimens 
Fexinidazole will be given orally, once daily after the main meal under direct observation 
of an authorized staff member, and preferably at the same time every day, and only during 
hospitalization.  
The daily doses are adjusted based on body weight and day of treatment, as follows: 
x Patients with a body weight  35 kg: 
 
 1800 mg (3 tablets) from day 1 to 4 
 
 1200 mg (2 tablets) from day 5 to 10 
x Patients with a body weight  20 and < 35 kg: 
 
 1200 mg (2 tablets) from day 1 to 4 
 
 600 mg (1 tablet) from day 5 to 10 
The tablets must not be broken nor crushed.  
The total treatment duration will be 10 days. Treatment compliance will be guaranteed by 
the direct observed administration of the drug exclusively by the assigned staff.  
Allocation of treatment 
All consenting individuals will be assigned to treatment with fexinidazole. 
Dose modification 
Patients who vomit shortly after dosing (within 2 hours of drug administration) will receive 
the daily dose of fexinidazole again. If vomiting occurs more than 2 hours after drug 
administration, fexinidazole will not be re-administered, as drug absorption is considered 
to be complete. 
The treatment might be discontinued for a maximum of one day (i.e. one dose of 
fexinidazole is missed), and end of treatment will therefore be delayed. Treatment can be 
resumed, if the Investigator in charge of the patient considers it to be appropriate. One 
day of treatment will be added to compensate for the missed dose. The patient should 
continue with the study visits and procedures as planned, taking into account the delay. 
The reason for the temporary treatment discontinuation should be recorded in the 
appropriate source documentation and CRF. More details on treatment interruption(s) are 
presented in Section 0 Rules for temporary interrupting the trial treatment 
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7.5 Trial treatments labelling, packaging 
Fexinidazole tablets will be packaged into aluminium/aluminium foil blisters containing 
the number of tablets for one day of treatment (i.e. for adult and children patients with a 
body weight  35 kg: 3 tablets/blister strip for the first 4 days, and then 2 tablets/blister 
strip for the following 6 days). Every patient is attributed a treatment kit in a cardboard 
box containing 10 foil blister strips for a total of 14 or 24 tablets depending on their body 
weight.  
All study drug supplies will be prepared and labelled according to the requirements of 
local law and legislation and applicable Good Manufacturing Practice (GMP) guidelines. 
Detailed information of study medication secondary packaging and labelling will be 
included in the Pharmacy Manual. 
Minimum information to be included at study medication primary package (wallet card): 
x Name address and phone number of sponsor (DNDi) 
x Name of investigator 
x Drug name, dosage form, strength and quantity 
x Route of administration 
x Batch number 
x Clinical protocol number 
x Directions for use – refer to study protocol 
x “For clinical trial use only” 
x Storage conditions 
x Expiry date 
7.6 Accountability 
Responsibility for drug accountability at the study site rests with the Investigator; however, 
the Investigator may assign some of the drug accountability duties to an appropriate 
qualified pharmacist or designee. Inventory and accountability records must be 
maintained and must be readily available for inspection by the study monitor and are open 
to inspection at any time by any applicable regulatory authorities. The Investigator or 
designee will be expected to collect and retain all used, unused, and partially used 
containers of study drug until the end of the study.  
The Investigator or designee must maintain records that document:  
• investigational product delivery to the study site
• the inventory at the site
• use by each subject
• return to the Investigator or designee.
These records should include dates, quantities, batch/serial numbers (if available), and 
the unique code numbers (if available) assigned to the investigational product and trial 
subjects.  
The investigational product must be used only in accordance with the protocol. The 
Investigator will also maintain records adequately documenting that the trial subjects 
were provided the study drug specified. Completed accountability records will be 
archived by the site.  
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At the completion of the study, the Investigator or designee will oversee shipment of any 
remaining study drug/empty kits back to the Sponsor or Sponsor’s designee according to 
institutional standard operating procedures. All unused medications will be carefully 
recorded and documented before destruction. 
If local procedures allow for site destruction of investigational supply, prior written 
approval must be obtained from DNDi before disposing of the study drug. If the study 
drug is destroyed locally, a destruction record will be provided to DNDi. 
Fexinidazole must not be used for purposes other than this protocol. Under no 
circumstances may the Investigator or site staff supply study fexinidazole to other 
Investigators or healthcare services or allow the drug to be used other than as directed 
by this protocol, without prior written authorisation from DNDi. 
7.7 Compliance 
All participants will receive their treatment under hospitalisation. Fexinidazole will 
be administered within 30 minutes from a meal. A study nurse will oversee patient’s 
food intake to make sure that the patient has eaten sufficiently (a meal equivalent to a 
dose of Plumpy'Nut®; if not, the patient will be provided with a bag of Plumpy'Nut®). 
Drug intake will be monitored by a study nurse to make sure that fexinidazole is 
swallowed. The compliance is assessed and reported in the CRF, as well as the timing 
of administration. 
 
7.8 Storage 
Fexinidazole can be shipped at room temperature. Storage at a temperature 
not exceeding 30°C is recommended. Fexinidazole must be stored protected from the 
light, a condition which is provided by the alu-alu foil blisters packaging. The stability of 
the tablets in the alu-alu foil blisters will be monitored as part of the regulatory 
stability studies.  Study drugs must be kept in a locked cabinet and/or in a room with 
restricted access, under the control of the Investigator or a delegated person i.e. the 
study pharmacist Site storage conditions and temperature should be monitored and 
recorded daily by the site personnel in a temperature log. Temperature excursions 
below or above the allowable range should be reported to the study monitor. 
7.9 Blinding and procedures for unblinding 
Not applicable. This is an open-labelled study 
7.10 Concomitant treatments 
7.10.1 Concomitant Medications/measures 
Patients may receive concomitant therapy for medical occurrences during the course of 
the study. The investigator shall refrain from giving comfort drugs and use concomitant 
treatment only in case of need, choosing drugs included in the National Essential 
Medicines Lists of their own country. 
-
Anti-malaria drugs: All patients will have a diagnostic test for malaria. All patients
with positive thick smear and/or Rapid Diagnostic Test (RDT) should be treated.
-
All existing ACT (Artemisinin-based Combination Therapy) against malaria have
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effects on QT. In case malaria is diagnosed, the Artemisinin-based combination of 
Artemether and Lumefantrine should be used for treatment as it is known to have 
only a moderate and well quantified effect on QT prolongation19. The choice was 
made to minimize confounding factors regarding the evaluation of QT prolongation 
due to fexinidazole treatment. In case of contraindication to Coartem®, the 
Investigator will be allowed to choose another antimalarial treatment, which should 
be documented. This treatment will be provided free of charge by the Sponsor. 
-
Anti-helminthics: The treatment of helminthiasis with mebendazole or albendazole
will be provided in compliance with the site’s routine practice. Costs for participants
will be covered by the Sponsor.
-
Other medications: Only the medications or treatments needed for the welfare of a
subject and not expected to interfere with the study drug may be administered at
the discretion of the Investigator.
All concomitant medications taken by the patient during the study, from the date of 
signature of the informed consent until the end of hospitalization, will be recorded in the 
appropriate section of the patients’ charts and in the appropriate sections of the CRF, 
with reason for use and dates of administration. 
All concomitant medications are to be entered under the International Non-proprietary 
Name (NNI) and will be reviewed for harmonization and coded at data management level. 
Any essential medication that is required during the trial period (until the 12-month follow-
up visit) will be provided free of charge to the patient, see Section 0 below. The WHO 
Model Lists of Essential Medicines for adults20 and children 21, the National Essential 
Medicines lists and the MSF (Médecins sans Frontières) essential drugs practical 
guidelines22 will serve as reference for treatment of any concurrent condition. For any 
chronic disease which develops or worsens during treatment, the study team will take all 
necessary measures to have the patient referred to the most appropriate medical centre 
of the area. 
7.10.2 Prohibited treatments 
Since the pathways involved in the formation, metabolism and elimination of the active 
M2 metabolite are unknown and as no drug-drug interaction studies have been 
performed, it is recommended not to administer any other concomitant medications with 
fexinidazole 
Due to pharmacodynamics interactions, the following concomitant uses is contra-
indicated:  
Rational 
Anti-arrhythmics class IA (e.g. quinidine, hydroquinidine, 
disopyramide) 
May 
prolonge 
the 
QT 
interval 
Anti-arrhythmics class III (e.g. amiodarone, sotalol, dofetilide, 
ibutilide) 
Tricyclic antidepressive agents (e.g. imipramine, amitriptyline) 
Certain antimicrobials including some antituberculosis agents 
(saquinavir, 
atazanavir, 
erythromycin 
IV, 
sparfloxacin, 
moxifloxacin, ofloxacin, levofloxacin, clofazimine, delamanid, 
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pentamidine, certain antimalarials particularly halofantrine) 
Certains antihistaminics (terfenadine, astemizole, mizolastine) 
Others (cisapride, vincamine IV, diphemanil, lithium,) 
loop and thiazide diuretics, laxatives and enemas at high 
doses, corticosteroids, amphothericin B 
May lead to proarrhythmic 
events 
beta-blockers, calcium channel blockers 
Alcohol (until 48hrs after the last dose) 
Risk of a disulfiram-like 
reaction (antabuse effect) 
characterized by flushing, 
rash, peripheral oedema, 
nausea and headache 
In case of medical emergency, these drugs may be administered under the responsibility 
of the investigator as needed. Close supervision will be required 
If patients are, or need to be treated with drugs known to prolong QT interval or to induce 
bradycardia or hypokalaemia, fexinidazole should not be initiated until such drugs are 
eliminated from the body (allow a washout period of 5 half-lives), or treatment with such 
drugs should not be started until fexinidazole and its active metabolites are eliminated 
from the body (allow a washout period of 7 days). 
Due to potential pharmacodynamic interactions, the following concomitant uses are not 
recommended:  
Rational 
Drugs metabolized by CYP1A2 (such as caffeine, 
duloxetine, 
melatonin, 
tacrine, 
tizanidine, 
theophylline) or CYP2C19 (such as omeprazole, 
mephenytoin, diazepam),  
Fexinidazole could potentially 
increase the exposures to these 
drugs 
Disulfiram 
Possible psychotic reactions 
Propylene glycol 
5-Nitroimidazoles interfere with
its metabolism
Traditional 
medicine: 
traditional 
or 
herbal 
medicine 
Potential 
interactions 
are 
unknown 
Some medications can be used with caution:  
Antipsychotics (in context of treatment of psychiatric events) could be used if required in 
hospitalised patients under close monitoring. 
7.10.3 Contraception Methods 
Women of childbearing potential will be advised not to become pregnant and will be 
encouraged to use contraception or practice abstinence from sexual intercourse during 
the treatment period and at least until 48hrs after the last dose of fexinidazole. Medically 
proven means of contraception (hormonal contraception and condoms) may be made 
available free of charge to study participants during the 12 months of the individual study 
follow-up. 
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7.11 Rescue treatment 
Patients with trypanosomes detectable at EOT visit, as well as patients with evidence of 
relapse (i.e. presence of T.b. rhodesiense in any body fluid) or probable relapse at any 
time during follow-up, will receive alternative HAT treatment according to the study site’s 
medical standards and recommendation from the National Sleeping Sickness Control 
Program. The rescue treatment will be provided by the Sponsor free of charge for the 
patient. 
Probable relapse at 1-month, 9-week, 6- and 12-month follow-up visit is defined as shown 
in Appendix 2 – Evaluation criteria of efficacy endpoints. 
8 Trial Assessments 
8.1 Timing of Assessments 
Ideal and acceptable timing for visits is indicated in the below table and are calculated 
based on D1. 
Visit type 
Ideal timing for visits 
Acceptable timing for visits 
End of Treatment (EoT) 
D11  
(D1 + 10 days) 
D11 to D12 
End of Hospitalization (EoH) 
Between D12 and D18 
D18 at the latest 
M1 
D31 (D1 + 30d) 
+/- 7 days 
D24 to D38 
W9 
D64 (D1 + 63d) 
 +/- 7 days 
D39 to D120 
M6 
D181 (D1 + 180d) 
+/- 30 days 
D121 to D300 
M12 
D361 (D1 + 360d) 
 +/- 30 days 
D301 to D421 
Details on the schedule of assessments can be found in Appendix 5 – Schedule of events 
8.1.1 Diagnosis of HAT 
As part of routine diagnostics, the following tests will be performed before signature of 
the informed consent, within 7 days of ICF signature. 
Diagnosis of a trypanosome infection will be based on the following parasitological 
methods: 
x 
Capillary or venous blood sampling and microscopic examination for 
parasite detection – blood samples should be processed according to the 
mini Anion Exchange Centrifugation Technique (mAECT). If mAECT is not 
available, the Micro-haematocrit Centrifugation Technique (Woo Test) or 
the thick or thin blood smear may be used for initial diagnosis.  
x 
If enlarged lymph node is detected in the cervical area, aspirate sampling 
and microscopic examination for parasite detection can be done, if routinely 
performed at the centre. 
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x 
Lumbar puncture and CSF collection followed by WBC count, modified 
single centrifugation and microscopic examination for parasite detection.  
x 
For details on these tests, please refer to the Study Lab Manual.  
Note:  
- 
If the subject is parasite-negative in the blood and/or lymph node aspirate 
and lumbar puncture has not been performed, the subject will not be 
proposed the study. If signs strongly suggestive for HAT are present, a 
lumbar puncture may be performed at discretion of the Investigator, and if 
trypanosomes are detected in CSF, a patient may be proposed for the study 
if compliant with all inclusion and exclusion criteria. 
Parasite-positive subjects will be informed about the study according to the process 
presented in Section 6. Enrolment procedures of this protocol and be offered to sign the 
Informed Consent Form before undergoing any further testing. Microscopic videos of the 
trypanosomes in the CSF and in the blood can be taken but will be transmitted to the 
Sponsor only after the patient signs the Informed Consent Form.  
8.1.2 Screening and Baseline Assessments 
The screening visit should occur within 7 days before starting the treatment and after 
obtaining the informed consent and will include the following procedures, to evaluate:  
 
At the screening visit, the following procedures are to be completed in order to evaluate 
patient eligibility for the study:  
x 
Demographic information  
x 
Body weight and height 
x Complete medical history and observation 
x Record of concomitant diseases and concomitant medications taken for the 7 
days-period prior to dosing with fexinidazole 
x Pregnancy test for women of reproductive age (12 years old) on the first day of 
screening 
x Karnofsky index 
x Pre-treatment of helminthiasis 
x Malaria rapid diagnostic test and/or thick blood smear and treatment if positive. 
 
The following assessments will be performed within 4 days before the first dose of 
medication is administered, in order to obtain baseline safety data and data for further 
comparative analyses and multiple parameter correlations:  
x 
Vital signs including blood pressure, heart rate, respiratory rate and body 
temperature 
x 
Physical and neurological examination 
x 
HAT signs and symptoms questionnaire 
x 
mAECT baseline examination for semi-quantitative evaluation of trypanosomes 
in blood if not done previously. Video to be recorded if trypanosomes are 
observed. 
x 
Clinical safety laboratory evaluations: haematology and biochemistry 
x 
Blood sampling for qPCR analysis. 
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x 
ECG digital recording (CarTouch®): a simple ECG will be recorded. Each 
screening ECG download will be sent to the centralised cardiologist for 
interpretation. All ECGs will be analysed by the cardiologist for rhythm and 
conduction abnormalities to help the Investigator with the subject inclusion 
x 
ECG digital recording (CarTouch®): a triplicate ECG at 2 min intervals will be 
recorded for QT evaluationPatients fulfilling all the inclusion criteria and none of 
the exclusion criteria will be eligible for fexinidazole treatment.  
Note: subjects who are not eligible for fexinidazole treatment or who decide not to 
participate in the trial for any reason will be treated with melarsoprol or suramin according 
to the national guidelines. 
8.1.3 Treatment period assessments 
All participants will receive fexinidazole treatment for 10 days.  
The following tests will be performed along the treatment period or at the specified time 
points: 
x 
Vital signs, every day from D1 to D10 
x 
Clinical status, including physical and neurological examination, on D5  
x 
Karnofsky index on D5 
x 
HAT signs and symptoms questionnaire on D5 
x 
ECG digital recording (CarTouch®): A single ECG will be recorded on D2 pre-
dose, D3 and D4 pre-dose. 
x 
Triplicate ECGs at 2 min intervals will be recorded on D4, 3h, and 12 hours after 
drug intake.   
x 
During treatment, other ECGs can be recorded at the Investigator’s discretion 
x 
mAECT on D5 for semi-quantitative evaluation of trypanosomes (If parasites are 
not seen, mAECT-BC may also be performed). Video to be recorded if 
trypanosomes are observed. 
x 
Blood sampling for PK and qPCR analysis on D1 and D4.  
x 
Biochemistry and haematology tests on D5.  
x 
During treatment, additional biochemistry and haematology tests can be recorded 
at the Investigator’s discretion  
8.1.4 Post-treatment period assessments 
The following tests will be performed at the end of treatment visit (EoT) on D11: 
x 
If enlarged cervical lymph node is present, then aspirate sampling followed by 
microscopic examination for parasite detection 
x 
mAECT for semi-quantitative evaluation of trypanosomes (If parasites are not 
seen, mAECT-BC will also be performed). Video to be recorded if trypanosomes 
are observed 
x 
Lumbar puncture and CSF collection followed by WBC count, modified single 
centrifugation and microscopic examination for parasite detection 
x 
Clinical status, including vital signs and physical and neurological examination 
x 
Karnofsky index 
x 
Haematology and biochemistry 
x 
Triplicate ECG at 2 min interval recorded 23 hours after last dose  
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x 
Blood sampling for PK analysis on D10H24 (D11) and on D10H48 (D12) and for 
qPCR analysis on D10H24. 
Before final discharge, between D12 and D18, patients will undergo the following 
exams: 
x 
Clinical status, including vital signs, physical and neurological examination, HAT 
signs and symptoms, Karnofsky index 
x 
Pregnancy test for women of reproductive age (12 years old) 
8.1.5 Follow-up period assessments  
All efforts should be made to follow-up the patients for 12 months.  
8.1.5.1 M1  
The 1-month follow-up visit will consist of a home visit of the patient by the physician, it 
should take place 30 days after D1 (+/- 7 days). He will check the clinical status, HAT 
signs and symptoms, Karnofsky index and make a physical and neurological 
examination. In case of suspected relapse, or bad clinical status, the patient will be 
transferred to the hospital for additional examinations. 
8.1.5.2 W9 
The following tests will be performed at the hospital 9 weeks after D1 on D64 (+/- 7 days): 
x 
If cervical lymph node is enlarged, then aspirate sampling followed by microscopic 
examination  
x 
mAECT and/or mAECT-BC and video if trypanosomes are observed 
x 
Lumbar puncture and CSF collection followed by WBC count, single modified 
centrifugation and microscopic examination for parasite detection and video if 
trypanosomes are observed 
x 
Blood sampling for qPCR analysis. 
x 
Clinical status, including vital signs (i.e. blood pressure, heart rate, respiratory rate 
and body temperature), physical and neurological examination, HAT signs and 
symptoms and Karnofsky index. 
x 
Body weight and height, the latter only in children  16 y.o. 
x 
Haematology and biochemistry 
x 
ECG digital recording (CarTouch®): triplicate ECGs at 2 min intervals will be 
recorded 
x 
Pregnancy test for women of reproductive age (12 years old) 
8.1.5.3 M6 and M12 (Test of Cure) 
6 months and 12 months after D1 (+/- 30 days), patients will undergo the following exams 
at the hospital: 
x 
If cervical lymph node is enlarged, then aspirate sampling followed by microscopic 
examination 
x 
mAECT and/or mAECT-BC and video if trypanosomes are observed  
x 
Lumbar puncture and CSF collection followed by WBC count, modified single 
centrifugation and microscopic examination for parasite detection and video if 
trypanosomes are observed  
x 
Blood sampling for qPCR analysis 
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x 
Clinical status, including vital signs (i.e. blood pressure, heart rate, respiratory rate 
and body temperature), physical and neurological examination, HAT signs and 
symptoms and Karnofsky index. 
x 
Body weight and height, only in children  16 years 
x 
Additional safety examinations such as biochemistry, haematology and ECG can 
be performed at Investigator’s discretion 
If the patient is unable or unwilling to attend the 12-month follow-up visit, direct evidence 
of a satisfactory patient’s clinical condition by the Investigator or a delegated staff from 
the trial team will be acceptable to assess the success for this patient. If the clinical 
condition is unclear, patient should be brought back to the hospital for clarification, 
including parasitological exams. 
8.1.6 Unscheduled visits 
If uncertain evolution is diagnosed (based on clinical examination or on WBC count in the 
CSF) at any visit, patients will be asked to come back after one to three months (at the 
Investigator’s discretion). The patient will also be invited to come back anytime if s/he 
feels sick, even if there is no clear relationship to treatment and/or to HAT. 
The following parameters will be measured: 
x 
Clinical status, including vital signs (i.e. blood pressure, heart rate, respiratory rate 
and body temperature), physical and neurological examination, HAT signs and 
symptoms 
x 
Diagnosis of concomitant disease which triggered the visit 
x 
Blood and/or lymph node aspirate sampling followed by microscopic examination 
for parasite detection (mAECT and/or mAECT-BC) if the patient presents clinical 
signs of HAT. 
x 
Lumbar puncture and CSF collection followed by WBC count, modified single 
centrifugation and microscopic examination for parasite detection, if disease 
progression is suspected 
x 
Karnofsky index 
x 
Additional safety examinations such as biochemistry, haematology and ECG can 
be performed at Investigator’s discretion 
8.2 Assessment of efficacy 
8.2.1 HAT diagnosis and staging 
HAT diagnostic tests will consist of blood and lymph node examination followed by CSF 
examination. 
These will be done at screening, EoT visit (D11) and during follow-up visits (W9, M6 
and M12) 
Refer to the diagnostic tree presented in Figure 2 – Diagnostic tree for more details.   
8.2.1.1 Lymph node examination 
Cervical lymph nodes (CLN) will be palpated to detect any enlarged node. Enlarged CLNs 
will be punctured and aspirates examined under the microscope to verify the presence of 
trypanosomes.23  
Depending on the result of this test, further tests will be performed, according to the 
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diagnostic tree presented in Figure 2 – Diagnostic 
tree 8.2.1.2 Blood examination 
Blood examination will consist of performing one or more of the below parasitological 
tests, listed in preference order:  
-
mAECT, on 500 ȝl heparinized venous blood 23
-
Micro-hematocrit centrifugation technique or Woo test. Can be used for initial
diagnosis only if mAECT are not available at the peripheral testing site.
All these examinations will be done via capillary or venous blood sampling and videos 
and images will be collected if the parasite is detected. These deidentified images and 
videos will be sent to the Sponsor only after the patient signs the ICF. 
Parasites in blood examination will be done at screening, D5, EoT visit (D11) and during 
follow-up visits (W9, M6 and M12). 
8.2.1.3 CSF examination  
Lumbar puncture will be done on patients with trypanosomes in blood and/or lymph to 
verify the presence of trypanosomes in the CSF for disease staging and to count the 
number of WBC. 
4 mL of CSF will be withdrawn and if trypanosomes are detected, videos will be taken 
and sent to the Sponsor (only after ICF signature, during screening, at D11, W9, M6 and 
M12).  
8.2.2 Medical History with emphasis on HAT signs and symptoms questionnaire 
The Medical History will be collected up to the first dose of study drug and should be 
reported in standard medical terminology and will be coded according to the most recent 
version of Medical Dictionary for Regulatory Activities (MedDRA). 
Signs and symptoms specific to HAT disease will be collected at baseline and at further 
visits (including unscheduled visits), using a specific questionnaire. 
8.2.3 Karnofsky Index 
The Karnofsky index24 will be calculated using the scale presented in Appendix 3 – 
Karnofsky Index at screening, D5, EoT, EoH, and during all follow-up visits, and during 
unscheduled visits.  
8.2.4 Physical and Neurological Examinations 
A comprehensive physical and neurological examination will be performed at Screening, 
D5, EoT visit, EoH visit, all follow-up visits and during unscheduled visits. 
-
The comprehensive physical examination will include height and body weight, all
relevant body systems including circulatory, respiratory, digestive, excretory (renal),
integumentary (skin), and lymphatic systems.
-
The neurological assessment will include a psychiatric observation (verbal flow,
psychomotricity, behavioral disturbances, mood, etc.), higher function, cranial nerves,
mobility, motor coordination and balance, primitive reflexes, and sensitivity.
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8.3 Other assessments 
8.3.1 PK sampling 
2mL of venous blood will be collected for PK analyses on D1, D4, D11 and D12 at the 
time points shown in the below table. 
Visit 
Timing after treatment administration 
D1 
30 min 
3h30 
6h  
D4 
3h30 
6h 
12h 
D10 
24h (D11) 
48h (D12) 
A small amount of blood will be placed on a DBS (Dried Blood Spot) card and shipped to 
the Central Laboratory for analyses. 
8.3.2 qPCR to detect trypanosome nucleic acids in patient blood  
In order to monitor treatment success, quantitative PCR (qPCR) will be carried out both 
on DNA and cDNA obtained after reverse transcription (RT) of ribonucleic acid (RNA) 
isolated from patient blood. The advantage of RT-qPCR is that it could be a finer way to 
describe this disappearance since presence of RNA implies that of live trypanosomes, 
while signals from DNA might persist even long after parasite clearance25. 
2 mL of venous blood will be collected for trypanosome genetic analyses at the following 
time points:  
Visit 
Timing after treatment administration 
D-4 to D-1
Baseline 
D1 
6h  
D4 
12h 
D10 
24h (D11) 
W9 
anytime 
M6 
anytime 
M12 
anytime 
The blood will be injected into PAXgene tubes to stabilize RNA for downstream extraction; 
we shall also make dry blood spots from which DNA will be extracted.  Samples will be 
transported at ambient conditions to the 
 laboratories. 
8.4 Assessment of Safety 
8.4.1 Vital Signs 
Vital sign measurements including body temperature, blood pressure (BP), heart rate 
(HR), and respiratory rate will be taken at screening, along the treatment period, at EoT 
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and EoH visits and during W9, M6 and M12 follow-up visits and during unscheduled visits. 
Vital signs will be performed with the subject in sitting position after at least 10 minutes of 
rest. 
8.4.2 Laboratory examinations 
Capillary or venous blood collection for biochemistry and haematology tests on D5. Blood 
samples will be analysed at each centre’s laboratory using standardised chemistry 
equipment provided by the Sponsor. Blood collection should be performed in fasting 
status, as much as possible. If the patient is not fasting, this shall be reported together 
with the test results. 
Refer to Lab Manual for further details. 
Any abnormal finding (after retesting) will be assessed for clinical significance. 
-
Haematology: haemoglobin, total WBC count, differential WBC count, platelet
count
-
Biochemistry: 
albumin 
(ALB), 
alkaline 
phosphatase 
(ALP), 
alanine
aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen
(BUN), chloride (Cl-), creatinine (CRE), glucose (GLU), potassium (K+), sodium
(Na+), calcium (Ca2+), total bilirubin (TBIL), bicarbonates (tCO2), total protein
(TP)
8.4.3 Pregnancy test 
Three urine pregnancy tests are planned during the study: on the first day of screening at 
discharge from hospital and at the 9-week visit.  
8.4.4 ECG 
ECG digital recording (CarTouch®) will be measured at the following time points: 
Single ECG 
Triplicate ECG 
D-4 to D-1
X  
X 
D2 
X (Pre-dose) 
D3 
X (Pre-dose) 
D4 
X (Pre-dose) 
X (D4H3, D4H12) 
D11 
X (D10H23) 
W9 
X 
M6 
At investigator’s discretion 
M12 
At investigator’s discretion 
o
A single ECG: a simple recording will be analysed by the Investigator to check the
QTcF value (corrected QT interval using the Fridericia’s formula – calculated
automatically). If QTcF value is equal or over 500 ms, another ECG should be
performed after 10-20 minutes rest. If the value is confirmed, the patient should be
withdrawn from the study and no additional fexinidazole should be administered.
o
Triplicate ECGs at 2 min intervals will be recorded (the latest ECGs should be used
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to evaluate patient’s safety before administration) 
o
During treatment, other ECGs can be recorded at the Investigator’s discretion
8.5 Adverse event definitions and reporting
Safety of the study treatment will be assessed through routine monitoring of adverse 
events, which will be done daily from screening to EoH and then during scheduled follow-
up visits. At each study visit, the patients will be enquired about current adverse events 
or any events observed during the period before the visit. During the follow-up period, 
patients will be advised to return to the clinic at any moment for additional AE (Adverse 
Event) assessment, in case they present any medical occurrence. 
In addition, evaluation of laboratory parameters, ECG recordings, regular measurement 
of vital signs and physical examinations will be made at scheduled follow-up visit, as 
detailed in Section 8.1.5. A pregnancy test for women  12y.o will be done at screening, 
EoH and W9 visits.  
8.5.1 Adverse Event definition 
An AE is defined as: 
 "Any untoward medical occurrence in a patient or clinical trial subject administered a 
medicinal product, and which does not necessarily have a causal relationship with that 
treatment.  
It can therefore be any unfavourable and unintended sign (for e.g. an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product." 
Definition of an AE includes worsening (in severity and frequency) of pre-existing 
conditions ("Medical history") before first IMP administration and abnormalities of 
procedures (i.e., ECG, X-ray, ophthalmologic or neurological examination etc.) or 
laboratory results which are assessed as "clinically significant".  
What is not an AE  
x Medical conditions present at the initial study visit that do not worsen in 
severity or frequency during the study are NOT considered as AEs. 
x Symptoms, exacerbation or worsening of the studied disease will NOT be 
considered as AE nor captured on the AE page of the CRF if consistent with 
the anticipated natural progression of the disease (overall and for this given 
subject).  
x Lack of efficacy of the IMP is not considered as AE. 
8.5.2 Assessment of Laboratory/Procedures Abnormalities 
For every laboratory/procedure assessment, the investigator will evaluate if the 
laboratory/procedure test is normal or abnormal. If abnormal (after repeat testing), the 
investigator will assess if this finding is “clinically significant” or not.  
An abnormal lab test must be compared with the previous value taking into account 
normal values in the studied population/country.  
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If a laboratory/procedure parameter is abnormal AND the abnormality assessed 
clinically significant, it should be reported as an AE.  
An AE is a new event appearing after the signature of the ICF or a worsening in the 
condition (in the case of laboratory/procedure tests, it is an increase in severity (clinical 
intensity) of the abnormality which is judged clinically significant by the investigator. 
Laboratory/procedures (i.e. ECG...) abnormalities (or worsening in severity or frequency 
of pre-existing abnormalities) should be assessed as “clinically significant” (and therefore 
have to be reported as an AE) if they meet at least one of the following conditions:  
x The abnormality suggests a disease and/or organ toxicity AND this abnormality was 
not present at the screening visit or is assessed as having evolved since the screening 
visit 
x The abnormality results in discontinuation of the study drug 
x The abnormality requires medical intervention or concomitant therapy 
When reporting an abnormal lab/procedure as an adverse event, an etiologic or 
syndromic clinical diagnosis should be recorded rather than the abnormal value itself, 
if available (eg: acute hepatitis instead of high levels of AST/ALT, TBIL, abdominal pain, 
vomiting, icterus.; eg: “hypokalemia” rather than “decreased potassium levels”; “anaemia” 
rather than “decreased red blood cell count”). 
8.5.3 Serious Adverse Event (SAE) 
An adverse event will be defined as serious if it: 
x results in death  
i.e. causes or contributes to the death.
A possibly related death is a death for which there are facts (some evidence) that suggest 
a toxicity of treatment or an insufficiency of efficacy of treatment to stop the progress of 
the disease and prevent death. 
An unrelated death is a death for which there are facts (evidence) that excludes the 
toxicity of the drug or lack of efficacy or the contribution of the drug and is generally due 
to an external event (accident, homicide, snake bite, …) or a pre-existing disease such 
as a cancer. 
x is life-threatening 
in this context refers to an AE in which the subject is at risk of death at the time of the AE; 
it does not refer to an AE that hypothetically might have caused death if more severe.  
x requires in-patient hospitalisation or prolongation of existing hospitalisation 
i.e. the AE requires at least an overnight admission or prolongs a hospitalisation beyond
the expected length of stay. Hospital admissions for surgery planned before study entry,
for social reasons, for any elective surgery (i.e. plastic surgery) or per protocol or for
normal disease management (including treatment adjustment) are NOT to be considered
as SAE according to this criterion (i.e. if the patient needs to stay overnight in order to get
the follow up visit exams the morning after).
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For the purposes of the study, hospitalisation for non-complicated delivery will not be 
considered as an SAE. 
x results in persistent or significant disability or incapacity 
i.e. the AE resulted in a substantial disruption of the subject’s ability to conduct normal
activities overtime.
x is a congenital anomaly / birth defect 
i.e. an AE outcome in a child or foetus of a subject exposed to the Investigational
Medicinal Product before conception or during pregnancy.
x is an important medical event, i.e. is medically significant 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious events/reactions, such as important medical events that 
might not be immediately life-threatening or result in death or hospitalisation but might 
jeopardise the subject or might require intervention to prevent one of the other outcomes 
listed above.  
Any suspected transmission via a medicinal product of an infectious agent is also 
considered a serious AE.  
In the study, ALT or AST levels above 3 times the upper limits of normal (ULN) associated 
with total bilirubin above 2 ULN will be considered SAEs. 
SAE onset/start date: 
Start date of SAE or date when the AE becomes serious (see seriousness criteria of an 
SAE). 
SAE end/stop date: 
SAE end date is the date of AE recovery. 
8.5.4 Adverse Event of Special Interest (AESI): 
AESI is defined as an adverse event (serious or non-serious) of scientific and medical 
concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
rapid communication by the investigator to the Sponsor may be appropriate. Such an 
event may require further investigation to characterize and understand it.  
AESI, are not all SAEs from a regulatory point of view but the Sponsor shall be informed 
in an expedited manner within same timelines (irrespective of the grade of the AESI) as 
required for SAEs but using the “AESI form”. Shall they meet any seriousness criteria 
(see Serious Adverse Event (SAE) 8.1.19) they should then comply for associated safety 
reporting requirements and be reported on BOTH the AE CRF and SAE form. 
In this study, we will consider as AESI any neuropsychiatric signs and symptoms 
(excluding headaches and insomnia, that will be reported as AE) requiring specialized 
therapeutic intervention (such as specific pharmacotherapy or psychotherapy 
(including psychological counseling). 
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8.5.5 Eliciting Adverse Event information 
The investigator is required to report all directly observed adverse events and all adverse 
events spontaneously reported by the trial patient using concise medical terminology.  
In addition, to avoid bias in eliciting AEs, each trial patient will be questioned about the 
occurrence of adverse events at scheduled visits (every day during hospitalization and 1 
month, 9 weeks, 6 months and then 12 months after D1), with general, non-leading 
questions such as: “Since the last visit have you had any health problem?” or “How are 
you feeling?”. 
In this study, all AEs (serious and non-serious) must be recorded on the source 
documents and case report forms (CRFs) regardless of the assumption of a causal 
relationship with the study drug until the EoH visit.  During the follow-up period only SAEs 
and AEs considered related to the study drug will be recorded in the CRF. The definition, 
reporting, and recording requirements for AEs are described in sections 8.1.17 and 
8.1.22.  
Information on adverse events must be evaluated by a physician. 
Each AE is to be classified by the investigator as serious or non-serious (see definition of 
a SAE in section 8.1.19). This classification will determine the reporting procedure for the 
event. 
In addition, the frequency, seriousness (see section 8.1.19), severity (see section 8.1.23), 
and causality (see section 8.1.24) assessment of AEs will be described. The frequency 
of AEs and AEs/SAEs leading to treatment discontinuation will be reported. 
Non-serious AEs are to be reported on the CRF, including description of the event, onset 
date, duration, severity, seriousness, relationship to all study drugs, actions taken and 
outcome.  
In the CRF, a given AE will be recorded only one time per subject, and the severity 
recorded will be the maximum level reached. If several distinct episodes of the same 
condition occur, their number will be recorded in the CRF. 
SAEs will be reported both on the AE CRF and the SAE forms. 
8.5.6 Adverse Event reporting period 
The AE reporting period begins upon patient enrolment in the trial (after signature of 
informed consent) and ends at the EoH visit.  
All AEs that occur during the adverse event reporting period specified in the protocol must 
be reported to DNDi, whether the event is considered study medication related or not.  
In addition, any serious AE that occurs subsequent to the adverse event reporting period 
and that the investigator assesses as related to the investigational medication should also 
be reported as an AE. 
After EoH until EoS (M12), only AEs considered as related to fexinidazole and SAEs will 
be reported. 
Screening failure: beyond the date of screening failure (to be recorded), only serious 
study-related events will be followed-up. 
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8.5.7 Grading of Adverse Event severity 
For each serious and non-serious AEs, the investigator is required to assess the severity. 
Please note the distinction between severity and seriousness of adverse events. A severe 
AE is not necessarily a SAE. 
The severity for an AE should be graded using the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (CTCAE, version 5.026 and a modified version of 
it, presented in Appendix 4 – modified CTCAE 5.0 ) as a guide in the grading of the 
severity of AEs.  
In case of AEs that are not described in the CTCAE v 5.0 AE severity grading system, 
the Investigator will use the terminology MILD, MODERATE, SEVERE, LIFE-
THREATENING or DEATH to describe the maximum severity of the adverse event as 
follows: 
Mild: 
The subject is aware of the event or symptom, but the event or 
symptom is easily tolerated (e.g. no reduction in daily activities is 
required). 
Moderate: 
The subject experiences sufficient discomfort to interfere with or 
reduces his or her usual level of activity. 
Severe: 
Significant impairment of functioning: the subject is unable to carry out 
usual activities and/or the subject’s life is at risk due to the event. 
Life-
Threatening: 
The subject is at significant risk of life; it does not refer to an event 
which hypothetically might have caused death if it were more severe 
(life-threatening consequences, urgent intervention required). 
Death: 
Death related to an event. 
This information will be entered in the AE case report forms. 
When the intensity of an AE changes over time, each change in intensity will be recorded 
in the source documents until the event resolves. However, only one AE and the 
maximum intensity will be recorded in the CRF for each separate event. If the AE resolves 
but then recurs, each will be recorded as a separate AE, with the appropriate start and 
stop times. 
8.5.8 Adverse Event causality assessment 
For each serious and non-serious AEs, the investigator is required to assess the possible 
relationship between the adverse event and the trial drug, i.e. to determine whether there 
exists a reasonable possibility that the trial drug caused or contributed to the AE(s). 
The following categories for relationship to treatment will be used during AE reporting: 
Related 
There is at least a reasonable possibility of a causal relationship 
between an AE and an investigational medicinal product. This 
means that there are facts (evidence) or arguments to suggest a 
causal relationship 
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Not related 
There is no reasonable possibility of causal relationship. 
To help investigators with the decision binary tree (Related/Not related) in the evaluation 
of causality, the CIOMS (Council for International Organizations of Medical Sciences) VI 
group recommends that investigators be asked to consider the following before reaching 
a decision: 
x Medical history (including presence of risk factors) 
x Lack of efficacy/worsening of existing condition 
x Trial medications 
x Other medications (concomitant or previous) 
x Withdrawal of trial medication, especially following trial discontinuation / end of trial 
medication 
x Erroneous treatment with trial medication (or concomitant) 
x Protocol related procedure 
8.5.9 Adverse Event reporting requirements 
Information on AEs must be evaluated by a physician. 
Each AE is to be classified by the investigator as serious or non-serious. This 
classification will determine the reporting procedure for the event. 
All serious adverse events (SAE) and adverse events of special interest (AESI) are to be 
reported immediately (within 24 hours of awareness of SAE by the investigator) 
to 
 using the SAE report form or AESI report form, 
respectively. This includes a description of the event, onset date and type, 
duration, severity, relationship to trial drug, outcome, measures taken and all other 
relevant clinical and laboratory data.  
The initial report is to be followed by submission of additional information (follow-up 
SAE/AESI form) as it becomes available. Any follow-up reports should be submitted as 
soon as possible, and if possible within 5 working days.  
SAE/AESIs should also be reported on the clinical trial adverse event case report form 
(CRF). It should be noted that the form for reporting of SAE/AESI (SAE or AESI form) is 
not the same as the AE section of the CRF. Where the same data are collected, the two 
forms must be completed in a consistent manner, and the same medical terminology 
should be used. 
In addition to immediately reporting SAE/AESIs to DNDi, the Investigator will 
immediately notify the Ethics Committee/Health Authorities of SAEs (not AESIs) 
that occur during this trial, if applicable, in accordance with the standard operating 
procedures/guidance/regulations issued by the Ethics Committees/Health Authorities. 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is a suspected AE 
related to an investigational medicinal product that is both unexpected and serious. 
DNDi, the Sponsor is responsible for determining the expectedness of the event, using 
the reference safety information (described in the fexinidazole Investigator Brochure) 
defined for this trial.  
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DNDi or the investigator will notify the Ethics Committee/Regulatory Authorities of all 
SUSARs/other types of SAEs (If applicable) in compliance with local safety reporting 
requirements). 
8.5.10 Exposure in utero 
Pregnant women can be included into the trial. This lies within the anticipated lower 
toxicity of fexinidazole as compared to the standard treatment with melarsoprol or 
suramin, resulting in a lower risk of developing severe secondary effects in patients 
undergoing study treatment. 
There are no data from the use of fexinidazole in pregnant women. 
In animals, effects of fexinidazole on embryo-fetal development were observed only at 
doses harmful to the dams. These effects were considered as secondary to maternal 
toxicity. Plasma concentrations of fexinidazole and of its metabolites at these dose levels 
were low as compared to clinical exposures.  
As a precautionary measure, it is preferable to avoid the use of fexinidazole during the 
1st trimester of pregnancy, that’s why the decision to include pregnant women in the study 
lies with the investigator after assessing the benefit/risk for the patient and women will be 
encouraged to use a contraceptive method at least during the hospitalization period. 
Nevertheless, women exposed during pregnancy will be closely monitored for safety 
during the entire duration of the study. 
If any trial subject becomes or is found to be pregnant (based on date start last 
menstruation period (LMP)) while receiving an investigational drug or is found pregnant 
at the EoH or at W9 visit, the investigator must report the event on a “Pregnancy 
Surveillance form”.  
This must be done irrespective of whether an AE has occurred. The information submitted 
should include the anticipated date of delivery. 
The investigator will follow the subject until completion of the pregnancy or until 
pregnancy termination (i.e., abortion). The investigator will provide pregnancy follow-up 
or outcome information on a “Pregnancy Surveillance Form”.  
In the case of a live birth, a medically qualified person should examine the infant at the 
time of birth and submit a “Child Surveillance form”. The Investigator will offer the 
parents follow-up on infants exposed to the study treatment in utero until they reach 24 
months of age. As far as possible, stillborn infants should be examined by a physician to 
assess the cause of death.  
A pregnancy is not an SAE. 
Any unfavorable outcome meeting at least one seriousness criteria i.e. in the case of 
unfavorable pregnancy outcome (abortion, stillbirth) or congenital abnormality shall be 
reported using the “SAE form” (in addition to the Pregnancy/Child Surveillance Form). 
Follow-up of such newborns should be proposed up to the age of 2 years. 
8.5.11 Exposure during breastfeeding 
Children breastfed whilst their mother was on treatment will also be closely followed-up 
until 2 years of age or until the mother’s last follow-up visit (12-month visit) whichever 
comes last, using the “Child-Surveillance Form” 
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8.5.12 Adverse event follow-up
All AEs should be followed until 
x they are resolved; or  
x the investigator assesses them as ‘chronic’ or ‘stable’; or  
x the patient’s participation in the trial ends (i.e., until a final report is completed for 
that patient, or otherwise the last contact with the subject). 
The following categories will be used to document outcome of each AE: 
Action taken: None, drug treatment, subject withdrawn, other (specified). 
Outcome:  
Completely recovered; recovered with sequelae; ongoing; death; unknown. 
The decision to suspend, and resume treatment or to permanently interrupt treatment due 
to an adverse event will be left to the clinician in charge. 
In addition, all SAEs (related or not) and those non-serious events assessed by the 
investigator as related to the investigational drug must continue to be followed even after 
the patient’s participation in the trial is over. Such events should be followed until they 
resolve or until the investigator assesses them as “chronic” or “stable.” Resolution of such 
events is to be documented on the AE page of the CRF and SAE form (if applicable). 
Note: The recording of such events in the CRF/clinical database is not possible after the 
end of the trial (after LPLV). In that case, the follow-up information should be reported to 
the organisation in charge of the pharmacovigilance of the trial and recorded in the safety 
database. 
9 Withdrawal criteria 
A subject may withdraw from the trial at any time at their own request, or they may be 
withdrawn at any time at the discretion of the Investigator or Sponsor for safety, 
behavioural, or administrative reasons. 
If a subject does not return for a scheduled visit, every effort should be made to contact 
the patient. In any circumstance, every effort should be made to document patient 
outcome, if possible. 
If the subject withdraws consent, no further evaluations should be performed, and no 
attempts should be made to collect additional data, with the exception of safety data, 
which should be collected if possible and in accordance with patient consent. The 
Sponsor may retain and continue to use any data collected before any withdrawal of 
consent. However, if the subject consents to follow-up but asks the Investigator to destroy 
all identifiable samples taken from the subject and/or not enter into the CRF results of the 
follow-up examinations, the Investigator will comply with the subject’s requests. 
9.1 Rules for temporary interrupting the trial treatment 
In the event that treatment is interrupted (e.g. due to an AE), the decision to resume 
treatment will be taken by the site Principal Investigator.  
Temporary interruption of treatment will not necessarily lead to patient withdrawal from 
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the study. In some cases, treatment may be interrupted for a maximum of one day, i.e. 
one missed dose of fexinidazole, and treatment completion will therefore be delayed. 
Treatment can be reintroduced at the discretion of the Investigator according to his 
assessment of the clinical status of the patient. One additional day of treatment will be 
added to make up for the missed dose, and the EoT visit will take place on Day 12. The 
patient should continue the visits and study procedures as planned, taking into account 
the delay. The reasons for interrupting treatment must be recorded in the CRF 
9.2 Rules for permanently interrupting trial treatment  
A subject can be withdrawn from the treatment for the following reasons: 
x In the Investigator’s medical judgment, further participation would be injurious to the 
subject’s health or well-being.  
x AE or laboratory abnormalities occurring that in the opinion of the Investigator may 
constitute a potential risk for continued participation by the subject. These patients will 
continue to be followed up within the study. 
x Clinically significant intercurrent illness which could compromise the safety of the 
subject or the scientific value of the trial 
x Need for, or use of, contraindicated medication which could compromise the safety of 
the subject or the scientific value of the trial. 
x Decision of the patient to stop the treatment 
A participant must be discontinued from the treatment if at least one of the following 
medical conditions occurs: 
x Severe skin reactions 
x ALT or AST > 8x ULN 
x ALT or AST > 3x ULN and total bilirubin > 2x ULN 
x ALT or AST > 3x ULN and onset of fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash and/or eosinophilia (> 5%) 
x Confirmed QTcF measurement  500 msec pre-dose (D2, D3, D4), i.e. after second 
ECG recording at a 10-20 minutes interval in resting position 
x Any other condition which, in the eyes of the Investigator, requires treatment 
interruption due to medical reasons 
The Investigator will make all necessary arrangements to ensure that the subject receives 
the appropriate treatment for HAT, if necessary and for any other relevant medical 
condition. Patients will be advised and offered the standard course of melarsoprol for 
stage-2 patients and suramin for stage-1 patients. 
The date the subject discontinued the trial medication, and the specific reason for 
discontinuation will be recorded in the CRF  
9.3 Patient withdrawal from the trial and patient replacement 
9.3.1 Rules in case of withdrawal from trial 
A subject can be withdrawn from the study for the following reasons: 
x Withdrawal of consent 
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x Significant non-compliance of the subject with the requirements of the trial. If a subject 
is non-compliant in the opinion of the Investigator, the Sponsor’s Medical Monitor 
should be consulted for instruction on handling the patient 
x Major protocol violation as discussed and agreed upon between the Sponsor and 
Investigator. 
x Termination of the study by the Sponsor. 
x Termination of the study by the local health or regulatory authority or IRB/IEC. 
If a subject discontinues the trial prior to completion, regardless of the reason: 
x The site must notify DNDi within 48 hours. 
x The reason(s) for withdrawal must be documented in the subject’s medical record and 
CRF (End of Study form and other appropriate CRF pages to be completed). 
x If the withdrawal is due to a SAE, the patient will be followed up according to the process 
detailed in section 8.1.28 Adverse events follow-up). 
x If the withdrawal is due to a treatment limiting AE, thorough efforts should be made to 
clearly document the outcome of that AE. 
x Reasonable efforts should be made to have the subject return for an early termination 
visit, with evaluations corresponding to those stipulated for the M12 end-of-study visit 
described in the schedule, to the extent feasible. 
x All trial subjects must be followed for safety until M12 end-of-study visit described in 
the schedule of events or until study drug related AEs resolve or stabilize, or are 
deemed irreversible, whichever is later. 
9.3.2 Patient replacement: 
Patients who die for unrelated causes or withdraw from the trial before the end of 
hospitalization will be replaced in order to reach the 34-evaluable stage-2 patients 
required for the study. 
10 Data Analysis and Statistical Methods 
10.1 Sample size determination 
A scientific hypothesis is a hypothesis that can be rejected in an experimentation through 
a statistical test or a given observed fact. If the sample size is too small, the null 
hypothesis is not rejected even if no deaths are observed (whatever the observed death 
rate, H0 is not rejected). The minimal sample size to get a possible rejection of H0 
(fatality rate at EoH = 8.5% or more) in favour of H1 (fatality rate < 8.5%) is 34 evaluable 
stage-2 patients for alpha = 0.05 one-sided. In that case if no patients died during 
treatment the exact one-sided test becomes significant (p = 0.0488). 
Consequently, the sample size is not set according to a minimal power of 80%, but 
according to the possible rejection of the null hypothesis. The second consequence of 
such an approach is: as soon as one death is observed at EoH, the study may be stopped 
for futility and failure (inconclusive result). To accept one failure and get a rejection of the 
null hypothesis once one failure is observed, the minimal sample size becomes 53 
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patients (p = 0.04967, for 1/53 deaths). Because this sample size cannot be reached 
within two years, the study is unfeasible if this hypothesis is applied.  
Even if the minimal sample size (n= 34) was retained to get a working hypothesis that 
can be rejected statistically, the power of the study remains quite reasonable. 
Fexinidazole was administered to 361 stage 2 patients suffering from HAT T.b 
gambiense. Two deaths were observed before the end of hospitalisation, considered 
unrelated to the treatment or disease. The fatality rate for any cause was therefore equal 
to 0.554%. These deaths were probably not due to treatment but considering the case of 
deaths regardless the cause, the power of the study in patients infected by T.b gambiense 
would be 82.79%. Using MSF data17, the fatality rate in r-HAT stage 2 patients treated 
with melarsoprol was twice (exactly 1.98) larger in T.b rhodesiense than in T.b gambiense 
stage 2 patients. If we consider it is due to the fragility of patients infected by rhodesiense 
trypanosomes, then the expected fatality rate for any cause with fexinidazole could reach 
1.097%. Using the corrected estimate (1.097%) as true then the exact power of the study 
is 68.73 %. Considering deaths possibly related to treatment or disease, the power should 
be larger than 70% that is a reasonable power in a rare and neglected disease.         
If one death attributable to the treatment or disease may occur, the DSMB will rule 
whether or not the use of fexinidazole shall continue until the sample size of 34 patients 
is reached but no statistical inference will be made with regards to the unacceptable limit 
of 8.5%. 
N.B. In case of non-evaluable patients, the sample size will be increased to reach 
34 evaluable patients that are required to get a testable hypothesis in the primary 
analysis (see primary analysis).  
The recruitment will be stopped once 34 evaluable stage-2 patients are recruited.  
10.2 Definition of trial populations included in the analysis 
The population of evaluable patients is composed of patients who took at least one dose 
of fexinidazole excluding those whose death during hospitalization (if any) is documented 
and clearly attributable to other causes than r-HAT or treatment according to the DSMB 
and those who escape from the hospital and were not retrieved later to know their status 
on the primary outcome. This is the primary population used in the primary analysis. The 
choice of this set as the primary one is justified by the fact that the study is inconclusive 
if only one death occurred. If a death is, according to the DSMB, clearly unrelated to r-
HAT or treatment such as poisoning, it is not reasonable to stop the trial for failure due to 
such an unrelated event. 
The secondary population is the modified intent to treat (mITT) set of patients consisting 
of all patients who took at least one dose of the study drug. This set will also be the safety 
set of patients. 
The intent to treat population (ITT set of patients: all recruited patients, who signed the 
informed consent and were eligible for treatment) will be used to describe the disposition 
of patients. 
The fexinidazole treatment completer set of patients will consist of all patients who 
terminate the 10 days of treatment with fexinidazole 
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10.3 Analyses 
10.3.1 Primary analysis 
The primary population is the evaluable set of stage-2 patients. 
The primary outcome is survival (alive or dead) at EoH. 
The primary parameter of interest is death rate at the EoH. 
In case of escape of a patient from the hospital and if the patient is not retrieved, the 
patient will be excluded from the population of evaluable patients and will be considered 
as a failure, but not a proven death.  
A one-sided exact test with respect to 8.5% (unacceptable fatality rate under H0) will be 
performed (alpha = 0.05 one-sided). 
The one-sided test is justified by the very small number of available patients.  
An algorithm will be presented in the Statistical Analysis Plan (SAP). 
Sensitivity analyses 
The same analysis will be performed on the mITT set of patients and on the set of 
treatment completers if at least 34 patients belong to these sets. 
10.3.2 Secondary analysis 
The first secondary analysis will consist of calculating the failure rate at end of 
hospitalisation in stage-2 patients and to compare it with the threshold of unacceptable 
failure rate (9%) through a one-sided exact test (alpha = 0.05 one-sided). 
The second secondary analysis will consist of estimating the failure rate at 12 months in 
stage-2 patients and comparing it with the unacceptable threshold of 12%. A one-sided 
exact test of comparison will be performed if the observed rate is below 12%.  
The fatality rate at EoH, failure rate at EoH and failure rate at 12 months will be estimated. 
Because the sample size will be very small, no null hypotheses will be testable. 
The estimate of fatality rate at EoH, failure rate at EoH and failure rate at 12 months for 
stage-1 and stage-2 combined will be calculated and tested against the unacceptable 
limit of 8.5%, 9% and 12%, respectively.    
10.4 Safety Analysis 
The safety analyses will be performed on the mITT population, i.e. all patients (stage-1 
and stage-2) who took at least one tablet of fexinidazole. 
The proportion of patients who experienced an SAE and/or an AE leading to treatment 
discontinuation will be provided by system-organ class using MedDRA terms and/or NCI 
(National Cancer Institute) CTCAE, version 5.026 and, for certain laboratory parameters, 
the modified CTCAE version 5.0 will be used (see Appendix 4 – modified CTCAE 5.0). 
The proportion and number of patients who experienced at least one AE will be provided. 
Events described using 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. 
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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 proportions of patients by category corresponding to the 
magnitude of the increase in relation to the ULN for liver function tests (< 1 ULN, 1–2 
ULN, 2–3 ULN etc.). Scatter grams with baseline values on the x-axis and post-treatment 
values on the y-axis with the bisector indicating the absence of change will be presented. 
Changes in blood levels over time will be presented in graphs. Shift tables will be provided 
to supplement signal detection. A listing of patients with clinically significant increases in 
laboratory parameters will be provided. 
Abnormalities, if any, on ECG tracings recorded until D11 will be described. 
10.5 Analysis of other endpoints 
10.5.1 PK analyses 
Analyses on PK samples will be performed on all patients who took at least one tablet of 
fexinidazole. 
The DBS concentrations of fexinidazole and its metabolites data of DNDi-FEX-07-HAT 
study will be pooled with those obtained from the DNDiFEX004 and DNDiFEX006 studies, 
in order to compare the exposure and the PK parameters of g-HAT and r-HAT patients 
through a population PK approach. Different and complementary timepoints will be looked 
at to complete the analysis of existing data. 
The structural model previously developed on these studies will be used, the model 
considered one compartment for fexinidazole, M1 and M2 assuming that fexinidazole was 
metabolized in metabolite M1, which was in turn metabolized in metabolite M2 (Sulfone 
Metabolite of fexinidazole), the model will be refined with study specifications. Covariates 
will also be investigated as HAT type, concomitant medications, HAT stage, and 
demographics characteristics.  
PK parameters in patients considered to be treatment failures or who experienced 
intolerance to fexinidazole will be described individually. 
NONMEM software will be used for the population PK analysis. 
All methods to be applied for the population modelling will be fully detailed in a dedicated 
analysis plan. 
10.5.2 ECG analysis 
The following study will investigate cardiovascular safety of fexinidazole on QTc interval, 
including all patients for whom matching ECG evaluations and PK samplings were 
obtained.  
QTc interval will be calculated from single or triplicate ECG using RR (Respiratory Rate) 
and QT intervals. In the case of triplicate ECG, the values for HR and QT will be average 
before to compute the QTc: 
o
Fridericia’s cube-root corrected QT1:  
QTcF (ms) = QT (ms) / RR(s)1/3
o Bazett’s square-root corrected QT2:  
QTcB (ms) = QT (ms) / RR(s)1/2 
Note: for all correction methods the RR is converted in second (RR (ms)/1000). 
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Individual ECG parameters will be listed.  
Continuous ECG variables will be summarized on observed values and changes from 
baseline, by time points, using the number of observations (N), mean, Standard Deviation 
(SD), min, median and max. The 90% confidence interval of the mean will be added on 
changes from baseline statistics. 
A Categorical analysis will be performed consisting on number and percentage of 
subjects, presenting at least one value on treatment above a pre-defined threshold (e.g. 
QTcF>450 ms, QTcF>480 ms, QTcF>500 ms, etc.). 
Incidence of subjects presenting at least one treatment emergent morphological finding 
will also be presented. 
To match PK-ECG data, a concentration-QTc analysis will be performed on change from 
baseline between QTcF and fexinidazole, M1 and M2. 
10.5.3  Trypanosome nucleid acids detection analysis.  
Standard protocols for extracting DNA and RNA will be applied, followed by Reverse 
transcription of the latter to obtain cDNA. Both templates will be used alongside each 
other to determine trypanosome nucleic acid presence in samples from the same patient 
at different time points. qPCR will be carried out as previously described25, only including 
primers and probes specific for T. brucei that will consequently amplify T. b. rhodesiense. 
Outputs will be stored in electronic form for future reference. 
10.6 Futility analysis  
Because it is a one arm design and because only one death can lead to a failure of the 
trial (inconclusive results), the DSMB will meet as soon as one death occurs and the study 
can be stopped depending on the DSMB recommendations (the DSMB can decide to 
continue the trial for exploratory purposes). 
Presence of trypanosomes or persistence of high white blood cells (WBC) in CSF at any 
time from the end of hospitalisation until the end of follow up will also be considered as 
failure and could also help the DSMB in their recommendation to stop the trial.   
In case of unsatisfactory clinical and/or parasitological response during the treatment 
period and if the patient’s survival is at risk for an assumed lack of efficacy of the study 
treatment, the investigator may introduce rescue treatment with suramin for stage 1 and 
melarsoprol for stage 2 patients according to the national treatment guidelines. These 
cases may also be taken into consideration by the DSMB in their recommendation. 
11 Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB), composed of at least 3 members independent 
of the investigator and sponsor, will be set up prior to trial initiation. The DSMB monitors 
the trial in order to ensure that harm is minimised, and benefits maximised for the trial 
patients. They will review the trial data at pre-determined intervals and issue 
recommendations about the trial. The data and intervals will be agreed prior to or soon 
after the trial initiation and documented in the DSMB Charter.  
Stopping rules 
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The study can be stopped prematurely after recommendation by the DSMB if the DSMB 
considers that the tolerance to treatment or efficacy is insufficient. 
12 Quality Assurance and Quality Control Procedures 
12.1 Investigator’s file 
The investigator must maintain adequate and accurate records to enable the conduct of 
the trial to be fully documented and the trial data to be subsequently verified. These 
documents include Investigator’s Site File, patient clinical source documents and 
screening / enrolment logs. The Investigator’s Site File will contain the protocol/protocol 
amendments, CRF/SAE/AESI/pregnancy/Child Surveillance Forms and query forms, IEC 
and regulatory approval with correspondence, sample informed consent, drug 
accountability records, staff curriculum vitae and authorization forms and other 
appropriate documents/correspondence etc.  
12.2 Case report forms (CRFs) 
Data will be collected by laboratory technicians, medical doctors, clinical officers and 
nurses authorized by the investigator. It will be supervised by the Investigator and signed 
by the investigator or by an authorised staff member. Trial-specific information will be 
entered into the Case Report Form (CRF) and forms/documents sent to data 
management and PV (Pharmacovigilance) (SAE/AESI/pregnancy/Child Surveillance 
Forms). Data that are derived should be consistent with the source documents or the 
discrepancies should be explained. All CRF data will be de-identified, i.e. identified by 
trial patient number only. 
The investigator at each trial site should ensure the accuracy, completeness, legibility, 
consistency, and timelines of all data reported to the sponsor in the CRFs and any other 
additional information (including SAE/AESI/pregnancy/Child Surveillance Forms and 
queries) that is required. The investigator is responsible for keeping all consent forms, 
screening forms, CRF and PV forms and the completed patient identification code list in 
a secure location. 
12.3 Source documents 
The verification of the CRF data must be by direct inspection of source documents. 
Source documents include patient hospital/clinic records, physician's and nurse's notes, 
appointment book, original laboratory reports, ECG, signed informed consent forms, 
consultant letters, and patient screening and enrolment logs. Specific pages from the 
CRF, including HAT sign and symptoms, neurological and physical examination will be 
used directly as source documents. 
The investigator must maintain source documents such as laboratory and consultation 
reports, history and physical examination reports, etc., for possible review and/or audit by 
DNDi and/or Regulatory Authorities. The Investigator / designee will record the date of 
each patient’s visit together with a summary of their status and progress in the trial. 
12.4 Record Retention 
The investigator must keep all trial documents on file for at least 25 years after completion 
or discontinuation of the trial. After that period of time the documents may be destroyed 
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with prior permission from DNDi, in compliance with local regulations. 
Should the investigator wish to assign the trial records to another party or move them to 
another location, DNDi must be notified in advance. 
12.5 Monitoring, audits and inspections 
Monitoring visits to the trial site will be made periodically by DNDi representatives or 
designated clinical monitors to ensure that GCP and all aspects of the protocol are 
followed.  Source documents will be reviewed for verification of consistency with data on 
CRFs. The investigator will ensure direct access to source documents by DNDi or 
designated representatives. It is important that the investigators and their relevant 
personnel are available during the monitoring visits. 
The investigators will permit representatives of DNDi and/or designated clinical monitors 
to inspect all CRFs, medical records, laboratory work sheets and to assess the status of 
drug storage, dispensing and retrieval at any time during the trial. The corresponding 
source documents for each patient will be made available provided that patient 
confidentiality is maintained in accord with local regulations. The inspections are for the 
purpose of verifying the adherence to the protocol and to ensure the trial is conducted 
according to GCP. It is important that the investigators and other trial site staff are 
available at these visits. 
The monitoring visits provide DNDi with the opportunity to evaluate the progress of the 
trial, verify the accuracy and completeness of CRFs/SAE/AESI/pregnancy/Child 
Surveillance Forms and queries, resolve any inconsistencies in the trial records, as well 
as to ensure that all protocol requirements, applicable regulations, and investigator's 
obligations are being fulfilled. Four visit types are planned: pre-trial, trial start, during the 
trial, and trial end. Visits may also be performed by regulatory authorities. All monitoring 
activities are detailed in the study clinical monitoring plan. 
The investigator agrees to cooperate with the clinical monitor to ensure that any problems 
detected in the course of these monitoring visits are resolved. 
12.6 Audits and inspections 
The trial site may also be subject to quality assurance audits by DNDi or designated 
representatives and/or to inspection by regulatory authorities or Independent Ethics 
Committees (IEC). 
It is important that the investigators and their relevant personnel are available for possible 
audits or inspections. 
12.7 Data Management  
After the CRF visit has been completed, reviewed, signed by the investigator (or delegate) 
and monitored by the clinical monitor on the study site, CRFs will be scanned and 
uploaded on a platform or sent by email to 
 for a 
centralized double data-entry in the electronic data capture system REDCap 
software system (www.project-redcap.org). The REDCap server will be kept in a 
locked server room at 
 and will only be accessible to authorized personnel.  
All data entered into the CRFs will be transferred to the database using Secure Sockets 
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Layer (SSL) encryption and a multi-level back-up system will be implemented.  
Data clarification will be issued at data entry level and afterwards in order to ensure data 
quality; queries will be issued and sent on site for resolution. 
Procedures to ensure good quality data will be detailed in the Data Management Plan, 
including details of the following: 
x CRFs versions and completion guidelines 
x Database structure, dictionary, data entry system and validation of the database 
x Methods of data collection 
x Type of data entry 
x Data preparation before entry onto electronic system 
x Data entry validation, data cleaning, data validation plan and data clarification 
form generation 
x Data flow 
x Database audit trail 
x Database lock 
x Data review checks to support monitoring 
x SAE reconciliation 
x Security/backup 
x Electronic data transfer rules 
x Archiving and security arrangements 
x Coding conventions 
12.8 Confidentiality of trial documents and patients’ records 
The investigator must assure that patients’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. On CRFs or other documents 
submitted to the sponsor, patients should not be identified by their names, but exclusively 
by an identification code. The investigator should keep a patient enrolment list showing 
codes, names, and addresses. The investigator should maintain documents for 
submission to sponsor authorized representatives, and patients signed written consent 
forms, in strict confidence.  
13 Protocol Amendments 
The Principal investigator will ensure that the trial protocol is strictly adhered to 
throughout, and that all data are collected and recorded correctly on the CRF. In case 
one or more laboratory or clinical assessments cannot be performed, the investigator will 
contact and discuss with the medical responsible person for the trial, to qualify whether 
the deviation is minor, or the patient has to do this assessment at an additional visit. 
All protocol modifications must be documented in writing. Any protocol amendment must 
be approved and signed by the sponsor and the Principal investigator and is to be 
submitted to the appropriate IEC for information and approval in accordance with local 
requirements, and to regulatory agencies if required.  
Approval by IEC (and Regulatory Authority, if applicable) must be awaited before any 
changes can be implemented, except for changes necessary to eliminate an immediate 
hazard to trial patients, or when the change involves only logistical or administrative 
aspects of the trial [e.g. change in clinical monitor[s], change of telephone number[s]. 
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The protocol amendment can be initiated by either sponsor or by any Principal 
investigator.  
The investigator will provide in writing the reasons for the proposed amendment and will 
discuss with the medical coordinator and sponsor.  
14 Early Termination of the Trial 
Both the sponsor and the investigator reserve the right to terminate the trial at any time 
prior to inclusion of the intended number of patients, but they intend to exercise this right 
only for valid scientific or administrative reasons. Should this be necessary, both parties 
will arrange the procedures on an individual trial basis after review and consultation. In 
terminating the trial, the sponsor and the investigator will assure that adequate 
consideration is given to the protection of the patient’s interest. 
Reasons for early termination by the sponsor(s) may include but not be limited to:  
x Too low enrolment rate. 
x Protocol violations. 
x Inaccurate or incomplete data. 
x Unsafe or unethical practices. 
x Questionable safety of the test article. 
x Suspected lack of efficacy of the test article. 
x Following the recommendation of the DSMB or IEC 
x Administrative decision. 
Reasons for early termination by the investigator may be: 
x Insufficient time or resource to conduct the trial 
x Lack of eligible patients 
In the event that a trial is early terminated either by the sponsor or by the investigator, the 
investigator has to: 
x Complete all CRFs to the greater extent possible 
x Return all test articles, CRF, and related trial materials to the sponsor who provided 
them 
x Answer all questions of the sponsors or their representatives related to data of 
patients enrolled at the site prior to trial termination 
x Ensure that patients enrolled in the trial who had not yet reached a follow up time 
point are followed up with the necessary medical care. 
x Provide in writing the reasons for his decision to the national health authority and 
the sponsor. 
15 Ethics 
The experimental protocol for this trial has been designed in accordance with the general 
ethical principles outlined in the Declaration of Helsinki and ICH guidelines for GCP (ICH-
GCP E6 (R2)).  
DNDi assures that it will comply with all applicable state, local and foreign laws for 
protecting the rights and welfare of human patients.   
This protocol and any protocol amendments will be reviewed / approved by all applicable 
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IECs before its implementation.  
It is the responsibility of the National Coordinating Investigator to apply for review to the 
IEC of the country where the trial takes place regarding local rules and regulations. 
Written approval from all involved IECs must be obtained before implementation of any 
protocol-specified intervention /investigation provided to the patient [such as patient 
information sheets or descriptions of the trial]. 
Any modifications made to the protocol after receipt of the IEC approval must also be 
submitted by the investigator in writing to the IEC in accordance with local procedures 
and regulatory requirements. (see section 13 Protocol Amendments). 
The protocol will be submitted for an opinion from the “Direction Générale de la Santé 
Commission Cantonale d'Ethique de la Recherche (CCER) “ in Geneva, Switzerland.  
15.1 Informed consent process 
Inclusion in the trial will occur only if the patient (for adults) or the parent/guardian (for 
children or incapacitated adult) gives written informed consent. It is the responsibility of 
the investigator / designee to obtain written informed consent from each individual 
participating in this trial, after adequate presentation of aims, methods, anticipated 
benefits, and potential hazards of the trial. The written informed consent document will be 
translated into the local language or a language understood by the patient(s). If needed, 
the person will be given time to discuss the information received with members of the 
community or family before deciding to consent. The patient or parent/guardian will be 
asked to provide written and signed consent. 
If the patient does not speak any of the national/local languages or the lingua franca and 
if a member of the study personal who speaks the patient’s local language/dialect has 
been identified and approved in advance, an ad hoc oral translation will be acceptable. 
The oral translation will be supported by use of the visual aids available and an impartial 
witness has to be present during the whole consent process. The patient will sign the 
document corresponding to the lingua franca in his/her country or region. The procedures 
followed for illiterate patients should be applied. The translation should be documented 
on the signed consent form (the person who provided the translation will indicate his/her 
name and the language/dialect used and will sign the form). 
Each centre will ensure that patients fully understand the information provided during the 
consent process and to that end may call upon a “translator/facilitator” who is known to 
the study team for his/her knowledge of the local language used by patients and for 
his/her communication skills with patients. Several facilitators may be designated in each 
centre to cover all local languages/dialects. Visual aids (drawings) will also be made 
available to the Investigator and the facilitator, describing the activities performed during 
the study, i.e. lumbar puncture, finger pricks, ECG, etc. 
If new safety information results in significant changes in the risk/benefit assessment, the 
consent form should be reviewed and updated if necessary. All patients (including those 
already being treated) should be informed of the new information, given a copy of the 
revised form and give their consent to continue in the trial.  
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15.1.1 Impartial Witness 
An impartial witness must be present when illiterate patients are recruited and/or if the 
legal representative is illiterate or if the patient is unable to give consent (see 15.1.2 
Illiterate Patients; 15.1.3 Patients Unable to Give Consent; and 15.1.4 Collection of 
Assent from Children (patients below 18 years old)). 
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 study team, 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.  
15.1.2 Illiterate Patients 
If the patient is illiterate, an impartial witness must be present throughout the information 
session.  
The Investigator will explain the information contained in the written document to the 
patient and ask whether he/she gives his/her consent to participate. The patient’s consent 
will be documented with his/her fingerprint on the form, and the witness will sign the form.  
15.1.3 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, non-inclusion 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 the patient’s legally acceptable representative. 
As is the case with minors, the eventual non-consent of the patient will prevail if s/he 
refuses to participate in the study. 
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. 
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15.1.4 Collection of Assent from Children (patients below 18 years old) 
Children who are eight (8) years old or above must give their assent after the parent or 
legal representative’s and/or guardian’s consent is obtained. Exceptions are made for 
emancipated young adults, as described in the last paragraph. 
Children who are between 6 and 8 years old will be asked to give their assent. It is difficult 
to obtain assent from children under 14 years of age as children have difficulty weighing 
up benefits and risks. It is, however, easier for a child to refuse to participate than to 
accept to comply with a protocol. The refusal may be expressed at the time when the 
protocol is explained or at any time during conduct of the study. Indeed, at any time, the 
child should be entitled to refuse to undergo an invasive protocol-related procedure, even 
after having agreed to take part in the study. Children will be informed of this at the start 
of the study and at other appropriate times during the study. If the child subsequently 
refuses to undergo an invasive procedure, this will not be prejudicial to his/her continued 
participation in the study, provided that treatment is correctly followed. 
Non-assent from the child will prevail if s/he refuses to take part in the study. 
If the parent or the legal representative is illiterate, a fingerprint should replace the 
signature and an impartial witness must attend the assent process and the consent 
process for the parent or legal representative (see 15.1.1 Section Impartial Witness). 
For young adults considered as emancipated because they are already married or having 
a child, according to specific local regulations, the consent can be obtained without 
requiring the signature from a legal representative or guardian. If the emancipated minor 
is illiterate, a fingerprint should replace the signature an impartial witness must attend the 
consent process. 
15.2 Ethical aspects of patient inclusion and trial procedures 
Blood 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 total volume of blood drawn up to the end of the study would be about 30mL.The 
maximal quantity during 1 visit is 5mL. 5 mL of blood is about the volume of a small tea 
spoon. 
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 fexinidazole, in France and 
then to Belgium. The samples collected in tubes and on filter paper for qPCR analyses 
will be sent to a Central Laboratory in 
. 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. 
The number of lumbar punctures will be kept to a minimum and the amount of CSF to be 
drawn will be 4mL per LP (Lumbar Puncture), i.e. 20ml in total up to the end of study.  
None of the samples will be retained after the end of the study. No biobank is to be set 
up. All remaining biological material will be destroyed once all the expected results are 
obtained and the destruction procedure will be recorded in a certificate of destruction. 
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15.3 Patient 
costs 
Patients will be reimbursed for travel costs to and from the trial site but will not receive 
any payment for trial participation. Any medication that is required during the trial period 
will be provided free of charge to the patient. Food during the in-patient treatment phase 
will also be provided free of charge to the patient and to the caregiver, irrespective of 
whether the patient is included in the study or not. This is seen as an essential part of the 
patient care plan bearing in mind the high prevalence of malnutrition and the poverty of 
these patients. 
15.4 Insurance and Liability 
DNDi is insured to indemnify the investigator against any claim for damages brought by 
a research patient who suffers from a research related injury during the performance of 
the trial according to the protocol. 
16 Reporting and Publication of Trial results 
All clinical trials will be registered with a recognised clinical trial registry such 
as www.clinicaltrials.gov or the Pan-African Clinical Trials Register. 
As a general rule, DNDi supports the timely communication of all research it sponsors, in 
accordance with its Policy for External Scientific and Clinical Communications. Thus, the 
Sponsor will facilitate publication of the findings of this study and/or presentation of the 
findings during scientific meetings. In this situation, the Investigator agrees to submit any 
manuscripts or abstracts to the Sponsor in advance. The Sponsor will promote 
communication of the overall study findings and not of individual findings related to a 
single investigational site. Any official publication of the study findings for which Sponsor 
personnel played a more important role than simple monitoring of study conduct will be 
considered as a joint publication by the Investigator and the Sponsor personnel 
concerned. The list of authors will be decided by mutual agreement in accordance with 
the authorship rules of international scientific journals. 
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17 References 
1.  
Simarro Pere P, Cecchi Giuliano, Franco Jose R, Paone M, Diarra A, Ruiz-
Postigo A, Fevre EM, Mattioli RC JJ. Estimating and Mapping the Population at 
Risk of Sleeping Sickness. PLoS Negl Trop Dis. 2012;6(10):1-12. 
doi:10.1371/journal.pntd.0001859 
2.  
World Health Organisation. First WHO Stakeholders Meeting Declaration on 
Rhodesiense Human African Trypanosomiasis Elimination. World Health 
Organization; 2016. 
http://www.who.int/trypanosomiasis_african/meeting_declaration_rhodesiense_20
14/en/. Accessed November 6, 2018. 
3.  
World Health Organisation. Report of a WHO Meeting on Elimination of African 
Trypanosomiasis (Trypanosoma brucei gambiense).; 2012. 
doi:10.1136/ebn.1.3.84 
4.  
World Health Organisation. Number of new reported cases (T.b.rhodesiense) 
Data by Country. Global Health Observatory data repository. 
http://apps.who.int/gho/data/node.main.A1637?lang=en. Accessed November 7, 
2018. 
5.  
Edielu A. Encephalopathic syndrome of trypanosoma brucei rhodesiense: 
Incidence, risk factors and predictive cerebrospinal fluid leukocyte count at Lwala 
Hospital, MSc dissertation, Uganda. 2013. 
6.  
Mwanakasale V, Songolo P, Babaniyi O, Simarro P. Clinical presentation of 
human African trypanosomiasis in Zambia is linked to the existence of strains of 
Trypanosoma brucei rhodesiense with varied virulence: Two case reports. J Med 
Case Rep. 2014;8(1):1-3. doi:10.1186/1752-1947-8-53 
7.  
MacLean LM, Odiit M, Chisi JE, Kennedy PGE, Sternberg JM. Focus-specific 
clinical profiles in human African trypanosomiasis caused by trypanosoma brucei 
rhodesiense. PLoS Negl Trop Dis. 2010;4(12):1-12. 
doi:10.1371/journal.pntd.0000906 
8.  
MacLean L, Chisi JE, Odiit M, et al. Severity of human african trypanosomiasis in 
East Africa is associated with geographic location, parasite genotype, and host 
inflammatory cytokine response profile. Infect Immun. 2004;72(12):7040-7044. 
doi:10.1128/IAI.72.12.7040-7044.2004 
9.  
Enyaru JCK, Stevens JR, Odiit M, Okuna NM, Carasco JF. Isoenzyme 
comparison of Trypanozoon isolates from two sleeping sickness areas of south-
eastern Uganda. Acta Trop. 1993;55(3):97-115. doi:10.1016/0001-
706X(93)90072-J 
10.  Pépin J, Milord F. The Treatment of Human African Trypanosomiasis. Adv 
Parasitol. 1994;33(C):1-47. doi:10.1016/S0065-308X(08)60410-8 
11.  Legros D, Evans S, Maiso F, Enyaru JCK, Mbulamberi D. Risk factors for 
treatment failure after melarsoprol for Trypanosoma brucei gambiense 
trypanosomiasis in Uganda. Trans R Soc Trop Med Hyg. 1999;93(4):439-442. 
doi:10.1016/S0035-9203(99)90151-7 
12.  Kaiser M, Bray MA, Cal M, Trunz BB, Torreele E, Brun R. Antitrypanosomal 
activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of 
sleeping sickness. Antimicrob Agents Chemother. 2011;55(12):5602-5608. 
doi:10.1128/AAC.00246-11 
13.  Tarral A, Blesson S, Mordt OV, et al. Determination of an optimal dosing regimen 
for fexinidazole, a novel oral drug for the treatment of human African 
trypanosomiasis: First-in-human studies. Clin Pharmacokinet. 2014;53(6):565-
580. doi:10.1007/s40262-014-0136-3 
14.  Mesu VKBK, Kalonji WM, Bardonneau C, et al. Oral fexinidazole for late-stage 
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African Trypanosoma brucei gambiense trypanosomiasis: A pivotal multicentre, 
randomised, non-inferiority trial. Lancet. 2017;6736(17):1-11. doi:10.1016/S0140-
6736(17)32758-7 
15.  Tweats D, Trunz BB, Torreele E. Genotoxicity profile of fexinidazole - A drug 
candidate in clinical development for human African trypanomiasis (sleeping 
sickness). Mutagenesis. 2012;27(5):523-532. doi:10.1093/mutage/ges015 
16.  Kuepfer I, Schmid C, Allan M, et al. Safety and Efficacy of the 10-Day Melarsoprol 
Schedule for the Treatment of Second Stage Rhodesiense Sleeping Sickness. 
PLoS Negl Trop Dis. 2012;6(8). doi:10.1371/journal.pntd.0001695 
17.  Hümbelin M. Definition of follow-up duration in clinical research of human African 
trypanosomiasis. Pharm Sci. 2006;Diploma. 
18.  WHO network for HAT elimination. Report of the Sixth Meeting of the Sub-Group 
“Integration of New Tools into National and Global Policies.” Geneva; 2016. 
19.  Falade C, Manyando C. Safety profile of Coartem: The evidence base. Malar J. 
2009;8(SUPPL. 1):1-14. doi:10.1186/1475-2875-8-S1-S6 
20.  World Health Organisation. WHO Model List of Essential Medicines. 
http://apps.who.int/iris/bitstream/handle/10665/273826/EML-20-eng.pdf?ua=1. 
Published 2017. 
21.  World Health Organisation. The WHO Model List of Essential Medicines for 
Children. http://apps.who.int/iris/bitstream/handle/10665/273825/EMLc-6-
eng.pdf?ua=1. Published 2017. 
22.  Pilon S. Essential Drugs: Practical Guide Intended for Physicians, Pharmacists, 
Nurses and Medical Auxiliaries. Vol 136. (Grouzard V, ed.). Médecins Sans 
Frontières; 2016. 
https://medicalguidelines.msf.org/viewport/EssDr/english/essential-drugs-
16682376.html. 
23.  Chappuis F., Loutan L., Simarro P. LV and BP. Options for field diagnosis of 
human African trypanosomiasis. Clin Microbiol Rev. 2005;18 (1)(Rev.):133-146. 
doi:10.1128/CMR.18.1.133 
24.  Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: 
Reliability, validity, and guidelines. J Clin Oncol. 1984;2(3):187-193. 
doi:10.1200/JCO.1984.2.3.187 
25.  Silbermayr K, Li F, Soudré A, Müller S, Sölkner J. A Novel qPCR Assay for the 
Detection of African Animal Trypanosomosis in Trypanotolerant and 
Trypanosusceptible Cattle Breeds. PLoS Negl Trop Dis. 2013;7(8). 
doi:10.1371/journal.pntd.0002345 
26.  U.S. Department Of Health And Human Services, National Institutes of Health 
NCI. Common Terminology Criteria for Adverse Events (CTCAE); 2017. 
 
 
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18 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. 
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, 
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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. 
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 
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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. 
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 
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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. 
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. 
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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 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 – Evaluation criteria of efficacy endpoints 
 
Category 
               Visit 
Death 
Relapse 
Probable Relapse 
Lost to Follow 
up 
Uncertain Evolution 
Favourable 
Evolution 
Probable Cure 
Cure 
EoH 
All 
deaths 
during 
hospitalisation, 
after 
the start of treatment 
or resulting from an 
event 
that 
started 
within 
that 
period, 
which 
cannot 
be 
clearly attributed to 
reasons 
other 
than 
HAT or the treatment 
itself 
Trypanosomes 
detected in any 
body fluid 
Tryps-negative 
patient 
who 
refuses 
lumbar 
puncture OR whose CSF 
is haemorrhagic AND 
who 
requires 
rescue 
treatment 
 
Tryps-negative 
patient 
whose clinical condition 
requires, in the opinion of 
the Investigator, a close 
follow-up 
Patient alive with no 
evidence 
of 
trypanosomes 
in 
any 
body fluid 
 
 
Intermediate follow up 
visits 
All 
deaths 
with 
a 
clinical 
picture 
certainly or possibly 
compatible with HAT, 
with the treatment or 
unknown, to which no 
alternative cause can 
be clearly attributed 
Trypanosomes 
detected in any 
body fluid 
Tryps-negative 
patient 
with increased WBC/l in 
CSF 
from 
previous 
values, 
whose 
WBC 
count is unlikely due to 
causes other than HAT 
OR who refuses lumbar 
puncture OR whose CSF 
is haemorrhagic AND 
who 
requires 
rescue 
treatment 
 
Tryps-negative 
patient 
who, in the opinion of the 
Investigator, requires a 
close 
follow-up 
exam 
because of a rising CSF 
WBC 
count 
OR 
a 
deterioration of clinical 
condition that might be 
due to HAT 
Tryps-negative 
patient 
with 5 WBC/l in CSF in 
a 
not 
haemorrhagic 
sample OR decreased 
from 
previous 
values 
AND for whom there is 
direct 
evidence 
of 
satisfactory 
clinical 
condition 
OR 
whose 
clinical status is unlikely 
due to HAT 
 
 
12-month 
All 
deaths 
with 
a 
clinical 
picture 
certainly or possibly 
compatible with HAT, 
with the treatment or 
unknown, to which no 
alternative cause can 
be clearly attributed 
Trypanosomes 
detected in any 
body fluid 
x 
Tryps-
negative patient with 
>20 WBC/l in CSF in a 
non-haemorrhagic 
sample, whose WBC 
count is unlikely due to 
causes other than HAT 
x 
Tryps-
negative patient who 
refuses lumbar puncture 
OR whose CSF is 
haemorrhagic AND who 
requires rescue 
treatment 
Patient who did not 
attend the 6 and 
the 
12 
months 
visits 
AND 
for 
whom there is no 
direct evidence of 
satisfactory clinical 
condition OR there 
is direct evidence 
of a clinical status 
likely due to HAT 
 
 
x 
Tryps-negative 
patient who refuses lumbar 
puncture OR whose CSF 
sample is haemorrhagic AND 
whose clinical condition is 
satisfactory OR whose clinical 
status is unlikely due to HAT 
x 
Patient who did not 
attend the 6 and the 12 
months visit AND for whom 
there is direct evidence of 
satisfactory clinical condition 
OR whose clinical status is 
unlikely due to HAT 
Tryps-negative 
patient whose CSF 
sample 
is 
not 
haemorrhagic with 
20 WBC/l 
Analysis 
Failure 
Failure 
Failure 
Failure 
To be assessed by an 
Independent 
evaluation committee 
To be assessed by an 
Independent 
evaluation committee 
Success 
Success 
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Appendix 3 – Karnofsky Index 
KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) 
CRITERIA 
 
The Karnofsky Performance Scale Index allows patients to be classified as to their 
functional impairment [24]. This can be used to compare effectiveness of different 
therapies and to assess the prognosis in individual patients. The lower the Karnofsky 
score, the more serious the impairment is. 
 
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 
 
 
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DNDi-FEX-07-HAT 
 
 
 
 
 
 
 
Fexinidazole 
Protocol version 6.0_19 Aug 2022 
Confidential  
 
 
 
 
 
 
Page 
77 
of 
83 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
Appendix 4 – modified CTCAE 5.0  
  
CTCAE v5.0 
SOC 
CTCAE v5.0 
Term 
units 
LLN ULN 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 
5 
CTCAE v5.0 AE Term Definition 
Hematology 
 
 
 
 
 
 
 
 
 
 
 
Hemoglobin Blood and 
lymphatic 
system 
disorders 
Anemia -  Man g/dL 
12.2 17.7 <12.2 - 10.0 
<10.0 - 8.0  
<8.0  
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
A disorder characterized by an 
reduction in the amount of hemoglobin 
in 100 ml of blood. Signs and 
symptoms of anemia may include 
pallor of the skin and mucous 
membranes, shortness of breath, 
palpitations of the heart, soft systolic 
murmurs, lethargy, and fatigability. 
  
Blood and 
lymphatic 
system 
disorders 
Anemia -  
Woman 
g/dL 
9.5 
15.8 <9.5 - 8.5 
<8.5 - 7.5  
<7.5  
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
CTC criteria 
Anemia  
g/dL 
  
  
<LLN - 10.0 g/dL 
<10.0 - 8.0  
 <8.0 g/dL 
transfusion 
indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Platelets 
Investigations 
Platelet count 
decreased 
nb/L 
126 
000 
438 
000 
<126,000 - 75,000 
<75,000 - 50,000 
<50,000 - 
25,000 
<25,000 
 - 
A finding based on laboratory test 
results that indicate a decrease in 
number of platelets in a blood 
specimen. 
CTC criteria 
Platelet count 
decreased 
nb/L 
  
  
<LLN - 75,000 
<75,000 - 50,000 
<50,000 - 
25,000 
<25,000 
- 
Leucocytes Blood and 
lymphatic 
system 
disorders 
Leukocytosis 
nb/L 
3100 9100  - 
 - 
>100,000 
Clinical manifestations 
of leucostasis; urgent 
intervention indicated 
Death 
A disorder characterized by laboratory 
test results that indicate an increased 
number of white blood cells in the 
blood. 
  
CTC criteria 
Leukocytosis 
nb/L 
  
  
  
  
>100,000 
Clinical manifestations 
of leucostasis; urgent 
intervention indicated 
Death 
  
  
Investigations 
White blood 
cell 
decreased 
nb/L 
3100 9100 <3100-2500 
<2500 - 2000 
<2000 - 1000 
<1000/mm3 
 - 
A finding based on laboratory test 
results that indicate an decrease in 
number of white blood cells in a blood 
specimen. 
CTC criteria 
White blood 
cell 
decreased 
nb/L 
  
  
<LLN - 3000 
<3000 - 2000 
<2000 - 1000 
<1000 
- 
Biochemistry 
 
 
 
 
 
 
 
 
 
 
 
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DNDi-FEX-07-HAT 
 
 
 
 
 
 
 
Fexinidazole 
Protocol version 6.0_19 Aug 2022 
 
Confidential  
Page 78 of 83 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
  
CTCAE v5.0 
SOC 
CTCAE v5.0 
Term 
units 
LLN ULN 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 
5 
CTCAE v5.0 AE Term Definition 
Na - Sodium Metabolism and 
nutrition 
disorders 
Hypernatremia mmol/L 128 
145 >145 - 150 
>150 - 155 
>155 - 160 ; 
hospitalization 
indicated 
>160 ; life-threatening 
consequences 
Death 
A disorder characterized by laboratory 
test results that indicate an elevation 
in the concentration of sodium in the 
blood. 
  
CTC criteria 
Hypernatremia mmol/L   
  
<ULN - 150 
>150 - 155; intervention 
indicated 
>155 - 160 ; 
hospitalization 
indicated 
>160 ; life-threatening 
consequences 
Death 
  
  
Metabolism and 
nutrition 
disorders 
Hyponatremia mmol/L 128 
145 - 
<128 - 125  
<125 - 120  
<120 ; life-threatening 
consequences 
Death 
A disorder characterized by laboratory 
test results that indicate a low 
concentration of sodium in the blood. 
 
CTC criteria 
Hyponatremia mmol/L   
  
<LLN - 130 
125-129 and 
asymptomatic 
<125 - 129 
symptomatic; 
120-124 
regardless of 
symptoms 
<120 ; life-threatening 
consequences 
Death 
 
K - 
Potassium 
Metabolism and 
nutrition 
disorders 
Hypokalemia 
mmol/L 3.6 
5.1 <3.6 - 3.0  
<3.6 - 3.0 ; 
symptomatic; 
intervention indicated 
<3.0 - 2.5 ; 
hospitalization 
indicated 
<2.5 ; life-threatening 
consequences 
Death 
A disorder characterized by laboratory 
test results that indicate a low 
concentration of potassium in the 
blood. 
  
CTC criteria 
Hypokalemia 
mmol/L   
  
<LLN - 3.0 
<LLN - 3.0 ; 
symptomatic; 
intervention indicated 
<3.0 - 2.5 ; 
hospitalization 
indicated 
<2.5 ; life-threatening 
consequences 
Death 
  
  
Metabolism and 
nutrition 
disorders 
Hyperkalemia mmol/L 3.6 
5.1 >5.1 - 5.5  
>5.5 - 6.0  
>6.0 - 7.0 ; 
hospitalization 
indicated 
>7.0 ; life-threatening 
consequences 
Death 
A disorder characterized by laboratory 
test results that indicate an elevation 
in the concentration of potassium in 
the blood; associated with kidney 
failure or sometimes with the use of 
diuretic drugs. 
CTC criteria 
Hyperkalemia mmol/L   
  
>ULN - 5.5  
>5.5 - 6.0; intervention 
initiated  
>6.0 - 7.0 ; 
hospitalization 
indicated 
>7.0 ; life-threatening 
consequences 
Death 
Bicarbonates   
  
mmol/L 18 
33 
to be assessed as: 
x"normal", 
x"abnormal not clinically significant" or 
x"abnormal clinically significant (to be graded by the investigator and declared as mild, moderate or severe)" 
  
 
 
 
 
 
 
 
 
 
 
 
 
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DNDi-FEX-07-HAT 
 
 
 
 
 
 
 
Fexinidazole 
Protocol version 6.0_19 Aug 2022 
 
Confidential  
Page 79 of 83 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
  
CTCAE v5.0 
SOC 
CTCAE v5.0 
Term 
units 
LLN ULN 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 
5 
CTCAE v5.0 AE Term Definition 
Chloride 
  
  
mmol/L 98 
108 to be assessed as: 
x"normal", 
x"abnormal not clinically significant" or 
x"abnormal clinically significant (to be graded by the investigator and declared as mild, moderate or severe)" 
  
 
 
 
 
 
 
 
 
 
 
 
 
Glucose 
Metabolism and 
nutrition 
disorders 
Hypoglycemia mg/dL 
73 
118 <73 - 55  
<55 - 40  
<40 - 30 
<30 ; life-threatening 
consequences; 
seizures 
Death 
A disorder characterized by laboratory 
test results that indicate a low 
concentration of glucose in the blood. 
  
CTC criteria 
Hypoglycemia mg/dL 
  
  
<LLN - 55  
<55 - 40  
<40 - 30 
<30 ; life-threatening 
consequences; 
seizures 
Death 
  
  
Metabolism and 
nutrition 
disorders 
Hyperglycemia mg/dL 
73 
118 Fasting glucose 
value >118 - 160  
Fasting glucose value 
>160 - 250  
>250 - 500 ;  
hospitalization 
indicated 
>500 ; life-threatening 
consequences 
Death 
A disorder characterized by laboratory 
test results that indicate an elevation 
in the concentration of blood sugar. It 
is usually an indication of diabetes 
mellitus or glucose intolerance. 
 
CTC criteria 
Hyperglycemia mg/dL 
  
  
Abnormal glucose 
above baseline with 
no medical 
intervention 
Change in daily 
management from 
baseline for a diabetic; 
oral antiglycemic agent 
initiated; workup for 
diabetes 
Insulin therapy 
initiated;  
hospitalization 
indicated 
 life-threatening 
consequences; urgent 
intervention indicated 
Death 
 
Ca - Calcium Metabolism and 
nutrition 
disorders 
Hypercalcemia mg/dL 
8.0 
10.3 >10.3 - 11.5 
>11.5 - 12.5 ; 
symptomatic 
>12.5 - 13.5 ; 
hospitalization 
indicated 
>13.5 ; life-threatening 
consequences 
Death 
A disorder characterized by laboratory 
test results that indicate an elevation 
in the concentration of calcium 
(corrected for albumin) in blood. 
  
CTC criteria 
Hypercalcemia mg/dL 
  
  
>ULN - 11.5 
>11.5 - 12.5 ; 
symptomatic 
>12.5 - 13.5 ; 
hospitalization 
indicated 
>13.5 ; life-threatening 
consequences 
Death 
  
  
Metabolism and 
nutrition 
disorders 
Hypocalcemia mg/dL 
8.0 
10.3 - 
<8.0 - 7.0 ; symptomatic <7.0 - 6.0 ; 
hospitalization 
indicated 
<6.0 ; life-threatening 
consequences 
Death 
A disorder characterized by laboratory 
test results that indicate a low 
concentration of calcium (corrected for 
albumin) in the blood. 
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DNDi-FEX-07-HAT 
 
 
 
 
 
 
 
Fexinidazole 
Protocol version 6.0_19 Aug 2022 
 
Confidential  
Page 80 of 83 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
  
CTCAE v5.0 
SOC 
CTCAE v5.0 
Term 
units 
LLN ULN 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 
5 
CTCAE v5.0 AE Term Definition 
 
CTC criteria 
Hypocalcemia mg/dL 
  
  
<LLN - 8.0 
<8.0 - 7.0 ; symptomatic <7.0 - 6.0 ; 
hospitalization 
indicated 
<6.0 ; life-threatening 
consequences 
Death 
 
Blood Urea 
Nitrogen 
  
  
mg/dL 
7 
22 
to be assessed as: 
x"normal", 
x"abnormal not clinically significant" or 
x"abnormal clinically significant (to be graded by the investigator and declared as mild, moderate or severe)" 
  
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine 
Investigations 
Creatinine 
increased 
mg/dL 
0.5 
1.2  >1.2 - 1.8 
>1.8 - 3.6 
>3.6 - 7.2 
>7.2 
 - 
A finding based on laboratory test 
results that indicate increased levels 
of creatinine in a biological specimen. 
 
CTC criteria 
Creatinine 
increased 
mg/dL 
  
  
 >ULN - 1.5 x ULN 
>1.5 - 3.0 x baseline; 
>1.5 - 3.0 x ULN 
>3.0 baseline; 
>3.0 - 6.0 x 
ULN 
>6.0 x ULN 
  
Navigational Note: Also consider 
Renal and Urinary disorders: Acute 
Kidney Injury 
Alkaline 
phosphatase 
Investigations 
Alkaline 
phosphatase 
increased 
U/L 
48 
164 >164 - 410 
>410 - 820 
>820 - 3280 
>3280 
 - 
A finding based on laboratory test 
results that indicate an increase in the 
level of alkaline phosphatase in a 
blood specimen. 
 
CTC criteria 
Alkaline 
phosphatase 
increased 
U/L 
  
  
>ULN - 2.5 x ULN if 
baseline was 
normal; 2.0-2.5 x 
baseline if baseline 
was abnormal 
>2.5 - 5.0 x ULN if 
baseline was normal; 
>2.5 - 5.0 x baseline if 
baseline was abnormal;  
>5.0 - 20.0 x 
ULN if baseline 
was normal; 
>5.0 - 20.0 x 
baseline if 
baseline was 
abnormal;  
>20.0 x ULN if baseline 
was normal; >20.0 x 
baseline if baseline 
was abnormal 
  
 
ALT (SGPT) Investigations 
Alanine 
aminotransfera
se 
increased 
U/L 
8 
61 
>61 - 183 
>183 - 305 
>305 - 1220 
>1220 
- 
A finding based on laboratory test 
results that indicate an increase in the 
level of alanine aminotransferase (ALT 
or SGPT) in the blood specimen. 
CTC criteria 
Alanine 
aminotransfera
se 
increased 
U/L 
  
  
>ULN - 3.0 x ULN if 
baseline was 
normal; 1.5-3.0 x 
baseline if baseline 
was abnormal 
>3.0 - 5.0 x ULN if 
baseline was normal; 
>3.0 - 5.0 x baseline if 
baseline was abnormal;  
>5.0 - 20.0 x 
ULN if baseline 
was normal; 
>5.0 - 20.0 x 
baseline if 
baseline was 
abnormal;  
>20.0 x ULN if baseline 
was normal; >20.0 x 
baseline if baseline 
was abnormal 
  
Navigational Note: Also consider 
Hepatobiliary disorders: Hepatic 
Failure 
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DNDi-FEX-07-HAT 
 
 
 
 
 
 
 
Fexinidazole 
Protocol version 6.0_19 Aug 2022 
 
Confidential  
Page 81 of 83 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
  
CTCAE v5.0 
SOC 
CTCAE v5.0 
Term 
units 
LLN ULN 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 
5 
CTCAE v5.0 AE Term Definition 
AST (SGOT) Investigations 
Aspartate 
aminotransfera
se 
increased 
U/L 
14 
60 
>60 - 180  
>180 - 300 
>300 - 1200 
>1200 
- 
A finding based on laboratory test 
results that indicate an increase in the 
level of aspartate aminotransferase 
(AST or SGOT) in a blood specimen. 
CTC criteria 
Aspartate 
aminotransfera
se 
increased 
U/L 
  
  
>ULN - 3.0 x ULN if 
baseline was 
normal; 1.5-3.0 x 
baseline if baseline 
was abnormal 
>3.0 - 5.0 x ULN if 
baseline was normal; 
>3.0 - 5.0 x baseline if 
baseline was abnormal;  
>5.0 - 20.0 x 
ULN if baseline 
was normal; 
>5.0 - 20.0 x 
baseline if 
baseline was 
abnormal;  
>20.0 x ULN if baseline 
was normal; >20.0 x 
baseline if baseline 
was abnormal 
  
Navigational Note: Also consider 
Hepatobiliary disorders: Hepatic 
Failure 
Total 
Bilirubin 
Investigations 
Blood bilirubin 
increased 
mg/dL 
0.2 
2.2 >2.2 - 3.3 
>3.3 - 6.6 
>6.6 - 22.0 
>22.0 
- 
A finding based on laboratory test 
results that indicate an abnormally 
high level of bilirubin in the blood. 
Excess bilirubin is associated with 
jaundice. 
 
CTC criteria 
Blood bilirubin 
increased 
mg/dL 
  
  
>ULN - 1.5 x ULN if 
baseline was 
normal; >1.0-1.5 x 
baseline if baseline 
was abnormal 
>1.5 - 3.0 x ULN if 
baseline was normal; 
>1.5 - 3.0 x baseline if 
baseline was abnormal;  
>3.0 - 10.0 x 
ULN if baseline 
was normal; 
>3.0 - 10.0 x 
baseline if 
baseline was 
abnormal;  
>10.0 x ULN if baseline 
was normal; >10.0 x 
baseline if baseline 
was abnormal 
  
Navigational Note: Also consider 
Hepatobiliary disorders: Hepatic 
Failure 
Albumin 
Metabolism and 
nutrition 
disorders 
Hypoalbumine
mia 
g/dL 
3.5 
5.2 <3.5 - 3  
<3 - 2  
<2 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
A disorder characterized by laboratory 
test results that indicate a low 
concentration of albumin in the blood. 
CTC criteria 
Hypoalbumine
mia 
g/dL 
  
  
<LLN - 3 
<3 - 2 
<2 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Total Protein   
  
g/dL 
5.8 
8.8 to be assessed as: 
x"normal", 
x"abnormal not clinically significant" or 
x"abnormal clinically significant (to be graded by the investigator and declared as mild, moderate or severe)" 
  
 
CTC criteria 
CTC differs from new 
biological values 
 
 
 
 
 
 
  
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DNDi-FEX-07-HAT 
 
 
 
 
 
 
 
Fexinidazole 
Protocol version 6.0_19 Aug 2022 
 
Confidential  
Page 82 of 83 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
Appendix 5 – Schedule of events  
Protocol Procedures and Forms 
to be completed 
Screening 
and 
Baseline 
Treatment Period 
EoT 
Visit 
EoH Visit 
Follow-up Visits 
Unschedu-
led Visit1 
Time 
D-7 to D-1 
D1 
D2 D3 
D4 
D5 D6 
D7 
D8 
D9 D10 D112 
D12-D182 M13 W9 
M6 
M12 
 
Thick/thin blood smear 
x 
 
  
  
  
  
  
  
  
  
  
 
  
 
 
 
 
 
mAECT4 
x 
 
  
  
  
x  
  
  
  
  
  
x 
  
 
x 
x 
(x)5 
 
Lymph node aspirate microscopic 
examination 
x 
 
  
  
  
  
  
  
  
  
  
x 
  
 
x 
x 
(x)5 
 
Lumbar Puncture  
x 
 
  
  
  
  
  
  
  
  
  
x 
  
 
x 
x 
(x)5 
 
Patient informed consent 
x 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Inclusion/Exclusion criteria review 
x 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Demographics 
x 
 
  
  
  
  
  
  
  
  
  
 
  
 
x6 
x6 
(x)5,6 
 
Medical history 
x 
 
  
  
  
  
  
  
  
  
  
 
  
 
 
 
 
 
Concomitant medications record 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
x 
Karnofsky index 
x 
 
  
  
  
x 
  
  
  
  
  
x 
x 
 x 
 x 
x  
x  
x 
Treatment of helminthiasis 
x 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Malaria rapid test and/or thick 
blood smear 
x 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Pre-treatment of malaria7 
x 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
1 Additional tests can be performed at investigator’s discretion, if medically needed 
2 EoT could be at D12 and EoH from D13 and D19 if there was a temporary interruption of treatment (max 24hours) 
3 M1 consists of a home visit to the patient by the investigator.  In case of clinical concerns, the investigator could request parasitological test 
4 If parasites show negative, mAECT-BC will also be performed. mAECT-BC to be used as as back-up method if mAECT not available 
5 If patient is unable or unwilling to attend M12 visit, direct evidence of a satisfactory patient’s clinical condition by the Investigator or a delegated staff from the trial team is 
sufficient. If the clinical condition is unclear, patient should be brought back to the hospital for parasitological exams 
6 Applied only to children 
7 Only if malaria test is positive 
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DNDi-FEX-07-HAT 
 
 
 
 
 
 
 
Fexinidazole 
Protocol version 6.0_19 Aug 2022 
 
Confidential  
Page 83 of 83 
Clinical Trial Protocol template_Version 1.2_02 June 2014 
Protocol Procedures and Forms 
to be completed 
Screening 
and 
Baseline 
Treatment Period 
EoT 
Visit 
EoH Visit 
Follow-up Visits 
Unschedu-
led Visit1 
Time 
D-7 to D-1 
D1 
D2 D3 
D4 
D5 D6 
D7 
D8 
D9 D10 D112 
D12-D182 M13 W9 
M6 
M12 
 
Vital signs 
x8 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
(x)5 
x 
Biochemistry 
x8 
 
  
  
  
x 
  
  
 
  
  
x 
  
 
x 
  
  
 
Haematology 
x8 
 
  
  
  
x 
  
  
 
  
  
x 
  
 
x 
  
  
 
PK sampling 
 
 
H0.5 
H3.5 
H6 
 
 
H3.5 
H6 
H12 
 
 
 
 
 
 
D10 
H24 
D10 
H48 
 
 
 
 
 
Blood sampling for qPCR 
x8 
H6 
 
 
H12 
 
 
 
 
 
 
D10H
24 
 
 
x 
x 
x 
 
ECG recording (safety) 
x8 
 
x9 
x9 
x9 
  
  
  
  
  
  
 
  
  
 
  
  
 
ECG recording (triplicate) 
x8 
 
  
  
H3 
H12 
  
  
  
  
  
 
D10 
H23 
 
  
x 
  
  
 
HAT 
signs 
and 
symptoms 
questionnaire 
x8 
 
  
  
  
x 
  
  
  
  
  
  
x 
x 
x 
x 
(x)5 
x 
Physical examination 
x8 
 
  
  
  
x 
  
  
 
  
  
x 
x 
x 
x 
x 
(x)5 
x 
Neurological examination 
x8 
 
  
  
  
x 
  
  
 
  
  
x 
x 
x 
x 
x 
(x)5 
x 
Pregnancy test 
x810 
 
  
  
  
  
  
  
  
  
  
  
x 
 
x 
  
  
 
Fexinidazole administration 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
  
  
  
  
  
 
Adverse events record 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x11 x11 
x11 
(x)5,11 
x 
Serious adverse events (SAEs) 
record 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x)5 
x 
 
 
8 Tests to be performed at baseline (D -4 to D -1) 
9 Pre-dose 
10 Test to be done on the first day of screening  
11 From M1 to M12: only AEs considered related to fexinidazole are to be reported 
 
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SAP_001.pdf: 
Statistical Analysis Plan DNDi-FEX-07-HAT Version 1.0 
 
Fexinidazole  
 
Confidential  
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Efficacy and safety of fexinidazole in patients  
with Human African Trypanosomiasis (HAT)  
due to Trypanosoma brucei rhodesiense:  
a multicentre, open-label clinical trial 
 
 
 
 
 
 
Registration number 
NCT03974178 
 
 
 
Version 1.0 – 25 August 2020 
 
 


DNDi FEX 007 HAT Statistical Analysis Plan_v1.0_25Aug2020 
1 
            
                     
 
 
 
 
 
 
Study Title:  
 
Efficacy and safety of fexinidazole in patients with Human African Trypanosomiasis (HAT) 
due to Trypanosoma brucei rhodesiense: a multicentre, open-label clinical trial  
 
Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
SAP 
Effective Date: 31Aug2020 
Version Number and Date: 1.0, 25 Aug 2020 
Revision  
List of changes: 
 
Name and function 
Date (DD-MMM-YYYY) 
Signature 
Author 
 
Biostatistician 
 
 
Reviewed by 
 
Director of Research department  
 
 
. Statistician 
 
 
Olaf Valverde. DNDi Medical 
manager 
 
 
 
 
 
Sep 1, 2020
Sep 2, 2020
Sep 10, 2020
T+2)
Sep 11, 2020
Page 2 of 46
DNDi 
Drugs for Neglected Diseases initiative 
I 
I 
 


DNDi FEX 007 HAT Statistical Analysis Plan_v1.0_25Aug2020 
2 
TABLE OF CONTENT 
ABBREVIATIONS .................................................................................................................... 3
1.
Introduction ........................................................................................................................ 5
2.
Study objectives ................................................................................................................. 5
3.
Study design ....................................................................................................................... 6
4.
Sample size calculation ...................................................................................................... 6
5.
Interventions ....................................................................................................................... 7
6.
Study plan ........................................................................................................................... 7
7.
Analysis sets and presentation of data .............................................................................. 10
7.1. 
Analysis variables ...................................................................................................... 10
7.1.1 Demographic and baseline characteristics .............................................................. 10
7.1.2 Dosing and adherence to the treatment ................................................................... 11
7.1.3 Efficacy variables .................................................................................................... 11
7.1.4 
Safety variables .................................................................................................. 14
7.2. 
Analysis populations.................................................................................................. 16
7.2.1 Safety population ..................................................................................................... 16
7.2.2 Efficacy population ................................................................................................. 16
7.2.3 Participant disposition ............................................................................................. 16
7.3. 
Statistical methods ..................................................................................................... 17
7.3.1 Demographic and baseline characteristics .............................................................. 17
7.3.2 Analysis of efficacy data ......................................................................................... 17
7.3.3 Analysis of safety data ............................................................................................ 18
7.3.4 Data handling convention ........................................................................................ 20
8.
Interim analysis ................................................................................................................ 20
9.
Software conventions ....................................................................................................... 20
Appendix 1 – Evaluation criteria of efficacy endpoints ....................................................... 21
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DNDi FEX 007 HAT Statistical Analysis Plan_v1.0_25Aug2020 
3 
ABBREVIATIONS 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CRF 
Case Report Form  
CSF 
Cerebrospinal Fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
Day 
DNDi 
Drugs for Neglected Diseases initiative 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
EoH 
End of Hospitalization 
EoT 
End of Treatment 
EoS 
End of Study 
GCP 
Good Clinical Practice 
H 
Hour 
ITT 
Intent to Treat 
M 
Month 
mAECT 
Mini Anion Exchange Centrifugation Technique 
mAECT-BC 
Mini Anion Exchange Centrifugation Technique on Buffy Coat 
MHCT 
Microhematocrit centrifugation test 
MSF 
Médecins sans Frontières 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PV 
Pharmacovigilance 
REDCap 
Research Electronic Data Capture 
r-HAT 
Rhodesiense Human African Trypanosomiasis 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
WBC 
White Blood Cell 
W 
Week 
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WHO 
World Health Organization 
 
 
 
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DNDi FEX 007 HAT Statistical Analysis Plan_v1.0_25Aug2020 
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1. Introduction 
This standard methodology document, the statistical analysis plan, explains the rules and 
conventions to be used in the presentation and analysis of efficacy and safety data for the 
study “Efficacy and safety of fexinidazole in patients with Human African Trypanosomiasis 
(HAT) due to Trypanosoma brucei rhodesiense: a multicentre, open-label clinical trial ”. 
It describes the data and endpoints to be summarized and analysed, including specifics of the 
statistical analyses to be performed and  is based on protocol “DNDi-FEX-07-HAT 
protocol_v4.0_23JAN2020”. Any ad hoc analyses not described in this SAP may be 
performed and will be detailed in the appropriate section of the clinical study report.  
 
2. Study objectives 
The primary objective is to show that the fatality rate (r-HAT or treatment related death) at the 
end of hospitalization in stage-2 patients treated with fexinidazole is smaller than a threshold 
of unacceptable rate of 8.5%. 
The secondary objectives are the followings: 
1. To show that the failure rate (r-HAT or treatment related death according to DSMB 
(Data Safety Monitoring Board) or presence of trypanosomes) at the end of 
hospitalisation in stage-2 patients treated with fexinidazole is smaller than a threshold 
of an unacceptable rate of 9% 
2. To show that the proven failure rate (r-HAT or treatment related death according to 
DSMB or relapse) at 12 months (or before) in stage-2 patients treated with fexinidazole 
is below an unacceptable rate of 12% 
3. To estimate the failure rate at EoH and at 12 months in stage-1 r-HAT patients treated 
with fexinidazole and to verify whether the estimates are smaller than that of suramin 
4. To estimate the fatality rate and success rate at 12 months in the overall population (late- 
and early-stage r-HAT patients) treated with fexinidazole 
5. To evaluate the safety profile of fexinidazole in late- and early-stage r-HAT patients 
and to compare it to the one of melarsoprol and suramin as reported in the literature16. 
And the exploratory objectives: 
1. To estimate the time course of relapse of fexinidazole from EoT to 12 months after the 
end of treatment 
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DNDi FEX 007 HAT Statistical Analysis Plan_v1.0_25Aug2020 
6 
2. To assess the PK (pharmacokinetics) of fexinidazole and its main metabolites in the 
blood  
3. To assess the reduction in the number of trypanosomes in the blood until the end of 
study visit 
The analyses on the PK component will be detailed in another document. 
 
3. Study design 
This is a multicentre, phase II/III, open-label, non-randomized clinical trial of r-HAT patients 
on efficacy and safety of fexinidazole. 
 
4. Sample size calculation 
The minimal sample size to get a possible rejection of H0 (fatality rate at EoH = 8.5% or more) 
in favour of H1 (fatality rate < 8.5%) is 34 evaluable stage-2 patients for alpha = 0.05 one-sided. 
In that case if no patients died during treatment the exact one-sided test becomes significant (p 
= 0.0488). 
Consequently, the sample size is not set according to a minimal power of 80%, but according 
to the possible rejection of the null hypothesis. The second consequence of such an approach 
is: as soon as one death is observed at EoH, the study may be stopped for futility and failure 
(inconclusive result). To accept one failure and get a rejection of the null hypothesis once one 
failure is observed, the minimal sample size becomes 53 patients (p = 0.04967, for 1/53 deaths). 
Because this sample size cannot be reached within two years, the study is unfeasible if this 
hypothesis is applied.  
Even if the minimal sample size (n= 34) was retained to get a working hypothesis that can be 
rejected statistically, the power of the study remains quite reasonable.  Fexinidazole was 
administered to 361 stage 2 patients suffering from HAT T.b gambiense. Two deaths were 
observed before the end of hospitalisation, considered unrelated to the treatment or disease. The 
fatality rate for any cause was therefore equal to 0.554%. These deaths were probably not due 
to treatment but considering the case of deaths regardless the cause, the power of the study in 
patients infected by T.b gambiense would be 82.79%. Using MSF data1, the fatality rate in r-
HAT stage 2 patients treated with melarsoprol was twice (exactly 1.98) larger in T.b 
rhodesiense than in T.b gambiense stage 2 patients. If we consider it is due to the fragility of 
patients infected by rhodesiense trypanosomes, then the expected fatality rate for any cause 
with fexinidazole could reach 1.097%. Using the corrected estimate (1.097%) as true then the 
exact power of the study is 68.73 %. Considering deaths possibly related to treatment or disease, 
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DNDi FEX 007 HAT Statistical Analysis Plan_v1.0_25Aug2020 
7 
the power should be larger than 70% that is a reasonable power in a rare and neglected disease. 
If one death attributable to the treatment or disease may occur, the DSMB will rule whether or 
not the use of fexinidazole shall continue until the sample size of 34 patients is reached but no 
statistical inference will be made with regards to the unacceptable limit of 8.5%. 
In case of non-evaluable patients, the sample size will be increased to reach 34 evaluable 
patients that are required to get a testable hypothesis in the primary analysis. 
The recruitment will be stopped once 34 evaluable stage-2 patients are recruited. 
 
5. Interventions 
Fexinidazole will be given orally, once daily after the main meal under direct observation of 
an authorized staff member, and preferably at the same time every day, and only during 
hospitalization.  
The daily doses are adjusted based on body weight and day of treatment, as follows: 
• Patients with a body weight ≥ 35 kg: 
− 
 1800 mg (3 tablets) from day 1 to 4 
− 
 1200 mg (2 tablets) from day 5 to 10 
• Patients with a body weight ≥ 20 and < 35 kg: 
− 
 1200 mg (2 tablets) from day 1 to 4 
− 
 600 mg (1 tablet) from day 5 to 10 
The tablets must not be broken nor crushed.  
The total treatment duration will be 10 days. Treatment compliance will be guaranteed by the 
direct observed administration of the drug exclusively by the assigned staff.  
 
6. Study plan 
The following time and events schedule provides all the assessments performed during the 
study up to the M12 visit.  
 
 
 
 
 
 
 
 
 
Page 8 of 46
-


DNDi FEX 007 HAT Statistical Analysis Plan_v1.0_25Aug2020 
8 
 
Protocol Procedures and Forms to 
be completed 
Screening 
and 
Baseline 
Treatment Period 
EoT 
Visit 
EoH Visit 
Follow-up Visits 
Unschedu-
led Visit1 
Time 
D-7 to D-1 
D1 
D2 D3 
D4 
D5 D6 
D7 
D8 
D9 D10 
D112 
D12-D182 
M13 W9 
M6 
M12 
 
Thick/thin blood smear 
x 
 
  
  
  
  
  
  
  
  
  
 
  
 
 
 
 
 
mAECT4 
x 
 
  
  
  
x  
  
  
  
  
  
x 
  
 
x 
x 
(x)5 
 
Lymph node aspirate microscopic 
examination 
x 
 
  
  
  
  
  
  
  
  
  
x 
  
 
x 
x 
(x)5 
 
Lumbar Puncture  
x 
 
  
  
  
  
  
  
  
  
  
x 
  
 
x 
x 
(x)5 
 
Patient informed consent 
x 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Inclusion/Exclusion criteria review 
x 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Demographics 
x 
 
  
  
  
  
  
  
  
  
  
 
  
 
x6 
x6 
(x)5,6 
 
Medical history 
x 
 
  
  
  
  
  
  
  
  
  
 
  
 
 
 
 
 
Concomitant medications record 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
X 
Karnofsky index 
x 
 
  
  
  
x 
  
  
  
  
  
x 
x 
 x 
 x 
x  
x  
X 
Treatment of helminthiasis 
x 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Malaria rapid test and/or thick blood 
smear 
x 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Pre-treatment of malaria7 
x 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Vital signs 
x8 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
(x)5 
X 
 
1 Additional tests can be performed at investigator’s discretion, if medically needed 
2 EoT could be at D12 and EoH from D13 and D19 if there was a temporary interruption of treatment (max 24hours) 
3 M1 consists of a home visit to the patient by the investigator.  In case of clinical concerns, the investigator could request parasitological test 
4 If parasites show negative, mAECT-BC will also be performed. mAECT-BC to be used as as back-up method if mAECT not available 
5 If patient is unable or unwilling to attend M12 visit, direct evidence of a satisfactory patient’s clinical condition by the Investigator or a delegated staff from the trial team is 
sufficient. If the clinical condition is unclear, patient should be brought back to the hospital for parasitological exams 
6 Applied only to children 
7 Only if malaria test is positive 
8 Tests to be performed at baseline (D -4 to D -1) 
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DNDi FEX 007 HAT Statistical Analysis Plan_v1.0_25Aug2020 
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Protocol Procedures and Forms to 
be completed 
Screening 
and 
Baseline 
Treatment Period 
EoT 
Visit 
EoH Visit 
Follow-up Visits 
Unschedu-
led Visit1 
Time 
D-7 to D-1 
D1 
D2 D3 
D4 
D5 D6 
D7 
D8 
D9 D10 
D112 
D12-D182 
M13 W9 
M6 
M12 
 
Biochemistry 
x8 
 
  
  
  
x 
  
  
 
  
  
x 
  
 
x 
  
  
 
Haematology 
x8 
 
  
  
  
x 
  
  
 
  
  
x 
  
 
x 
  
  
 
PK sampling 
 
 
H0.5 
H3.5 
H6 
 
 
H3.5 
H6 
H12 
 
 
 
 
 
 
D10 
H24 
D10 
H48 
 
 
 
 
 
Blood sampling for qPCR 
x8 
H6 
 
 
H12 
 
 
 
 
 
 
D10H
24 
 
 
x 
x 
x 
 
ECG recording (safety) 
x8 
 
x9 
x9 
x9 
  
  
  
  
  
  
 
  
  
 
  
  
 
ECG recording (triplicate) 
x8 
 
  
  
H3 
H12 
  
  
  
  
  
 
D10 
H23 
 
  
x 
  
  
 
HAT signs and symptoms 
questionnaire 
x8 
 
  
  
  
x 
  
  
  
  
  
  
x 
x 
x 
x 
(x)5 
X 
Physical examination 
x8 
 
  
  
  
x 
  
  
 
  
  
x 
x 
x 
x 
x 
(x)5 
X 
Neurological examination 
x8 
 
  
  
  
x 
  
  
 
  
  
x 
x 
x 
x 
x 
(x)5 
X 
Pregnancy test 
x810 
 
  
  
  
  
  
  
  
  
  
  
x 
 
x 
  
  
 
Fexinidazole administration 
  
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
  
  
  
  
  
 
Adverse events record 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x11 
x11 
x11 
(x)5,11 
X 
Serious adverse events (SAEs) 
record 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x)5 
X 
 
 
9 Pre-dose 
10 Test to be done on the first day of screening  
11 From M1 to M12: only AEs considered related to fexinidazole are to be reported 
 
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DNDi FEX 007 HAT Statistical Analysis Plan_v1.0_25Aug2020 
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7. Analysis sets and presentation of data
7.1. Analysis variables
7.1.1 Demographic and baseline characteristics 
The following variables will be described for demographic and baseline characteristics. 
Demographics characteristics: 
•
Age (derived from the date of birth or as reported in years, if date of birth unknown),
sex
Laboratory characteristics for diagnosis of HAT 
•
Results of blood and lymph tests (including the mAECT test and the number of
trypanosomes observed (Semi-quantification), the mAECT-BC test, the lymph node
aspirate test, mHCT (Woo test), Thin/Thick blood smear
•
Results of Cerebrospinal fluid test including the presence of trypanosome, the used
method and the value of WBC/µl
•
HAT stage (stage 1 is defined as at least one test for trypanosomes detected in blood
and/or lymph is positive,  and absent in the CSF and WBC≤5/µl of CSF, and stage 2 is
defined as the presence of trypanosome in the CSF with any number of WBC in CSF
and/or any positive trypanosome test in blood, lymph and/or CSF with WBC>5/µl of
CSF.
Clinical and other baseline characteristics: 
•
History of HAT (stage and treatment received during the last episode of HAT if any)
•
Medical history (including allergies, psychiatric disorders, metabolic disturbances,
active malignancy, drug abuse, seizure disorders, cardiovascular disease, HIV and
others if any)
•
Results of malaria test (including malaria rapid diagnostic test and thick smear test)
•
Vital signs (including temperature, Heart Rate, Respiratory rate, blood pressure),
weight, height, BMI and a general health status
•
Signs and symptoms of trypanosomiasis (presence of the sign/symptom, time from the
first sign/symptom, continuous or intermittent and grade)
•
Physical and neurological examinations (presence of any abnormality)
•
Hematology and biochemistry results (result, presence of abnormality and CTCAE
grade if clinically significant)
•
Pregnancy status for women and trimester for pregnant women
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DNDi FEX 007 HAT Statistical Analysis Plan_v1.0_25Aug2020 
11 
7.1.2 Dosing and adherence to the treatment 
The total dose of Fexinidazole to which the participant was exposed will be calculated, taking 
into account the need to replace vomited doses within 2 hours after administration, considering 
the re-administered doses following vomiting (if any). The total dose will be compared to the 
theoretical dose the patient should have received following the posology: 
For patients with a body weight ≥35kg), the theoretical total dose is:  
−
1800 mg (3 tablets) from day 1 to 4
−
1200 mg (2 tablets) from day 5 to 10
Leading to a total dose of 14400 mg. 
Patients with a body weight ≥ 20 and < 35 kg: 
−
1200 mg (2 tablets) from day 1 to 4
−
600 mg (1 tablet) from day 5 to 10
Leading to a total dose of 8400 mg. 
Adherence (in %) to Fexinidazole as described in the protocol, i.e. not taken into account the 
vomited doses within two hours after administration, will be calculated following the formula: 
[(Total dose (mg) intake-vomited doses)/Total theoretical dose (mg)] x100. The total dose will 
include re administered doses after vomiting but not the vomited doses.  
Duration of the treatment will be also stated in number of days, and the reasons for longer or 
shorter duration that 10 days will be shown in a table. 
Additionally, the following will be displayed: 
• Patients who completed the full course of treatment (i.e. at least 10 days) (yes/no)
• Patients fully compliant (i.e. children with body weight less than 35 kg who took exactly 14
tablets or children with body weight who took exactly 24 tablets or adults who took exactly
24 tablets) (yes/no)
• Patients who always took their treatment during a meal (yes/no)
• Patients who had at least one re-administration (yes/no)
• Patients who had at least one re-administration due to vomiting (yes/no)
• Patients who had at least one re-administration due to other reason (yes/no)
• Number of re-administration(s) by patient (0, 1, 2, …)
7.1.3 Efficacy variables 
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DNDi FEX 007 HAT Statistical Analysis Plan_v1.0_25Aug2020 
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The primary efficacy variable is the death possibly related to r-HAT or to Fexinidazole, 
according to DSMB, up to the end of hospitalisation in stage 2 r-HAT patients.  
Any death not related to r-HAT nor to the treatment during the hospitalisation will not be taken 
into account and the patient will be considered as not evaluable. Any patient leaving the hospital 
on his own will before the planned end of  hospitalisation period and for whom no outcome 
could be retrieved will also be considered as non-evaluable. 
The secondary efficacy variables are: 
1. The success and failure at the end of hospitalisation in stage 1 and stage 2 r-HAT
patients. The success is defined by:
•
the absence of trypanosome at the end of treatment visit
•
and the patient alive at the EoH visit
The failure is defined as: 
•
the presence of trypanosome in any fluid at the end of treatment visit
•
or the death of the patient possibly related to r-HAT or treatment, according to
DSMB.
•
or absence of clinical improvement leading to the use of rescue treatment
Any death not related to r-HAT nor to the treatment, during the hospitalisation will not be taken 
into account and the patient will be considered as not evaluable for this efficacy variable. In the 
absence of lumbar puncture at EoT visit, the patient will be considered as non-evaluable for 
this specific variable, unless a lumbar puncture is done before the EoH visit. 
2. The success and failure at the M12 visit. A modification of the WHO recommendations
is used to determine success and failure for stage-1 and stage-2 r-HAT patients
(Appendix 1 - Evaluation criteria of efficacy endpoints).
The success is defined as:
•
any patient with a success at EoH,
and
•
absence of trypanosomes in any body fluid, with WBC in the CSF ≤20 /µl at the
M12 visit, OR
•
absence of trypanosomes in blood but without lumbar puncture results and
presence of a satisfactory clinical condition according to the investigator (ability
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DNDi FEX 007 HAT Statistical Analysis Plan_v1.0_25Aug2020 
13 
to have an active life without relevant symptoms of disease) or a clinical status 
unlikely due to HAT at the M12 visit, OR 
•
any patient who did not attend the M6 and the M12 visits but with reports of
either a satisfactory clinical condition or a clinical status unlikely due to HAT at
the M12, according to the investigator or delegated staff from the trial team.
•
any patient fitting to one of the definitions above and not qualifying as failure
according to the definitions below.
A patient is considered as a failure at the M12 visit, in case of any of the following 
condition: 
•
patient with a failure at EoH, or
•
any death with a clinical picture certainly or possibly compatible with HAT,
with the treatment or unknown, to which no alternative cause can be clearly
attributed, between the EoH visit and the theoretical date of M12 visit (D1 +306
days), or
•
presence of trypanosomes at any visit after EoH up to the M12 visit, or
•
result of the cerebrospinal fluid test negative for the presence of trypanosome
and with WBC in the CSF >20 /µl at any visit after EoH visit in CSF in a non-
hemorrhagic sample, whose WBC count is unlikely due to causes other than
HAT, or
•
result of the blood or lymph node aspiration (if done) tests negative for the
presence of trypanosome but without lumbar puncture OR whose CSF is
haemorrhagic AND who requires rescue treatment at any visit after EoH visit
•
patient who did not attend M6 and M12 visits and for whom there is no direct
evidence of satisfactory clinical condition or there is a direct evidence of a
clinical status likely due to HAT
3. Unsatisfactory clinical and parasitological response during the observation period and
at the EoT visit. In order to evaluate this unsatisfactory response, the following will be
be displayed:
•
Persistence of any initially reported signs and symptoms  with the same grade as
compared to baseline or occurrence of new sign(s) of HAT at the end of
hospitalisation visit,
•
Persistence of abnormal laboratory test results as compared to baseline or
occurrence of new abnormalities at the end of hospitalization,
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DNDi FEX 007 HAT Statistical Analysis Plan_v1.0_25Aug2020 
14 
•
Persistence of positive result in parasitological tests as compared to baseline at
the end of treatment visit
The exploratory efficacy variables to assess the efficacy are: 
•
The earliest time to detect a relapse defined as:
o
presence of trypanosomes in any body fluid from the EoT visit to
12 months after D1, or
o
The date of death if attributable to r-HAT or treatment administration
according to the DSMB or
o
The administration of rescue medication
•
The quantification of trypanosomes in blood at all visits
•
Trypanosome nucleid acids detection until the end of study (analyses described
elsewhere)
7.1.4 Safety variables 
The safety analysis will be based on the reported adverse events (AEs)/adverse events of special 
interest (AESIs)/Serious Adverse Events (SAEs) in the case report forms, and other safety 
information, such as vital signs, laboratory examinations, ECG, physical and neurological 
examinations during the hospitalization and the follow-up of the study. 
7.1.4.1 Adverse events 
An adverse event refers to any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product, and which does not necessarily have a causal relationship 
with that treatment. It can therefore be any unfavourable and unintended sign (for e.g. an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
Definition of an AE includes worsening (in severity and frequency) of pre-existing conditions 
("Medical history") before first IMP administration and abnormalities of procedures (i.e., ECG, 
X-ray, ophthalmologic or neurological examination etc.) or laboratory results which are 
assessed as "clinically significant". In this study, will be considered as AESI any 
neuropsychiatric signs and symptoms (excluding headaches and insomnia, that will be reported 
as AE) requiring specialized therapeutic intervention (such as specific pharmacotherapy or 
psychotherapy (including psychological counseling).
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DNDi FEX 007 HAT Statistical Analysis Plan_v1.0_25Aug2020 
15 
Adverse events will be collected all along the study duration, following as detailed below: 
•
during the screening period, with potential AE that may be linked to study
procedure;
•
during the hospitalization period, any worsening pre-existing condition of the
medical history (not HAT signs/symptoms) or any new event occurring after
treatment initiation
•
during the follow-up visits, only AE(s) related to Fexinidazole, or SAE or AESI
7.1.4.2 Clinical signs 
Vital sign measurements including body temperature, blood pressure (BP), heart rate (HR), and 
respiratory rate will be taken at screening, during the treatment period, at EoT, at EoH visits 
and during W9, M6 and M12 follow-up visits and can be reported also during unscheduled 
visits. 
Physical and neurological assessments will be performed at screening, during the treatment 
period, at EoT, at EoH visits and during W9, M6 and M12 follow-up visits and can be reported 
also during unscheduled visits.  
7.1.4.3 Laboratory assessments 
Biochemistry and haematology tests will be performed at screening, D5, EoT, at W9 visit and 
at unscheduled visit if needed.  
The following parameters will be measured: 
-
Haematology: haemoglobin, total WBC count, differential WBC count, platelet count
-
Biochemistry: albumin (ALB), alkaline phosphatase (ALP), alanine aminotransferase
(ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), chloride (CI-),
creatinine (CRE), glucose (GLU), potassium (K+) sodium (Na+), calcium (Ca2+), total
bilirubin (TBIL), total carbon dioxyde (tCO2), total protein (TP)
Any abnormal finding will be assessed for clinical significance and graded when appropriate. 
7.1.4.4 Other data 
Single ECG will be performed at screening, D2, D3, D4 and during unscheduled visits if 
needed. A centralized reading will be performed by 
and results will be reported 
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DNDi FEX 007 HAT Statistical Analysis Plan_v1.0_25Aug2020 
16 
separately. 
Triplicates ECG will be performed at screening, D4, EoT, W9 and during unscheduled visits if 
needed. A centralized reading will be performed by 
and results will be reported 
separately.. 
Pregnancy tests will be performed at screening, EoH and W9 visit. Any woman exposed during 
pregnancy will be monitored for safety up to the outcome of the pregnancy, and the child 
followed up until 2 years of age as feasible (information reported in the DNDi PV database).  
7.2. Analysis populations 
The intent to treat (ITT) population, including all recruited patients who signed the informed 
consent and included in the study will be used for the disposition of patients. 
7.2.1 Safety population 
The safety population includes all patients who took at least one dose of the study drug, 
regardless of study deviations/violations and stage of r-HAT. This corresponds also to the 
modified intent to treat population (mITT) defined in the efficacy population section. 
7.2.2 Efficacy population 
The modified intent to treat (mITT) population, consisting of all patients from the ITT who 
took at least one dose of fexinidazole, will be used for sensitivity analyses . This set will also 
be the safety population. 
The primary population for efficacy analyses is the population of evaluable patients, excluding 
from the mITT population, patients whose death during hospitalization (if any) is documented 
and clearly attributable to other causes than r-HAT or treatment according to the DSMB and 
patients who escaped from the hospital and were not retrieved later to know their status on the 
primary outcome.  
Another population for efficacy is composed of patients from the mITT who completed the 
treatment with fexinidazole, either in 10 days or in 11 days if one dose of fexinidazole is missed. 
7.2.3 Participant disposition 
The total number of participants for each of the following categories will be presented: 
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17 
•
Screened participants and reason for non-inclusion
•
ITT population
•
mITT population
•
Evaluable population
•
Treatment Completer population
•
Participants who discontinued the treatment and reason for discontinuation
•
Participants who completed the follow-up
•
Participants who discontinued the follow-up and reason for discontinuation
7.3. Statistical methods 
Continuous variables will be summarized using the number of observations available (N), 
median and IQR (interquartile range) or mean and standard deviation (SD) and min/max  when 
more appropriate; categorical data will be summarized for each category using counts of non-
missing data and percentages. 95% confidence intervals (CIs) for binomial proportions will be 
estimated using the Clopper-Person exact method. Nevertheless, comparisons to pre-specified 
thresholds will be done using a one-sided exact test at the significance level of 5%. 
7.3.1 Demographic and baseline characteristics 
Descriptive statistics will be displayed to summarize the demographic and baseline 
characteristics data on the safety population. 
7.3.2 Analysis of efficacy data 
7.3.2.1 Analysis of the primary endpoint 
The primary analysis of the primary endpoint is the comparison of the proportion (pdeath) of 
deaths possibly related to r-HAT or to Fexinidazole at the end of the hospitalization (as 
defined in section 7.1.3) to the threshold of 8.5%. 
The hypotheses of test will be under H0: pdeath≥8.5% vs H1 pdeath<8.5%. The hypothesis will 
be tested using a one-sided exact test for proportions, at the 0.05 significance level. 
This comparison will be performed on the stage 2 patients from the evaluable population which 
must be composed of at least 34 patients.  
Sensitivity analyses will be performed by repeated this comparison on stage-2 patients from the 
mITT and completers if those populations contain at least 34 patients.  
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7.3.2.2 Analysis of the secondary endpoints 
The proportion of failure at the end of hospitalisation  will be compared  to the thresholds of 
9% on stage 2 patients from the mITT and completer populations.  
The fatality rate at EoH, failure rate at EoH and failure rate at 12 months will be estimated. 
Because the sample size will be very small, no null hypotheses will be testable. 
The estimate of fatality rate at EoH, failure rate at EoH and failure rate at 12 months for stage-
1 and stage-2 combined will be calculated and tested against the unacceptable limit of 8.5%, 
9% and 12%, respectively.    
 
The failure rate at the M12 visit will be compared to the threshold of 12% on the stage-2 r-HAT 
patients from the mITT and treatment completer populations, using a one-sided test if the 
observed rate if below 12%.  
The fatality rate at EoH, failure rate at EoH and failure rate at 12 months will be estimated and 
presented with a 95%CI, on the stage-2 r-HAT patients from the mITT and treatment completer 
populations. No comparison to pre specified thresholds will be performed. 
The fatality rate at EoH, failure rate at EoT, and failure rate at the month12 visit will then be 
estimated in the entire (stage-1 and stage 2-patients) evaluable population and compared 
respectively to the pre specified threshold of 8.5%, 9% and 12%. The comparisons will be 
repeated on the mITT and completers.  
 
All comparisons will be done using a one-sided exact test for proportions, at the 0.05 
significance level (one sided). 
Time to failure (as defined previously)  and time to reduction in the number of trypanosomes 
in the blood will be estimated using survival analysis. 
 
7.3.3 Analysis of safety data 
The analyses of safety data will be performed on the safety population (mITT). AE(s) will be 
tabulated overall and by grade, and by period of reporting as appropriate: 
• During the screening period (AE(s) potentially linked to study procedure) 
• During hospitalization (all AE(s), including AESI(s) and SAE(s)) 
• Follow up (AE(s) related to Fexinidazole, SAE(s) and AESI(s)) 
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19 
If a patient experiences several events described with the same term, the event with the maximal 
severity will be included in the analysis. 
The SAE(s) and AESI(s) will be tabulated overall during the entire follow-up including the 
hospitalization and by period.  
 
7.3.3.1 Analyses of adverse events 
Each AE will be coded to a “Preferred Term” (PT) and primary associated “System-Organ 
Class” (SOC) according to the MedDRA dictionary (Medical Dictionary for Regulatory 
Activities, version 22.0 or higher). Counts will be provided overall and for each PT within each 
SOC. The coding will be updated to the latest available version of MedDRA at the time of the 
database lock. 
 
The summaries of AE will include: 
• The number and percentage of participants with at least one AE  
• The number and percentage of participants with at least one AE in a specific PT/SOC 
 
Number and percentage of participants with at least one AE of the following categories will 
also be provided, by SOC and PT: 
• AEs related to the IP 
• AEs leading to follow-up discontinuation 
• Serious AEs  
• AESI 
• AEs leading to death 
 
7.3.3.2 Analyses of clinical signs 
 
Descriptive statistics of vital signs, weight and BMI parameter at baseline and change from 
baseline will be presented at each visit whenever applicable. Summaries will be displayed for 
participants having at least one baseline and one post baseline values. 
For the physical examination, findings and changes from baseline will be summarized at each 
visit it was planned to be assessed. 
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7.3.3.3 Analyses of laboratory data 
Haematology and biochemistry parameters will be described with the number and % of 
abnormal results clinically significant by visit, and quantitative description at each visit.  
Shift plots will be provided comparing baseline with values collected at EoT and W9.  
 
7.3.4 Data handling convention 
The baseline value is defined as the latest measured value of a parameter before the first drug 
intake of Fexinidazole. A post baseline value is a value obtained after the first drug intake.  
 
The BMI will be calculated at each visit the weight is collected using the height collected at 
screening for adults, and using the height for less than 15 yo at its latest measure.  
 
8. Interim analysis 
A Data Safety Monitoring Board (DSMB) is implemented and will conduct review of data 
following the developed charter in use for this study. 
 
9. Software conventions  
All analyses will be performed using STATA version 15.0 or higher for the final analysis. 
 
 
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DNDi FEX 007 HAT Statistical Analysis Plan_v1.0_25Aug2020 
 
 
Appendix 1 – Evaluation criteria of efficacy endpoints 
 
Category 
               Visit 
Death 
Relapse 
Probable Relapse 
Lost to Follow up 
Uncertain Evolution 
Favourable Evolution 
Probable Cure 
Cure 
EoH 
All deaths during 
hospitalisation, after the 
start of treatment or 
resulting from an event 
that started within that 
period, which cannot be 
clearly attributed to 
reasons other than HAT 
or the treatment itself 
Trypanosomes 
detected in any 
body fluid 
Tryps-negative patient 
who refuses lumbar 
puncture OR whose CSF is 
haemorrhagic AND who 
requires rescue treatment 
 
Tryps-negative patient 
whose clinical condition 
requires, in the opinion of 
the Investigator, a close 
follow-up 
Patient alive with no 
evidence of trypanosomes 
in any body fluid 
 
 
Intermediate follow up visits 
All deaths with a 
clinical picture certainly 
or possibly compatible 
with HAT, with the 
treatment or unknown, 
to which no alternative 
cause can be clearly 
attributed 
Trypanosomes 
detected in any 
body fluid 
Tryps-negative patient 
with increased WBC/µl in 
CSF from previous values, 
whose WBC count is 
unlikely due to causes 
other than HAT OR who 
refuses lumbar puncture 
OR whose CSF is 
haemorrhagic AND who 
requires rescue treatment 
 
Tryps-negative patient 
who, in the opinion of the 
Investigator, requires a 
close follow-up exam 
because of a rising CSF 
WBC count OR a 
deterioration of clinical 
condition that might be due 
to HAT 
Tryps-negative patient 
with ≤5 WBC/µl in CSF in 
a not haemorrhagic sample 
OR decreased from 
previous values AND for 
whom there is direct 
evidence of satisfactory 
clinical condition OR 
whose clinical status is 
unlikely due to HAT 
 
 
12-month 
All deaths with a 
clinical picture certainly 
or possibly compatible 
with HAT, with the 
treatment or unknown, 
to which no alternative 
cause can be clearly 
attributed 
Trypanosomes 
detected in any 
body fluid 
• 
Tryps-negative 
patient with >20 WBC/µl in 
CSF in a non-haemorrhagic 
sample, whose WBC count 
is unlikely due to causes 
other than HAT 
• 
Tryps-negative 
patient who refuses 
lumbar puncture OR 
whose CSF is 
haemorrhagic AND who 
requires rescue treatment 
Patient who did not 
attend the 6 and the 
12 months visits 
AND for whom 
there is no direct 
evidence of 
satisfactory clinical 
condition OR there 
is direct evidence of 
a clinical status 
likely due to HAT 
 
 
• 
Tryps-negative 
patient who refuses lumbar 
puncture OR whose CSF sample 
is haemorrhagic AND whose 
clinical condition is satisfactory 
OR whose clinical status is 
unlikely due to HAT 
• 
Patient who did not 
attend the 6 and the 12 months 
visit AND for whom there is 
direct evidence of satisfactory 
clinical condition OR whose 
clinical status is unlikely due to 
HAT 
Tryps-negative 
patient whose CSF 
sample is not 
haemorrhagic with 
≤20 WBC/µl 
Analysis 
Failure 
Failure 
Failure 
Failure 
To be assessed by an 
Independent evaluation 
committee 
To be assessed by an 
Independent evaluation 
committee 
Success 
Success 
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