Clinical trial NCT03025789
Conditions: Trypanosomiasis, African Sleeping Sickness Trypanosomiasis; Gambian
Keywords: T.b gambiense HAT outpatients
Sponsor: Drugs for Neglected Diseases
Start date: 2016-11-10; Completion date: 2021-02-01
Enrollment: 174 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates the effectiveness of fexinidazole administered to patients with human African trypanosomiasis due to T. b. gambiense (g-HAT) at all stages of the disease. The aim of the present study is to provide additional information on the effectiveness and safety of fexinidazole and to assess its use under conditions as close as possible to those in real life, both in patients treated on an out-patient basis and in the hospital setting, depending on clinical status.

Participants will receive fexinidazole oral treatment for 10 days. Regular blood draws and lumbar punctures will be performed over 18 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. Treatment compliance, feasibility, and packaging acceptability will be thoroughly assessed in the participants receiving treatment at home. Those participants will complete questionnaires to check that instructions for fexinidazole administration are clear enough and followed correctly.

Detailed description:
See attached protocol.

Arms: arm 1: Participants received fexinidazole orally for 10 days as inpatients (at the hospital) arm 2: Participants received fexinidazole orally for 10 days as outpatients (at home)
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-09-HAT Version 3.0 
Fexinidazole 
 
Confidential 
Page 1 of 83 
 
 
CLINICAL STUDY PROTOCOL 
 
An open-label study assessing effectiveness, safety 
and compliance with fexinidazole in patients 
with human African Trypanosomiasis due 
to T.b. gambiense at any stage 
 
Name of Investigational Product Fexinidazole 
Therapeutic class  
Antiprotozoal 
Phase 
IIIb Cohort study 
Indication 
Human African Trypanosomiasis (HAT) due to 
Trypanosoma brucei gambiense at any stage 
Protocol number 
DNDi-FEX-09-HAT 
Registration number 
NCT03025789 
Sponsor 
Drugs for Neglected Diseases initiative (DNDi) 
15 chemin Louis Dunant, 1202 Geneva, Switzerland  
 Tel: +41 22 906 9230 
Principal Investigator 
Dr Victor Kande Betu Kumeso 
Ministère de la Santé 
Kinshasa, République Démocratique du Congo 
Coordinating Investigator 
Dr Médard Ilunga Wa Kyhi 
PNLTHA 
Kinshasa, Democratic Republic of the Congo 
National Coordinator in Guinea 
Dr Mamadou Camara 
PNLTHA, Conakry, Guinea 
Protocol version / date 
Version 3.0 / 26 June 2020 
Protocol amendment 
N°2, 26 June 2020 
 
The information contained in this document is confidential. It is intended solely for the 
investigators, potential investigators, consultants or applicable independent ethics 
committees. It is understood that this information will not be disclosed to others without 
prior written authorisation from DNDi, except where required by applicable local laws.


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole 
 
Confidential 
Page 2 of 83 
CONTACTS  
 
• Name and address of the monitors (if different from Sponsor): 
Democratic Republic of the Congo:  
- Christian Mpia Moke: DNDi Kinshasa, Avenue Milambo, N° 4, Quartier Socimat, 
Gombe, Kinshasa, DRC 
- Edmond Mulamba: DNDi Kinshasa, Avenue Milambo, N° 4, Quartier Socimat, 
Gombe, Kinshasa, DRC 
Guinea:  
- Marguerite Crato Cissé: Santé Plus, SB.P: 7328 Dakar, Soumbédiuone, Senegal 
- Maimouna Mbaye (back-up): Santé Plus, SB.P: 7328 Dakar, Soumbédiuone, 
Senegal 
 
• Name, title, address and phone number of Sponsor’s medical experts for 
the study 
- Dr Olaf Valverde Mordt, Medical Manager, DNDi, 15 chemin Louis Dunant, 1202 
Geneva, Switzerland. Tel : +41 22 906 92 39 / Mobile: +41 79 543 17 13 
- Dr Antoine Tarral: Head of HAT Clinical Program, DNDi, 15 chemin Louis Dunant, 
1202 Geneva, Switzerland 
 
• Name and title of the Investigators responsible for the study conduct, 
address and phone number of the sites:  
Refer to the Study Contact List. 
 
• Name and address of the clinical laboratories and other medical and/or 
technical departments and/or institutions involved in the study:  
• 
PK Logistics : Theradis Pharma. 41-45 Chemin des Pressses. 06800 Cagnes-sur-Mer, France 
• 
PK Analyses: SGS Belgium S.A. Vieux Chemin du Poète, 10. 1301 Wavre, Belgium 
• 
Centre for centralized ECGs reading: Cardiabase/Banook Group. 84, avenue du 20ème Corps. 
54000 Nancy, France 
• 
PK and ECG statistical reports: PhinC Development. 36 rue Victor Basch, 91300 Massy, France 
 
 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole 
 
Confidential 
Page 3 of 83 
SIGNATURES 
 
Study Leader 
Signature 
 
 
 
 
Date of signature 
(DD/MM/YYYY) 
 
Name  
Christelle Perdrieu 
Title 
Clinical Project Manager 
Organisation 
Drugs for Neglected Diseases initiative 
Address 
15, chemin Louis Dunant 
1202 Geneva, Switzerland 
Head of HAT Clinical Programme 
Signature 
 
 
 
 
Date of signature 
(DD/MM/YYYY) 
 
Name  
Dr. Antoine Tarral 
Title 
Head of HAT Clinical Programme 
Organisation 
Drugs for Neglected Diseases initiative 
Address 
15, chemin Louis Dunant 
1202 Geneva, Switzerland 
 
 
 
Medical Responsible 
 
Signature 
 
 
 
 
 
 
Date of signature 
(DD/MM/YYYY) 
Name  
Dr. Olaf Valverde Mordt, MSc 
Title 
Medical Manager 
Organisation 
Drugs for Neglected Diseases initiative 
Address 
15, chemin Louis Dunant 
1202 Geneva, Switzerland 
 
 
Statistician 
 
 
 
 
Signature 
 
 
 
Date of signature 
(DD/MM/YYYY) 
  
Name  
Frederic Mistretta 
Title 
Head of Biostatistics 
Organisation 
RCTs 
Address 
38 Rue du Plat 
69002 Lyon, France 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole 
 
Confidential 
Page 4 of 83 
Investigator Signature Page 
 
I have read this protocol and confirm that it contains all of the information required to conduct 
the study. I agree to conduct the study in compliance with the protocol, the Good Clinical 
Practice (GCP) guidelines and national regulatory requirements and I will complete the study 
within the specified timeframe. 
I will provide copies of the protocol and all relevant information to all individuals participating 
in the study under my responsibility. I will ensure that they are given all of the necessary 
information on the study treatment and the procedures of the study. 
I will use only the informed consent form approved by the Sponsor or its representative, and I 
agree to submit all relevant documentation to the Independent Ethics Committee (IEC) 
responsible for the study. 
I also agree that the Sponsor or its representatives shall have access to all source documents 
from which data entered in the case report forms was generated. 
 
Principal Investigator and National Investigator for the DRC 
 
Signature of 
Investigator 
 
 
Date of signature 
(DD/MM/YYYY) 
 
Name  
Victor Kande Betu Kumeso 
Title 
Expert in Human African Trypanosomiasis 
Organisation 
Ministry of Health 
Programme for Neglected Tropical Diseases 
General Secretariat for Health 
Address 
31, avenue de la Justice C/Gombe 
Post Box 340 Kinshasa 1 
Democratic Republic of the Congo 
 
 
 
 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole 
 
Confidential 
Page 5 of 83 
Investigator Signature Page 
 
I have read this protocol and confirm that it contains all of the information required to conduct 
the study. I agree to conduct the study in compliance with the protocol, the Good Clinical 
Practice (GCP) guidelines and national regulatory requirements and I will complete the study 
within the specified timeframe. 
I will provide copies of the protocol and all relevant information to all individuals participating 
in the study under my responsibility. I will ensure that they are given all of the necessary 
information on the study treatment and the procedures of the study. 
I will use only the informed consent form approved by the Sponsor or its representative, and I 
agree to submit all relevant documentation to the Independent Ethics Committee (IEC) 
responsible for the study. 
I also agree that the Sponsor or its representatives shall have access to all source documents 
from which data entered in the case report forms was generated. 
 
Coordinating Investigator 
 
Signature of 
Investigator  
 
 
Date of signature 
(DD/MM/YYYY) 
 
Name  
Médard Ilunga Wa Kyhi 
Title 
Treating Physician for PNLTHA  
Organisation 
National HAT Control Programme (PNLTHA) in RDC 
Address 
c/o Bureau DNDi Kinshasa Avenue Milambo 4 (Gombe)  
Commune de NGALIEMA  
Kinshasa Democratic Republic of the Congo  
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole 
 
Confidential 
Page 6 of 83 
Investigator Signature Page 
 
I have read this protocol and confirm that it contains all of the information required to conduct 
the study. I agree to conduct the study in compliance with the protocol, the Good Clinical 
Practice (GCP) guidelines and national regulatory requirements, and I will complete the study 
within the specified timeframe. 
I will provide copies of the protocol and all relevant information to all individuals participating 
in the study under my responsibility. I will ensure that they are given all of the necessary 
information on the study treatment and the procedures of the study. 
I will use only the informed consent form approved by the Sponsor or its representative, and I 
agree to submit all relevant documentation to the Independent Ethics Committee (IEC) 
responsible for the study. 
I also agree that the Sponsor or its representatives shall have access to all source documents 
from which data entered in the case report forms was generated. 
 
Investigator  
 
Signature of 
Investigator 
 
 
Date of signature 
(DD/MM/YYYY) 
Name 
 
Title 
 
Organisation 
 
Address 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole 
 
Confidential 
Page 7 of 83 
 
TABLE OF CONTENTS 
Abbreviations – Glossary of Terms ..................................................................................10 
Protocol Summary .............................................................................................................12 
1. 
Background and Study Rationale ...........................................................................18 
1.1. 
Epidemiology ......................................................................................................18 
1.2. 
Clinical Presentation of HAT ...............................................................................18 
1.3. 
Diagnostic Process for Patients in the Study .......................................................19 
1.4. 
Investigational Medicinal Product ........................................................................21 
1.5. 
Choice of the Dose and Dosing Regimen ...........................................................21 
1.6. 
Rationale for the Study Design and Target Population ........................................21 
2. 
Study Objectives and Endpoints ............................................................................23 
2.1. 
Objectives ...........................................................................................................23 
2.1.1. 
Primary Objective ..........................................................................................23 
2.1.2. 
Secondary Objectives ...................................................................................23 
2.2. 
Study Endpoints .................................................................................................24 
2.2.1. 
Primary Endpoint – Effectiveness ..................................................................24 
2.2.2. 
Secondary Endpoints - Safety .......................................................................24 
2.2.3. 
Secondary Endpoints - Compliance ..............................................................24 
2.2.4. 
Secondary Endpoints - Feasibility .................................................................25 
2.2.5. 
Secondary Endpoints - Packaging ................................................................25 
2.2.6. 
Secondary Endpoints - PK ............................................................................25 
3. 
Study Design ............................................................................................................25 
4. 
Eligibility Criteria .....................................................................................................26 
4.1. 
Inclusion Criteria .................................................................................................26 
4.2. 
Non-inclusion Criteria .........................................................................................26 
4.3. 
Eligibility Criteria for Out-patient Treatment .........................................................27 
5. 
Study Treatment ......................................................................................................28 
5.1. 
Investigational Medicinal Product ........................................................................28 
5.2. 
Treatment Allocation ...........................................................................................28 
5.3. 
Packaging of IMP ................................................................................................28 
5.4. 
Accountability of IMP ..........................................................................................28 
5.5. 
Storage of IMP ....................................................................................................29 
5.6. 
Concomitant Treatment ......................................................................................29 
5.6.1. 
Malaria ..........................................................................................................29 
5.6.2. 
Helminthiasis .................................................................................................30 
5.6.3. 
Contraception ................................................................................................30 
5.6.4. 
Other Medicines ............................................................................................30 
5.6.5. 
Rescue Treatment .........................................................................................31 
6. 
Schedule of Study Procedures and Assessments ................................................32 
6.1. 
Timing of Assessments .......................................................................................32 
6.2. 
Screening and Baseline Assessment ..................................................................33 
6.2.1. 
Screening ......................................................................................................33 
6.2.2. 
Baseline Assessment ....................................................................................34 
6.3. 
IMP Dispensing: Day 0 .......................................................................................35 
6.4. 
Procedures during Treatment Period for Patients Treated In Hospital: Day 1 to Day 
10 
35 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole 
 
Confidential 
Page 8 of 83 
6.4.1. 
Clinical Signs and Symptoms ........................................................................35 
6.4.2. 
ECG Recordings ...........................................................................................36 
6.4.3. 
PK Analyses ..................................................................................................36 
6.5. 
Treatment Period for Patients Treated on an Out-patient Basis ..........................36 
6.6. 
Procedures at the EoT Visit – Day 11 .................................................................37 
6.7. 
Procedures at Follow-up Visits ............................................................................38 
6.7.1. 
Procedures at EoH Visit - Day 13 to Day 18 ..................................................38 
6.7.2. 
Procedures at Follow-up Visits at 3, 6, 12 and 18 months .............................38 
6.7.3. 
Procedures at Unscheduled Visits .................................................................39 
6.8. 
Safety Assessments ...........................................................................................40 
6.8.1. 
Definitions .....................................................................................................40 
6.8.2. 
Collection of Information on AEs ...................................................................41 
6.8.3. 
Follow-up on AEs ..........................................................................................42 
6.8.4. 
AE Collection Period .....................................................................................42 
6.8.5. 
Reporting Requirement for AEs .....................................................................42 
6.8.6. 
Grading of AE Severity ..................................................................................43 
6.8.7. 
Assessment of AE Causality .........................................................................44 
6.8.8. 
Exposure in utero ..........................................................................................44 
6.8.9. 
Exposure During Breastfeeding .....................................................................45 
7. 
Study Duration .........................................................................................................45 
8. 
Withdrawal Criteria ..................................................................................................46 
8.1. 
Temporary Interruption of Treatment ..................................................................46 
8.2. 
Definitive Discontinuation of Treatment ...............................................................46 
8.3. 
Patient Withdrawal from the Study and Replacement of Patients ........................46 
8.4. 
Patients Lost to Follow-up ...................................................................................47 
9. 
Data Analysis and Statistical Methods ...................................................................47 
9.1. 
Sample Size Determination ................................................................................47 
9.2. 
Definition of Study Populations included in the Analyses ....................................48 
9.3. 
Patient Disposition ..............................................................................................48 
9.4. 
Description of Patients at Baseline .....................................................................49 
9.5. 
Effectiveness Analyses .......................................................................................49 
9.5.1. 
Primary Analysis - Effectiveness ...................................................................49 
9.5.2. 
Sensitivity Analysis ........................................................................................50 
9.5.3. 
Secondary Analysis - Effectiveness...............................................................50 
9.6. 
Secondary Analyses ...........................................................................................50 
9.6.1. 
Secondary Analysis - Safety .........................................................................50 
9.6.2. 
Secondary Analysis - Compliance .................................................................51 
9.6.3. 
Secondary Analysis - Feasibility ....................................................................51 
9.6.4. 
Secondary Analysis - Packaging ...................................................................52 
9.6.5. 
Secondary Analysis - PK ...............................................................................52 
9.7. 
Interim Analyses .................................................................................................52 
9.8. 
Handling of Missing Data and Patients Lost to Follow-up ....................................52 
9.9. 
Handling of Centres ............................................................................................53 
10. 
Data and Safety Monitoring Board ......................................................................53 
11. 
Quality Assurance and Quality Control Procedures ..........................................53 
11.1. 
Investigator Site File ........................................................................................54 
11.2. 
Case Report Forms .........................................................................................54 
11.3. 
Source Documents ..........................................................................................54 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole 
 
Confidential 
Page 9 of 83 
11.4. 
Retention of Documents ..................................................................................55 
11.5. 
Monitoring .......................................................................................................55 
11.6. 
Audits and Inspections ....................................................................................56 
11.7. 
Data Management ...........................................................................................56 
11.8. 
Data Confidentiality .........................................................................................56 
12. 
Protocol Amendments .........................................................................................57 
13. 
Early Termination of Study ..................................................................................57 
14. 
Ethical Considerations ........................................................................................58 
14.1. 
Information of Communities.............................................................................59 
14.2. 
Informed Consent Process ..............................................................................59 
14.2.1. Overall Procedure .........................................................................................60 
14.2.2. Impartial Witness ...........................................................................................61 
14.2.3. Illiterate Patients............................................................................................62 
14.2.4. Patients Unable to Give Consent ..................................................................62 
14.2.5. Patients Under Legal Age .............................................................................62 
14.2.6. Collection of Assent from Children ................................................................63 
14.2.7. Changes in the Benefit-to-Risk Ratio during the Study ..................................63 
14.3. 
Ethical Aspects of Study Treatment and Sampling for Laboratory Tests .........63 
14.4. 
Costs for Patients ............................................................................................64 
15. 
Insurance and Liability ........................................................................................64 
16. 
Rapports and Publication ....................................................................................65 
17. 
References ............................................................................................................66 
Appendices .........................................................................................................................68 
Appendix 1 – Declaration of Helsinki .......................................................................... 68 
Appendix 2 – Karnofsky Performance Status Scale .................................................. 74 
Appendix 3  – Laboratory Tests ................................................................................... 75 
Appendix 4 - Study Schedule ....................................................................................... 78 
Appendix 5 - Packaging of IMP ................................................................................... 79 
Appendix 6 – CTCAE version 4.03 adapted ............................................................... 81 
Appendix 7 - Schedule of Study Events ...................................................................... 82 
 
List of Tables 
 
Table 1 – Clinical Classification of Patients .............................................................. 31 
Table 2  - Theoretical Schedule of Visits and Acceptable Leeway ........................... 33 
Table 3 – PK Sampling Times during the Treatment Period ..................................... 36 
Table 4 – PK Sampling Times at the End of the Treatment Period .......................... 37 
Table 5  – Schedule of Events - Patients treated in hospital .................................... 82 
Table 6 – Schedule of Events - Patients treated on an out-patient basis ................. 83 
 
List of Figures 
 
Figure 1 – Decision Tree for the Diagnosis of HAT in the Context of the Study ....... 19 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole 
 
Confidential 
Page 10 of 83 
 
Abbreviations – Glossary of Terms 
 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
Body mass index 
BUN 
blood urea nitrogen 
CATT 
card agglutination test for trypanosomiasis 
CI 
confidence interval 
CRF 
Case report form 
CSF 
cerebrospinal fluid 
CTC 
capillary tube centrifugation 
CTCAE 
Common Toxicity Criteria for Adverse Events 
D 
day 
DART 
Development and Reproductive Toxicology 
DNDi 
Drugs for Neglected Diseases initiative 
DRC 
Democratic Republic of the Congo 
DSMB 
Data and Safety Monitoring Board 
e.g. 
exempli gratia (for example) 
ECG 
electrocardiogram 
EoH 
end of hospitalisation 
EoT 
end of treatment 
g-HAT 
Human African Trypanosomiasis due to T.b. gambiense 
GCP 
Good Clinical Practice 
H 
hour 
HAT 
human African trypanosomiasis 
i.e. 
id est (that is to say) 
ICH 
International Council on Harmonisation 
IMP 
investigational medicinal product 
ITT 
intention to treat 
M 
month 
mAECT 
mini-anion exchange column test 
mAECT-BC 
mini-anion exchange column test - buffy coat 
MedDRA 
Medical Dictionary for Regulatory Affairs 
mITT 
modified intention to treat 
NCI 
National Cancer Institute 
NECT 
Nifurtimox-Eflornithine Combination Therapy 
PK 
pharmacokinetic 
PNLTHA 
Programme National de Lutte contre la Trypanosomiase Humaine 
Africaine 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole 
 
Confidential 
Page 11 of 83 
PP 
per protocol 
QT 
QT interval on electrocardiogram (time interval between electrical 
depolarisation and repolarisation of the left and right cardiac 
ventricles) 
RDT 
rapid diagnostic test 
SAE 
serious adverse event  
SAP 
statistical analysis plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T.b. 
Trypanosoma brucei 
ULN 
upper limit of normal 
WBC 
White blood cell or white blood cell count 
WHO 
World Health Organisation 
Y 
year 
µL 
microlitre 
 
 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole 
 
Confidential 
Page 12 of 83 
Protocol Summary 
 
Study Title 
 
An open-label study assessing effectiveness, safety and compliance 
with fexinidazole in patients with human African Trypanosomiasis 
due to T.b. gambiense at any stage 
Study Phase 
IIIb Cohort study 
Indication 
Human African Trypanosomiasis (HAT) due to Trypanosoma brucei 
gambiense at any stage 
Protocol Number  DNDi-FEX-09-HAT 
Study Rationale 
Human African Trypanosomiasis (HAT) is a potentially fatal, 
neglected disease. 
Currently, the choice of drug used to treat HAT due to T.b. gambiense 
is based on the stage of the disease: pentamidine in patients with 
early-stage HAT and nifurtimox-eflornithine combined therapy 
(NECT) for patients with late-stage HAT. Patients with HAT must 
therefore undergo lumbar puncture for disease staging before 
treatment can begin. 
Fexinidazole is a 2-substituted 5-nitroimidazole, orally active in vitro 
and in vivo against the two parasites that cause HAT. 
The aim of the present study is to provide additional information on 
the effectiveness and safety of fexinidazole and to assess its use 
under conditions as close as possible to those in real life, both in 
patients treated on an out-patient basis and in the hospital setting, 
depending on clinical status. 
Study Objectives  Primary Objective 
o To assess the effectiveness of fexinidazole administered to in- 
and out-patients with g-HAT at all stages of the disease. 
 
Secondary Objectives 
o To assess the safety of fexinidazole in patients with g-HAT at 
all stages, treated in hospital or as out-patients. 
For patients treated on an out-patient basis: 
o To assess treatment compliance; 
o To assess the feasibility of treatment management by the 
patient him/herself or with the help of a caregiver under the 
recommended conditions; 
o To assess the acceptability of the proposed final packaging and 
understanding of the instructions for use. 
For patients treated in hospital: 
o To assess the PK of fexinidazole and its main metabolites in the 
blood. 
Primary Endpoint 
Effectiveness  


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole 
 
Confidential 
Page 13 of 83 
 
Outcome (success or failure) at 12 months and 18 months after the 
end of treatment. Success is defined as a cure, according to the 
criteria adapted from the WHO (21). 
Secondary 
Endpoints 
Safety 
 Occurrence of grade ≥ 3 adverse events (AEs), including 
laboratory and haematological abnormalities (if considered 
clinically significant), between the first intake of fexinidazole and 
the end of the observation period* or the follow-up period (18 
months) for non-serious AEs assessed as related to fexinidazole. 
AE severity will be graded according to the National Cancer 
Institute (NCI) Common Toxicity Criteria for AEs (CTCAE), 
Version 4.03 (14) and, for certain laboratory parameters, modified 
CTCAE will be used. 
 Occurrence of any serious adverse event (SAE) between the first 
intake of fexinidazole and the end of the follow-up period (18 
months). 
 Number of patients who discontinued treatment or were 
hospitalised during treatment for reasons related to safety, 
including overdose. 
* The observation period extends from the first intake of fexinidazole on Day 1 
until the end-of-hospitalisation visit (between Day 13 and Day 18) for patients 
treated in hospital. For out-patients, the observation period extends to the end-
of-treatment visit on Day 11. 
Treatment Compliance in Out-patients 
 Presence of fexinidazole and/or its metabolites in the blood 
sample collected on Day 11 and/or at any unscheduled visit 
between Day 1 and the EoT visit, number of patients who brought 
unused tablets back at end of treatment, number of tablets brought 
back at the end of treatment (D11) and patients’ responses to the 
questionnaire at the compliance interview. 
Feasibility of Out-patient Treatment 
 On the basis of examination of packaging at the end of treatment 
and on interview with patients and/or the caregiver: number of 
patients who temporarily interrupted treatment, number of patients 
who prematurely discontinued treatment, number of patients who 
delayed starting treatment, number of patients who mislaid 
treatment units, number of patients who were hospitalised during 
treatment for reasons related to non-compliance, number of 
patients who took treatment regularly, according to the patients 
themselves, number of patients who understood the instructions 
concerning the dosing regimen of fexinidazole (questionnaire on 
Day 0), number of patients who complied with the dosing regimen 
(questionnaire on Day 11). 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole 
 
Confidential 
Page 14 of 83 
Acceptability of Packaging in Out-patients 
 Questionnaire on Day 0 and Day 11 (patients and/or caregivers*) 
Pharmacokinetics (PK) Parameters in Patients Treated in 
Hospital 
 PK parameters for fexinidazole and its metabolites in whole blood, 
measured in all patients treated in hospital. 
* 
Caregiver definition: accompanying person designated to take care of 
the patient during the treatment period and, more specifically, to ensure 
that fexinidazole is taken according to instructions. If several persons 
accompany the patient, a choice must be made by the patient (if 
possible) together with the Investigator to designate the most suitable 
person to fulfil the role. 
Study Design 
This is a prospective, multicentre, open-label, study, assessing the 
effectiveness of fexinidazole in a cohort of adults and children with 
HAT at any stage, with follow-up over 18 months. 
It is planned to include 174 patients in 4 centres or more in the 
Democratic Republic of the Congo and in Guinea. 
The duration of treatment is 10 days. Patients will be treated on an 
out-patient basis or in hospital. 
Inclusion and 
Exclusion 
Criteria 
 
Inclusion Criteria: 
 
Male or female patient, including breastfeeding or pregnant 
women in the second or third trimester. 
 
≥ 6 years of age. 
 
≥ 20 kg body weight. 
 
Signed Informed Consent Form and Assent Form for patients less 
than 18 years of age. 
 
Trypanosomes detected in any body fluid. 
 
Physically able to ingest at least one solid meal per day. 
 
Able to take oral medication. 
 
Karnofsky Performance Status > 40%. 
 
Able to comply with the schedule of follow-up visits and with the 
study constraints. 
 
Easily reachable during the out-patient follow-up period. 
 
Willing to undergo lumbar punctures. 
Non-inclusion Criteria: 
 
Active clinically relevant medical conditions other than HAT that, 
in the Investigator’s opinion, could jeopardise patient safety or 
interfere with participation in the study, including but not limited to 
significant liver or cardiovascular diseases, HIV infection, CNS 
trauma or seizure disorders, coma or altered consciousness not 
related to HAT. 
 
Severe renal or hepatic impairment defined as: 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole 
 
Confidential 
Page 15 of 83 
o elevated creatinine at > 3 times the upper limit of normal (ULN) 
o elevated 
alanine 
aminotransferase 
(ALT), 
aspartate 
aminotransferase (AST) or bilirubin at > 3 ULN 
 
Severely deteriorated general condition, such as cardiovascular 
shock, respiratory distress or terminal illness. 
 
Any condition (except symptoms of HAT) that compromises ability 
to communicate with the Investigator as required for completion 
of the study. 
 
Any 
contraindication 
to 
imidazole 
products 
(known 
hypersensitivity to imidazoles). 
 
Treatment for HAT within 2 years prior to inclusion. 
 
Prior enrolment in the study or prior intake of fexinidazole. 
 
Foreseeable difficulty in complying with the schedule of follow-up 
visits (migrants, refugees, itinerant traders, etc.). 
Temporary Non-inclusion Criteria: 
 
Recovery period after antimalarial treatment and/or treatment of 
helminthiasis (at least 3 days). 
 
Uncontrolled diabetes or hypertension or any patients requiring 
clinical stabilisation; wait until appropriate treatment to control the 
disease has been initiated. 
 
First trimester of pregnancy. 
 
Traumatic lumbar puncture at Screening, that is to say (i.e). red 
blood cells visible in cerebrospinal fluid (CSF); wait for 48 hours 
before repeating lumbar puncture. 
Eligibility Criteria for Out-patient Treatment: 
 
Accepting to be treated on an out-patient basis. 
 
Karnofsky Performance Status > 50%. 
 
Good understanding of the method of administration of 
fexinidazole by the patient and/or caregiver (checked using a 
questionnaire at the time of IMP dispensing). 
 
Residing close to the investigational centre, i.e. at most one hour 
by road and/or boat, during the treatment period*. 
 
Easily reachable during the treatment period. 
 
No medical or psychiatric contraindications for treatment as out-
patient. 
 
No pregnancy or breastfeeding. 
 
No neurological symptoms. 
* The patient (and caregiver) is permitted to reside in a place different from 
his/her main place of residence during the treatment period. 
Study Duration 
Based on an enrolment period of approximately 36 months and a 
follow-up period of 18 months, the total duration of the study will be 
54 months. 
Each patient’s participation in the study will last approximately 19 
months, i.e. Screening (1 to 15 days), Treatment Period (10 days) 
and Follow-up Period (18 months). 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole 
 
Confidential 
Page 16 of 83 
Investigational 
Medicinal 
Product 
Investigational Medicinal Product 
Fexinidazole, 600 mg tablets, to be taken by the oral route in a single 
intake during the main meal of the day at the daily dose of: 
Adult patients and children with body weight equal to or above 35 kg: 
 1800 mg (3 tablets) for 4 days, followed by 
 1200 mg (2 tablets) for 6 days. 
Children with body weight of at least 20 kg and below 35 kg: 
 1200 mg (2 tablets) for 4 days, followed by 
 600 mg (1 tablet) for 6 days. 
The total duration of treatment will be 10 days. 
Study Schedule 
 Screening and baseline assessment: Day -15 to Day -1 
Patients treated in hospital: 
 Treatment period: Day 1 to Day 10 
 End-of-treatment Visit: Day 11 
 End-of-hospitalisation Visit: between Day 13 and Day 18 
Patients treated on an out-patient basis: 
 Visit for dispensing prior to first intake of IMP: Day 0 
 End-of-treatment Visit at investigational centre: Day 11 
Follow-up visits for all patients 
 3 months, 6 months, 12 months and 18 months. 
Statistical 
Analyses 
Primary Analysis 
The primary analysis will be performed on the modified intention-to-
treat (mITT) population. The success rate at 12 months and the 
success rate at 18 months will be estimated, bearing in mind that 18 
months provides a more reliable estimate of the cure rate. The 95% 
exact confidence interval will be provided. 
Secondary Analyses 
The success rates at 12 and 18 months will be estimated in the 
subgroup of early-stage patients, as well as the subgroup of late-
stage patients. 
Secondary analyses concerning safety, compliance, feasibility of out-
patient treatment, correct understanding of packaging and PK 
parameters will be performed. 
Interim Analyses on Safety and Compliance 
Interim analyses on safety and compliance will be performed during 
the study in order to supplement the registration file for fexinidazole 
with data from patients who have completed the treatment period, as 
well as data from patients treated in hospital who have completed the 
hospitalisation period. 
Data from follow-up visits completed at the time of data base lock will 
also be included in the analysis. 
Sample Size Determination 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole 
 
Confidential 
Page 17 of 83 
The sample size determination is based on the primary analysis. The 
expected success rate is between 87% and 91% depending on the 
percentage of early-stage patients included in the sample. The 
success rate for patients with late-stage HAT should be slightly below 
the expected success rate of 89% in the pivotal study, 
DNDiHATFEX004, which has a restricted, more homogeneous 
population. 
As concerns early-stage patients, a meta-analysis (11) performed on 
a sample of 2524 patients treated with pentamidine and indexed in 4 
databases maintained by non-governmental organisations showed a 
relapse rate (presence of trypanosomes or CSF WBC ≥ 20/µL) of 
5.63% in patients followed for 6 months or less (142/2524), 8.20% in 
patients followed for 12 months or less (207/2524) and 9.23% in 
patients followed for 18 months or less. The expected success rate 
for early-stage patients should be close to 92%. 
A sample size of 174 patients at all stages of the disease provides a 
precision of 5% in the estimate if the expected success rate is 87% 
and if a Wald confidence interval is used. 
Because the confidence interval will be calculated with an exact 
method (Clopper-Pearson approach) the length of the lower arm of 
the 95% CI will be larger than that of the upper arm. The precision for 
the lower arm will be close to 6% and that of the upper arm will be 
close to 4.5 % if we consider an expected success rate of 87%. The 
precision will be greater if the success rate is higher. 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 18 of 83 
 
1. Background and Study Rationale 
 
1.1. 
Epidemiology 
Human African trypanosomiasis (HAT), or sleeping sickness, is a vector-borne 
parasitic disease that is present in sub-Saharan Africa. It is transmitted by the bite 
of the tsetse fly and, if left untreated, it invariably leads to the patient’s death. The 
parasites responsible for HAT are the protozoa, Trypanosoma brucei gambiense 
and Trypanosoma brucei rhodesiense, which are found only in foci in regions of 
sub-Saharan Africa where the tsetse fly is endemic (1, 12, 18). Twenty-four 
countries are considered to be endemic for HAT due to T.b. gambiense (g-HAT), 
however, since 2005, cases have been reported in only 14 of these countries. 
Thirteen countries are considered to be endemic for HAT due to T.b. rhodesiense, 
however cases have been reported in only 6 of the countries. Uganda is the only 
country where both subspecies of parasite are found. In 2014, the WHO identified 
3 796 cases of g-HAT worldwide, 87% of which in the Democratic Republic of the 
Congo (DRC) alone (13, 17, 22, 23). According to the same source, however, the 
actual number of cases may be as high as 20,000 and as many as 65 million 
people may actually be exposed to the disease. With nearly a hundred cases 
reported every year, Guinea is now the West African  country the most affected by 
sleeping sickness. 
 
1.2. 
Clinical Presentation of HAT 
There are two successive stages in the clinical course of HAT. In the first stage, 
called the haemolymphatic or early stage, trypanosomes are present only in the 
blood and lymphatic system. The clinical signs and symptoms are mild and non-
specific, including bouts of fever, headache, joint pain, itching and lymph node 
enlargement. Patients diagnosed with early-stage HAT due to T.b. gambiense (g-
HAT) receive intramuscular injections of pentamidine for 7 days. If left 
undiagnosed and untreated, patients progress to the next stage, called the 
meningoencephalitic stage or late stage, in which parasites invade the central 
nervous system. At this stage, patients display neurological signs including mental 
confusion, behavioural changes, sensory disturbances, sleep disturbances and, 
eventually, coma and death. Patients diagnosed with late-stage HAT are 
hospitalised for treatment with nifurtimox-eflornithine combination therapy (NECT). 
There is also an intermediate stage in which no parasites are detected in the 
cerebrospinal fluid (CSF), however the white blood cell count (WBC) in the CSF is 
between 6 and 20/µL (1, 12, 168). Patients with intermediate-stage HAT can be 
treated with pentamidine. 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 19 of 83 
1.3. 
Diagnostic Process for Patients in the Study 
HAT due to T.b. gambiense may be diagnosed either in the context of passive 
screening in patients who present spontaneously to the hospital or to one of the 
outlying healthcare centres or in the context of active screening by mobile teams 
or prospections in the field. Whatever the context, the diagnostic process will 
consistently include the following three steps: screening for potential infection 
using clinical and serological assessments, detection of the parasite and staging 
of the disease by lumbar puncture and CSF analysis (see Figure 1). 
Figure 1 – Decision Tree for the Diagnosis of HAT in the Context of the Study 
 
Screening, which consists in investigation of potential infection, will be performed 
by assessing clinical signs, including the presence of swollen cervical lymph 
nodes, and by serological tests. In the community, outlying healthcare centre or 
hospital, serological screening will be performed using a rapid diagnostic test 
(RDT) (3) or the card agglutination test for trypanosomiasis (CATT) (10). 
For patients with a positive result on serological screening, tests to detect the 
parasite will be performed on fresh samples, i.e. on lymph node aspirate collected 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 20 of 83 
by needle biopsy and in the blood preferably using one of the concentration 
methods that allow for microscopic detection of motile parasites using the Woo test 
(capillary tube centrifugation) or the mini-anion exchange centrifugation test 
(mAECT) (2) or, if concentration methods are not available, by examination of a 
stained thick blood smear. 
In the context of the study, the improved technique, called the “mini-anion 
exchange centrifugation test on buffy coats” (mAECT-BC) (4), will be used 
whenever possible in patients with positive serological tests and negative findings 
on the usual parasitological tests, i.e. Woo test or mAECT, in addition to the usual 
procedures. 
Because the serological tests currently available are not 100% reliable, an 
individual may have negative serological tests, but still show clinical signs 
suggestive of HAT. In this case, the individual will undergo the parasitological tests 
described above. 
The diagnostic tests will be performed in the investigational centre for all patients, 
including patients diagnosed outside the centre. Lumbar puncture for disease 
staging will be performed only at the investigational centre. It is planned to perform 
lumbar puncture, whenever possible, using a local anaesthetic cream, i.e. an 
Emla® patch, as well as an atraumatic needle. Parasitological tests will be 
performed after modified single centrifugation (MSC) of the CSF using Pasteur 
disposable plastic pipettes. 
Only patients in whom the presence of parasites is confirmed by at least two team 
members at the investigational centre and approved by the Investigator, will be 
included in the study, regardless of the findings reported by the mobile teams. For 
quality control purposes, it is planned to record digital images of the parasitological 
tests and CSF WBC counts at the time of the initial diagnosis, as well as during 
follow-up visits. 
In the context of the study, a CSF WBC count of 20/µL, as well as the presence of 
parasites in any body fluid, will be used to stage the disease, in accordance with 
the WHO guidelines for clinical studies assessing treatments for late-stage HAT 
(21). 
All patients included in the study will receive fexinidazole, regardless of the stage 
of the disease. Disease staging based on analysis of CSF obtained on lumbar 
puncture is necessary because the treatments currently available are not the same 
for early-stage and late-stage HAT and, in the context of the study, it will provide 
confirmation of the efficacy of fexinidazole against both stages of HAT. 
The end-of-treatment assessment of patients will be based on parasitological tests 
on the blood and/or lymph on Day 11 and at the 3-month, 6-month, 12-month and 
18-month visits, in accordance with the WHO guidelines (21). At the 3-month 
follow-up visit, lumbar puncture will be performed only in patients with clinical signs 
of relapse. Lumbar puncture will be routinely performed at the 6-, 12- and 18-month 
follow-up visits, unless the patient explicitly refuses the test. 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 21 of 83 
 
1.4. 
Investigational Medicinal Product 
Fexinidazole is a 2-substituted 5-nitroimidazole, orally active in vitro and in vivo 
against the two parasites T.b. rhodesiense and T.b. gambiense. The compound 
acts primarily as a biologically active prodrug, with the sulfoxyde and sulfone 
metabolites providing most of the trypanocidal activity. The efficacy of fexinidazole 
and of its metabolites in the treatment of HAT has been demonstrated in an 
extensive programme of preclinical and phase-I studies (179, 7). 
Fexinidazole has received a positive opinion from the European Medicines Agency 
(EMA) and its use has been approved by the Democratic Republic of the Congo 
and Guinea. 
To date, approximately 617 patients have received fexinidazole in the three 
studies, including 322 patients (52%) with late-stage HAT and 295 patients (48%) 
with early- or intermediate-stage HAT. Initial data on the safety of fexinidazole from 
the on-going studies in HAT indicate that the overall safety profile is satisfactory. 
No treatment interruptions have been reported. The most frequently observed 
adverse reactions in phase-I studies, which included a total of 154 healthy 
volunteers, primarily involved the central nervous system (headache) and 
gastrointestinal tract (nausea, vomiting, diarrhoea). In a phase-II/III study on 
fexinidazole for the treatment of Chagas disease, adverse reactions involving liver 
function, as well as cases of transient, reversible, asymptomatic neutropenia at 
grade 3 and 4, were reported (7). 
 
1.5. 
Choice of the Dose and Dosing Regimen 
The dose and the dosing regimen were chosen on the basis of phase-I studies in 
healthy volunteers. In particular, the DNDiFEX003 study demonstrated that the 
optimal dosing regimen should include a loading dose of 1800 mg for 4 days, 
followed by a maintenance dose of 1200 mg for 6 days in order to rapidly reach 
exposure levels in the brain at least twice as high as the minimal inhibitory 
concentration for M2. Use of a loading dose also leads to a shorter duration of 
treatment, which in turn avoids fexinidazole-related increases in liver enzyme 
levels. The optimal dosing regimen should also include concomitant intake of food 
in order to maximise exposure over a short period of time and to reduce the dose 
administered. Pharmacokinetic (PK) findings in adults and children included in the 
on-going clinical studies confirmed the dosing regimen chosen (7). 
 
1.6. 
Rationale for the Study Design and Target Population 
The decision to conduct an open-label study was prompted by the need to collect 
additional information on the efficacy and safety of fexinidazole under clinical 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 22 of 83 
conditions close to those in real life and thus to confirm the feasibility of treating 
patients outside the hospital setting. 
It is also necessary to collect information on the effectiveness and safety of 
fexinidazole in a wider set of patients who are more representative of the patients 
who will be treated in the future. Thus, the target population will include patients 
who were not included in the earlier studies, such as breastfeeding and pregnant 
women. This decision is supported by data from the full development and 
reproductive toxicology (DART) studies showing that there is no risk of toxicity on 
foetal or post-natal development with fexinidazole: 
A full programme of regulatory-compliant DART studies was conducted in rats and 
rabbits. Doses of 0 (vehicle alone), 50, 200 and 800 mg/kg/day in rats and of 0 
(vehicle alone), 10, 20 and 40 mg/kg/day in rabbits were administered from 
gestation day 6 to gestation day 20. 
All of the findings presented in the full report on the DART studies clearly indicate 
that fexinidazole and its two metabolites: 
- 
do not cause any disturbances in fertility in male or female rats. This is 
consistent with the findings from repeated-dose toxicity studies; 
- 
do not cause any disturbances in gestation in rats or rabbits or any adverse 
effects on conceptuses, and no evidence of teratogenic potential was noted 
at any dose; 
- 
do not cause any adverse effects on pregnant or lactating females, on the 
development of the embryo or foetus, or on newborns up to weaning.  
These findings therefore confirm that fexinidazole can be tested in pregnant 
women. All of the findings of reproduction studies, as well as from a standard 
battery of genotoxicity tests, are available, as required by International Council on 
Harmonization (ICH) Topic M3 (2008). The findings from preclinical studies show 
that fexinidazole and/or its metabolites do not induce any toxicity on reproductive 
function. 
A study on fexinidazole concentrations in milk was conducted on lactating female 
albino rats after the administration of 800 mgeq/kg of [14C]-fexinidazole. 
Radioactive drug-related material was detected in milk at a concentration similar 
to that in plasma and in blood. Exposure to the radioactive drug-related material 
was approximately 80% of that measured in plasma, in terms of both Cmax and 
AUC values. 
On the basis of these findings, the same extent of exposure can be expected in 
breastfed human newborns. Median and maximum plasma exposure to M2, the 
main metabolite, observed in women participating in the FEX004 study were 529 
and 930 µg•h/mL respectively. This corresponds to a plasma M2 concentration of 
approximately 22 to 39 µg/mL, from which it can be inferred that the concentration 
in breast milk will be from 18 to 31 µg/mL. Thus, for newborns with a mean weight 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 23 of 83 
of 3 kg who consume around 500 mL of breast milk per day, this corresponds to 
total exposure to M2 in the range of 9.0 to 15.5 mg/day, i.e. 3.0 to 5.2 mg/kg. 
Nevertheless, as a precautionary measure, pregnant women will be eligible to 
participate in the study only once they have reached the second trimester of 
pregnancy and will not be eligible for treatment on an out-patient basis. 
The target population will also include patients whose health status is not as good 
as in earlier studies, within medically acceptable limits, as this is likely to be the 
case for some patients who will be treated in the future. Thus, the eligibility criteria 
for patients in the study are less strict that those in earlier studies on fexinidazole 
with, in particular, deletion of some criteria based on laboratory tests and on body-
mass index (BMI). 
As in early studies, in particular DNDiHATFEX006, children under 6 years of age 
will not be part of the target population for practical reasons related to the size of 
the tablets and difficulty in swallowing them. 
Lastly, the study will provide additional laboratory data at 3 months and 6 months 
to supplement the existing laboratory safety database, with a particular focus on 
haematological and hepatic functions. 
 
2. Study Objectives and Endpoints 
 
2.1. 
Objectives 
 
2.1.1. Primary Objective 
 To assess the effectiveness of fexinidazole administered to in- and out-patients 
with g-HAT at all stages of the disease. 
 
2.1.2. Secondary Objectives 
 To assess the safety of fexinidazole in patients with g-HAT at all stages, treated 
in hospital or as out-patients. 
For patients treated on an out-patient basis: 
 To assess treatment compliance; 
 To assess the feasibility of treatment management by the patient him/herself or 
with the help of a caregiver under the recommended conditions; 
 To assess the acceptability of the packaging and understanding of the 
instructions for use. 
For patients treated in hospital: 
 To assess the PK of fexinidazole and its main metabolites in the blood. 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 24 of 83 
 
2.2. 
Study Endpoints 
 
2.2.1. Primary Endpoint – Effectiveness 
The primary endpoint for the assessment of effectiveness will be: 
 Outcome (success or failure) at 12 months and 18 months after the end of 
treatment. Success is defined as a cure, according to the criteria adapted from 
the WHO (21). 
 
2.2.2. Secondary Endpoints - Safety 
The secondary endpoints for the assessment of the safety of fexinidazole will be: 
 Occurrence of grade ≥ 3 adverse events (AEs), including laboratory and 
haematological abnormalities (if considered clinically significant), between the 
first intake of fexinidazole and the end of the observation period* or the follow-
up period (18 months) for non-serious AEs assessed as related to fexinidazole. 
AE severity will be graded according to the National Cancer Institute (NCI) 
Common Toxicity Criteria for AEs (CTCAE), Version 4.03 (12) and, for certain 
laboratory parameters, modified CTCAE will be used. 
 Occurrence of any serious adverse event (SAE) between the first intake of 
fexinidazole and the end of the follow-up period (18 months). 
 Number of patients who discontinued treatment or were hospitalised during 
treatment for reasons related to safety, including overdose. 
*The observation period extends from the first intake of fexinidazole on Day 1 until the end-of-
hospitalisation visit (between Day 13 and Day 18) for patients treated in hospital. For out-patients, the 
observation period extends to the end-of-treatment visit on Day 11. 
 
2.2.3. Secondary Endpoints - Compliance 
The secondary endpoints for the assessment of compliance with treatment in 
patients treated on an out-patient basis will be: 
 Presence of fexinidazole and/or its main metabolites in the blood sample 
collected on Day 11 and/or at any unscheduled visit between Day 1 and the 
end-of-treatment (EoT) visit; 
 Number of patients who brought unused tablets back at the end of treatment; 
 Number of tablets brought back at the end of treatment (D11) 
 Patients’ responses to the questionnaire at the compliance interview. 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 25 of 83 
2.2.4. Secondary Endpoints - Feasibility 
In patients treated on an out-patient basis, the secondary endpoints for 
assessment of the feasibility of self-management of treatment intake, or with the 
assistance of the caregiver* under recommended conditions, will be: 
 Number of patients who temporarily interrupted treatment; 
 Number of patients who prematurely discontinued treatment; 
 Number of patients who delayed starting treatment; 
 Number of patients who mislaid treatment units; 
 Number of patients who were hospitalised during treatment for reasons related 
to non-compliance; 
 Number of patients who took treatment regularly, according to the patients 
themselves (compliance interview at Day 11); 
 Number of patients who understood the instructions concerning the dosing 
regimen of fexinidazole (questionnaire on Day 0); 
 Number of patients who complied with the dosing regimen, including intake of 
treatment during a meal (questionnaire on Day 11). 
* Caregiver definition: accompanying person designated to take care of the patient during the 
treatment period and, more specifically, to ensure that fexinidazole is taken according to 
instructions. If several persons accompany the patient, a choice must be made by the patient (if 
possible) together with the Investigator to designate the most suitable person to fulfil the role. 
 
2.2.5. Secondary Endpoints - Packaging 
The secondary endpoint for assessment of understanding and acceptability of the 
packaging by out-patients will be: 
 Questionnaire on Day 0 and Day 11 (patients and/or caregivers) 
 
2.2.6. Secondary Endpoints - PK 
The secondary endpoint for the PK assessment will be: 
 PK parameters of fexinidazole and its metabolites in whole blood, measured in 
all patients treated in hospital. 
 
3. Study Design 
This is a prospective, multicentre, open-label study, assessing the effectiveness of 
fexinidazole in a cohort of adults and children with HAT at any stage, with follow-
up over 18 months. 
It is planned to include 174 patients in 4 investigational centres or more in the DRC 
and in Guinea that have experience in the treatment of patients with HAT. 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 26 of 83 
The duration of treatment is 10 days. Patients will be treated on an out-patient 
basis or in hospital, in accordance with pre-set inclusion and non-inclusion criteria. 
The end of study corresponds to the last visit of the last patient. 
 
4. Eligibility Criteria  
 
4.1. 
Inclusion Criteria 
To be included in the study, the patient must fulfil all of the following criteria: 
 Male or female patient, including breastfeeding or pregnant women in the 
second or third trimester; 
 ≥ 6 years of age; 
 ≥ 20 kg body weight; 
 Signed Informed Consent Form and Assent Form for patients less than 18 years 
of age; 
 Trypanosomes detected in any body fluid; 
 Physically able to ingest at least one solid meal per day; 
 Able to take oral medication; 
 Karnofsky Performance Status > 40% (see Appendix 2 - Performance Status 
Scale, p74); 
 Able to comply with the schedule of follow-up visits and with the study 
constraints; 
 Easily reachable during the out-patient follow-up period; 
 Willing to undergo lumbar punctures. 
 
4.2. 
Non-inclusion Criteria 
To be included in the study, the patient must not fulfil any of the following exclusion 
criteria: 
 Active clinically relevant medical conditions other than HAT that, in the 
Investigator’s opinion, could jeopardise patient safety or interfere with 
participation in the study, including but not limited to significant liver and 
cardiovascular diseases, HIV infection, CNS trauma or seizure disorders, coma 
or altered consciousness not related to HAT; 
 Severe renal or hepatic impairment defined as: 
o elevated creatinine at > 3 times the upper limit of normal (ULN); 
o elevated ALT, AST or bilirubin at > 3 X ULN; 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 27 of 83 
 Severely deteriorated general condition, such as cardiovascular shock, 
respiratory distress, or terminal illness; 
 Any condition (except symptoms of HAT) that compromises ability to 
communicate with the Investigator as required for completion of the study; 
 Any contraindication to imidazole products (known hypersensitivity to 
imidazoles); 
 Treatment for HAT within 2 years prior to inclusion; 
 Prior enrolment in the study or prior intake of fexinidazole; 
 Foreseeable difficulty in complying with the schedule of follow-up visits 
(migrants, refugees, itinerant traders, etc.). 
The following criteria are considered as temporary non-inclusion criteria: 
 Recovery period after antimalarial treatment and/or treatment of helminthiasis 
(at least 3 days); 
 Uncontrolled diabetes or hypertension or any patients requiring clinical 
stabilisation; wait until appropriate treatment to control the disease has been 
initiated; 
 First trimester of pregnancy (based on date of last menstrual period); 
 Traumatic lumbar puncture at Screening i.e. red blood cells visible in CSF; wait 
for 48 hours before repeating lumbar puncture. 
Ineligible patients will be treated according to the protocol of the National HAT 
Control Program (PNLTHA) and will receive the same support from the Sponsor 
during the treatment period. 
 
4.3. 
Eligibility Criteria for Out-patient Treatment 
To be eligible for treatment on an out-patient basis, the patient must fulfil all of the 
following criteria: 
 Accepting to be treated on an out-patient basis; 
 Karnofsky Performance Status > 50%; 
 Good understanding of the method of administration of fexinidazole by the 
patient and/or caregiver (checked using a questionnaire at the time of 
dispensing fexinidazole); 
 Residing close to the investigational centre, i.e. at most one hour by road and/or 
boat, during the treatment period*; 
 Easily reachable during the treatment period; 
 No medical or psychiatric contraindications for treatment as out-patient; 
 No pregnancy or breastfeeding; 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 28 of 83 
 No neurological symptoms. 
* The patient (and caregiver) is permitted to reside in a place different from his/her main place of 
residence during the treatment period. 
 
5. Study Treatment 
 
5.1. 
Investigational Medicinal Product 
The investigational medicinal product (IMP) is fexinidazole as 600-mg tablets, to 
be taken orally in a single intake during the main meal of the day at the daily dose 
of: 
Adult patients and children with body weight equal to or above 35 kg: 
 1800 mg (3 tablets) for 4 days, followed by 
 1200 mg (2 tablets) for 6 days. 
Children with body weight of at least 20 kg and below 35 kg: 
 1200 mg (2 tablets) for 4 days, followed by 
 600 mg (1 tablets) for 6 days. 
The total duration of treatment will be 10 days. 
 
5.2. 
Treatment Allocation 
All patients who give informed consent/assent to participate in the study and who 
fulfil the eligibility criteria will receive the IMP. 
 
5.3. 
Packaging of IMP 
The tablets of fexinidazole will be presented in the commercial packaging that has 
been designed for use once the product has obtained marketing authorisation. The 
packaging will be different depending on the body weight and age of the patient. 
The tablets will be packaged in aluminium/aluminium blister packs and presented 
as a wallet, i.e. a cardboard pack with three folding panels. Each pack contains the 
number of tablets required for 10 days of treatment. 
Mock-ups of the packaging intended for patients are presented in Appendix 5, 
Packaging of IMP, p79. 
 
5.4. 
Accountability of IMP  
Fexinidazole will be sent to the study coordination sites. 
Study-specific forms will be used for accountability of fexinidazole and will be kept 
up to date by the person designated as responsible for the pharmacy in the 
investigational centre, under the responsibility of the Investigator, or by the 
Investigator him/herself. During on-site monitoring, the study monitors will check 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 29 of 83 
that the forms are up to date. In the course of the study, the monitors will perform 
reconciliation between the quantities of fexinidazole delivered to the centre and the 
quantities dispensed to patients, as well as used and unused quantities. 
Fexinidazole must not under any circumstances be used outside the context of the 
study without prior written approval from the Sponsor. 
Each patient who is to be treated on an out-patient basis (or the caregiver) will be 
given the appropriate size pack, based on age and weight, containing sufficient 
quantity of fexinidazole for 10 days of treatment. The patient will also be given 
precise instructions on how to store fexinidazole and how to take the tablets. At 
the EoT visit (Day 11), the patient and/or the caregiver must return the original 
treatment pack to the centre so that treatment compliance can be checked and 
recorded. 
For patients treated in hospital, accountability of fexinidazole will be ensured by 
the person responsible for the pharmacy in the investigational centre, under the 
responsibility of the Investigator, or by the Investigator him/herself. 
 
5.5. 
Storage of IMP 
Fexinidazole should be stored at a temperature not exceeding 30°C. Regulatory-
compliant stability studies are currently on-going. Data currently available indicate 
that fexinidazole remains stable for 18 months when stored at 30°C with 75% 
relative humidity and for 6 months at 40°C with 75% relative humidity. 
Fexinidazole will be stored in a locked room at the investigational centre, or a 
locked cabinet, with access restricted to the person responsible for the pharmacy 
and/or the Investigator. The storage conditions, including the temperature, must 
be monitored by the person responsible for the pharmacy in the centre. Appropriate 
records must be available. 
Patients who are eligible for treatment on an out-patient basis will receive precise 
instructions on how to store the IMP and on the recommended dosing regimen. 
 
5.6. 
Concomitant Treatment 
5.6.1. Malaria 
All patients will undergo a thick blood smear and/or rapid diagnostic test (RDT) to 
detect malaria at Screening. All patients with a positive result will receive treatment. 
 Prior to starting treatment with fexinidazole, malaria will be treated for 3 days with 
the combination artemether-lumefantrine (Coartem®) unless the patient has 
personal contraindications, such as severe malaria or hypersensitivity to one of the 
components, i.e. artemether or lumefantrine. All of the existing artemisinin-based 
combination therapies used against malaria have effects on the QT interval. 
Coartem® was chosen because its effects on QT-interval prolongation are known 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 30 of 83 
to be moderate and well quantified (9). The choice was made to minimise 
confounding factors in the assessment of fexinidazole-related QT-interval 
prolongation. Coartem® will be provided free of charge by the Sponsor. 
In patients with a contraindication to Coartem®, the Investigator can choose 
another antimalarial agent. The choice must be recorded in the CRF. 
Treatment will be followed by a recovery period of at least 3 days between the last 
dose of Coartem® and the start of treatment with fexinidazole. 
 
5.6.2. Helminthiasis 
All patients will receive treatment for helminthiasis, with mebendazole or 
albendazole, in accordance with the usual practice in the centre. The Sponsor will 
cover the cost of treatment. 
Treatment for helminthiasis must be followed by a 3-day recovery period before 
starting treatment with fexinidazole, in accordance with the usual practice in the 
centres. 
 
5.6.3. Contraception 
Women of child-bearing age will be advised not to become pregnant and therefore 
to use a method of contraception or sexual abstinence throughout the entire 
treatment period and, if possible, until 48 hours after the EoT. 
 
5.6.4. Other Medicines 
Any medicines required to treat concomitant chronic conditions should remain 
unchanged during the treatment period with fexinidazole. 
The list of medicines showing to have interactions with fexinidazole is described in 
the Investigator’s Brochure for fexinidazole. 
For patients treated in hospital, any medicine used between the Screening visit 
(Day -15 to Day -1) and the EoH visit (Day 13 to Day 18) must be recorded in the 
CRF, specifying the reason for use. For patients treated on an out-patient basis, 
any medicines taken during the Screening visit (Day -15 to Day -1) will be recorded 
in the same manner as for patients treated at hospital, while any medicines taken 
during the treatment period will be collected at the EoT visit and recorded in the 
CRF, specifying the reason for use. 
Any medicines administered to treat an SAE during the follow-up period, i.e. up to 
the visit at 18 months, must be recorded in the CRF (see Section 6.8 Safety 
Assessments, Definitions; p 40). Other medicines used to treat other non-serious 
medical events will be recorded only in the patient’s medical file. 
Any medicine required during the study, i.e. at any time up to the visit at 18 months 
will be provided free of charge to the patient. The WHO List of Essential Medicines 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 31 of 83 
and the Essential Drugs guide (2010 edition) published by Médecins Sans 
Frontières will be used as a reference for the treatment of any concomitant 
condition. The study team will take all necessary measures to ensure that the 
patient receives appropriate care for any concomitant condition during the course 
of the study. 
 
5.6.5. Rescue Treatment 
Patients in whom no response is observed on parasitological testing at the EoH 
visit, as well as patients who show signs of relapse at any time during follow-up, 
will receive the treatment recommended by the PNLTHA. 
If a patient treated on an out-patient basis interrupts treatment with the IMP after 
Day 4, s/he will be followed up in the usual manner by the investigational centre in 
order to detect a possible relapse. In this situation, rescue treatment will be the 
treatment recommended by the PNLTHA. 
If a patient treated on an out-patient basis interrupts treatment with the IMP before 
Day 4, s/he will receive rescue treatment with NECT if s/he has late-stage HAT or 
with pentamidine if s/he has early-stage HAT. 
Rescue treatment for HAT must be recorded in the appropriate section of the CRF 
and not as concomitant medication. 
Probable relapse at the 6-month, 12-month or 18-month follow-up visit is defined 
as shown below. 
 
Table 1 – Clinical Classification of Patients 
Visit 
Ideal timing of 
visit after end 
of treatment 
Favourable outcome 
Uncertain outcome 
Probable relapse 
Proven relapse 
24 hours 
after EoT 
24 hours after 
the End of 
Treatment 
(EoT) 
• Patient alive with no 
evidence of 
trypanosomes in any 
body fluid  (19) 
 
 
• Evidence of 
trypanosome
s in any body 
fluid 
3 months 
 
3 months  
± 1 week  
• Patient alive with no 
evidence of 
trypanosomes in any 
body fluid (no lumbar 
puncture at 3 months 
unless Investigator 
suspects relapse) 
• Any reason 
prompting the 
Investigator to 
request an additional 
follow-up visit 
• Neurological 
signs or symptoms 
leading to use of 
rescue treatment 
• Evidence of 
trypanosome
s in any body 
fluid 
6 months  
 
 
 
6 months 
± 1 week 
• Patient alive with no 
evidence of 
trypanosomes in any 
body fluid and CSF 
WBC ≤ 20/µL  
• CSF WBC 
between 20 and 
50/µL and additional 
visit requested within 
1-3 months 
• Any reason 
prompting the 
• CSF WBC 
≥ 50/µL (24) 
• Neurological 
signs or symptoms 
leading to use of 
rescue treatment 
• Evidence of 
trypanosome
s in any body 
fluid 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 32 of 83 
 
 
6. Schedule of Study Procedures and Assessments 
 
6.1. 
Timing of Assessments  
Study procedures will be performed in accordance with the following schedule (see 
also Table 2 – Theoretical Schedule of Visits and Acceptable Leeway): 
 Day -15 to Day -1: screening and baseline assessment 
Then, depending on the type of patient: 
Patients treated in hospital: 
 Treatment period: Day 1 to Day 10 
 EoT visit: Day 11 
 EoH visit: between Day 13 and Day 18 
Patients on an out-patient basis: 
 IMP dispensing visit prior to first intake of IMP: Day 0 
 Compulsory EoT visit at investigational centre: Day 11 
Out-patient follow-up visits for all patients: 
 3 months, 6 months, 12 months and 18 months 
 
The schedule of visits is calculated from the first day of treatment (Day 1). 
 
 
Investigator to 
request an additional 
follow-up visit 
12 
months 
12 months 
± 4 weeks 
• Patient alive with no 
evidence of 
trypanosomes in any 
body fluid and CSF WBC 
≤ 20/µL  
• CSF WBS between 20 
and 50/µL, and lower as 
compared to prior 
value(s) 
• CSF WBC > 20/µL 
and non-significant 
increase from a 
clinical standpoint in 
relation to prior 
value(s) 
• Any reason 
prompting the 
Investigator to 
request an additional 
follow-up visit 
• CSF WBC > 
20/µL and 
significant increase 
from a clinical 
standpoint in 
relation to prior 
value(s) 
• Neurological 
signs or symptoms 
leading to use of 
rescue treatment 
• Evidence of 
trypanosome
s in any body 
fluid 
18 
months 
18 months ± 4 
weeks 
• Patient alive with no 
evidence of 
trypanosomes in any 
body fluid and CSF WBC 
≤ 20/µL  
• Patient with no signs 
of HAT and who refuses 
to undergo lumbar 
puncture and who, in the 
opinion of the 
Investigator does not 
require rescue treatment 
or an additional follow-up 
visit 
• Any reason 
prompting the 
Investigator to 
request an additional 
follow-up visit 
• CSF WBC > 
20/µL 
• Neurological 
signs or symptoms 
leading to use of 
rescue treatment 
• Evidence of 
trypanosome
s in any body 
fluid 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 33 of 83 
 
Table 2  - Theoretical Schedule of Visits and Acceptable Leeway 
 
Type of Visit 
Schedule of Visits and 
Acceptable Time Window  
Acceptable leeway* 
EoT Visit 
Day 11 
Day 11 + 1 day 
End-of-Hospitalisation Visit, 
only for patients treated in 
hospital 
Between Day 13 and Day 18 
Day 18 at the latest 
3-month follow-up visit 
3 months ± 1 week after Day 1 
2 to 4 months, i.e. 60 to 
149 days, after Day 1 
6month follow-up visit 
6 months ± 1 week after Day 1 
5 to 9 months, i.e. 150 to 
299 days, after Day 1 
12-month follow-up visit 
12 months ± 4 weeks after Day 1 
10 to 16 months, i.e. 300 to 
509 days, after Day 1 
18-month follow-up visit 
18 months ± 4 weeks after Day 1 
17 to 21 months, i.e. 510 to 
659 days, after Day 1 
* The acceptable leeway for the visit starts on the first day of the period mentioned and ends on 
the last day of the period mentioned. 
 
Additional unscheduled visits may take place and must be recorded in the CRF. 
See also Appendix 7 - Schedule of Study Events (p 82). 
 
6.2. 
Screening and Baseline Assessment 
 
6.2.1. Screening 
Patients who are to participate in the study will be recruited either through active 
screening, i.e. patients already diagnosed by the mobile teams and referred to the 
investigational centre, or through passive screening, i.e. patients diagnosed at the 
investigational centre or nearby.  
 In the context of active screening, the mobiliser of the mobile team will inform 
the communities in the villages of the HAT screening activities, as is usually the 
case (see Section 14.1 Information of the Communities; p 59). Specific 
information concerning the study will be provided to the community, i.e. a brief 
description of the aim of the study, explanation of the process for collecting 
informed consent, duration and importance of follow-up. 
 In the context of passive screening, specific information concerning the study 
will be provided by static healthcare structures located near the investigational 
centre in order to refer patients to the investigational centre. 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 34 of 83 
 Diagnosis of HAT and staging of the disease will be performed at the 
investigational centre. 
The following diagnostic tests will be performed at the investigational centre 
between Day -15 and Day -1 to confirm the diagnosis of HAT:   
 Serological testing (RDT or CATT); 
 Collection of blood and/or lymph samples for testing for parasites; 
If a patient has been diagnosed as HAT-positive in the context of another clinical 
study sponsored by DNDi, the results of diagnostic tests, i.e. blood and/or lymph 
samples or lumbar puncture, can be used in the present study if they were 
performed less than 7 days before Screening.  
Patients will be invited to participate in the study and the Investigator (or a 
designee) will provide the information required to collect the patient’s informed 
consent. Once the patient has signed the informed consent, s/he will be considered 
as a “screened patient” and s/he will receive a patient ID number. 
 
6.2.2. Baseline Assessment  
Whether the patient is being considered for treatment in hospital or as an out-
patient, the following procedures will be performed between Day -15 and Day -1 in 
order to stage the disease, to collect medical history and safety data, and to check 
the inclusion and non-inclusion criteria. 
 Collection of informed consent / assent prior to administering any additional 
medication or to performing any non-routine assessment; 
 Collection of CSF sample for WBC and disease staging;  
 Karnofsky Performance Status, 
 Review of inclusion and non-inclusion criteria 
 Collection of demographic data; 
 Collection of full medical history; 
 Collection of signs and symptoms of HAT, in particular severity and time since 
the start of symptoms;  
 Vital signs: body temperature, blood pressure, heart rate and respiratory rate; 
 Diagnosis of malaria using RDT and/or thick blood smear and, if the result is 
positive, administration of antimalarial treatment; 
 Treatment of helminthiasis, according to routine practices; 
 Collection of concomitant medication; 
 Physical and neurological examinations; 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 35 of 83 
 Laboratory safety assessments (see Appendix 3  – Laboratory Tests; p 75) – 
when possible, samples will be collected in the morning from patients in the 
fasting state; 
o Haemoglobin; 
o Haematology: WBC, platelet count; 
o Biochemistry: 
albumin, 
alkaline 
phosphatase 
(ALP), 
alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), blood urea 
nitrogen (BUN), chloride, creatinine, glucose, potassium, sodium, calcium, 
total bilirubin, bicarbonates and total protein; 
o Urine analysis (leucocytes, nitrites, pH, protein, glucose, ketone bodies, 
urobilinogen, bilirubin, blood and haemoglobin); 
 Urine pregnancy test for women of child-bearing potential, to be done on Day -1; 
 Triplicate digital ECG (CarTouch®), to be done on Day -1; 
 Collection of SAEs. 
 
6.3. 
IMP Dispensing: Day 0 
If the patient is to be treated on an out-patient basis, the following procedures will 
be performed before s/he returns home to begin treatment. 
 Check that all procedures for baseline assessment have been performed. 
 Dispensing of IMP and, before returning home, reminder concerning instructions 
for taking the IMP and interview with Investigator to collect responses to 
questionnaire and ensure good understanding of the instructions by the patient 
and/or the caregiver; 
 Collection of SAEs since signature of informed consent. 
 
6.4. 
Procedures during Treatment Period for Patients Treated In 
Hospital: Day 1 to Day 10 
 
6.4.1. Clinical Signs and Symptoms 
 Patients will be questioned each day concerning possible AEs during the 
hospitalisation period and at each subsequent follow-up visit (see Section 6.8 
Safety Assessments, Definitions; p 40); 
 Collection of concomitant medication.  
If indicated by the patient’s clinical status, the following procedures will be 
performed on Day 8: 
 Vital signs: body temperature, blood pressure, heart rate and respiratory rate; 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 36 of 83 
 Physical and neurological examinations. 
 
6.4.2.  ECG Recordings 
Two digital ECGs (CarTouch®) will be recorded in triplicate to assess QT-interval: 
 4 hours after intake of IMP on Day 4; 
 23 hours after intake of IMP, i.e. 1 hour before intake of IMP on Day 5. 
 
6.4.3.  PK Analyses 
The procedure for sampling and the assay method will be described in the 
Laboratory Manual. 
During the treatment phase, four samples will be collected for PK analyses. 
Whole blood, approximately 2 mL each time, collected by venipuncture will be 
deposited on filter paper using the dry blood spot (DBS) technique at the following 
timepoints:  
Table 3 – PK Sampling Times during the Treatment Period 
Ideal timing for sample collection  
Acceptable leeway 
Day 8: 3 hours 15 minutes after 
intake of the IMP 
± 15 min 
Day 9: 3 hours after intake of the 
IMP 
± 15 min 
Day 10: 3 hours and 7 hour 15 
minutes after intake of the IMP 
± 15 min 
 
6.5. 
Treatment Period for Patients Treated on an Out-patient Basis 
Patients treated on an out-patient basis who require hospitalisation, for whatever 
reason, will undergo the same procedures as patients initially treated in hospital, 
up to the end of the hospitalisation period, as provided for in the protocol. During 
this period, and up to Day 13 or Day 18, the reasons for hospitalisation will not be 
considered to be SAEs solely based on the criterion of hospitalisation, but may be 
considered to be SAEs based on other criteria (see Section 6.8.1). 
PK sampling should be performed at any unscheduled visit between Day 1 and 
Day 10, regardless of the day on which the visit takes place. 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 37 of 83 
6.6. 
Procedures at the EoT Visit – Day 11 
Whether the patient is being treated in hospital or as an out-patient, the following 
procedures will be performed at the EoT visit on Day 11: 
 Collection of blood and/or lymph samples for testing for parasites; 
 Collection of signs and symptoms of HAT, if any; 
 Karnofsky Performance Status; 
 Vital signs: body temperature, blood pressure, heart rate and respiratory rate; 
 Physical and neurological examinations; 
 Collection of concomitant medication and AEs; 
 Urine pregnancy test for women of child-bearing potential; 
 Laboratory safety assessments (see Appendix 3  – Laboratory Tests; p 75) – 
when possible, samples will be collected in the morning from patients in the 
fasting state; 
o Haemoglobin; 
o Haematology: WBC, platelet count; 
o Biochemistry: albumin, ALP, ALT, AST, BUN, chloride, creatinine, glucose, 
potassium, sodium, calcium, total bilirubin, bicarbonates and total protein; 
o Urine analysis (leucocytes, nitrites, pH, protein, glucose, ketone bodies, 
urobilinogen, bilirubin, blood and haemoglobin); 
 Triplicate digital ECG (CarTouch®);  
 Collection of blood sample 24 hours after the last intake of the IMP (Day 11) for 
PK analyses. If the patient was treated on an out-patient basis, the sample will 
be used to check treatment compliance. If the patient was treated in hospital, a 
second blood sample will be collected 48 hours (Day 12) after the last intake of 
the IMP for PK analyses. 
Table 4 – PK Sampling Times at the End of the Treatment Period 
 
Ideal timing for sample collection  
Acceptable leeway 
Day 11: 24 hours after the last intake of the IMP 
± 1 hour 
Day 12: 48 hours after the last intake of the IMP (only 
for patients treated in hospital) 
± 1 hour 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 38 of 83 
If the patient was treated on an out-patient basis, the following procedures will be 
performed: 
 Interview for collection of AEs observed by the patient during the treatment 
period and collection of concomitant medication; 
 Interview for compliance with accountability of fexinidazole tablets; 
 Questionnaire to assess acceptability of packaging of IMP. 
 
6.7. 
Procedures at Follow-up Visits 
 
6.7.1. Procedures at EoH Visit - Day 13 to Day 18 
If the patient was treated in hospital, the following procedures will be performed on 
the day of discharge: 
 Vital signs: body temperature, blood pressure, heart rate and respiratory rate; 
 Physical and neurological examinations; 
 Collection of concomitant medication and AEs. 
 
6.7.2. Procedures at Follow-up Visits at 3, 6, 12 and 18 months 
Whether the patient is being treated in hospital or as an out-patient, the following 
procedures will be performed at Follow-up Visits at 3, 6, 12 and 18 months: 
 Collection of blood and/or lymph samples for testing for parasites; 
 Collection of CSF for WBC and detection of trypanosomes. At the 3-month 
follow-up visit, lumbar puncture will be performed only if indicated by the 
patient’s clinical status; 
 Collection of signs and symptoms of HAT, if any; 
 Karnofsky Performance Status; 
 Vital signs: body temperature, blood pressure, heart rate and respiratory rate; 
 Physical and neurological examinations;  
 Urine pregnancy test for women of child-bearing potential, only at 3-month and 
6-month visits; 
 Collection of SAEs 
 Collection of non-serious AEs assessed as related to fexinidazole; 
 Laboratory safety assessments (see Appendix 3  – Laboratory Tests; p 75) – 
when possible, samples will be collected in the morning from patients in the 
fasting state: 
o Haemoglobin; 
o Haematology: WBC, platelet count; 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 39 of 83 
o Biochemistry: albumin, ALP, ALT, AST, BUN, chloride, creatinine, glucose, 
potassium, sodium, calcium, total bilirubin, bicarbonates and total protein. 
Laboratory safety assessments will be performed at the 12-month and 18-month 
visits only if indicated by the patient’s clinical status. 
In the event that a patient moves house or is travelling away from home during the 
follow-up period, the Investigator accompanied by any necessary study team 
members may travel to the patient’s new place of residence in order to perform 
one or more follow-up visits.  
The patient could also attend one or more follow-up visits in another investigational 
centre or in a satellite centre. The patient would then be managed by the 
Investigator in the other investigational centre or by the Coordinating Investigator 
at the PNLTHA.  
The site investigator and his/her study team can also travel to the satellite site to 
monitor the patient.  
In that case, the Investigator in the patient’s original investigational centre should 
inform the Coordinating Investigator and the person in charge of monitoring that a 
visit is planned to take place in a different investigational centre.  
Data collected at such visits will then be sent, within a reasonable timeframe after 
the visit, to the patient’s original investigational centre in order to be recorded in 
the CRF.  
The patient’s original investigational centre is responsible for entry of the data and 
retains medical responsibility for the patient.  
 
6.7.3. Procedures at Unscheduled Visits 
At any time during the study, the patient may make unscheduled visits to the 
investigational centre, as required by his/her clinical status. The following 
procedures may be performed, at the Investigator’s discretion: 
 Physical and neurological examinations; 
 Collection of signs and symptoms of HAT, if any, since the previous visit; 
 Investigation of any concomitant condition that could have prompted the visit; 
 Collection of blood and/or lymph samples for testing for parasites, if indicated; 
 Collection of CSF, only if symptoms suggesting a relapse of HAT are present; 
 Additional safety assessments such as ECG, haematology, biochemistry or 
urine analysis. 
 Collection of AEs, in accordance with Section 6.8.4.  
 For patients treated on an out-patient basis, blood sampling for PK analysis in 
the event of an unscheduled visit between Day 1 and Day 11. 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 40 of 83 
 
6.8. 
Safety Assessments 
 
6.8.1. Definitions 
Adverse Event 
An adverse event (AE) is 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 this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory test or ECG finding, for example), symptom or disease 
temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
The definition of an AE includes worsening of any pre-existing conditions or any 
abnormality on a test procedure (e.g. ECG) or laboratory test (haematology, 
biochemistry) that occurs or worsens (in severity or frequency) after starting the 
IMP and that the Investigator considers to be clinically significant, unless it is 
associated with a previously reported clinical event. 
Of note, lack of efficacy is not an AE.  
Laboratory test abnormalities may be considered to be “clinically significant”, and 
should therefore be reported as AEs, if they fulfil any of the following criteria: 
 The abnormality suggests a disease and/or organ toxicity and the abnormality 
was not present at baseline or is considered to have worsened abnormally from 
baseline, 
 The abnormality leads to discontinuation of the IMP, 
 The abnormality requires a medical intervention or treatment. 
 
Serious Adverse Event 
A serious adverse event (SAE) is any event that: 
 results in death; 
o i.e. causes or contributes to death; 
 is life-threatening; 
o i.e. in this context refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that 
hypothetically might have caused death if it had been more severe; 
 requires hospitalisation or prolongation of existing hospitalisation; 
o i.e. the AE required hospitalisation for at least 24 hours or prolonged 
hospitalisation beyond the duration initially expected. Hospitalisation for 
surgery planned prior to study entry, for social reasons, for elective surgery 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 41 of 83 
(e.g. cosmetic surgery) or in the context of usual management of the 
disease (including treatment adjustment) will not be considered as an 
SAE. Similarly, hospitalisation of patients initially treated on an out-patient 
basis will not be considered as an SAE solely based on the criterion of 
hospitalisation because, in accordance with Section 6.5, they are to remain 
in hospital, as are patients initially hospitalised, up to Day 13 or 18. The 
other seriousness criteria remain valid. This includes hospitalisation for 
reasons related to non-compliance with treatment, including for a non-
serious AE based on the other seriousness criteria; 
 results in persistent or significant disability or incapacity; 
o i.e. an AE that leads to significant impairment of the patient’s ability to carry 
out normal activities; 
 is a congenital anomaly or birth defect in the child or foetus of a female patient 
exposed to treatment prior to conception or during pregnancy; 
 is an important medical event, i.e. an event that may not be immediately life-
threatening or result in death, but that jeopardises the patient’s safety or 
requires an intervention to prevent one of the outcomes above. 
In the study, ALT or AST levels above 3 ULN associated with total bilirubin above 
2 ULN will be considered to be SAEs. 
Any suspected transmission of an infectious agent via the IMP will also be 
considered as an SAE. 
Any other event defined as serious in the protocol will be reported as an AE and 
as an SAE in accordance with the procedure described in Section 6.8.5. 
 
For the purposes of the study, hospitalisation for non-complicated delivery will not 
be considered as an SAE. 
 
6.8.2. Collection of Information on AEs 
AEs may be observed directly by the medical personnel or spontaneously reported 
by the patient or his/her caregiver. For patients treated in hospital, potential AEs 
will be collected by the medical personnel each day during the treatment period 
and up to the EoH visit. The Investigator or qualified study personnel should 
examine any patient who experiences an AE as soon as possible. All medical 
measures necessary to ensure the patient’s safety and well-being must be 
implemented. For patients treated on an out-patient basis, potential AEs that occur 
during the treatment period will be collected at the EoT visit, i.e. Day 11, or at any 
unscheduled visit to the centre between Day 1 and Day 11. 
After the end of the periods mentioned above, AEs will be collected as described 
in Section 6.8.4. 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 42 of 83 
Information on AEs will be recorded in the corresponding section of the CRF using 
concise medical terms and avoiding vague, ambiguous or colloquial language. 
When a clinically significant laboratory abnormality is reported, whenever possible, 
a clinical diagnosis should be reported as the AE rather than simply an abnormal 
value, e.g. “anaemia” instead of “reduced red blood cell count”. 
 
6.8.3. Follow-up on AEs 
Any AE must be followed up until it resolves, until the Investigator considers it to 
be “stable” or “chronic”, or until the end of the patient’s participation in the study, 
i.e. until the end-of-study page of the CRF for the patient has been completed. 
If the AE is a clinically significant laboratory test abnormality, a repeat test is to be 
performed 2 to 4 days later and then at regular intervals until the value returns to 
normal or to the baseline level. 
 
6.8.4. AE Collection Period 
The collection period for AEs that occur in the context of the study is defined as 
follows: 
 For any AE that is not considered to be an SAE: from the first intake of 
fexinidazole on Day 1 until the EoH visit (Day 13-18) for patients treated in 
hospital. For patients treated on an out-patient basis, the observation period 
extends to the EoT visit (Day 11). 
 For any SAE: from the time of enrolment of the patient in the study (i.e. after 
signing the informed consent) and until the end of follow-up (18 months). 
AEs that occur during the Screening period (after signing the informed consent) 
prior to the start of treatment and that are considered to be related (i.e. a 
reasonable possibility) to participation in the study, will also be collected by the 
medical personnel and recorded in the CRF. 
In addition, any non-serious AE that occurs after the collection period and that the 
Investigator considers to be related (i.e. a reasonable possibility) to the IMP, must 
also be collected. 
 
6.8.5. Reporting Requirement for AEs 
Information on AEs must be assessed by a physician. The Investigator must 
determine whether the AE is considered to be serious or not, if necessary with the 
assistance of the Coordinating Investigator and the study monitor. This 
classification will determine the reporting procedure for the event. 
All SAEs must be reported to the study monitor immediately, and at the latest 
24 hours after the Investigator becomes aware of the event. The information must 
be reported, initially, by telephone and/or Short Messaging Service (SMS), and 
then using the SAE reporting form, which is to be sent by e-mail. The report must 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 43 of 83 
include the nature of the SAE (if possible a clinical diagnosis), the date and nature 
of onset, duration, severity, relationship to IMP (assessed with the assistance of 
the Coordinating Investigator, as needed; reasonable possibility see Section 
6.8.7.), measures taken and outcome, as well as any other relevant clinical or 
laboratory data. 
Additional information must be sent as soon as it becomes available, using the 
SAE follow-up reporting form. All follow-up reports must be sent as quickly as 
possible and, if possible, within 5 working days after the new information becomes 
available. A close-out follow-up report must be sent after the final assessment of 
the case, specifying the outcome of the SAE as “recovery”, “recovery with 
sequelae”, “death” etc. 
SAEs must be reported using the AE reporting form in the CRF and the SAE 
reporting form. It should be noted that the SAE reporting form is not the same as 
the form in the AE section of the CRF. The two forms must be completed in a 
consistent manner, using the same medical terminology. 
All AEs must be recorded in the CRF. 
For the purposes of this study, the Coordinating Investigator will be responsible for 
reporting suspected unexpected serious adverse reactions (SUSARs), considered 
to be related to the IMP (reasonable possibility), as well as all SAEs, to the Ethics 
Committee of the country and to other appropriate governing bodies in accordance  
with national regulatory requirements.  
The Sponsor will be responsible for reporting SUSARs and SAEs to the regulatory 
authorities in accordance with current regulations. The Investigator Brochure will 
be used as the reference safety information on the IMP, and the expectedness of 
Aes will be assessed by the Sponsor using this information. 
 
6.8.6. Grading of AE Severity 
The severity of the AE will be graded according to NCI CTCAE, version 4.03   (14) 
and, for certain laboratory parameters, modified CTCAE (see Appendix 6- CTCAE 
v4.03 adapted, p 81). If the AE is not described in the CTCAE, version 4.03, the 
Investigator will use the terms “mild”, “moderate” or “severe” to describe the 
maximum severity, as defined below: 
Mild 
The patient is conscious of the event or symptom, which is easily 
tolerated; the event does not lead to any reduction in the patient’s 
activities of daily life. 
Moderate The patient feels discomfort such that it reduces or interferes with the 
patient’s activities of daily life. 
Severe  
Significant functional impairment: the patient is unable to carry out 
activities of daily life and/or the event is life threatening. 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 44 of 83 
Information on the severity of the AE must be recorded in the Adverse Events 
section of the CRF. 
It is important to distinguish between the severity and the seriousness of an AE: a 
severe AE is not necessarily a serious AE, since the criteria for seriousness (see 
Section 6.8.1 Definitions, Serious Adverse Event; p 40) are different from the 
criteria for severity. 
 
6.8.7. Assessment of AE Causality 
For each AE, the Investigator must assess the possible causal relationship 
between the IMP and the AE, with the assistance of the Coordinating Investigator, 
in order to determine whether there is a reasonable possibility that the IMP caused 
or contributed to the AE. 
The causal relationship between the IMP and the AE is assessed by the 
Investigator after a detailed analysis of the event in terms of the biological 
plausibility, taking into account possible unrelated causes, pre-existing medical 
conditions, concomitant medication, the temporal relationship between intake of 
the IMP and onset or worsening of the AE, and the known patterns of response to 
fexinidazole in general. 
The two types of causal relationships are defined as follows: 
 Not related: there is no reasonable possibility of a causal relationship. 
 Related: there is at least a reasonable possibility of a causal relationship 
between the IMP and the AE. This means that there are facts (evidence) or 
features that suggest a causal relationship. 
 
6.8.8. Exposure in utero 
Four pregnancy tests are planned during the study: at Screening (Day -1), at the 
EoT visit (Day 11), and at the 3-month and 6-month follow-up visits. Pregnancy is 
not a non-inclusion criterion. Women in the second or third trimester of pregnancy 
will be allowed to participate in the study, however they will be treated in hospital. 
First-trimester pregnancy is considered to be a temporary non-inclusion criterion 
(see Section 4.2 Non-inclusion Criteria; p 26). 
Pregnancy is not considered to be an AE, regardless of when it is detected. 
Nevertheless, the Investigator must report any pregnancy that occurs during the 
treatment period or that is detected at the 3-month or 6-month follow-up visits, 
using the appropriate Pregnancy Reporting Form. The pregnancy must be 
reported whether or not an AE occurred. If known, the due date should be 
specified. 
The Investigator must monitor the patient until the term of the pregnancy, i.e. full 
term or preterm, in the event of a miscarriage. The Investigator must provide 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 45 of 83 
information on the outcome of the pregnancy using the pregnancy follow-up 
reporting form. 
A physician, preferably a paediatrician, should examine the infant at birth and 
submit a report using a Newborn Follow-up Form. The child’s age must be 
collected and recorded on the form. The child will undergo diagnostic testing, in 
accordance with PNLTHA procedures, in order to rule out vertical transmission of 
the parasite. If the child is found to be HAT-positive, s/he will be managed by the 
PNLTHA. 
The Investigator will offer the patient follow-up on infants exposed to the IMP in 
utero until they reach 24 months of age. As far as possible, stillborn infants should 
be examined by a physician to ascertain the cause of death. 
Any SAE that occurs in a pregnant patient (exposed to the IMP or who is found to 
be pregnant any time up to the 18-month visit) or that concerns the pregnancy or 
the foetus, will be reported using the SAE reporting form in the same manner as 
any other SAE. Any non-serious AE concerning a pregnant patient that occurs 
during the AE reporting period will be collected using the AE form in the CRF (see 
Section 6.8.4. AE Collection Period, p 42). 
 
6.8.9. Exposure During Breastfeeding 
The Investigator will offer the patient follow-up on infants exposed to the IMP via 
breastfeeding, until they reach 24 months of age. Follow-up will be recorded using 
the Newborn Follow-up Form, where the child’s age must be recorded. 
The child will undergo diagnostic testing, in accordance with routine practice, in 
order to rule out transmission of the parasite via the mother’s milk. 
If the child is found to be HAT-positive, s/he will be managed by the PNLTHA. 
 
7. Study Duration 
Based on an enrolment period of approximately 36 months and a follow-up period 
of 18 months, the duration of the study will be 54 months.  
Each patient’s participation in the study will last approximately 19 months and will 
include: 
 a Screening period (including treatment of concomitant disease) of up to 15 
days; 
 a treatment period of 10 days; 
 an in-hospital follow-up period of 3 to 8 days;  
 an out-patient follow-up period of 18 months. 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 46 of 83 
8. Withdrawal Criteria 
8.1. 
Temporary Interruption of Treatment 
Patients treated on an out-patient basis must not under any circumstances 
discontinue treatment, even temporarily. However, if temporary interruption of 
treatment seems inevitable, the patient must contact the Investigator or come to 
the investigational centre before interrupting treatment. The Investigator will decide 
on the appropriate course of action and will inform the Sponsor as quickly as 
possible. 
Temporary interruption of treatment will not necessarily lead to patient withdrawal 
from the study. In some cases, treatment may be interrupted for a maximum of one 
day, i.e. one missed dose of fexinidazole, and treatment will therefore be delayed. 
Treatment may be reintroduced at the discretion of the Investigator. 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. 
 
8.2. 
Definitive Discontinuation of Treatment 
The Investigator, in agreement with the Principal Investigator, will discontinue the 
study treatment in the following cases:  
 Severe skin reaction; 
 ALT or AST > 8 ULN; 
 ALT or AST > 3 ULN in association with total bilirubin > 2 ULN; 
 ALT or AST > 3 ULN in association with fatigue, nausea, vomiting, abdominal 
pain or tenderness in the right upper quadrant, fever, rash and/or eosinophilia 
(> 5%); 
 Any condition that requires treatment discontinuation for medical reasons, as 
decided by the Investigator.  
If a patient is withdrawn from the study before the end of treatment, the physician 
will make all necessary arrangements to ensure that s/he receives the appropriate 
treatment for the condition in question. 
 
8.3. 
Patient Withdrawal from the Study and Replacement of Patients  
A patient may be withdrawn from the study in the following cases: 
 Withdrawal of consent by the patient or his/her legal representative; 
 Study termination by the Sponsor. 
If the patient withdraws his/her consent, the Investigator must ensure the patients 
safety and well-being and take appropriate measures. When possible, the 
Investigator should perform an end-of-study examination. 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 47 of 83 
If a patient decides to withdraw from the study, the Investigator must ensure that 
withdrawal is not related to an AE. If a patient withdraws from the study due to an 
AE, all measures must be taken as needed to clearly document the outcome of the 
AE. 
Data collected prior to withdrawal of the patient will be taken into account in the 
PK, efficacy and safety analyses. 
Patients withdrawn from the study will not be replaced. 
 
8.4. 
Patients Lost to Follow-up 
If a patient does not attend a protocol-planned visit, all possible measures must be 
taken to contact him/her. In all cases, the Investigator must take all possible 
measures to document the course of the patient’s condition. 
 
9. Data Analysis and Statistical Methods 
A first draft of the full Statistical Analysis Plan (SAP) will be prepared. It will provide 
a more detailed description of the statistical methods. The SAP will be reviewed 
and, if necessary, amended prior to final database lock. Successive versions will 
be dated and numbered. 
 
9.1. 
Sample Size Determination 
The sample size determination is based on the primary analysis. The expected 
success rate is between 87% and 91% depending on the percentage of early-stage 
patients included in the sample. The success rate for patients with late-stage HAT 
should be slightly below the expected success rate of 89% in the pivotal study, 
DNDIHATFEX004, which has a restricted, more homogeneous population. 
As concerns early-stage patients, a meta-analysis performed by Hümbelin (11), on 
a sample of 2524 patients treated with pentamidine and indexed in the databases 
of four non-governmental organisations showed a relapse rate (presence of 
trypanosomes or CSF WBC ≥ 20/µL) of 5.63% in patients followed for 6 months or 
less (142/2524), 8.20% in patients followed for 12 months or less (207/2524) and 
9.23% in patients followed for 18 months or less. The expected success rate for 
early-stage patients should be close to 92%. 
A sample size of 174 patients provides a precision of ± 5% in the estimate if the 
expected success rate is 87% and if a Wald confidence interval is used. 
Because the confidence interval will be calculated with an exact method (Clopper-
Pearson approach) the lower arm of the 95% CI will be longer than the upper arm. 
The precision for the lower arm will be close to 6% and that of the upper arm will 
be close to 4.5 % if we consider an expected success rate of 87%. The precision 
will be greater if the success rate is higher. 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 48 of 83 
 
9.2. 
Definition of Study Populations included in the Analyses 
Three patient populations will be used in the statistical analyses, as follows: 
 The intent-to-treat (ITT) population, comprising all patients included in the study, 
regardless of whether or not they took the IMP; 
 The modified intent-to-treat (mITT) population, comprising all patients who took 
at least one tablet of fexinidazole; 
 The per protocol (PP) population, comprising all patients who completed the 
study in accordance with the protocol with no major violations that could 
interfere with the efficacy evaluation. Premature withdrawal from the study due 
to treatment inefficacy or intolerance will not be considered as a protocol 
violation. 
 
9.3. 
Patient Disposition 
At the end of the study, the following categories of patients will be described: 
• Number of patients who underwent Screening; 
• Number of patients who were not included in the study due to non-fulfilment of 
eligibility criteria, and reasons for non-inclusion; 
• Number of patients included (i.e. who signed the Informed Consent form, ITT 
patients); 
• Number of patients included by stage of HAT and by treatment modality, i.e. in 
hospital or on an out-patient basis; 
• Number of patients included who took at least one tablet of fexinidazole (mITT 
patients) by disease stage; 
• Number of patients included, by disease stage, who completed treatment and 
who received all of the protocol-planned doses (treatment completers); 
• Number of patients included, by disease stage, who took at least one tablet of 
fexinidazole, excepting those who died for reasons clearly unrelated to efficacy 
or safety of the IMP (evaluable patients); 
• Number of patients included, by disease stage, with no major protocol violations 
(PP patients); 
• Number of patients included, by disease stage, treated on an out-patient basis, 
who: 
o temporarily interrupted treatment,  
o prematurely discontinued treatment,  
o were hospitalised for reasons related to non-compliance, 
o were hospitalised for a safety problem (non-exhaustive list); 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 49 of 83 
• Number of patients included, by disease stage, who underwent the following 
visits:  
o Screening, 
o Dispensing (Day 0), for patients treated an out-patient basis, 
o Visits during Treatment Period (Day 1 to Day 10), 
o EoT Visit, 
o EoH Visit (Day 13 to Day 18), for patients treated in hospital, 
o 3-month Follow-up Visit, 
o 6-month Follow-up Visit, 
o 12-month Follow-up Visit, 
o 18-month Follow-up Visit. 
• Number of patients included, by disease stage, withdrawn from the study, 
categorised by reason for withdrawal. 
 
9.4. 
Description of Patients at Baseline 
Descriptive statistics (n, mean, standard deviation, median, minimum, maximum) 
or frequencies and percentages will be presented for the following patient baseline 
characteristics, by disease stage and overall: 
 Demographic data 
 Medical history 
 Physical examination 
 Vital signs 
 Urine pregnancy test (for women of child-bearing potential) 
 Laboratory tests 
 Karnofsky Performance Status (separating patients treated on an out-patient 
basis and patients treated in hospital) 
 Neurological examination 
 Concomitant medication 
 
9.5. 
Effectiveness Analyses 
 
9.5.1. Primary Analysis - Effectiveness 
The primary analysis will be performed on the mITT population. The success rate 
at 12 months and the success rate at 18 months will be estimated, bearing in mind 
that 18 months provides a more reliable estimate of the cure rate. The 95% exact 
confidence interval of the percentage will be provided. 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 50 of 83 
9.5.2. Sensitivity Analysis 
The success rates at 12 and 18 months will be estimated along with the 95% exact 
confidence intervals on the per protocol population of patients. 
 
9.5.3. Secondary Analysis - Effectiveness 
The success rates at 12 and 18 months will be estimated in the sub-group of early-
stage patients as well as the sub-group of late-stage patients. The Clopper-
Pearson (exact) 95% confidence interval will be provided. The expected success 
rate in late-stage patients is slightly higher than that in early-stage patients, 
however, given the precision of the estimates, the observed rate may be lower. 
The proportion of early-stage patients in the study sample will also be estimated. 
 
9.6. 
Secondary Analyses 
 
9.6.1. Secondary Analysis - Safety 
The secondary safety analyses will be performed on the mITT population, i.e. all 
patients 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 described by system-organ class using Medical 
Dictionary for Regulatory Affairs (MedDRA) terms and/or NCI CTCAE, version 4.03 
(14) and, for certain laboratory parameters, modified CTCAE will be used (see 
Appendix 6 – CTCAE v4.03 adapted, p 81). 
The proportion of patients who experienced at least one AE will be described. 
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. 
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 size of the increase in relation to the ULN for liver function 
tests (< 1 ULN, 1–2 ULN, 2–3 ULN etc.). Scatter graphs 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. 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 51 of 83 
Abnormalities, if any, on ECG tracings recorded on Day 11 will be described. 
The proportion of patients hospitalised for a safety problem, including overdose, 
will also be presented. 
 
9.6.2. Secondary Analysis - Compliance 
Compliance will be assessed on the sub-group of out-patients from the ITT 
population, i.e. all patients who were considered as eligible for treatment on an 
out-patient basis and to whom the IMP was dispensed, regardless of whether or 
not they took the IMP. 
The number and percentage of patients in whom the presence of fexinidazole or 
its main metabolites was detected in the blood sample collected on D11 will be 
presented, as well as the success rate in this sub-group of patients and in the sub-
group of patients in whom no trace of fexinidazole or its main metabolites was 
detected. The distribution of the frequency of patients with unused tablets 
remaining at the end of the treatment period will be presented, and the relation 
between the success rate and the number of tablets remaining will be determined 
using a logistical regression or a sub-group analysis. The distribution of the 
frequencies of responses from patients during the compliance interview will be 
presented. 
The information provided by the PK analyses, the number of tablets remaining and 
the questionnaire will be combined to define perfect compliance and non-
compliance. Perfect compliance corresponds to a patient in whom fexinidazole is 
detected in the blood, who has no remaining tablets and whose report on full 
compliance with treatment seems unquestionable. The success rate in patients 
with perfect compliance will be compared to that in non-compliant patients. 
 
9.6.3. Secondary Analysis - Feasibility 
The secondary analyses concerning the feasibility of patient self-management of 
treatment intake under recommended conditions will be performed on the sub-
group of out-patients from the ITT population, i.e. all patients who were considered 
as eligible for treatment on an out-patient basis and to whom the IMP was 
dispensed, regardless of whether or not they took the IMP. The endpoints analysed 
will be as follows: 
 Number and proportion of patients who temporarily interrupted treatment; 
 Number and proportion of patients who prematurely discontinued treatment; 
 Number and proportion of patients who delayed starting treatment; 
 Number and proportion of patients who mislaid treatment units; 
 Number and proportion of patients who were hospitalised for reasons related to 
non-compliance. 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 52 of 83 
For each of the endpoints, the proportion of patients will be presented with the 95% 
Confidence Interval (CI). 
 
9.6.4. Secondary Analysis - Packaging 
Descriptive results will be presented for the questionnaire completed by the patient 
and/or caregiver at the dispensing visit (Day 0) and at the EoT visit (Day 11) for 
the patients treated on an out-patient basis (sub-group of out-patients from the ITT 
population). 
 
9.6.5. Secondary Analysis - PK 
The secondary analyses concerning PK will be performed on the sub-group of 
patients treated in hospital. Concentrations of fexinidazole and its metabolites in 
whole blood, as well as estimates of PK parameters derived from a population 
model will be presented. The data will provide confirmation of data from phase-I 
studies on a larger scale and, in particular, will provide confirmation that data in 
patients not included in earlier studies (e.g. pregnant or breastfeeding women) are 
consistent with those in patients in other studies. PK parameters in patients 
considered to be treatment failures or who experienced intolerance to fexinidazole 
will be described individually. 
 
9.7. 
Interim Analyses 
No interim analysis is planned for this study. 
 
9.8. 
Handling of Missing Data and Patients Lost to Follow-up 
The endpoints are based on the outcome at 18 months. 
For patients who attended the 18-month visit, but who refused the lumbar puncture 
planned at the visit, the primary imputation method will consist in checking for 
signs or symptoms of HAT. If no signs or symptoms of HAT are present and 
trypanosomes are negative, and if the outcome was considered as favourable at 
the last available assessment, the patients will be considered as treatment 
successes. 
If these criteria are not fulfilled, the patients will be considered as treatment failures. 
The outcome for patients who did not attend the 18-month visit or later will also be 
considered as a failure, except for patients who fled the region due to armed 
conflict or natural disaster. 
For the analysis at 12 months, if the lumbar puncture at 12 months is missing, data 
from the last available assessment will be used: 
 the outcome at 18 months will be used, if a lumbar puncture was performed at 
that visit. 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 53 of 83 
 if a lumbar puncture was performed at 6 months, but not at 18 months, the 
patient will be considered as a success if the CSF WBC was ≤ 5/µL and lower 
as compared to prior values, if no trypanosomes were detected and if no HAT-
related symptoms were present at 12 months. 
 if a lumbar puncture was performed at 6 months and at 18 months, the outcome 
at 18 months will prevail. 
In situations other than those described above and if no lumbar puncture is 
available after the start of treatment, the patients will be considered as failures. 
 
9.9. 
Handling of Centres 
The primary analysis will not be stratified by centre because the weight of each 
centre in the overall population is unknown. Nevertheless, the results by centre will 
be presented and a test of homogeneity (a likelihood-ratio test) will be performed 
on the success rates. A centre effect is entirely possible. In this case, an estimate 
of the overall success rate will also be provided, giving equal weight to each centre 
rather than weighting the centres based on the number of patients. The estimate 
of the rate will be given by p = ∑ Wh ph where Wh is the weight of each centre, i.e. 
the inverse of the number (k) of the centre (k-1). La variance of the estimator will 
be equal to Var(Ph) = ∑ Wh2. ph(1-ph) / nh where nh is the number of patients in 
centre h. In addition, a Forest plot will be presented to determine whether the 
heterogeneity is quantitative (dispersion around a central value) or qualitative 
(presence of entirely atypical centres). 
 
10. 
Data and Safety Monitoring Board  
A DSMB, composed of at least 3 members independent of the Investigators and 
the Sponsor, will be set up prior to the start of the study. The DSMB will monitor 
the study in order to minimise any risk of harm to the patients included in the study. 
At each of its meetings, the DSMB will examine safety data at predetermined 
intervals and all information related to SAEs, and will issue recommendations 
regarding the study if the benefit-to-risk ratio for patients seems to be in jeopardy. 
The data and the intervals for review will be decided before, or shortly after the 
start of the study and will be recorded in the DSMB Charter. 
The organisation of the DSMB will be described in the DSMB Charter, which will 
be prepared and approved prior to the first planned meeting. 
Additional ad hoc members may be invited to join the DSMB if any safety concerns 
emerge, in order to give additional support to the competencies already present. 
 
11. 
Quality Assurance and Quality Control Procedures 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 54 of 83 
11.1. Investigator Site File 
The Investigator must maintain appropriate accurate records to ensure that all 
aspects of study conduct are fully documented, and that study data can be verified 
at the end of the study. These documents include the Investigator Site File, the 
patients’ clinical source documents, screening/enrolment logs and other study-
specific forms. 
The Investigator’s Site File must contain the protocol and protocol amendments, 
Independent Ethics Committee (IEC) and regulatory approval with all 
correspondence, a copy of the patient information and informed consent form, the 
Investigator Brochure, drug accountability records, Curriculum Vitae (CV) for study 
personnel, as well as authorisation forms and any other relevant documents or 
correspondence in accordance with Good Clinical Practice (GCP) and the 
Sponsor’s standard operating procedures. 
 
11.2. Case Report Forms 
Data will be collected by laboratory technicians, physicians, nursing staff or care-
providers authorised by the Investigator. Data collection will be supervised by the 
Investigator. Study-specific information will be entered in a CRF in paper format. 
Data generated from this information must be consistent with the source 
documents and any discrepancies must be accounted for. All data that are 
recorded directly in the CRF must be rendered anonymous, i.e. such that they can 
only be identified by the patient’s number.  
The Investigator must ensure the accuracy, completeness, legibility and timely 
entry of all data reported to the Sponsor via the CRF, as well as any additional 
information that may be requested. The Investigator is responsible for ensuring 
that all informed consent forms and screening forms for all patients are stored in a 
secure location. After each visit, data will be entered in the CRF, scanned and sent 
by Internet to the data manager for entry (double data entry) in the database. The 
CRF will be signed by the Investigator as the study advances and the CRF pages 
are sent. 
 
11.3. Source Documents 
The data in the CRF must be verified by direct inspection of the source documents. 
The source documents are the patient’s medical files, the physicians’ and nursing 
staff’s notes, appointment books, originals of laboratory test results, ECG tracings, 
reports on specific assessments, signed informed consent forms, recorded images 
of microscopic examinations and patient screening/enrolment logs. The 
questionnaires on D0 and D11 on product packaging are also considered as 
source documents. 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 55 of 83 
In the study, 100% source document verification will not be carried out. Instead, 
the focus will be on monitoring for data consistency (cf. the monitoring plan). 
The Investigator must keep the source documents up to date, i.e. reports on 
laboratory tests and consultations, records of medical history and physical 
examination reports, so that they can be examined and/or audited by the Sponsor 
/ designated clinical monitors and/or by the Regulatory Authorities, if appropriate.  
 
11.4. Retention of Documents 
The Investigator must retain all essential documents for at least 25 years after the 
official stop date of clinical development of the IMP. However, study documents 
may need to be retained for a longer period of time if required by local regulations 
in effect or by agreement with the Sponsor. It is the responsibility of the Sponsor 
to inform the Investigator/institution as to when these documents no longer need 
to be retained. After that date, the documents may be destroyed with prior 
permission from the Sponsor, subject to local regulations. 
The Sponsor must be notified in advance if the Investigator plans to assign the 
study records to another party or move them to another location. 
 
11.5. Monitoring 
Clinical monitors will perform regular monitoring visits during which they will verify 
source data, Informed Consent Forms, medical records, laboratory test results, 
imaging reports, CRFs, drug dispensing logs and protocol violations. The monitors 
will be given access to the corresponding source documents for each patient on 
condition that that the patient’s confidentiality is maintained in accordance with 
local regulations. 
Monitoring visits at the investigational sites will be performed periodically by 
representatives of the Sponsor or designated clinical monitors to ensure 
compliance with Good Clinical Practice and all aspects of the protocol. Source 
documents will be reviewed for verification of consistency with the data in the CRFs 
and SAE forms or information provided in response to queries from the 
Pharmacovigilance Unit at DNDi. The clinical monitor will be responsible for 
inspecting the CRFs at regular intervals. The Investigator will ensure that the 
Sponsor’s designated representatives have direct access to source documents. It 
is important that the Investigators and the personnel concerned are available 
during monitoring visits. The Investigator agrees to cooperate with the clinical 
monitor to ensure that any problems detected during monitoring visits are resolved. 
The monitoring visits provide the Sponsor with the opportunity to assess progress 
of the study, to verify the accuracy and completeness of the CRFs and to resolve 
any inconsistencies in the study records, as well as to ensure compliance with all 
protocol requirements, applicable regulations and Investigator obligations. 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 56 of 83 
Four types of visit are planned: a site assessment visit, an initiation visit, monitoring 
visits and a close-out visit. 
In addition, data quality will be checked on a regular basis by representatives of 
the Sponsor in the context of centralised monitoring in order to detect any missing 
data, inconsistencies, discrepancies and deviations, with analysis of the 
performance of the investigational centres in order to adapt and/or optimise the 
monitoring visits and to implement corrective and/or preventive actions, including 
the need for training, depending on the risks identified and/or deficiencies 
observed. 
 
11.6. Audits and Inspections 
The investigational centre may also be subject to quality assurance audits by the 
Sponsor or designated representatives, and/or to inspection by regulatory 
authorities or IEC members. 
The purpose of the audits and/or inspections is to verify adherence to the protocol 
and to ensure that the study is being conducted in accordance with Good Clinical 
Practice. It is important that the Investigators and the personnel concerned are 
available for any audits or inspections. 
 
11.7. Data Management 
A CRF must be completed for each patient who gives informed consent to 
participate in the study. A paper CRF will be used in the study. The study data will 
be stored in a computer database that ensures confidentiality of the data, in 
accordance with national legislation on data protection. 
All data will be entered in the CRF under the responsibility of the Investigator or a 
designated qualified staff member. 
The clinical monitor will monitor the data continuously. Data queries will be 
generated, documented and resolved continuously throughout the study. 
 
11.8. Data Confidentiality 
The Investigator must ensure that the anonymity of patients is maintained and that 
their identity is protected from unauthorised third parties. Patients must not be 
identified by their names in the CRF or on any other documents or imaging 
submitted to the Sponsor. Only the patient number should appear. The Investigator 
must keep a patient enrolment log containing the number, name and address of 
patients. The Investigator must ensure the confidentiality of all documents 
submitted to the Sponsor’s authorised representatives, including the signed 
informed consent form. 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 57 of 83 
The findings of any assessments, including laboratory tests, will remain strictly 
confidential to the patient him/herself, except in the case of patients under legal 
age and vulnerable patients whose findings will also be communicated to the legal 
representative. Particular attention will be paid to the confidentiality of the results 
of pregnancy tests and tests related to concomitant diseases. 
 
12. 
Protocol Amendments  
The Investigators will ensure that the study is conducted in strict compliance with 
the protocol, and that all data are collected and recorded in the CRF. 
All protocol modifications must be documented in writing. A protocol amendment 
can be initiated by either the Sponsor or any Investigator. The Investigator will 
provide the reasons for the proposed amendment in writing and will discuss it with 
the Sponsor and the Principal Investigator.  
Any protocol amendment must be approved and signed by the Sponsor and the 
Principal Investigator, and must be submitted to the appropriate IEC for information 
and approval in accordance with local requirements, and to regulatory agencies, if 
required. A favourable opinion must be received from the IEC, and the regulatory 
authorities, if applicable, before any changes can be implemented, with the 
exception of changes required to avert an immediate danger for study participants, 
or when the change involves only logistical or administrative aspects of the study, 
e.g. changes in telephone numbers. 
 
13. 
Early Termination of Study 
Both the Sponsor and the Principal Investigator will have the right to terminate the 
study early, i.e. at any time prior to inclusion of the planned number of patients, but 
they may exercise this right only for valid scientific or administrative reasons. If this 
is necessary, the two parties will define the procedures for terminating the study 
after consultation. The Sponsor and the Principal Investigator will ensure that early 
termination of the study takes place in such a way as to protect the patients’ 
interests. 
Reasons for which the study may be terminated by the Sponsor include, but are 
not limited to:  
 Insufficient enrolment rate; 
 Protocol violations; 
 Inaccurate or incomplete data;  
 Dangerous or unethical practices;  
 Recommendation from the DSMB or IEC. 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 58 of 83 
Reasons for which the study may be terminated by the Investigator include, but 
are not limited to: 
 Insufficient time or resources to conduct the study; 
 Lack of eligible patients. 
 
If the study is terminated early by the Sponsor or the Investigator, the latter must: 
 Complete all CRFs to the fullest extent possible. 
 Return all study-related articles and equipment to the Sponsor who provided 
them. 
 Answer all queries from the Sponsor, or delegated representatives, related to 
data on patients enrolled by the centre prior to study termination. 
 Ensure that patients enrolled in the study who have not yet attended any follow-
up visits receive all necessary medical care. 
 Provide the IEC, the Regulatory Authorities and, if appropriate, the Sponsor with 
a written explanation of the decision to terminate the study. 
 
14. 
Ethical Considerations 
The protocol for this study was prepared in accordance with the general ethical 
principles set out in the Declaration of Helsinki of the World Medical Association 
(see Appendix 1 - Declaration of Helsinki; p 68) and International Council on 
Harmonisation (ICH) guidelines for Good Clinical Practice (ICH Harmonised 
Tripartite Guideline - Guideline For Good Clinical Practice E6(R1) - current Step 4 
version, dated 10 June 1996). DNDi commits to respect all applicable laws for the 
protection of the rights and welfare of human subjects.  
The protocol will be submitted by the Principal Investigator for official approval to 
the Ethics Committee of the Protestant University in Congo and to the National 
Ethics Committee for Health Research in Guinea (CNERS) . 
Approval must be received from the Ethics Committee prior to performing any 
study-specific procedures on any patient.  
Any changes made to the protocol after it has been approved by the IEC must be 
submitted in writing to the IEC by the Principal Investigator in accordance with local 
procedures and regulatory requirements in effect (see Section 12 Protocol 
Amendments; p57). 
The protocol must be submitted along with the appendices related to the 
information and safety of patients, including the Patient Information Sheet, the 
Informed Consent/Assent Form and the Investigator Brochure. The set of photo 
cards provided to Investigators as a visual aid to explain the study procedures will 
be presented the Ethics Committees. The information sheet for patients and the 
informed consent/assent form, translated into the local language or a language 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 59 of 83 
understood by the patients will be submitted for official approval from the Ethics 
Committee.  
The protocol has received a positive opinion from the Committee for the Protection 
of Persons at the Hôpital Necker in Paris, France.  
 
14.1. Information of Communities 
The study will be conducted in collaboration with the National Sleeping Sickness 
Control Program (PNLTHA). The program brings together all activities related to 
the prevention and treatment of HAT in the DRC, in particular the supervision and 
coordination of the teams in charge of HAT screening activities (mobile teams and 
prospect activities). The PNLTHA is fully involved in the design and implementation 
of the study. 
Information of the communities participating in the study will follow the procedures 
of the PNLTHA. 
The following information on the study will be disseminated to the community at 
various levels: 
 Routine procedures for detection and diagnosis of HAT; 
 Primary objective of the study, i.e. to develop a safe oral drug to treat HAT that 
will be made available to the local population; 
 Information on the new drug, the availability of a rescue treatment and on 
concomitant medication as needed; 
 Information on the duration of hospitalisation, number of follow-up visits up to 
18 months as compared to routine treatment, importance of attending follow-up 
visits and possibility of visits by study staff at village level if the patient does not 
attend the follow-up visits at the centre; 
 Information on provision of food to for patients treated at hospital; 
 Information on organisation of transportation and/or reimbursement of travel 
costs from their village to the investigational centre for patients included in the 
study, as well as for the caregiver for patients treated on an out-patient basis; 
 Importance of the freedom of each individual to accept or to refuse to take part 
in the study, after full explanation of the study. Availability of treatment in either 
case;  
 Need for minors and patients with impaired cognitive capacities to come to the 
centre accompanied by a legal guardian/representative. 
At the end of the study, the community will receive information on the results using 
the same means of communication, i.e. community mobilisers. 
 
14.2. Informed Consent Process  
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 60 of 83 
14.2.1. Overall Procedure 
The patient will not be included in the study until after s/he has given informed 
consent in writing. It is the responsibility of the Investigator to obtain, for each 
individual who participates in the study, voluntary written informed consent after 
having provided adequate explanation of the aims, methods, anticipated benefits 
and potential hazards of the study. For patients under legal age, consent must be 
obtained from the patient’s legal representative. During their visits in the field, the 
mobile teams will inform the communities of the necessity for children to be 
accompanied by a legal representative during visits to the investigational centre.  
The patient information and the informed consent form will be available in the 
following national/local languages or the lingua franca : French, Lingala, and 
Kituba/Kikongo and Tshiluba, corresponding to the languages spoken in the 
regions where the study is to be conducted. The document will be submitted to the 
IEC for approval. 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. 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 and to that 
end may call upon a “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, including photographs, drawings and 
samples, 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. 
The information session will be held in a separate room in order to ensure patient 
confidentiality, with only one facilitator present.  
The patient and his/her caregiver will first be informed about the disease, i.e. HAT, 
with a clear description of the signs and symptoms. 
The information provided during the session will address the following topics: 
 Currently available treatments; 
 Study objective and need for scientific evaluation of a new treatment; 
 Information on the new drug from prior and on-going studies (safety, PK/PD…) 
 Number of patients to be enrolled and the duration of the study; 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 61 of 83 
 Criteria to fulfil to be eligible for inclusion in the study; 
 Patient’s commitments during the study, i.e. time, compliance with study-
specific procedures, compliance with out-patient treatment and attendance at 
follow-up visits; 
 Samples to be collected for laboratory tests and purpose of tests; 
 Benefits and risks associated with study participation; 
 Compensation for travel costs and provision of food for patients treated at 
hospital: 
 Patients’ rights regarding withdrawal, rescue treatment, additional information, 
etc. 
If the patient or, in the case of patients under legal age, the legal representative 
wishes, s/he will be given time to discuss the information received with members 
of his/her community or family before giving consent. If s/he chooses to take part 
in the study, the patient or, in the case of patients under legal age, the legal 
representative will give written consent by signing the form, provided that the 
Investigator and/or the facilitator is convinced that the patient has fully understood 
what was explained. If applicable, assent may be requested from children (see 
Section 14.2.6 Collection of Assent from Children; p 63). 
 
14.2.2. 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 
Section 14.2.3. Illiterate Patients; p62; Section 14.2.4. Patients Unable to Give 
Consent; p62; Section 14.2.5. Patients Under Legal Age p62; and Section 14.2.6. 
Collection of Assent from Children; p63). 
The witness should have no connection with the study team, and, whenever 
possible, should be chosen by the patient. The witness must be literate, i.e. able 
to read. If the patient does not know any appropriate witness, the team will propose 
someone from the hospital staff who is not working in the HAT clinical unit, or any 
literate person from the neighbourhood who is willing to act as a witness. The study 
team will take all necessary measures to prepare a list of possible witnesses before 
the start of the study and keep this list updated, in order to find a witness quickly, 
whenever necessary. 
The witness will sign the consent form to attest to the completeness of the 
information given to the patient, and its compliance with the written information in 
the patient information sheet. The witness must be present throughout the entire 
information session.  
The witness will confirm that the patient has freely given his/her informed consent 
to participate in the study.  


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 62 of 83 
 
14.2.3. 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.  
 
14.2.4. Patients Unable to Give Consent 
Some patients with late-stage HAT may already have impaired cognitive capacities 
or behavioural abnormalities that preclude them from giving free and informed 
consent.  
Considering the frequency of such symptoms in late-stage HAT, 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 legal 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. 
 
14.2.5. Patients Under Legal Age 
For patients under legal age, i.e. between 15 and 18 years old, considered as 
adolescents/young adults, the consent of one of their parents or another culturally 
acceptable, legal representative will be required in addition to their own personal 
assent. During field visits by the mobile team, adolescents/young adult patients will 
be advised to come to the study centre accompanied by a legal representative. 
No specific patient information sheet or specific form will be used to collect assent 
from adolescents/young adults recruited to the study, since the data in the patient 
information sheet is considered to be comprehensible by both adolescents and 
adults. 
The form must be signed by both the adolescent/young adult and his/her legal 
representative. If the patient or the legal representative is illiterate, a fingerprint 
should replace the signature. If the legal representative is illiterate, an impartial 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 63 of 83 
witness must attend the assent process and the consent process for the legal 
representative (see Section 14.2.2 Impartial Witness; p 61). 
For young adults considered as emancipated because they are already married, 
the legal representative may be the spouse. If they are not married, but are living 
on their own, they may be included with their own consent, provided that an 
impartial witness is present during the consent process to confirm their 
understanding of the study, to confirm the probability that they are indeed 
emancipated and to sign the consent form along with them. 
 
14.2.6. Collection of Assent from Children 
No specific patient information sheet or specific form will be used to collect assent 
from children recruited to the study. Instead, priority will be given to oral information 
in order to adapt the information to what the child is able to understand. It is difficult 
to obtain assent from children under 14 years of age as children have difficulty 
weighing up benefits and risks (15). 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 (15, 20). 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.  
 
14.2.7. Changes in the Benefit-to-Risk Ratio during the Study  
If new safety information results in significant changes in the benefit-to-risk ratio, 
the patient information sheet and consent form will be reviewed and updated. 
Patients currently being treated will be informed of the new information, given a 
copy of the revised patient information and asked to renew their consent to 
continue the study. 
 
14.3. Ethical Aspects of Study Treatment and Sampling for Laboratory 
Tests 
Experimental data suggest that fexinidazole has significant potential for the 
treatment of T.b. gambiense infections. 
No screened patients will be left without treatment. Patients not eligible for the 
study will be offered alternative treatment. 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 64 of 83 
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 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. 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. 
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 and the destruction 
procedure will be recorded in a certificate of destruction. 
 
14.4. Costs for Patients 
Travel costs to and from the investigational centre will be reimbursed for patients 
and for the caregivers of patients treated on an out-patient basis, however no 
compensation will be provided for their participation in the study. For patients 
treated at hospital, food will be provided free of charge for the in-patient treatment 
phase. Food may or may not be prepared for the patients, depending on usual 
practice in each investigational centre. If not, the family will prepare the food. 
Sufficient food will be provided to cover the needs of the relatives accompanying 
the patient during hospitalisation.  
For follow-up visits, the patients’ travels costs will be covered depending on the 
particular practices in each investigational centre with regard to payment of taxi 
fares, use of a study-specific vehicle, transport by mobile teams, reimbursement 
at a flat rate, etc. Missed days of work due to travel for follow-up visits may be 
compensated, depending on requirements from local IECs. 
To ensure that patients are free to decide whether or not to participate in the study, 
all patients who are diagnosed with HAT and who are treated at hospital will 
receive food during the in-hospital treatment phase, even if they are not included 
in the study, regardless of whether this is because they do not fulfil the inclusion 
criteria or because they do not wish to participate in the study. 
Any medication that is required during the study will be provided to the patients 
free of charge. The WHO List of Essential Medicines and the guides entitled 
“Clinical Guidelines” and “Essential Medicines” (2013 edition), published by 
Doctors Without Borders, will be used as reference guides for the treatment of all 
concomitant conditions. For chronic conditions, the study team will take all 
necessary measures to ensure that the patient is referred to the most appropriate 
local healthcare facility in the region for treatment free of charge. 
 
15. Insurance and Liability 
DNDi will take out an insurance policy to cover any claims arising from the study, 
with the exception of claims that arise from malpractice and/or negligence, in which 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 65 of 83 
case the Investigator or the institution will be held liable. In addition, DNDi will cover 
the costs of treating patients in the study in the event of study-related injuries, in 
accordance with applicable local regulatory requirements. 
 
16. Rapports and Publication 
The study will be registered with a recognised international registry of clinical trials, 
i.e. 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. 
 
 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 66 of 83 
17. References 
1. Blum J, Schmid C, Burri C. "Clinical aspects of 2541 patients with second 
stage human African trypanosomiasis”. Acta Trop 2006;97(1):55-64 
 
2. Büscher P, Mumba Ngoyi D, Kaboré J, Lejon V, Robays J, Jamonneau V, 
Bebronne N, Van Der Veken W, Biéler S. “Improved Models of Mini Anion 
Exchange Centrifugation Technique (mAECT) and Modified Single 
Centrifugation (MSC) for Sleeping Sickness Diagnosis and Staging”. PloS 
Negl Trop Dis 2009;3(11):e471 
 
3. Büscher P, Gilleman Q, Lejon V. “Rapid diagnostic test for sleeping 
sickness”, New England J Med 2013;368:11 
 
4. Camara M, Camara O, Ilboudo H, Sakande H, Kaboré J, N’Dri L, 
Jamonneau V, Bucheton B. “Sleeping sickness diagnosis: use of buffy 
coats improves the sensitivity of the mini anion exchange centrifugation 
test”. Trop Med Int Health 2010;15(7):796-9 
 
5. DNDi – Investigator Brochure for Fexinidazole, Edition 4.0, dated 11 April 
2016. 
 
6. Doyle D, Hanks G, MacDonald N. “Oxford Textbook of Palliative Medicine”. 
Oxford University Press. 845 pp, illustrated New York 1993;109. ISBN: 0-
19-262028-2 
 
7. Falade C, Manyando C. “Safety profile of Coartem®: the evidence base”. 
Malaria Journal 2009, 8(Suppl 1):S6. 
 
8. Hasker E, Mitashi P, Baelmans R, Lutumba P, Jacquet D, Lejon V, Kande 
V, Declercq J, Van der Veken W, Boelaert M. “A new format of the CATT 
test for the detection of Human African Trypanosomiasis, designed for use 
in peripheral health Facilities” Trop Med Int Health 2010;15(2):263-7 
 
9. Hümbelin M. “Definition of follow-up duration in clinical research of 
human African trypanosomiasis”. Thesis/Dissertation in Pharmaceutical 
Sciences at University of Basel, Suisse (2006) 
 
10. Malvy D, Chappuis F. “Sleeping sickness”. Clin Microbiol Infect 
2011;17(7):986-95. doi: 10.1111/j.1469-0691.2011.03536.x 
 
11. Mumba D, Bohorquez E, Messina J, Kande V, Taylor SM, Tshefu AK, 
Muwonga J, Kashamuka MM, Emch M, Tidwell R, Büscher P, Meshnick 
SR. “Prevalence of Human African Trypanosomiasis in the Democratic 
Republic of the Congo”. PloS Negl Trop Dis 2011;5(8):e1246 
 
12. National Cancer Institute. Common Terminology Criteria for Adverse 
Events (CTCAE) V4.0. Published: May 28, 2009 (v4.03: June 14, 2010). 
Accessed on 25 May 2016 at http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
 
13. Roth-Cline M. et al. “Parental permission and child assent in research 
on children”, Yale Journal of Biology and Medicine 2013;86:291-301 
 
14. Schag CC, Heinrich RL, Ganz PA. “Karnofsky performance status 
revisited: reliability, validity, and guidelines”. J Clin Oncology. 
1984;2:187-193 
 
15. Simarro PP, Diarra A, Ruiz Postigo JA, Franco JR, Jannin JG. “The  


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 67 of 83 
Human African Trypanosomiasis Control and Surveillance Programme 
of the World Health Organisation 2000–2009: The Way Forward”. PloS 
Negl Trop Dis 2011;5(2):e1007 
16. Stich A, Abel PM, Krishna S. “Human African trypanosomiasis”. BMJ 
2002;325(7357):203–6 
 
17. Torreele E, Trunz BB, Tweats D, Kaiser M, Brun R, Mazué G, Bray MA, 
Pécoul B. “Fexinidazole – A New Oral Nitroimidazole Drug Candidate 
Entering Clinical Development for the Treatment of Sleeping Sickness”. 
PloS Negl Trop Dis 2010;4(12):e923. 
 
18. Wendler, D.S. “Assent in paediatric research: theoretical and practical 
considerations” J Med Ethics (2006), 32:229-234 
 
19. WHO (2007). "Recommendations of the Informal Consultation on Issues 
for Clinical Product Development for Human African Trypanosomiasis." 
World Health Organisation. WHO/CDS/NTD/IDM/2007.1. 
 
20. WHO (2011). "New cases of human African trypanosomiasis continue to 
drop." World Health Organisation. Consulted on January 30th, 2012, at 
http://www.who.int/neglected_diseases/disease_management/HAT_case
s_drop/en/index.html 
21. WHO (May 2015) Factsheet n°259 “Human African Trypanosomiasis 
(sleeping 
sickness)” 
http://www.who.int/mediacentre/factsheets/fs259/fr/ 
22. Mumba Ngoyi D, Lejon V, N’Siesi FX, Boelaert M, Büscher P. “Comparison 
of operational criteria for treatment outcome in gambiense human African 
trypanosomiasis.” Trop Med Int Health 2009;14(4):438-44. 
 
 
 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 68 of 83 
 
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 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 69 of 83 
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, 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. 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 70 of 83 
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 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. 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 71 of 83 
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 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 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 72 of 83 
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. 
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 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 73 of 83 
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. 
 
 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 74 of 83 
 
Appendix 2 – Karnofsky Performance Status Scale 
 
KARNOFSKY PERFORMANCE STATUS SCALE 
Definitions of Rating Criteria (%) 
The Karnofsky Performance Scale Index allows patients to be classified in terms 
of their functional impairment. (16, 8). This can be used to compare effectiveness 
of different therapies and to assess the prognosis in individual patients. The lower 
the Karnofsky score, the worse the survival for most serious illnesses.  
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. 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 75 of 83 
Appendix 3  – Laboratory Tests 
 
Laboratory Tests and Methods 
 
All laboratory assessments will be described in a laboratory manual. Laboratory 
technicians have received specific training on these standard methods. 
 
Biochemical tests 
 
14 parameters will be analysed: 
Albumin 
Calcium 
Alkaline phosphatase  
Glucose 
Alanine aminotransferase 
Bicarbonates  
Aspartate aminotransferase 
Blood urea nitrogen 
Total bilirubin  
Sodium 
Total protein 
Chloride 
Creatinine 
Potassium 
 
Haematological tests  
• Haemoglobin assay  
• White blood cells: count and differential count 
• Platelets: count 
• Microscope: full blood cell count (visual count) (see Investigator Manual) 
 
Urine analysis 
• Urine dipsticks for laboratory safety analyses / Combur 9 Test® 
White blood cells  
Nitrites 
pH 
Glucose  
Protein 
Ketone bodies 
Urobilinogen  
Bilirubin 
Blood  
Haemoglobin 
 
• Urine pregnancy test 
CSF analysis (see Investigator Manual) 
• Modified Single Centrifugation (MSC): detection of parasites 
• Counting chamber: WBC count  
Blood parasitology tests (see Investigator Manual) 
• Thick/thin blood smears  
• Woo test /CTC  
• mAECT  
• mAECT-BC  


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 76 of 83 
 
Quantities of biological fluids required at each sampling timepoint 
 
Screening Visit (Day -15 to Day -1) 
 
 
Type of test 
Specific test  
Number of 
samples 
Quantity per 
sample 
(approx.) 
Total 
quantity 
Blood 
Parasitology  
Woo/CTC 
1 
100 µL 
≤ 400 µL 
Thin/thick blood 
smear 
1 
≤ 300 µL 
mAECT (±BC)  
1 
5 mL 
5 mL 
Haematology 
Haemoglobin  
1 
20 µL 
170 µL 
(capillary 
blood1) 
WBC 
1 
20 µL 
Platelet count 
1 
10 µL 
Differential WBC 
1 
20 µL 
Biochemistry 
14 parameters 
1 
100 µL 
Lymph 
Parasitology  
If lymph nodes 
detectable 
 
 
 
CSF 
Parasitology  
Modified Single 
Centrifugation  
1 
4 mL 
4 mL 
Urine 
Pregnancy 
 
1 
5 mL 
10 mL 
Urine analysis  
Combur 9 Test®  
1 
5 mL 
 
End-of-Treatment Visit (Day 11) 
 
 
Type of test 
Specific test  
Number of 
samples 
Quantity 
per sample 
(approx.) 
Total 
quantity 
Blood 
Parasitology  
Woo/CTC 
1 
100 µL 
≤ 400 µL 
Thin/thick blood 
smear 
1 
≤ 300 µL 
mAECT (±BC)  
1 
5 mL 
5 mL 
Haematology 
Haemoglobin  
1 
20 µL 
170 µL 
(capillary 
blood1) 
WBC 
1 
20 µL 
Platelet count 
1 
10 µL 
Differential WBC 
1 
20 µL 
Biochemistry 
14 parameters 
1 
100 µL 
Lymph 
Parasitology  
If lymph nodes 
detectable 
 
 
 
Urine 
Pregnancy 
 
1 
5 mL 
10 mL 
Urine analysis  
Combur 9 Test®  
1 
5 mL 
 
 
 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 77 of 83 
 
Follow-up Visits at 3, 6, 12 and 18 months (per visit) 
 
 
Type of test 
Specific test  
Number of 
samples 
Quantity 
per 
sample 
(approx.) 
Total 
volume 
per visit 
Blood 
Parasitology  
Woo/CTC 
1 
100 µL 
≤ 400 µL 
Thin/thick blood 
smear 
1 
≤ 300 µL 
mAECT (±BC)  
1 
5 mL 
5 mL  
Haematology 
(M3 and M6) 
Haemoglobin  
1 
20 µL 
170 µL 
(capillary 
blood1)  
WBC 
1 
20 µL 
Platelet count 
1 
10 µL 
Differential WBC 
1 
20 µL 
Biochemistry 
(M3 and M6) 
14 parameters 
1 
100 µL 
Lymph 
Parasitology  
If lymph nodes 
detectable 
 
 
 
CSF 
Parasitology  
Modified Single 
Centrifugation  
1 
4 mL 
4 mL 
Urine 
Pregnancy (M3 
and M6) 
 
1 
5 mL 
5 mL 
 
 
Quantity of blood required for PK analyses  
 
 
Entire study 
 
 
 
Type of test 
Number of 
samples 
Quantity per sample 
(approx.) 
Total volume  
Blood 
PK 
6  
2mL 
12 mL 
 
 All haematological and biochemical analyses can be performed using a single finger-prick with a 
Tenderlett® device or similar. 
 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 78 of 83 
Appendix 4 - Study Schedule 
 
 
Final protocol available 
August 2016 
IMP available 
October 2016 
First patient first visit 
November 2016 
Duration of recruitment period  
36 months 
Duration of follow-up period 
18 months  
Last patient last visit 
1st quarter 2021 
Final clinical study report 
3rd quarter 2021 
 
Organisation of Study 
 
Country 
DRC and Guinea 
Planned number of 
patients 
174 patients  
Number of sites 
At least 4 sites  
Number of patients 
per site 
Between 20 and 50 
Role of DSMB 
A DSMB will be appointed, in charge of safety issues in the 
same way as for study DNDiFEX004. 
Role of partners 
 
Ministry of Health, Kinshasa, DRC 
• Principal Investigator  
PNLTHA, Kinshasa, DRC 
• Supervision of investigational site teams  
• Coordination of supplies and active screening teams 
IRD and PNLTHA in Guinea 
• Supervision of investigational site teams 
• Coordination of supplies and active screening teams 
Other particular 
needs 
Mobile teams for active case screening 
Equipment and supplies for biochemical and haematological 
analyses 
Telecommunication facilities and computing equipment 
 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 79 of 83 
Appendix 5 - Packaging of IMP 
 
Mock-up of Packaging  
a. 
Adults and children with body weight 35 kg or more 
 
 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 80 of 83 
b. 
Children with body weight less than 35 kg 
 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
Fexinidazole  
 
 
Confidential  
Page 81 of 83 
Appendix 6 – CTCAE version 4.03 adapted 
 
 
CTCAE v4.0 SOC
CTCAE v4.0 Term
units
LLN
ULN
Grade 1   
Grade 2   
Grade 3   
Grade 4   
Grade 5
CTCAE v4.0 AE Term Definition
Hematologie
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
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/µL
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/µL
<LLN - 75,000
<75,000 - 50,000
<50,000 - 25,000
<25,000
-
Leucocytes
Blood and 
lymphatic system 
disorders
Leukocytosis
nb/µL
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/µL
>100,000
Clinical manifestations of 
leucostasis; urgent intervention 
indicated
Death
Investigations
White blood cell
decreased
nb/µL
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/µL
<LLN - 3000
<3000 - 2000
<2000 - 1000
<1000
-
Biochimie
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
>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
-
<130 - 120
<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
<3.6 - 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
>5.1 - 5.5 
>5.5 - 6.0 
>6.0 - 7.0 ; hospitalization 
indicated
>7.0 ; life-threatening 
consequences
Death
Bicarbonates
mmol/L
18
33
Chloride
mmol/L
98
108
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
<73 - 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
Fasting glucose value >118 - 160 Fasting glucose value >160 - 250 >250 - 500 ;  hospitalization 
indicated
>500 ; life-threatening 
consequences
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
>10.3 - 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.
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
Azote uréique sanguin
mg/dL
7
22
Créatinine
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
>1 - 1.5 x baseline; >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
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
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
ALT (SGPT)
Investigations
Alanine aminotransferase
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 aminotransferase
increased
U/L
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
AST (SGOT)
Investigations
Aspartate aminotransferase
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 aminotransferase
increased
U/L
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
Bilirubine totale
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
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
Albumine
Metabolism and 
nutrition disorders
Hypoalbuminemia
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
Hypoalbuminemia
g/dL
<LLN - 3
<3 - 2
<2
Life-threatening consequences; 
urgent intervention indicated
Death
Protéine Totale
g/dL
5.8
8.8
CTC criteria
CTC differs from nouvelles 
valeurs bio
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.
to be assessed as:
•    "normal",
•    "abnormal not clinically significant" or
•    "abnormal clinically significant (to be graded by the investigator and declared as mild, moderate or severe)"
to be assessed as:
•    "normal",
•    "abnormal not clinically significant" or
•    "abnormal clinically significant (to be graded by the investigator and declared as mild, moderate or severe)"
to be assessed as:
•    "normal",
•    "abnormal not clinically significant" or
•    "abnormal clinically significant (to be graded by the investigator and declared as mild, moderate or severe)"
to be assessed as:
•    "normal",
•    "abnormal not clinically significant" or
•    "abnormal clinically significant (to be graded by the investigator and declared as mild, moderate or severe)"


Protocol DNDi-FEX-09-HAT Version 3.0 
 
Fexinidazole  
 
Confidential  
Page 82 of 83 
Appendix 7 - Schedule of Study Events 
Table 5  – Schedule of Events - Patients treated in hospital 
Protocol-planned procedures 
and forms to be completed 
Screening  
Treatment period 
In-hospital Follow-up  
Follow-up period 
Timepoint   
D-15 to D-1 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 (EoT) 
D12 
D13-D18 
(EoH) 
3 – 6 – 12 – 18 months 
Rapid Diagnostic Test or CATT  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Detection of parasite in blood and/or lymph 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
Informed consent (before any additional medicines or study-
specific procedures) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lumbar puncture  
(parasite and white blood cells in CSF) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x1 
Pretreatment of helminthiasis2 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rapid Diagnostic Test and/or thick blood smear for 
diagnosis of malaria and, if necessary, treatment2 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Performance Status 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
Inclusion and exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signs and symptoms of HAT 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
Vital signs3 
x 
 
 
 
 
 
 
 
x4 
 
 
x 
 
x 
x 
Physical and neurological examinations 
x 
 
 
 
 
 
 
 
x4 
 
 
x 
 
x 
x 
Haematology and biochemistry 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x5 
 
Urine analysis 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
Urine pregnancy test 
x (D-1) 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x (3 and 6 months only) 
 
Triplicate ECG 
 x (D-1) 
 
 
 
x 
D4 H4  
x    
D4 H23
 
 
 
 
 
x 
 
 
 
Administration of fexinidazole  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Blood sampling for PK analyses (specific patient groups) 
 
 
 
 
 
 
 
 
x 
H3.15 
x 
H3 
x H3 
H7.15 
x D10H24 
x 
D10H48 
 
 
Adverse event (AE) collection 
x (if considered related 
to study participation) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x (If reasonable possibility of 
relation to treatment) 
Serious adverse event (SAE) collection from signature of 
consent form to last study visit 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Collection of concomitant medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
1 At 3 months, only if indicated by patient’s clinical status. 
2 Treatment according to national guidelines. 
3 Temperature, blood pressure, heart rate and respiratory frequency. 
4 Only if indicated by patient’s clinical status. 
5 At 3 and 6 months. At 12 and 18 months only if indicated by patient’s clinical status. 
 


Protocol DNDi-FEX-09-HAT Version 3.0 
 
Fexinidazole  
 
Confidential  
Page 83 of 83 
Table 6 – Schedule of Events - Patients treated on an out-patient basis 
Protocol-planned procedures 
and forms to be completed 
Screening  
Dispensing 
Treatment period 
Follow-up period 
Timepoint   
D-15 to D-1 
D0 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 (EoT) 
3 – 6 – 12 – 18 months 
Rapid Diagnostic Test or CATT  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Detection of parasite in blood and/or lymph 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Informed consent (before any additional medicines or study-specific 
procedures) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lumbar puncture  
(parasite and white blood cells in CSF) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x1 
Pretreatment of helminthiasis2 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rapid Diagnostic Test and/or thick blood smear for diagnosis of malaria 
and, if necessary, treatment2 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Performance Status 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Inclusion and exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signs and symptoms of HAT 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Vital signs3 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Physical and neurological examinations 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Haematology and biochemistry 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
x4 
 
Urine analysis 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Urine pregnancy test 
x (D-1) 
 
 
 
 
 
 
 
 
 
 
 
x 
x (3 and 6 months only) 
 
Triplicate ECG 
x (D-1) 
 
 
 
 
 
 
 
 
 
 
 
x 
 
IMP dispensing / Discharge from hospital 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of fexinidazole  
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Blood sampling for PK analyses 
 
 
 
 
 
 
 
 
 
 
 
 
x D10H245 
 
Assessment of understanding of instructions for treatment (questionnaire) 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment compliance (interview) 
 
 
 
 
 
 
 
 
 
 
 
 
x  
 
Acceptability of packaging (questionnaire) 
 
 
 
 
 
 
 
 
 
 
 
 
x  
 
Adverse event (AE) collection 
x (if considered related 
to study participation) 
 
 
 
 
 
 
 
 
 
 
 
x (interview) 
x (If reasonable possibility of relation 
to treatment) 
Serious adverse event (SAE) collection from signature of consent form to 
last study visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of concomitant medication 
x 
 
 
 
 
 
 
 
 
 
 
 
x (interview) 
 
1 At 3 months, only if indicated by patient’s clinical status. 
2 Treatment according to national guidelines. 
3 Temperature, blood pressure, heart rate and respiratory frequency. 
4 Only if indicated by patient’s clinical status. 
5 Additional sampling for PK may be performed between Day 1 and Day 11 if the patient returns to the centre for an unscheduled visit 

SAP_001.pdf: 
Statistical Analysis Plan DNDi-FEX-09-HAT Version 3.0 
 
Fexinidazole  
 
Confidential  
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
An open-label study assessing effectiveness, safety 
and compliance with fexinidazole in patients 
with human African Trypanosomiasis due 
to T.b. gambiense at any stage 
 
 
 
 
 
 
Registration number 
NCT03025789 
 
 
 
Version 3.0 – 30 September 2022 
 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 1 / 37
 
 
 
DNDi‐FEX‐09‐HAT 
 
An open‐label study assessing effectiveness, safety and 
compliance with fexinidazole in patients with human 
African Trypanosomiasis due to T.b. gambiense at any 
stage 
 
STATISTICAL ANALYSIS PLAN 
 
Version 3.0 – 30/09/2022 
Written by RCTs 
 
 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 2 / 37
 
Table of contents 
TABLE OF CONTENTS ..................................................................................................................................... 2 
1. 
STATISTICAL ANALYSIS PLAN ‐ APPROVAL FORM ................................................................................... 4 
2. 
VERSION HISTORY ................................................................................................................................. 5 
3. 
ABBREVIATIONS .................................................................................................................................... 6 
4. 
PROTOCOL ............................................................................................................................................ 7 
5. 
ANALYSIS SETS AND SUBGROUPS .......................................................................................................... 7 
6. 
ENDPOINTS ........................................................................................................................................... 8 
6.1. 
PRIMARY ENDPOINT .................................................................................................................................... 8 
6.2. 
SECONDARY ENDPOINTS ............................................................................................................................... 8 
6.2.1. 
Intermediate endpoint at 12 months ............................................................................................ 8 
6.2.2. 
Compliance ................................................................................................................................... 8 
6.2.3. 
Feasibility ...................................................................................................................................... 9 
6.2.4. 
Packaging .................................................................................................................................... 10 
6.2.5. 
Pharmacokinetic (PK) .................................................................................................................. 10 
6.3. 
SAFETY ENDPOINTS ................................................................................................................................... 10 
6.3.1. 
Adverse events ............................................................................................................................ 11 
6.3.2. 
Laboratory examination.............................................................................................................. 11 
6.3.3. 
Electrocardiogram ...................................................................................................................... 11 
6.3.4. 
Other safety endpoints................................................................................................................ 11 
6.4. 
OTHER ENDPOINTS AND VARIABLES .............................................................................................................. 12 
6.4.1. 
Demographic and other baseline characteristics ........................................................................ 12 
6.4.2. 
Medical history ........................................................................................................................... 12 
6.4.3. 
Prior and concomitant therapies ................................................................................................ 12 
6.4.4. 
Extent of exposure ...................................................................................................................... 12 
7. 
DATA ANALYSIS CONSIDERATIONS ...................................................................................................... 13 
7.1. 
STATISTICAL SOFTWARE.............................................................................................................................. 13 
7.2. 
TYPE I ERROR ........................................................................................................................................... 13 
7.3. 
CENTRE EFFECT ........................................................................................................................................ 13 
7.4. 
DESCRIPTIVE ANALYSES OF QUANTITATIVE AND QUALITATIVE VARIABLES .............................................................. 13 
7.5. 
DEFINITION OF BASELINE, TIME‐WINDOWS AND ANALYSIS PERIODS ..................................................................... 13 
7.6. 
HANDLING OF MISSING DATA AND OUTLIERS .................................................................................................. 14 
8. 
PLANNED STATISTICAL ANALYSES ........................................................................................................ 16 
8.1. 
DISPOSITION OF PATIENTS .......................................................................................................................... 16 
8.2. 
PROTOCOL DEVIATIONS .............................................................................................................................. 17 
8.3. 
ANALYSIS SETS AND SUBGROUPS .................................................................................................................. 17 
8.4. 
DEMOGRAPHIC DATA AND BASELINE CHARACTERISTICS, INCLUDING MEDICAL HISTORY AND THERAPIES ....................... 17 
8.5. 
EXTENT OF EXPOSURE ................................................................................................................................ 17 
8.6. 
ANALYSIS OF THE PRIMARY ENDPOINT ........................................................................................................... 17 
8.7. 
ANALYSIS OF THE SECONDARY ENDPOINTS ...................................................................................................... 18 
8.7.1. 
Analysis of the endpoint at 12 months ....................................................................................... 18 
8.7.2. 
Analysis of failures ...................................................................................................................... 18 
8.7.3. 
Compliance ................................................................................................................................. 18 
8.7.4. 
Feasibility .................................................................................................................................... 19 
8.7.5. 
Packaging .................................................................................................................................... 19 
8.7.6. 
PK ................................................................................................................................................ 19 
8.8. 
SAFETY ANALYSIS ...................................................................................................................................... 19 
8.8.1. 
Secondary endpoints for assessment of safety ........................................................................... 19 
8.8.2. 
Adverse events ............................................................................................................................ 19 
8.8.3. 
Laboratory examination.............................................................................................................. 20 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 3 / 37
 
8.8.4. 
Electrocardiogram ...................................................................................................................... 20 
8.8.5. 
Other safety endpoints................................................................................................................ 20 
8.9. 
ANALYSIS OF OTHER ENDPOINTS AND VARIABLES ............................................................................................. 21 
8.9.1. 
Vital signs .................................................................................................................................... 21 
8.9.2. 
Clinical signs and symptoms of HAT ............................................................................................ 21 
8.9.3. 
Physical examination .................................................................................................................. 21 
8.9.4. 
Neurological examination ........................................................................................................... 21 
8.9.5. 
HAT diagnosis (i.e. examination of blood, lymph and CSF samples) ........................................... 21 
8.9.6. 
Pharmacokinetics ........................................................................................................................ 21 
8.9.7. 
Electrocardiogram ...................................................................................................................... 21 
8.10. 
INTERIM ANALYSES .................................................................................................................................... 21 
8.11. 
UNSCHEDULED VISIT .................................................................................................................................. 21 
8.12. 
DATA AND SAFETY MONITORING BOARD (DSMB) .......................................................................................... 21 
9. 
DISPLAY TEMPLATES ........................................................................................................................... 23 
9.1. 
LIST OF TABLES, FIGURES AND LISTINGS ........................................................................................................ 23 
9.2. 
DISPLAY TEMPLATES .................................................................................................................................. 27 
9.2.1. 
Disposition of patients ................................................................................................................ 27 
9.2.2. 
Protocol deviations ..................................................................................................................... 28 
9.2.3. 
Analysis datasets ........................................................................................................................ 29 
9.2.4. 
Continuous variable .................................................................................................................... 29 
9.2.5. 
Categorical variables................................................................................................................... 29 
9.2.6. 
Medical history ........................................................................................................................... 30 
9.2.7. 
Concomitant medication ............................................................................................................. 30 
9.2.8. 
Analysis of the primary endpoint ................................................................................................ 30 
9.2.9. 
Overall summary of adverse event ............................................................................................. 31 
9.2.10. 
Adverse event by SOC and PT ...................................................................................................... 31 
9.2.11. 
Shift table for laboratory parameters ......................................................................................... 32 
10. 
KEY DERIVED VARIABLES ................................................................................................................. 33 
10.1. 
OUTCOME AT 18 MONTHS ......................................................................................................................... 33 
10.2. 
OUTCOME AT 12 MONTHS ......................................................................................................................... 35 
11. 
CHANGES IN THE STATISTICAL METHODS FROM THOSE STATED IN THE PROTOCOL .......................... 37 
12. 
QUALITY CONTROL .......................................................................................................................... 37 
 
 
 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 4 / 37
 
1. 
STATISTICAL ANALYSIS PLAN ‐ APPROVAL FORM 
 
 
 
Function 
Name 
Signature 
Date 
Clinical Project 
Manager 
Caroline Menetrey 
 
 
HAT Clinical Program 
Team Leader 
Olaf Valverde 
 
 
 
 
 
 
 
 
 
Function 
Name 
Signature 
Date 
Head of Biostatistics 
M. Flavien ROUX 
 
 
 
 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 5 / 37
 
2. 
VERSION HISTORY 
Version 
Date 
Author 
Comment / changes 
0.1 
24/10/2016 
RCTs 
Initial draft version (based on protocol version 
1.0  dated  of  10/08/2016  and  CRF  version  1.0 
dated of 27/09/2016) 
0.2 
21/03/2017 
RCTs 
Add comments from DNDi 
0.3 
12/12/2017 
RCTs 
Add  comments  from  DNDi  and  B.  Scherrer
Version based on protocol version 2.0 dated of 
17/03/2017) 
0.4 
22/03/2018 
RCTs 
Add comments from DNDi and B. Scherrer 
1.0 
27/04/2018 
RCTs 
First approved and signed version 
2.0 
23/09/2022 
RCTs 
Second approved and signed version. 
Included changes as requested by DSMB on 03‐
AUG‐2022. 
3.0 
23/09/2022 
RCTs 
third approved and signed version. 
Included changes on algorithms. 
 
 
 
 
 
 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 6 / 37
 
3. 
ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
CATT 
Card Agglutination Test for Trypanosomiasis 
CI 
Confidence Interval 
CRF 
Case Report Form 
CSF 
Cerebrospinal Fluid 
D 
Day 
DNDi 
Drugs For Neglected Diseases Initiative 
DSMB 
Data And Safety Monitoring Board 
e.g. 
Exempli Gratia (For Example) 
ECG 
Electrocardiogram 
EoH 
End Of Hospitalisation 
EoT 
End Of Treatment 
g‐HAT 
Human African Trypanosomiasis due to T.B. Gambiense 
H 
Hour 
HAT 
Human African Trypanosomiasis 
i.e. 
Id Est (That is to say) 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
ITT 
Intention To Treat 
mAECT 
Mini‐Anion Exchange Column Test 
mAECT‐BC 
Mini‐Anion Exchange Column Test ‐ Buffy Coat 
MedDRA 
Medical Dictionary For Regulatory Affairs 
mITT 
Modified Intention To Treat 
PK 
Pharmacokinetic 
PP 
Per Protocol 
QT 
QT interval on ECG (time interval between electrical depolarisation and 
repolarisation of the left and right cardiac ventricles) 
RDT 
Rapid Diagnostic Test 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
T.b. 
Trypanosoma Brucei 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell Or White Blood Cell Count 
WHO 
World Health Organisation 
μL 
Microlitre 
 
 
 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 7 / 37
 
4. 
PROTOCOL 
The overall study design, plan description, study objectives, inclusion and exclusion criteria and sample 
size calculation are described in the Protocol version 2.0 dated of 17/03/2017. 
 
5. 
ANALYSIS SETS AND SUBGROUPS 
The analysis sets are the following. 
 Screened HAT positive patients: all HAT positive patients who signed the informed consent. 
 Intent‐to‐treat (ITT) population: all patients included in the study, regardless of whether or not 
they took the IMP (but the treatment unit was provided to the outpatient); 
 Modified  intent‐to‐treat  (mITT)  population:  all  patients  who  took  at  least  one  tablet  of 
fexinidazole; 
 Evaluable patients: patients included in the mITT and excluding: 
o Patients lost to follow‐up at 18 months (for primary efficacy endpoint and secondary efficacy 
outcome at 18 month), patients lost to follow‐up at 12 months (for secondary efficacy outcome 
at 12 month), except those who were a failure before being lost to follow‐up. 
o Patients with no post‐treatment lumbar puncture 
o Patients who died for reasons clearly unrelated to efficacy or safety or disease evolution (**). 
 Per protocol (PP): all patients who completed the study in accordance with the protocol with no 
major violations (cf. Section 8.2) that could interfere with the efficacy evaluation. An out‐patient 
who did not take any tablet of the IMP or with a compliance below 75% of the expected number of 
tablets is not per protocol unless it is due to lack of tolerance. Premature withdrawal from the study 
due to treatment inefficacy or intolerance will not be considered as a protocol violation.  
 
Two study cohorts are defined: 
 Inpatients: patients treated in hospital, 
 Outpatients: patients treated on an outpatient basis. Note that outpatients that would require 
hospitalization  (for  any  reason)  will  be  analyzed  according  to  their  initial  cohort  (i.e.  as 
“outpatients”). 
 
The following subgroups are defined according to the stage and severity of disease at inclusion: 
 Stage 1 
 Intermediate stage 
 Stage 1 + Intermediate stage 
 Stage 2 
 WBC in CSF ≤ 100 / µL 
 100 < WBC in CSF ≤ 400 / µL 
 WBC in CSF > 400 / µL 
For the analysis, these subgroups will be calculated as described in Table 1. Subgroups analyses are 
specified in Section 8. 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 8 / 37
 
Table 1 : Classification of patients according to stage/severity at inclusion 
Tryps in CSF 
WBC in CSF
≤ 5/µl 
[6‐20/µl] 
> 20/µl 
Tryps in CSF (positive) 
Stage 2 
Stage 2 
Stage 2 
No tryps in CSF 
(negative) 
Stage 1 
Intermediate stage 
Stage 2 
 
6. 
ENDPOINTS 
6.1. Primary endpoint 
The primary endpoint for the assessment of effectiveness will be the outcome (success or failure) at 
18 months after the end of treatment. Success is defined as a cure, according to the criteria adapted 
from the WHO. 
The  outcome  (success  or  failure)  at  18  months  will  be  calculated  using  the  algorithm  defined  in 
Section 10.1. 
6.2. Secondary endpoints 
6.2.1. Intermediate endpoint at 12 months 
The endpoint for an early assessment of effectiveness will be the outcome (success or failure) at 12 
months after the end of treatment. Success is defined as a cure, according to the criteria adapted from 
the WHO. 
The  outcome  (success  or  failure)  at  12  months  will  be  calculated  using  the  algorithm  defined  in 
Section 10.2. 
6.2.2. Compliance 
As defined in the protocol, the secondary endpoints for the assessment of compliance with treatment 
in patients treated on an outpatient basis will be: 
 Presence of  fexinidazole  and/or its  main metabolites in the blood sample collected on  Day 11 
and/or at any unscheduled visit between Day 1 and the end‐of‐treatment (EoT) visit (note: this 
endpoint will be analyzed by Phinc Development) 
 Patients who had tablets left over at the end of treatment (i.e. number of tablets returned on day 
11 > 0) (yes/no) 
 Number of tablets left over at the end of treatment (i.e. number of tablets returned on day 11) (0, 
1, 2, …) 
 Patients’ responses to the questionnaire at the compliance interview on Day 11: Questions 5, 5.1, 
5.2, 5.3 and 5.4. 
 
In addition, the following endpoints will be assessed on all patients (i.e. inpatients and outpatients): 
 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) 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 9 / 37
 
 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, …) 
 Overall compliance defined as: 
o For patients with body weight < 35 kg (Children): 
Compliance ሺ%ሻൌ
100 ൈActual dose taken ሺmgሻ
8 400 mg ሺi. e. 1200 mg ൈ 4 days ൅600 mg ൈ 6 daysሻ 
o For patients with body weight ≥ 35 kg (Children) or Adults: 
Compliance ሺ%ሻൌ
100 ൈActual dose taken ሺmgሻ
14 400 mg ሺi. e. 1800 mg ൈ 4 days ൅1200 mg ൈ 6 daysሻ 
Note for overall compliance:  
Actual dose taken (mg) = 600 mg X number of tablets taken 
Number of tablets taken = (sum of tablets taken from Day 1 to Day 11) + (sum of tablets taken for re‐
administration from D1 to D11) 
Patients with one day delayed treatment (missing dose compensated at the end of treatment) should 
be considered as treatment completers. In case of death during the treatment, compliance will be 
calculated according to theoretical dose expected until the death. 
6.2.3. Feasibility 
As  defined  in  the  protocol,  the  secondary  endpoints  for  assessment  of  the  feasibility  of  self‐
management  of  treatment  intake,  or  with  the  assistance  of  the  caregiver  under  recommended 
conditions are the following for patients treated on an outpatient basis: 
 Patients who temporarily discontinued their treatment (yes/no) 
 Patients  who  prematurely  (i.e.  prior  to  Day  10)  discontinued  their  treatment  (permanent 
interruption) (yes/no) 
 Patients who delayed starting treatment (i.e. date of D1 – date of D0 > 1 day) (yes/no) 
 Patients who mislaid treatment units (i.e. number of tablets left over>0) (yes/no) 
 Patients who were hospitalized during their treatment period 
 Patients with: 
o 1, 2, 3, …, 9, 10 days of treatment administration performed at the hospital. 
o 0 days (=treatment adminstration performed at home only). 
 Patients who took treatment regularly, according to the patients themselves (=questionnaire on 
Day 11: Question 5 “How did you take your treatment?”) (yes/no) 
 Patients  who  understood  the  instructions  concerning  the  dosing  regimen  of  fexinidazole 
(=questionnaire on Day 0: patients who correctly answered to the 8 questions) (yes/no) 
 Patients  who  complied  with  the  dosing  regimen,  including  intake  of  treatment  during  a  meal 
(=questionnaire on Day 11: patients who correctly answered to the 4 questions 5.1 to 5.4) (yes/no) 
In addition, the following data will be listed: 
 Reasons of temporary treatment discontinuation 
 Reasons of premature and permanent treatment discontinuation 
 Reasons of hospitalization during the treatment period 
 
The following data will also be described in patients treated in hospital: 
 Patients who temporarily discontinued their treatment (yes/no) 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 10 / 37
 
 Patients who prematurely discontinued their treatment (permanent interruption) (yes/no) 
The following data will also be listed in patients treated in hospital: 
 Reasons of temporary treatment discontinuation 
 Reasons of premature and permanent treatment discontinuation 
6.2.4. Packaging 
As defined in the protocol, the secondary endpoint for assessment of understanding and acceptability 
of the packaging by outpatients will be: 
 Questionnaire on Day 0 (patients and/or caregivers): 
o Questions 1 to 8, separately 
 Questionnaire on Day 11 (patients and/or caregivers): 
o Question 3: “Did you need help to take the treatment?” 
o Question 4: “Was the instruction manual (provided with the treatment) useful?” 
6.2.5. 
Pharmacokinetic (PK) 
As defined in the protocol, the secondary endpoint for the PK assessment will be: 
 PK parameters in whole blood, measured in all patients treated in hospital. 
Statistical analyses of the PK parameters will be performed by PhinC Development. These analyses will 
be defined in a separate statistical analysis plan, written by PhinC Development. 
6.3. Safety endpoints 
As defined in the protocol (Section 2.2.2), the secondary endpoints for the assessment of the safety of 
fexinidazole will be: 
 Occurrence  of  grade  ≥  3  adverse  events  (AEs),  including  laboratory  and  haematological 
abnormalities (if considered clinically significant), between the first intake of fexinidazole and the 
end of the observation period* or the follow‐up period (18 months) for non‐serious AEs assessed 
as related to fexinidazole. 
 Occurrence of any serious adverse event (SAE) between the first intake of fexinidazole and the end 
of the follow‐up period (18 months). 
 Number  of  patients  who  prematurely  discontinued  treatment  (i.e.  prior  to  Day  10)  or  were 
hospitalised for reasons related to safety** (e.g. including overdose). 
*  The  observation  period  extends  from  the  first  intake  of  fexinidazole  on  Day  1  until  the  end‐of 
hospitalisation visit (between Day 13 and Day 18) for patients treated in hospital. For outpatients, the 
observation period extends to the end‐of‐treatment visit on Day 11. 
** A patient will be considered as “hospitalised for reasons related to safety” if he/she experienced a 
SAE during the treatment period and he/she was initially planned to be treated as an outpatient and 
he/she was hospitalized during the treatment period. 
Clarifications: 
Only laboratory and haematological abnormalities reported as AEs by investigators (cf. Section 6.8.1 
of the protocol for further details) will be analyzed as AEs. 
Additional secondary safety endpoints are defined in this SAP (cf. sections 6.3.1, 6.3.2 and 6.3.4). 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 11 / 37
 
6.3.1. Adverse events 
The following AE categories will be studied: 
 Treatment‐emergent adverse events (TEAE) 
 TEAE leading to treatment discontinuation (i.e. permanent or temporary) 
 TEAE leading to permanent treatment discontinuation 
 Mild/moderate TEAE (grade 1, grade 2, mild or moderate) 
 Severe TEAE (grade 3, grade 4, grade 5 or severe) 
 Drug‐related TEAE 
 Serious TEAE 
 Serious TEAE leading to treatment discontinuation (i.e. permanent or temporary) 
 Serious TEAE leading to permanent treatment discontinuation 
 Serious drug‐related TEAE 
Definition of treatment‐emergent AEs: 
Treatment‐emergent AEs are defined as any AE which occurs on or after the date of the first study‐
drug administration until the end of the follow‐up visit (i.e. 18‐month visit). 
6.3.2. Laboratory examination 
All  laboratory  parameters  recorded  in  the  CRF  in  sections  “Hematology”,  “Biochemistry”  and 
“Urinalysis” will be used. For continuous data, the absolute change from baseline to each timepoints 
will be derived. In addition, continuous laboratory values will be compared to their reference ranges 
and classified as “<LLN”, “Normal” and “>ULN” at baseline and each timepoints. 
For the following parameters, CTCAE grades will be derived as defined in Appendix 6 of the protocol:  
 Hemoglobin 
 Platelets 
 Leukocytes 
 Sodium 
 Potassium 
 Calcium 
 Bicarbonates 
 Chloride 
 Glucose 
 BUN 
 Creatinine 
 Alkaline phosphatase 
 ALAT 
 ASAT 
 Total bilirubin 
 Albumin 
 Total protein 
6.3.3. Electrocardiogram 
Statistical analyses of ECG parameters will be performed by Cardiabase. These analyses will be defined 
in a separate statistical analysis plan, written by Cardiabase. 
6.3.4. Other safety endpoints 
 Number of patients who discontinued treatment for safety reason*, 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 12 / 37
 
 Number of patients who were hospitalized for reasons related to safety*, including overdose. 
* Reasons collected in the CRF comments will be classified by a medical review as “safety reason” or 
“other reason”. 
6.4. Other endpoints and variables 
6.4.1. Demographic and other baseline characteristics 
The following standard characteristics (gender, BMI, etc.) will be used as recorded in the CRF: 
 Demographic characteristics 
 Vital signs at baseline 
 Clinical signs and symptoms of HAT at baseline 
 Physical examination at baseline 
 Neurological examination at baseline 
 HAT diagnosis (i.e. examination of blood, lymph and CSF samples) 
The following data will be derived: 
 Age (years) will be used as collected in eCRF. If not available then it will be calculated as the exact 
duration in years between date of birth and date of informed consent 
 BMI classified according to the World Health Organization (WHO): 
o <18.5 – Underweight 
o 18.5 ‐ <25 – Normal weight 
o 25 ‐ <30 – Overweight 
o ≥30 – Obesity 
6.4.2. Medical history 
Medical  and  surgical  history  will  be  coded  using  MedDRA  dictionary  (last  available  version  at  the 
beginning of the coding). 
6.4.3. Prior and concomitant therapies 
Prior and concomitant therapies will be coded with WHO‐Drug Dictionary September 2013 C‐format. 
 Prior therapies are therapies which stopped before the first study drug administration. 
 Concomitant therapies are therapies which ended on or after the first study drug administration or 
are ongoing at the end of the trial. 
6.4.4. Extent of exposure 
Extent of exposure will be derived as follows: 
 Extent  of  exposure  (days)  =  Date  of  last  study  drug  administration  ‐  Date  of  first  study  drug 
administration + 1 
 
 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 13 / 37
 
7. 
DATA ANALYSIS CONSIDERATIONS 
7.1. Statistical software 
The statistical analysis will be performed using SAS® software v9.4 (or a later version). 
7.2. Type I error 
For all analyses, the type I error (α) is set to 0.05 two‐sided. 
7.3. Centre effect 
The primary analysis will not be stratified by centre because the weight of each centre in the overall 
population is unknown. Nevertheless, the results by centre for each cohort will be presented and a 
test of homogeneity (a likelihood‐ratio test) will be performed on the success rates. A centre effect is 
possible. In this case, an estimate of the overall success rate will also be provided, giving equal weight 
to  each  centre  rather  than  weighting  the  centres  based  on  the  number  of  treated  patients.  The 
estimate of the rate will be given by p = Wh ph where Wh is the weight of each centre, i.e. the inverse 
of the number (h) of centres (1/h). The variance of the estimator will be equal to Var(Ph) =  Wh2. ph(1‐
ph) / nh where nh is the number of patients in centre h. In addition, a Forest plot will be presented to 
assess whether the heterogeneity is quantitative (dispersion around a central value) or qualitative 
(presence of very atypical centres). 
7.4. Descriptive analyses of quantitative and qualitative variables 
Quantitative variables will be described by: N (number of patients with non‐missing data), missing 
(number of patients with missing data), mean, standard deviation (SD), minimum, maximum, median, 
first quartile (Q1) and third quartile (Q3).  
Categorical variables will  be described by frequency and percentage of patients in  each  category. 
Percentages will be expressed with one decimal place. The Clopper‐Pearson (exact) 95% confidence 
interval will be provided, if required in Section 8. 
7.5. Definition of baseline, time‐windows and analysis periods 
Baseline: 
Baseline  is  defined  by  data  collected  during  the  D‐15  to  D‐1  period  before  the  beginning  of  the 
treatment. 
Analysis periods: 
Study procedures will be performed in accordance with the following schedule: 
 
Between D‐15 to D‐1: screening and baseline assessment,  
 
D0: IMP dispensing visit prior to first intake of IMP (Patients on an outpatient basis only) 
 
D1 to D10: treatment period,  
 
D11: End of Treatment (EoT) visit 
 
Between D13 to D18 : End of Hospitalization (EoH) visit (Patients treated in hospital only) 
Follow‐up visits for all patients will be performed at 3 months, 6 months, 12 months and 18 months.  
Time‐windows: 
The timing of follow‐up visits is calculated from the first day of treatment (D1). 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 14 / 37
 
The table below defines the theoretical schedule of follow‐up visits and the acceptable Leeway: 
Type of visit 
Schedule of visit and ideal timing 
of visits 
Acceptable Leeway* 
End‐of‐hospitalisation (EoH) visit, 
only for patients treated in 
hospital 
Between D13 and D18 after D1 
D18 at the latest 
3 months 
3 months ± 1 week after D1 
2 to 4 months, i.e. 60 to 
149 days, after Day 1 
6 months 
6 months ± 1 weeks after D1 
5 to 9 months, i.e. 150 to 
299 days, after Day 1 
12 months 
12 months ± 4 weeks after D1 
10 to 16 months, i.e. 300 
to 509 days, after Day 1 
18 months 
18 months ± 4 weeks after D1 
17 to 21 months, i.e. 510 
to 659 days, after Day 1 
* The acceptable leeway for the visit starts on the first day of the period mentioned and ends on the 
last day of the period mentioned. 
Any additional unscheduled visits that may take place must be recorded in the CRF. Real timing of 
unscheduled visits will be calculated and they will be analysed in the corresponding time‐window (see 
table above). 
7.6. Handling of missing data and outliers 
Handling of missing data for primary and secondary efficacy endpoints: 
Handling of missing data is described in Section 9.8 of the Protocol and is included in the derivation 
algorithms for outcome at 18 and 12 months (cf. Section 10). 
Handling of missing AE attributes:  
Missing relationship, missing seriousness, and/or missing severity will not be replaced and will be 
analysed as such. 
Onset date of AE will be imputed as below. The general rule in the absence of information is to retain 
a conservative imputation. 
Onset date of AE 
Imputed AE onset date 
Completely missing 
For AEs collected in the “Screening” form: Date of informed consent 
For  AEs  collected  in  the  “Follow‐up”  forms:  Date  of  first  study  drug 
administration 
Day is missing 
First day of the month. 
For AEs collected in the “Screening” form:  
If imputed date is prior to date of informed consent, then replace with date 
of informed consent. 
For AEs collected in the “Follow‐up” forms: 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 15 / 37
 
Onset date of AE 
Imputed AE onset date 
If imputed date is prior to date of first study drug administration, then 
replace with date of first study drug administration. 
Day  and  month  are 
missing 
First of January. 
For AEs collected in the “Screening” form:  
If imputed date is prior to date of informed consent, then replace with date 
of informed consent. 
For AEs collected in the “Follow‐up” forms: 
If imputed date is prior to first study drug administration, then replace with 
date of first study drug administration. 
Note: partially or completely missing end dates of AE will not be imputed. 
 
Handling of missing stop dates of prior and concomitant therapies: 
For therapies marked as “ongoing”: the stop date will not be imputed. 
For therapies marked as “not ongoing”, the stop date will be imputed as below. 
Stop date of therapy 
Imputed stop date 
Completely missing 
No  imputation.  The  therapy  will  be  considered  as  “ongoing”  for  the 
analysis. 
Day is missing 
Last day of the month. 
For therapy collected in the “Screening” form: if imputed date is later than 
the  end  of  hospitalisation  visit  date,  then  replace  with  the  end  of 
hospitalisation visit date. 
For therapy collected in the “Follow‐up” form: if imputed date is later than 
the date of last contact, then replace with the date of last contact. 
Day  and  month  are 
missing 
31 December 
For therapy collected in the “Screening” form: if imputed date is later than 
the  end  of  hospitalisation  visit  date,  then  replace  with  the  end  of 
hospitalisation visit date. 
For therapy collected in the “Follow‐up” form: if imputed date is later than 
the date of last contact, then replace with the date of last contact. 
Note: partially or completely missing start dates of therapies will not be imputed. 
 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 16 / 37
 
8. 
PLANNED STATISTICAL ANALYSES 
8.1. Disposition of patients 
Disposition  of  patients  and  reasons  for  premature  discontinuations  will  be  tabulated  overall,  by 
cohorts (i.e. “inpatients” and “outpatients”) and in each subgroups defined in Section 5 (i.e. “Stage 1”, 
“Intermediate stage”, “Stage 1 + intermediate stage” and “Stage 2”): 
 Number of screened HAT positive patients (i.e. patients who gave informed consent) 
 Amongst screened HAT positive patients: 
o Number  and  percentage  of  patients  who  attended  the  dispensation  visit  (i.e.  Day  0),  for 
“inpatients” 
o Number and percentage of patients who attended visit “Day 1”, for “outpatients” 
 Number of patients included (i.e. which meets all the criteria for inclusion and has no exclusion 
criteria) 
 Number of patients treated (i.er. who received at least one tablet of fexinidazole) 
 Amongst treated patients: 
o Number and percentage of patients who withdrew from the study prematurely, listed by reason 
for withdrawal 
o Number and percentage of patients who completed the trial according to the protocol 
 The following data will also be provided amongst treated patients: 
o Number and percentage of patients who received all of the protocol‐planned doses (=treatment 
completers) 
o Number and percentage of patients who died for reasons clearly unrelated to the IP or HAT 
o Number and percentage of patients who had at least one minor protocol violation 
o Number and percentage of patients who had at least one major protocol violation 
o Number  and  percentage  of  patients  who  underwent  lumbar  puncture  at  the  end‐of‐
hospitalisation, at the 3‐month visit, at the 6‐month visit, the 12‐month visit and the 18‐month 
o Number and percentage of patients who attended visits “Day 1” to “Day 10” (for inpatients 
only),  the  end‐of‐treatment  (EoT)  visit,  the  end‐of‐hospitalisation  (EoH)  visit  (for  inpatients 
only), the 3‐month, 6‐month, 12‐month and 18‐month visits. 
In addition the following data will be provided: 
 Date of first patient screened 
 Date of first administration of the first patient 
 Date of first administration of the last patient 
 Date of last patient last visit (i.e. last visit performed) 
 Study duration (days) = date of last patient last visit ‐ date of first administration of the first patient 
 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 17 / 37
 
8.2. Protocol deviations 
Minor and major protocol violations will be described separately, by cohort, by subgroups and overall 
on the mITT. 
Protocol violations will be listed and finalised prior to the data review meeting. The sponsor will be 
responsible for classifying all violations as either major or minor. Patients with at least one major 
protocol violation will be excluded from the PP set. A specific data review plan will provide a more 
detailed  description  on  deviation  review.  All  decision  taken  by  the  data  review  members  will  be 
reported in the Data review document. 
8.3. Analysis sets and subgroups 
Frequency  and  percentage  of  patients  included  in  each  analysis  sets  defined  in  Section 5  will  be 
provided by cohorts, subgroups and overall. 
8.4. Demographic data and baseline characteristics, including medical 
history and therapies 
Descriptive analyses will be provided by cohorts, subgroups and overall on the mITT. 
Number and percentage of patients included in each subgroups defined in Section 5 will be provided 
by cohorts and overall on the mITT. 
Medical and surgical history will be analyzed by MedDRA SOC and PT. Medical and surgical history will 
be tabulated with number of history, number and percentage of patients with at least one history 
classified by SOC and PT. 
Prior therapies and concomitant treatments will be tabulated with number of treatments, number and 
percentage of patients with at least one treatment classified by therapeutic class (ATC2) and preferred 
name. 
8.5. Extent of exposure 
Descriptive analyses will be provided by cohorts, subgroups and overall on the mITT. 
The same analyses will be provided according to expected dose: 
 Adult patients and children with body weight equal to or above 35 kg (i.e. who should took 24 
tablets) 
 Children with body weight of at least 20 kg and below 35 kg (i.e. who should took 12 tablets) 
8.6. Analysis of the primary endpoint 
Primary analysis 
A descriptive analysis of the primary efficacy endpoint with the 95% exact Clopper‐Pearson confidence 
intervals will be provided on the mITT (overall). 
Sensitivity analysis 
A descriptive analysis of the primary efficacy endpoint with the 95% exact Clopper‐Pearson confidence 
intervals will be provided on the Evaluable patients set and PP set (overall). 
Secondary analysis 
A descriptive analysis of the primary efficacy endpoint with the 95% exact Clopper‐Pearson confidence 
intervals will be provided by cohorts and by subgroups on the mITT. 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 18 / 37
 
8.7. Analysis of the secondary endpoints 
8.7.1. Analysis of the endpoint at 12 months 
The  endpoint  at  12  months  will  be  analysed  as  described  for  the  primary  endpoint  (see  above 
Section 8.6: “primary”, “sensitivity” and “secondary” analyses). 
8.7.2. Analysis of failures 
Analysis of failures will be provided on the mITT (overall). 
Description: 
A listing of failures will provide for each failure: 
 The time to failure (since the first treatment administration) 
 Signs of failure observed: WBC in CSF >20/µL, death (cause if known), presence of trypanosomes in 
blood or lymph, rescue medication and LTFU 
 Number of WBC in CSF at inclusion 
 WBC in CSF at inclusion classified as follows: ≤ 100, 100‐400 and > 400/µL 
 Presence of trypanosomes in CSF 
 Presence of the following symptoms at inclusion: sleepiness, prurit, tremor, asthenia and headache 
 Number of tablets left over at the end of treatment. 
Statistical modeling: logistic regression 
 Model 1: the failure rate will be related to the loge of the number of WBC in CSF (/µL) at inclusion. 
 Model 2: the failure rate will be related to the compliance (number of tablets left over at the end 
of treatment) 
 Model 3: the failure rate will be related to the score equal to the sum of weighted symptoms at 
inclusion (5 points if sleepiness observed at entry, 4 points for prurit, 3 points for tremor, 2 points 
for asthenia and 1 point for headache).  
 Model 4: the failure rate will be related to the presence of a symptom score of 12 or more (see 
model 3). 
8.7.3. Compliance 
Descriptive  analyses  will  be  provided  on  outpatients  from  the  ITT  population  for  the  following 
endpoints: 
 Presence of  fexinidazole  and/or its  main metabolites in the blood sample collected on  Day 11 
and/or at any unscheduled visit between Day 1 and the end‐of‐treatment (EoT) visit (note: this 
endpoint will be analyzed by Phinc Development) 
 Patients who had tablets left over at the end of treatment (i.e. number of tablets returned on day 
11 > 0) (yes/no) 
 Number of tablets left over at the end of treatment (i.e. number of tablets returned on day 11) (0, 
1, 2, …) 
 Patients’ responses to the questionnaire at the compliance interview on Day 11: Questions 5, 5.1, 
5.2, 5.3 and 5.4. 
 
Descriptive  analyses  of  other  endpoints  listed  in  Section 6.2.2  will  be  provided  by  cohorts,  by 
subgroups and overall on the ITT. 
Patients for whom the number of tablets taken is different from 24 (14 for children <35 kg) or number 
of treatment day is different from 10 or number of tablets remaining is different from 0 or number of 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 19 / 37
 
re‐administered  tablets  is  different  from  0  or  had  treatment  discontinuation  (permanent  or 
temporary) will be listed with all the information concerning their treatment. 
The following analysis defined in Section 9.6.2 of the protocol will be provided by Phinc Development: 
“the number and percentage of patients in whom the presence of fexinidazole or its main metabolites 
was detected in the blood sample collected on D11 will be presented, as well as the success rate in this 
sub‐group of patients and in the subgroup of patients in whom no trace of fexinidazole or its main 
metabolites was detected. The distribution of the frequency of the number of tablets remaining at the 
end of the treatment period will be presented, and the relationship between the success rate and the 
number of tablets remaining will be determined using a logistic regression or a sub‐group analysis. The 
distribution  of  the  frequencies  of  responses  from patients  during  the  compliance  interview  will  be 
presented. The information provided by the PK analyses, the number of tablets remaining and the 
questionnaire will be combined to define perfect compliance and noncompliance. Perfect compliance 
corresponds to a patient in whom fexinidazole is detected in the blood, who has no remaining tablets 
and whose report on full compliance with treatment seems unquestionable. The success rate in patients 
with perfect compliance will be compared to that in non‐compliant patients”. 
8.7.4. Feasibility 
The secondary analyses concerning the feasibility of patient self‐management of treatment intake 
under  recommended  conditions  will  be  performed  on  outpatients  from  the  ITT  population.  The 
endpoints analysed will be those defined in Section 6.2.3. For each of the endpoints, the proportion of 
patients will be presented with the 95% CI. 
8.7.5. Packaging 
Descriptive results of the questionnaires completed at D0 and D11 by the patients and/or caregivers 
will be presented on an outpatient and/or caregivers basis (sub‐group of outpatients from the ITT 
population). 
8.7.6. PK 
The statistical analysis of the pharmacokinetic data will be performed by Phinc Development and is not 
covered in the current statistical analysis plan. A separate statistical analysis plan will be prepared by 
PhinC Development for these analyses. Cf. protocol, Section 9.6.5 for further details. 
8.8. Safety analysis 
Safety analyses will be performed on the mITT. 
8.8.1. Secondary endpoints for assessment of safety 
Analysis  of  “occurrence  of  grade  ≥  3  AEs”  and  “occurrence  of  any  SAE”  is  described  below  in 
Section 8.8.2. 
A descriptive analysis will be provided by cohorts, subgroups and overall for the following endpoint: 
“number of patients who discontinued treatment or were hospitalized for reasons related to safety, 
including overdose”. 
8.8.2. Adverse events 
Analysis of adverse events will be based on the concept of treatment‐emergent adverse events (TEAE) 
(cf. definition in Section 6.3.1). 
An overall summary of TEAEs occurring during the 18 months follow‐up period (i.e. from first drug 
intake up‐to end of follow‐up) will be presented by cohorts, subgroups and overall. The following 
information will be tabulated (the number, percentage of patient and 95% CI): 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 20 / 37
 
 At least one TEAE 
 At least one TEAE leading to treatment discontinuation (i.e. permanent or temporary) 
 At least one TEAE leading to permanent treatment discontinuation 
 At least one mild/moderate TEAE (grade 1, grade 2, mild or moderate) 
 At least one severe TEAE (grade 3, grade 4, grade 5 or severe) 
 At least one drug‐related TEAE 
 At least one serious TEAE 
 At least one serious TEAE leading to treatment discontinuation (i.e. permanent or temporary) 
 At least one serious TEAE leading to permanent treatment discontinuation 
 At least one serious drug‐related TEAE 
For the following descriptions the number and percentage of patients and also the number of 
occurrences of TEAE will be presented by cohorts, subgroups and overall, and by MedDRA SOC and 
PT: 
 TEAE 
 Drug‐related TEAE 
 Serious TEAE 
 Serious drug‐related TEAE 
All  AEs  and  SAEs  will  be  listed.  In  addition,  TEAE  leading  to  permanent  or  temporary  treatment 
discontinuation and Drug‐related TEAE which occurred during the treatment period (i.e. between the 
first  study‐drug  intake  (included)  and  the  last  study‐drug  intake  (included))  will  be  listed  (cf. 
Section 9.1). 
8.8.3. Laboratory examination 
For continuous data, a descriptive analysis will be provided for baseline, at each time point and for the 
changes from baseline at each time point, by cohorts, subgroups and overall. 
Changes in blood levels over time will be presented in graphs. 
Shift tables between baseline severity (normal value, abnormal not clinically significant, abnormal 
clinically  significant)  and  severity  at  each  timepoint  (i.e.  D5,  D11,  M3,  M6,  M12,  M18)  for  each 
laboratory parameters will be provided by cohorts, subgroups and overall. 
Scattergrams between baseline value and value at each timepoint (i.e. D5, D11, M3, M6, M12, M18), 
for each laboratory parameters will be provided by cohorts, subgroups and overall. 
Proportions of patients by category corresponding to the size of the increase in relation to the ULN for 
liver function tests (i.e. ALT, AST, total bilirubin and alkaline phosphatase) will be described (< 1 ULN, 
1–2 ULN, 2–3 ULN etc.) by cohorts, subgroups and overall. 
A listing of patients with clinically significant abnormalities in laboratory parameters will be provided 
(cf. Section 9.1). 
8.8.4. Electrocardiogram 
The statistical analysis of ECG data will be performed by Cardiabase and is not covered in the current 
statistical analysis plan. A separate statistical analysis plan will be prepared by Cardiabase for these 
analyses. 
8.8.5. Other safety endpoints 
Descriptive analyses will be provided by cohorts, subgroups and overall on the mITT. 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 21 / 37
 
8.9. Analysis of other endpoints and variables 
Analyses of other endpoints will be performed on the mITT. Results will be displayed by cohorts, 
subgroups and overall. 
8.9.1. Vital signs 
Descriptive statistics will be provided by visit.  
8.9.2. Clinical signs and symptoms of HAT 
Descriptive statistics will be provided by visit.  
8.9.3. Physical examination 
Descriptive statistics will be provided by visit.  
8.9.4. Neurological examination 
Descriptive statistics will be provided by visit.  
8.9.5. HAT diagnosis (i.e. examination of blood, lymph and CSF samples) 
Descriptive statistics will be provided by visit.  
8.9.6. Pharmacokinetics 
The statistical analysis will be performed by Phinc Development and will be described in a separate 
statistical analysis plan. 
8.9.7. Electrocardiogram 
The statistical analysis will be performed by Cardiabase and will be described in a separate statistical 
analysis plan. 
8.10. Interim analyses 
No interim analysis is planned. This a change from the analysis planned in the protocol (cf. Section 11 
for further details). 
8.11. Unscheduled visit 
During the data review, any efficacy and safety data from unscheduled visit which must be taken into 
account in the analysis will be identified. 
Other data from unscheduled visits will only be tabulated in listings except for time to event analyses 
where they will be taken into account. 
8.12. Data and Safety Monitoring Board (DSMB) 
A DSMB, composed of at least 3 members independent of the Investigators and the Sponsor, will be 
set up prior to the start of the study. The DSMB will monitor the study in order to minimize any risk of 
harm to the patients included in the study.  
At each of its meetings, the DSMB will examine safety data and all information related to SAEs, and 
will issue recommendations regarding the study if the benefit‐to‐risk ratio for patients seems to be in 
jeopardy. The data and the intervals for review will be decided before, or shortly after the start of the 
study and will be recorded in the DSMB Charter. 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 22 / 37
 
The organization of the DSMB will be described in the DSMB Charter, which will be prepared and 
approved prior to the first planned futility analysis. 
Additional ad hoc members may be invited to join the DSMB if any safety concerns emerge, in order 
to give additional support to the competencies already present. 
 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 23 / 37
 
9. 
DISPLAY TEMPLATES  
9.1. List of Tables, Figures and Listings 
1. TRIAL PATIENTS: 
1.1 Disposition of patients 
Statistical Table 1.1.1: Disposition of patients 
1.2 Important protocol deviations 
Statistical Table 1.2.1: Protocol deviations (ITT) 
1.3 Analysis sets 
Statistical Table 1.3.1: Analysis datasets 
1.4 Demographic data and baseline characteristics 
Statistical Table 1.4.1: Demographic data (mITT) 
Statistical Table 1.4.2: Vital signs at baseline (mITT) 
Statistical Table 1.4.3: Clinical signs and symptoms of HAT at baseline (mITT) 
Statistical Table 1.4.4: Physical examination at baseline (mITT) 
Statistical Table 1.4.5: Neurological examination at baseline (mITT) 
Statistical Table 1.4.6: HAT diagnosis (examination of blood, lymph and CSF samples) at screening 
(mITT) 
1.5 Medical history 
Statistical Table 1.5.1: Medical history (mITT) 
1.6 Prior and concomitant therapies 
Statistical Table 1.6.1: Prior therapies (mITT) 
Statistical Table 1.6.2: Concomitant treatments (mITT) 
1.7 Extent of exposure  
Statistical Table 1.7.1: Extent of exposure (mITT) 
 
2. Primary and secondary endpoints 
2.1 Primary efficacy endpoint 
2.1.1 Primary analysis 
Statistical Table 2.1.1.1: Success rate at 18 months (mITT ‐ overall) 
2.1.2 Sensitivity analyses 
Statistical Table 2.1.2.1: Success rate at 18 months (PP ‐ overall) 
Statistical Table 2.1.2.2: Success rate at 18 months (Evaluable set ‐ overall) 
2.1.3 Secondary analyses 
Statistical Table 2.1.3.1: Success rate at 18 months by cohorts and subgroups (mITT) 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 24 / 37
 
2.2 Secondary endpoints 
2.2.1 Endpoint at 12 months 
Same outputs as in Section 2.1. 
2.2.2 Analysis of failures 
Statistical Table 2.2.2.1: Logistic regression: Model 1 – all patients (mITT) 
Statistical Table 2.2.2.2: Logistic regression: Model 2 – all patients (mITT) 
Statistical Table 2.2.2.3: Logistic regression: Model 3 – all patients (mITT) 
Statistical Table 2.2.2.4: Logistic regression: Model 4 – all patients (mITT) 
Statistical Table 2.2.2.5: Logistic regression: Model 5 – all patients (mITT) 
 
2.2.3 Compliance 
Statistical Table 2.2.3.1: Compliance – outpatients (ITT) 
Statistical Table 2.2.3.2: Compliance – all patients (ITT) 
2.2.4 Feasibility 
Statistical Table 2.2.4.1: Feasibility – outpatients (ITT) 
2.2.5 Packaging 
Statistical Table 2.2.5.1: Packaging – outpatients (ITT) 
 
3. Safety 
3.1 Adverse events 
Statistical Table 3.1.1: Overall summary of AEs (mITT) 
Statistical Table 3.1.2: TEAE by SOC and PT (mITT) 
Statistical Table 3.1.4: Drug‐related TEAE by SOC and PT (mITT) 
Statistical Table 3.1.5: Serious TEAE by SOC and PT (mITT) 
Statistical Table 3.1.7: Serious drug‐related TEAE by SOC and PT (mITT) 
 
3.2 Laboratory examinations 
3.2.1 Haematology: 
Statistical Table 3.2.1.1: Descriptive analysis of haematology  parameters at baseline, at each time 
points and changes from baseline at each time points (mITT) 
Statistical Figure 3.2.1.2: Changes over time of each haematology parameters (mITT) 
Statistical  Table  3.2.1.3:  Shift  tables  between  baseline  and  each  time  points  of  haematology 
parameters’ severity (mITT) 
Statistical  Table  3.2.1.4:  Shift  tables  of  CTCAE  grades  between  baseline  and  each  time  points  of 
haematology parameters (mITT) 
Statistical Figure 3.2.1.5: Scattergrams between baseline value and value at each time points of each 
haematology parameters (mITT) 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 25 / 37
 
 
3.2.2 Biochemistry: 
Same outputs as above (except Figure 3.2.1.2). 
Statistical Table 3.2.1.6: Liver function tests (mITT) 
 
3.2.3 Urinalysis: 
Statistical Table 3.2.3.1: Shift tables between baseline and each time points of urinalysis parameters 
(mITT) 
 
4. Other endpoints 
Statistical Table 4.1: Descriptive analysis of vital signs by visit (mITT)  
Statistical Table 4.2: Descriptive analysis of clinical signs and symptoms of HAT by visit (mITT) 
Statistical Table 4.3: Descriptive analysis of physical examination by visit (mITT)  
Statistical Table 4.4: Descriptive analysis of neurological examination by visit (mITT)  
Statistical  Table  4.5:  Descriptive  analysis  of  HAT  diagnosis  (examination  of  blood,  lymph  and  CSF 
samples) by visit (mITT)  
 
5. Individual data listings: 
The following listings will be included in the clinical study report. They will include all patients included 
in the study and all visit information will be presented chronologically (including unscheduled visits). 
5.1 Discontinued patients 
 Disposition of patients – all patients 
 Study discontinuation – all patients 
5.2 Protocol deviations 
 Informed consent 
 Inclusion/Exclusion criteria 
 Eligibility 
 Protocol deviation 
5.3 Patients excluded from the efficacy analysis 
 Patients excluded from ITT 
 Patients excluded from Treated set 
 Patients excluded from PPS 
5.4 Demographic data 
 Patients characteristics 
 Diagnosis‐parasite in blood and/or lymph 
 Lumbar puncture (parasite and WBC) 
5.5 Medical history, prior and concomitant therapies 
 Medical history  
 Pre‐treatment of helminthiasis 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 26 / 37
 
 Pre‐treatment of malaria 
 Prior medications  
 Concomitant treatments 
5.6 Compliance and/or drug concentration data 
 Treatment administration 
 Compliance 
5.7 Individual efficacy response data 
 Diagnosis‐parasite in blood and/or lymph 
 Lumbar puncture (parasite and WBC in CSF) 
 Efficacy outcomes at 18 and 12 months 
 Listing of failures 
5.8 Adverse event listings 
 All Adverse Events 
 Serious Adverse Events 
 TEAE leading to permanent or temporary treatment discontinuation 
 Drug‐related TEAE which occurred during the treatment period 
5.9 Individual laboratory measurements 
 Haematology 
 Biochemistry 
 Thyroid function 
 Patients with clinically significant abnormalities in laboratory parameters 
5.10 Other endpoints  
 Vital Signs 
 Clinical signs and symptoms of HAT  
 Physical examination 
 Neurological examination 
 HAT diagnosis (examination of blood, lymph and CSF samples) 
 
 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 27 / 37
 
9.2. Display templates 
The display templates in this section are designed for 4 groups. They will be adapted to display 2 groups 
or 3 groups, when specified in Section 8. 
9.2.1. Disposition of patients 
Disposition of patients 
Inpatients
(N=XX) 
Outpatients
(N=XX) 
Stage 1 and 
Intermediate
(N=XX) 
Stage 2 
(N=XX) 
Total 
(N=XX) 
Screened positive (=informed consent signed) 
xxx 
xxx 
xxx 
xxx 
xxx 
  - Visit Day 0 (for outpatients) or Day 1 
(for inpatients) performed? 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Included (=all in/ex criteria respected) 
xxx 
xxx 
xxx 
xxx 
xxx 
Treated 
xxx 
xxx 
xxx 
xxx 
xxx 
  - Study completed according to protocol 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  - Premature withdrawal: 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    - Death 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    - Lost to follow-up 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    - Withdrawal of consent 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    - Investigator's decision 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    - Adverse event (AE) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    - Rescue treat. prescribed < D11 (1) 
NA 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    - Rescue treat. due to relapse 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    - Other reason 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
  - Treatment completers (2) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  - Death not related to the IP or HAT 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  - Minor PV 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  - Major PV 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  - Lumbar puncture performed at EoH 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  - Lumbar puncture performed at M3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  - (…) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  - Attended visit D1 
xx (xx.x%) 
NA 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  - Attended visit (…) 
(…) 
NA 
(…) 
(…) 
(…) 
  - Attended visit D10 
xx (xx.x%) 
NA 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  - Attended visit EoT 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  - Attended visit EoH 
xx (xx.x%) 
NA 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  - (…) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  - Attended visit M18 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
First patient screened 
 
 
 
 
dd-mmm-yy 
First study-drug admin. of the first patient 
 
 
 
 
dd-mmm-yy 
First study-drug admin. of the last patient 
 
 
 
 
dd-mmm-yy 
Last patient last visit 
 
 
 
 
dd-mmm-yy 
Study duration (days) 
 
 
 
 
xxx 
(1) Rescue treatment prescribed for outpatients before Day 11. 
(2) Patients who received all of the protocol‐planned doses. 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 28 / 37 
 
9.2.2. Protocol deviations 
Protocol Deviations 
Inpatients 
(N=XX) 
Outpatients 
(N=XX) 
Stage 1 and Intermediate
(N=XXX) 
Stage 2 
(N=XXX) 
Total 
(N=XXX) 
 
 
n Patients nDeviations
nPatients nDeviations
nPatients nDeviations
nPatients nDeviations
nPatients nDeviations
Major protocol 
deviation 
Yes 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
Type of major 
protocol deviation 
Type 1 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
 
Type 2 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
 
Type … 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
 
Type n 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
Minor protocol 
deviation 
Yes 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
Type of minor 
protocol deviation 
Type 1 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
 
Type 2 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
 
Type … 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
 
Type n 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
n (xx.x%) 
xx 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 29 / 37
 
9.2.3. Analysis datasets 
Analysis datasets 
Inpatients
(N=XX) 
Outpatients
(N=XX) 
Stage 1 and 
Intermediate
(N=XX) 
Stage 2 
(N=XX) 
Total 
(N=XX) 
Screened positive set - N (%) 
 
 
 
 
 
  Missing 
xxx 
xxx 
xxx 
xxx 
xxx 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Total 
xxx 
xxx 
xxx 
xxx 
xxx 
ITT set - N (%) 
 
 
 
 
 
  Missing 
xxx 
xxx 
xxx 
xxx 
xxx 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Total 
xxx 
xxx 
xxx 
xxx 
xxx 
mITT set - N (%) 
 
 
 
 
 
  Missing 
xxx 
xxx 
xxx 
xxx 
xxx 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Total 
xxx 
xxx 
xxx 
xxx 
xxx 
Evaluable set - N (%) 
 
 
 
 
 
  Missing 
xxx 
xxx 
xxx 
xxx 
xxx 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Total 
xxx 
xxx 
xxx 
xxx 
xxx 
PP set - N (%) 
 
 
 
 
 
  Missing 
xxx 
xxx 
xxx 
xxx 
xxx 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Total 
xxx 
xxx 
xxx 
xxx 
xxx 
 
9.2.4. Continuous variable 
Quantitative variable 
Inpatients 
(N=XX) 
Outpatients 
(N=XX) 
Stage 1 or 
intermediate
(N=XX) 
Stage 2 
(N=XX) 
Total 
(N=XX) 
Missing 
x
x
x
x 
x
N 
xx
xx
xx
xx 
xx
Mean (±SD) 
x.x (±x.x)
x.x (±x.x)
x.x (±x.x)
x.x (±x.x) 
x.x (±x.x)
Median 
x.x
x.x
x.x
x.x 
x.x
Q1-Q3 
[x.x;x.x]
[x.x;x.x]
[x.x;x.x]
[x.x;x.x] 
[x.x;x.x]
Min-Max 
[x.x;x.x]
[x.x;x.x]
[x.x;x.x]
[x.x;x.x] 
[x.x;x.x]
 
9.2.5. Categorical variables 
Categorical variable 
Inpatients 
(N=XX) 
Outpatients 
(N=XX) 
Stage 1 or 
intermediate
(N=XX) 
Stage 2 
(N=XX) 
Total 
(N=XX) 
Categorical variable - N (%) 
 
Missing 
x
x
x
x 
x
Class 1 
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%) 
xx (xx.x%)
Class 2 
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%) 
xx (xx.x%)


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 30 / 37
 
Class (…) 
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%) 
xx (xx.x%)
Total 
xx
xx
xx
xx 
xx
 
9.2.6. Medical history  
 
Inpatients 
(N=XX) 
Outpatients 
(N=XX) 
Stage 1 or 
intermediate
(N=XX) 
Stage 2 
(N=XX) 
Total 
(N=XX) 
System Organ Class / 
Preferred Term 
Nb 
MH 
Nb 
pat 
% 
pat 
Nb
MH 
Nb
pat 
% 
pat 
Nb
MH 
Nb
pat 
% 
pat 
Nb
MH 
Nb
pat 
% 
pat 
Nb 
MH 
Nb 
pat 
%
pat 
At least 1 MH 
XX 
XX XX.X
XX
XX
XX.X
XX
XX
XX.X
XX
XX
XX.X 
XX 
XX XX.X
System Organ Class 1 
X 
X XX.X
XX
XX
XX.X
XX
XX
XX.X
XX
XX
XX.X 
XX 
XX XX.X
  - Preferred Term 1 
X 
X 
X.X
X
X
XX.X
X
X
XX.X
X
X
XX.X 
X 
X XX.X
  - Preferred Term 2 
X 
X XX.X
X
X
XX.X
X
X
XX.X
X
X
XX.X 
X 
X XX.X
  - Preferred Term 3 
X 
X 
X.X
X
X
XX.X
X
X
X.X
X
X
X.X 
X 
X 
X.X
System Organ Class 2 
X 
X XX.X
X
X
XX.X
XX
XX
XX.X
XX
XX
XX.X 
XX 
XX XX.X
  - Preferred Term 1 
X 
X 
X.X
X
X
X.X
X
X
X.X
X
X
X.X 
X 
X 
X.X
  - Preferred Term 2 
X 
X 
X.X
X
X
X.X
X
X
X.X
X
X
X.X 
X 
X 
X.X
  - Preferred Term 3 
X 
X 
X.X
X
X
X.X
X
X
X.X
X
X
X.X 
X 
X 
X.X
 
9.2.7. Concomitant medication 
 
Inpatients 
(N=XX) 
Outpatients 
(N=XX) 
Stage 1 or 
intermediate
(N=XX) 
Stage 2 
(N=XX) 
Total 
(N=XX) 
Therapeutic Class / 
Preferred name 
Nb 
TRT 
Nb 
pat 
% 
pat 
Nb
TRT 
Nb
pat 
% 
pat 
Nb
TRT 
Nb
pat 
% 
pat 
Nb
TRT 
Nb
pat 
% 
pat 
Nb 
TRT 
Nb 
pat 
%
pat 
At least 1 TRT 
XX 
XX XX.X
XX
XX
XX.X
XX
XX
XX.X
XX
XX
XX.X 
XX 
XX XX.X
Therapeutic Class 1 
X 
X XX.X
XX
XX
XX.X
XX
XX
XX.X
XX
XX
XX.X 
XX 
XX XX.X
  - Preferred name 1 
X 
X 
X.X
X
X
XX.X
X
X
XX.X
X
X
XX.X 
X 
X XX.X
  - Preferred name 2 
X 
X XX.X
X
X
XX.X
X
X
XX.X
X
X
XX.X 
X 
X XX.X
  - Preferred name 3 
X 
X 
X.X
X
X
XX.X
X
X
X.X
X
X
X.X 
X 
X 
X.X
Therapeutic Class 2 
X 
X XX.X
X
X
XX.X
XX
XX
XX.X
XX
XX
XX.X 
XX 
XX XX.X
  - Preferred name 1 
X 
X 
X.X
X
X
X.X
X
X
X.X
X
X
X.X 
X 
X 
X.X
  - Preferred name 2 
X 
X 
X.X
X
X
X.X
X
X
X.X
X
X
X.X 
X 
X 
X.X
  - Preferred name 3 
X 
X 
X.X
X
X
X.X
X
X
X.X
X
X
X.X 
X 
X 
X.X
 
9.2.8. Analysis of the primary endpoint 
Description 
Statistics 
Total 
(N=XXX) 
 
Success Rate  
N 
XXX 
Missing 
X 
n (%) – Yes [95CI] 
n (XX.X%) [XX.X ; XX.X] 
n (%) -  No [95CI] 
n (XX.X%) [XX.X ; XX.X] 
 
 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 31 / 37
 
9.2.9. Overall summary of adverse event 
Adverse Event summary 
Inpatients 
(N=XX) 
Outpatients 
(N=XX) 
Stage 1 or 
intermediate
(N=XX) 
Stage 2 
(N=XX) 
Total 
(N=XX) 
At least one TEAE - N (%) IC95% 
Yes 
xx (xx.x%) 
[xx.x ; xx.x]
xx (xx.x%) 
[xx.x ; xx.x]
xx (xx.x%) 
[xx.x ; xx.x]
xx (xx.x%) 
[xx.x ; xx.x] 
xx (xx.x%) 
[xx.x ; xx.x]
 
 
At least one TEAE leading to treatment discontinuation (temporary or permanent)- N (%) IC95% 
Yes 
xx (xx.x%) 
[xx.x ; xx.x]
xx (xx.x%) 
[xx.x ; xx.x]
xx (xx.x%) 
[xx.x ; xx.x]
xx (xx.x%) 
[xx.x ; xx.x] 
xx (xx.x%) 
[xx.x ; xx.x]
 
 
At least one TEAE leading to permanent treatment discontinuation - N (%) IC95% 
Yes 
xx (xx.x%) 
[xx.x ; xx.x]
xx (xx.x%) 
[xx.x ; xx.x]
xx (xx.x%) 
[xx.x ; xx.x]
xx (xx.x%) 
[xx.x ; xx.x] 
xx (xx.x%) 
[xx.x ; xx.x]
 
 
(etc.) 
 
 
 
At least one Serious TEAE - N (%) IC95% 
Yes 
xx (xx.x%) 
[xx.x ; xx.x]
xx (xx.x%) 
[xx.x ; xx.x]
xx (xx.x%) 
[xx.x ; xx.x]
xx (xx.x%) 
[xx.x ; xx.x] 
xx (xx.x%) 
[xx.x ; xx.x]
 
 
(etc.) 
 
 
 
 
9.2.10. Adverse event by SOC and PT 
 
Inpatients 
(N=XX) 
Outpatients 
(N=XX) 
Stage 1 or 
intermediate
(N=XX) 
Stage 2 
(N=XX) 
Total 
(N=XX) 
System Organ Class / 
Preferred Term 
Nb 
AE 
Nb 
pat 
% 
pat 
Nb
AE 
Nb
pat 
% 
pat 
Nb
AE 
Nb
pat 
% 
pat 
Nb
AE 
Nb
pat 
% 
pat 
Nb 
AE 
Nb 
pat 
%
pat 
At least 1 AE 
XX 
XX XX.X
XX
XX
XX.X
XX
XX
XX.X
XX
XX
XX.X 
XX 
XX XX.X
System Organ Class 1 
X 
X XX.X
XX
XX
XX.X
XX
XX
XX.X
XX
XX
XX.X 
XX 
XX XX.X
  - Preferred Term 1 
X 
X 
X.X
X
X
XX.X
X
X
XX.X
X
X
XX.X 
X 
X XX.X
  - Preferred Term 2 
X 
X XX.X
X
X
XX.X
X
X
XX.X
X
X
XX.X 
X 
X XX.X
  - Preferred Term 3 
X 
X 
X.X
X
X
XX.X
X
X
X.X
X
X
X.X 
X 
X 
X.X
System Organ Class 2 
X 
X XX.X
X
X
XX.X
XX
XX
XX.X
XX
XX
XX.X 
XX 
XX XX.X
  - Preferred Term 1 
X 
X 
X.X
X
X
X.X
X
X
X.X
X
X
X.X 
X 
X 
X.X
  - Preferred Term 2 
X 
X 
X.X
X
X
X.X
X
X
X.X
X
X
X.X 
X 
X 
X.X
  - Preferred Term 3 
X 
X 
X.X
X
X
X.X
X
X
X.X
X
X
X.X 
X 
X 
X.X
 
 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 32 / 37
 
9.2.11. Shift table for laboratory parameters 
Template by severity: 
 
Laboratory parameter – Visit A 
Parameter XXXX 
Normal 
Abnormal NCS 
Abnormal CS 
Missing 
Visit B 
 
  - Normal 
X  (XX.X%)
XX  (XX.X%)
X  (XX.X%) 
X  (XX.X%)
  - Abnormal NCS 
X  (XX.X%)
X  (XX.X%)
XX  (XX.X%) 
XX  (XX.X%)
  - Abnormal CS 
X  (XX.X%)
X  (XX.X%)
XX  (XX.X%) 
XX  (XX.X%)
  - Missing 
X  (XX.X%)
X   (X.X%)
X  (XX.X%) 
XX  (XX.X%)
 
Template by CTCAE grades: 
 
Laboratory parameter – Visit A 
Parameter XXXX 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Visit B 
 
  - Grade 1 
X  (XX.X%)
X  (XX.X%)
XX  (XX.X%)
X  (XX.X%) 
X  (XX.X%)
  - Grade 2 
X  (XX.X%)
X  (XX.X%)
X  (XX.X%)
XX  (XX.X%) 
XX  (XX.X%)
  - Grade 3 
X  (XX.X%)
X  (XX.X%)
X  (XX.X%)
XX  (XX.X%) 
XX  (XX.X%)
  - Grade 4 
X  (XX.X%)
X  (XX.X%)
X  (XX.X%)
X  (XX.X%) 
XX  (XX.X%)
  - Grade 5 
X  (XX.X%)
X  (XX.X%)
X   (X.X%)
X  (XX.X%) 
XX  (XX.X%)
 
 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 33 / 37
 
10. KEY DERIVED VARIABLES 
10.1. Outcome at 18 months 
Derivation algorithm for 
stage 1 and intermediate stage (Month 18) 
Derivation algorithm for  
stage 2 (Month 18) 
Patient is dead (any reason of death and any time between drug intake and M18) 
 YES  Failure (stop) 
 
NO (patient alive) 
 
Patient requires rescue medication for HAT at M18 or required it before (between drug intake and M18)  
 YES  (definitive) Failure (stop) 
 
NO rescue medication so far 
 
Evidence of trypanosomes in any body fluid between drug intake and M18 visit  
 YES  (definitive) Failure (stop) 
 
NO observed trypanosomes 
 
Patient Lost to follow‐up at M18 (no survival information at M18 and later) 
 YES  Failure (Stop) 
 
NO (the patient is not lost to follow‐up) 
 
Non‐haemorrhagic lumbar puncture at M18 and WBC in CSF at M18 >20 cells  
 YES  Failure (stop) 
 
NO (WBC in CSF at M18 20 cells or no reliable data concerning WBC in CSF at M18) 
 
Non‐haemorrhagic lumbar puncture at M18 and WBC in CSF 20 cells 
YES  Success (stop) 
 
NO (haemorrhagic CSF sample or no lumbar puncture at M18 for any reason) 
 
No lumbar puncture at M18 or no reliable count of WBC in CSF at M18 but reliable number of WBC in CSF 
reported later (M24 or other additional visit) 
 YES  WBC in CSF >20  Failure (Stop) 
 YES  WBC in CSF 20  Success (Stop) 
 
NO (No lumbar puncture at M18 and no later reliable count of WBC in CSF) 
 
 
Patient has clinical signs or symptoms at M18 
evoking a failure  
 YES  Failure (stop) 
 
 
 
NO (no clinical signs or symptoms evoking a relapse 
at M18) 
 
WBC in CSF 20 at M12 or absence of lumbar 
puncture at M12 and no sign and symptoms  
 
Earlier (before M18) unfavourable outcome: WBC 
in CSF >50 at M6 or WBC in CSF >20 at M12 or 
increasing between M6 and M12  
 YES  Failure (stop) 
 
NO (no information or no earlier unfavourable 
assessment) 
 
Patient has clinical signs or symptoms at M18 
evoking a failure  
 YES  Failure (stop) 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 34 / 37
 
Derivation algorithm for 
stage 1 and intermediate stage (Month 18) 
Derivation algorithm for  
stage 2 (Month 18) 
at M18 evoking a relapse:  
 
 YES  Success (stop) 
 
NO (at least one criterion not met)  
 
Patient refused all post treatment lumbar 
punctures  
 YES  Failure (stop) 
 
All other cases  Failure 
 
 
NO (no clinical signs or symptoms evoking a relapse 
at M18) 
 
WBC in CSF 20 at M12 or in absence of lumbar 
puncture at M12 and for both cases WBC in CSF 50 
at M6 and no signs and symptoms at M18 evoking a 
relapse:  
 YES  Success (Stop) 
 
NO (at least one criterion not met)  
 
Patient refused all post treatment lumbar 
punctures  
 YES  Failure (Stop)  
 
All other cases  Failure 
 
 
Note : 
Modification of the algorithm due to an undetected error, as there was no lumbar puncture at the end 
of hospitalisation visit foreseen in the protocol. 
 
 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 35 / 37
 
10.2. Outcome at 12 months 
Derivation algorithm for  
stage 1 and intermediate stage (Month 12) 
Derivation algorithm for  
stage 2 (Month 12) 
Patient is dead (any reason of death and any time between drug intake and M12) 
 YES  (definitive) Failure (stop) 
 
NO (patient alive) 
 
Patient requires rescue medication for HAT at M12 or before 
 YES  Failure (stop) 
 
NO rescue medication so far 
 
Evidence of trypanosomes in any body fluid at M12 or between drug intake and M12 visit  
 YES  (definitive) Failure (stop) 
 
NO observed trypanosomes so far  
 
Patient Lost to follow‐up at 12M (no survival information at M12 and later) 
 YES  Failure (Stop) 
 
NO (the patient is not lost to follow‐up) 
 
 
Non‐haemorrhagic lumbar puncture at M12 and  
WBC in CSF >20 cells 
YES  Failure (stop) 
 
NO (WBC in CSF at M12 20 cells or no reliable 
count of WBC in CSF at M12) 
 
Non‐haemorrhagic lumbar puncture at M12 and  
WBC in CSF at M12 20 cells 
 YES  Success (Stop) 
 
NO (no reliable count of WBC in CSF at M12) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Non‐haemorrhagic lumbar puncture at M12 and  
WBC in CSF at M12  50 cells 
 YES  Failure (stop) 
 
NO (WBC in CSF at M12 <50 cells or no reliable 
count of WBC in CSF at M12) 
 
Non‐haemorrhagic lumbar puncture at M12 and 
WBC in CSF at M12 20 cells 
 YES  Success (Stop) 
 
NO (no reliable count of WBC in CSF at M12) 
 
Non‐haemorrhagic lumbar puncture at M12 with 
WBC in CSF <50 but >20 and increase of WBC in CSF 
with respect to M6 or sign and symptoms evoking a 
failure 
 YES  Failure (stop) 
 
NO (patient did not meet at least one of the 
previous criteria at M12) 
 
Non‐haemorrhagic lumbar puncture at M12 with 
WBC in CSF<50 but >20 cells and decrease of WBC 
in CSF with respect to M6 and no signs and 
symptoms evoking a failure (success at M18 if 
status is available) 
 YES  Success (stop) 
 
NO (patient did not meet at least one of the 
previous criteria) 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 36 / 37
 
Derivation algorithm for  
stage 1 and intermediate stage (Month 12) 
Derivation algorithm for  
stage 2 (Month 12) 
 
No lumbar puncture at M12 or no reliable count of 
WBC in CSF at M12 but reliable number of WBC in  
CSF reported later (M18 or other additional visit)  
 YES  WBC in CSF >20  Failure (Stop) 
 YES  WBC in CSF 20 and no signs or 
symptoms evoking a relapse  Success 
(Stop) 
 
NO (no later reliable count of WBC in CSF) 
 
No reliable WBC count in CSF at M12 and later and 
Failure at M18 for any reason  
 YES  Failure at M12 (Stop) 
 
NO 
 
Patient refused all post‐treatment lumbar  
punctures but was met at M24 or later with no  
signs and symptoms evoking a relapse (normal 
activity) 
 YES  Success at M12  
 
NO (Patient not met at M24 or later) 
 
Patient refused all post treatment lumbar  
punctures  
 YES  Failure (Stop) 
 
 
No lumbar puncture at M12 or no reliable count of 
WBC in CSF at M12 but reliable number of WBC in 
CSF reported later (M18 or other additional visit)  
 YES  WBC in CSF >20  Failure 
(Stop) 
 YES  WBC in CSF 20  Success 
(Stop) 
 
NO (no later reliable count of WBC in CSF) 
 
No WBC count in CSF at M12 and later and Failure 
at M18 for any reason  
 YES  Failure at M12 (Stop)  
 
NO 
 
No reliable count of WBC in CSF at M18 and M12 
but WBC counts at M6 available and no sign and 
symptoms evoking relapse at M12 or M18 
 YES  WBC in CSF at M6 20 cells  
 Success (stop) 
 
NO  WBC in CSF at M6 >20 cells  Failure 
(Stop) 
 
NO (no lumbar puncture at M6, M12 and M18) 
 
Patient refused all post‐treatment lumbar 
punctures but was met at M24 or later with no 
signs and symptoms evoking a relapse (normal 
activity) 
 YES  Success at M12  
 
NO (Patient not met at M24 or later) 
 
Patient refused all post treatment lumbar 
punctures  
 YES  Failure (Stop) 
 
 
 
 


DNDi‐FEX‐09‐HAT (DNDi) 
Statistical Analysis Plan 
Version 3.0 – 30/09/2022 
Page 37 / 37
 
11. CHANGES IN THE STATISTICAL METHODS FROM THOSE STATED IN 
THE PROTOCOL 
Changes in the analysis of adverse events: 
The part below of Section 9.6.1 of the Protocol will not be taken into account: “Events described with 
the same term and that occur several times in the same patient will be counted only once. If a patient 
experiences several events described with the same term, the event with the maximal severity will be 
included in the analysis.” 
Actually, if several events are described with the same preferred terms for a subject, all events will be 
included in the analysis. The number of occurrence of events, the number and percentage of patients 
with at least one event will be calculated by SOC and Preferred term. 
Removal of interim analyses: 
Interim analyses were planned in Section 9.7 of the protocol in order to supplement the registration 
file for fexinidazole. These interim analyses are not required anymore and will not be performed. 
Post‐DBL changes : 
Modification of the algorithm by an undetected error, as there was no LP in the end of treatment visit 
foreseen in the protocol. 
 
12. QUALITY CONTROL 
The statistician in charge of the analysis will validate the whole derived variables, using an exhaustive 
method whenever it is possible. When an exhaustive control is impossible, 10% of patients will be 
randomly drawn and checked in order to validate derived variables. 
The primary endpoint will be exhaustively validated and double‐checked (i.e. head of biostatistics or 
another statistician).