Clinical trial NCT04913610
Conditions: Onchocerciasis
Keywords: Onchocerciasis Onchocerca volvulus River blindness ABBV-4083 Tylamac
Sponsor: AbbVie
Start date: 2021-05-22; Completion date: 2023-08-29
Enrollment: 153 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Onchocerciasis is a major public health problem in affected countries that causes disease-induced disability, and overall loss of economic productivity. The purpose of this study is to determine how safe and effective ABBV-4083 in combination with albendazole is in treating participants with Onchocerciasis.

ABBV-4083 is an investigational drug being developed for the treatment of onchocerciasis. This study is conducted in 2 parts. In part 1, participants are randomly assigned to 1 of 5 groups, called treatment arms to determine the most efficient treatment combination. Each group receives a different treatment. In part 2, participants are randomly assigned to 1 of 4 treatment arms. Approximately 444 or 486 adult participants with a diagnosis of onchocerciasis will be enrolled in approximately 2 sites in Democratic Republic of Congo.

Participants in Part 1 will receive different treatment combinations of ABBV-4083 and/or albendazole and/or matching placebo capsules for 14 days. Participants in Part 2 will receive the most effective treatment combination(s) determined in Part 1 for 14 days followed by ivermectin or matching placebo capsules at Month 6; duration of treatment is 24 months.

There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests and checking for side effects.

Detailed description:
The study was terminated at the conclusion of Part 1, and Part 2 of the study was not conducted.

Arms: arm 1: Participants received ABBV-4083 400 mg administered orally as capsules plus placebo capsules for albendazole for 7 days followed by placebo capsules for ABBV-4083 for 7 days. arm 2: Participants received ABBV-4083 400 mg administered orally as capsules plus placebo capsules for albendazole for 7 days followed by ABBV-4083 400 mg administered orally as capsules for 7 days. arm 3: Participants received ABBV-4083 400 mg administered orally as capsules plus albendazole 400 mg capsules for 7 days followed by placebo capsules for ABBV-4083 for 7 days. arm 4: Participants received ABBV-4083 400 mg administered orally as capsules plus albendazole 400 mg capsules for 3 days followed by ABBV-4083 400 mg and placebo capsules for albendazole for 4 days followed by placebo capsules for ABBV-4083 for 7 days. arm 5: Participants received placebo for ABBV-4083 administered orally as capsules plus albendazole 400 mg capsules for 7 days followed by placebo capsules for ABBV-4083 for 7 days.
Interventions: intervention 1: ABBV-4083 intervention 2: Placebo for ABBV-4083 intervention 3: Albendazole intervention 4: Placebo for Albendazole
Intervention descriptions: intervention 1: Oral Capsule intervention 2: Oral Capsule intervention 3: Oral encapsulated tablets intervention 4: Oral Capsule

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol DNDI-TYL-01 
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CLINICAL TRIAL PROTOCOL 
 
A Phase-II, Randomised, Double-blind, Parallel-group, Proof-of-concept 
Trial to Investigate ABBV-4083 given for 7 or 14 Days or in Combination 
with Albendazole in Subjects with Onchocerca volvulus Infection, 
comprising: 
Part 1 to Investigate Safety, Tolerability, Efficacy for Dose-Ranging and 
Pharmacokinetics; 
Part 2 to Investigate Efficacy of Selected Doses, Safety, Tolerability and 
Pharmacokinetics 
Short title 
Tylamac phase II trial for treatment of onchocerciasis 
Name of product 
Chemical Name: Tylosin, 4B O-[(4-fluorophenyl)methyl]  
Associated name: ABBV-4083 
Drug Class 
Macrolide 
Phase 
II 
Indication 
Treatment of onchocerciasis (river blindness) 
Trial Protocol Number 
AbbVie Protocol B18-894 / DNDi-TYL-01 
Sponsor 
DNDi, Chemin Camille-Vidart, 15, 1202 Geneva, 
Switzerland 
Trial Protocol 
Version/Date 
Version 2.0 dated 09 November 2021 
Protocol Amendment 
Number/Date 
Amendment 1 dated 09 November 2021 
Registry number 
ClinicalTrials.gov identifier: NCT04913610 
Pan African Clinical Trials Registry: PACTR202104600961505 
 
The information contained in this document is confidential. It is to be used by Investigators, 
potential Investigators, consultants, or applicable independent ethics committees. It is 
understood that this information will not be disclosed to others without prior written approval 
from DNDi, except where required by applicable local laws. 
 
 
 
 
 
 
 
NCT04913610


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Contact Details 
 
TRIAL SPONSOR 
DNDi 
Chemin Camille-Vidart, 15 
1202 Geneva, Switzerland 
 
• Sponsor’s Medical Expert (24 Hours) 
Dr. 
 MD 
 
DNDi 
Rua São Jose, 70 – Sala 601, 20010-020, Centro – Rio de Janeiro, Brazil 
Telephone: 
 
 
Mobile: 
 
E-mail: 
 
 
• Clinical Project Managers 
 MSc 
 
 
 
 BSc (Hons) 
DNDi 
 
 
 
 
 
DNDi 
Chemin Camille-Vidart, 15, 1202 Geneva, Switzerland 
Telephone (switchboard): 
 
Mobile: 
 
 
 
Mobile: 
 
E-mail: 
 
 
 
E-mail: 
 
 
• Serious Adverse Event (SAE) Reporting 
Sponsor contact details for SAE reporting  
DNDi Clinical Team, e-mail: SAETYL01study@dndi.org 
 
(See Section 9.3.4.8 for full details) 
 
INSTITUTION: 
PNLMTN- CTP will ensure the preparation and management of the clinical trial sites as 
well as the conduct and coordination of the clinical trial in DRC sites.  
 
PNLMTN-CTP 
Avenue de la Justice N°36 , Commune de la Gombe 
Kinshasa , République Démocratique du Congo 
Telephone: +243 81 782 25 66 
 
 
The full list of contacts involved in this clinical trial including the clinical sites can be found in 
the clinical trial contact list. 
 






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Investigator Signature 
 
I have read this protocol and agree that it contains all information necessary to carry out the 
study. I will conduct the study as described herein.  
I will provide copies of the protocol and all pertinent information to all individuals responsible 
to me who assist in the conduct of the study. I will discuss this material with them to ensure 
they are fully informed regarding the Investigational Medicinal Product and the conduct of the 
study.  
I will use only the Informed Consent Forms approved by the Sponsor or its representative and 
the Ethics Committee(s) and (where applicable) the Regulatory Authority, and will fulfil all 
responsibilities for submitting pertinent information to the Ethics Committee (EC) responsible 
for the study if required by national law.  
I agree that the Sponsor or its representatives, and respective Ethics Committee(s) 
and Regulatory Authorities shall have access to any source documents from which case report 
form information may have been generated.  
I agree that the study will be conducted in accordance with all applicable laws and regulations, 
including, but not limited to, the International Conference on Harmonisation (ICH) Guideline 
for Good Clinical Practice (GCP), the ethical principles that have their origins in the Declaration 
of Helsinki, and applicable privacy laws.  
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care under applicable regulations.  
  
Name:  
Affiliation:  
Date:  
Signature:  
 
 
Signed copies of this signature page are stored in the Sponsor’s study file and in the 
Investigator Site File at the investigational centre.  
In the protocol document, this page may remain unsigned.  
 
 
 
 


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Table of Contents 
Contact Details .......................................................................................................................... 2 
Sponsor Signatures ................................................................................................................... 3 
Investigator Signature .............................................................................................................. 5 
Table of Contents ..................................................................................................................... 6 
Protocol Amendment 1 rationale  ......................................................................................... 11 
1 
Synopsis ....................................................................................................................... 17 
2 
Introduction ................................................................................................................ 26 
2.1 
Background Information on Onchocerciasis ................................................................ 26 
2.2 
Summary of Non-clinical Data .................................................................................... 27 
2.2.1 
Summary of Non-clinical Efficacy .......................................................................... 27 
2.2.2 
Summary of Safety Pharmacology Data .................................................................. 27 
2.2.3 
Summary of Non-clinical Pharmacokinetic and Drug Metabolism Data ................ 28 
2.2.4 
Summary of Toxicology Data .................................................................................. 29 
2.3 
Summary of Clinical Data ............................................................................................ 29 
2.3.1 
Phase-I Study in Healthy Subjects ........................................................................... 29 
2.3.2 
Conclusion on Clinical Data to Date ........................................................................ 31 
2.4 
Design and Rationale for Study ................................................................................... 31 
2.4.1 
Overview of Study Design ....................................................................................... 31 
2.4.2 
Rationale for the Study ............................................................................................. 32 
2.4.3 
Rationale for Dose Selection .................................................................................... 33 
3 
Study Design ............................................................................................................... 34 
3.1 
Overall Study Design ................................................................................................... 34 
3.2 
Study Design - Part 1 ................................................................................................... 35 
3.3 
Study Design - Part 2 ................................................................................................... 36 
3.4 
End of Study ................................................................................................................. 38 
3.5 
Assessment and Management of Risks ........................................................................ 39 
3.5.1 
Risks associated with the IMPs ................................................................................ 39 
3.5.2 
Adverse Event and Toxicity Management ............................................................... 41 
3.5.3 
Risks Associated with Disease Progression ............................................................. 42 
3.5.4 
Risks Associated with Epidemics ............................................................................ 43 
4 
Study Objectives ......................................................................................................... 44 
4.1 
Primary Objectives ....................................................................................................... 44 
4.2 
Secondary Objectives ................................................................................................... 44 
4.2.1 
Key Secondary Objectives for Part 2 ....................................................................... 44 
4.2.2 
Other Secondary Objectives ..................................................................................... 44 
4.3 
Exploratory Objectives for Parts 1 and 2 ..................................................................... 45 
5 
Study Endpoints ......................................................................................................... 45 
5.1 
Primary Efficacy Endpoints ......................................................................................... 45 


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5.2 
Secondary Efficacy Endpoints ..................................................................................... 46 
5.2.1 
Key Secondary Efficacy Endpoints in Part 2 ........................................................... 46 
5.2.2 
Other Secondary Efficacy Endpoints ....................................................................... 46 
5.3 
Exploratory Endpoints in Parts 1 and 2 ........................................................................ 46 
5.4 
Additional Endpoint in Alternative Scenario in Part 2 ................................................ 47 
5.5 
Safety and Tolerability Endpoints in Parts 1 and 2 ...................................................... 47 
5.6 
PK and PK/PD Endpoints in Parts 1 and 2 ................................................................... 47 
6 
Study Population ........................................................................................................ 47 
6.1 
Inclusion Criteria .......................................................................................................... 47 
6.2 
Exclusion Criteria ......................................................................................................... 48 
6.3 
Rationale for Study Population .................................................................................... 50 
6.4 
Subject Identification ................................................................................................... 50 
6.5 
Discontinuation and Withdrawal Criteria .................................................................... 51 
6.5.1 
Screening Failure ...................................................................................................... 51 
6.5.2 
Interruption or Discontinuation of IMP ................................................................... 51 
6.5.3 
Withdrawal from the Trial ........................................................................................ 52 
6.5.4 
Lost to Follow-up ..................................................................................................... 52 
6.5.5 
Subject Replacement ................................................................................................ 53 
7 
Investigational Medicinal Products. ......................................................................... 53 
7.1 
Test Investigational and Reference Medicinal Products .............................................. 53 
7.1.1 
ABBV-4083 and Matching Placebo ......................................................................... 53 
7.1.2 
Albendazole and Matching Placebo ......................................................................... 53 
7.1.3 
Ivermectin and Matching Placebo ............................................................................ 54 
7.2 
IMP Supply and Storage .............................................................................................. 55 
7.3 
IMP Assignment and Administration ........................................................................... 55 
7.3.1 
IMP Assignment and Administration in Part 1 ........................................................ 55 
7.3.2 
IMP Assignment and Administration in Part 2 ........................................................ 56 
7.4 
Blinding ........................................................................................................................ 57 
7.4.1 
Blinding Measures .................................................................................................... 57 
7.4.2 
Unblinding Measures ............................................................................................... 57 
7.5 
IMP Logistics and Accountability ................................................................................ 58 
7.6 
Treatment Compliance ................................................................................................. 58 
8 
Non-study Medication ................................................................................................ 58 
8.1 
Prior and Concomitant Medication .............................................................................. 58 
8.2 
Contraception/Birth Control ......................................................................................... 59 
8.3 
Ivermectin: Rescue Medication, Post-Study, Screening Failures ................................ 59 
8.3.1 
Rescue Medication in Part 1 ..................................................................................... 60 
8.3.2 
Rescue Medication in Part 2 ..................................................................................... 60 
8.4 
Post-study Ivermectin ................................................................................................... 60 


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9 
Study Procedures and Assessments .......................................................................... 60 
9.1 
Conduct of Study Procedures and Assessments ........................................................... 60 
9.2 
Description of Study Periods ........................................................................................ 61 
9.2.1 
Overview of Study Periods ...................................................................................... 61 
9.2.2 
Screening Period ...................................................................................................... 62 
9.2.3 
Randomisation .......................................................................................................... 62 
9.2.4 
Treatment Period ...................................................................................................... 62 
9.2.5 
Follow-up Period ...................................................................................................... 63 
9.2.6 
Early Termination Visit ............................................................................................ 63 
9.2.7 
Accommodation ....................................................................................................... 64 
9.2.8 
Dietary and Lifestyle Guidelines in Parts 1 and 2 .................................................... 64 
9.3 
Summary of Study Procedures and Assessments ......................................................... 64 
9.3.1 
Subject Characteristics ............................................................................................. 64 
9.3.2 
Pharmacokinetics and Pharmacodynamics .............................................................. 65 
9.3.3 
Efficacy and Safety .................................................................................................. 65 
9.3.4 
Safety - Adverse Event Definitions and reporting ................................................... 70 
10 
Statistical Analyses ..................................................................................................... 76 
10.1 
Statistical Hypotheses .................................................................................................. 76 
10.1.1 
Primary Hypothesis in Part 1 ................................................................................... 76 
10.1.2 
Primary Hypotheses in Part 2 ................................................................................... 77 
10.1.3 
Key Secondary Hypotheses in Part 2 ....................................................................... 77 
10.2 
Analysis Sets ................................................................................................................ 78 
10.3 
Determination of Sample Size ...................................................................................... 79 
10.3.1 
Determination of Sample Size in Part 1 ................................................................... 79 
10.3.2 
Determination of Sample Size in Part 2 ................................................................... 79 
10.4 
Handling of Potential Intercurrent Events for the Primary and Key Secondary Endpoints
 
………………………………………………………………………………………..80 
10.5 
Population Level Summary and Analysis for the Primary Endpoints ......................... 80 
10.6 
Population Level Summary and Analysis for the Key Secondary Endpoints .............. 81 
10.7 
Multiplicity Adjustment ............................................................................................... 82 
10.8 
Statistical Analysis of Safety ........................................................................................ 82 
10.9 
Interim Analysis of Part 1 and DSMB Recommendation to Proceed to Part 2 ........... 83 
10.10 
Interim Analysis of Part 2 and DSMB Recommendation for Phase III ................... 83 
11 
Data Handling and Quality Assurance ..................................................................... 83 
11.1 
Data Collection ............................................................................................................. 83 
11.1.1 
Investigator Site File ................................................................................................ 83 
11.1.2 
Case Report Forms ................................................................................................... 84 
11.1.3 
Source Documents .................................................................................................... 84 
11.1.4 
Data from Screening Failures ................................................................................... 84 


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11.2 
Study Monitoring ......................................................................................................... 84 
11.3 
Data Processing ............................................................................................................ 85 
11.4 
Missing Data ................................................................................................................ 85 
11.5 
Audit and Inspection .................................................................................................... 85 
11.6 
Archiving of Essential Study Documents .................................................................... 86 
12 
Premature Study Termination .................................................................................. 86 
13 
Ethical and Legal Aspects.......................................................................................... 87 
13.1 
Investigator and Other Study Personnel ....................................................................... 87 
13.2 
Safety Review Committee ............................................................................................ 87 
13.3 
Data and Safety Monitoring Board .............................................................................. 87 
13.4 
Funding and Financial Disclosure ................................................................................ 88 
13.4.1 
Funding of the Study ................................................................................................ 88 
13.4.2 
Financial Disclosure ................................................................................................. 88 
13.4.3 
Costs for Subjects ..................................................................................................... 88 
13.5 
Ethical and Legal Conduct of the Study ....................................................................... 89 
13.6 
Subject Information and Informed Consent ................................................................. 89 
13.7 
Publication Policy and Use of Study Data ................................................................... 89 
13.8 
Insurance ...................................................................................................................... 90 
13.9 
Confidentiality and Protection of Privacy .................................................................... 90 
14 
List of References ....................................................................................................... 91 
15 
Appendices .................................................................................................................. 96 
 
 
 
List of Tables 
Table 1. Dose Adjustment Recommendations for Toxicity Management in Part 1 ................ 42 
Table 2. Composition of ABBV-4083 and Matching Placebo................................................. 53 
Table 3. Composition of Albendazole and Matching Placebo ................................................. 53 
Table 4. Composition of Ivermectin and Matching Placebo .................................................... 54 
Table 5. Dose of Ivermectin by Body Weight ......................................................................... 54 
Table 6. Dietary and Lifestyle Guidelines - Part 1 and Part 2 ................................................. 64 
Table 7. Schedule of Events for Part 1 ..................................................................................... 97 
Table 8. Schedule of Events in Part 2 .................................................................................... 101 
Table 9. Total Blood Volume in Part 1 .................................................................................. 105 
Table 10. Total Blood Volume in Part 2 - Phase II ................................................................ 106 
Table 11. Parameters of Laboratory Analyses ....................................................................... 107 
 
 
 


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List of Figures 
Figure 1. Overall Design for Part 1 .......................................................................................... 36 
Figure 2. Overall Design for Part 2 - Base Scenario ................................................................ 37 
Figure 3. Overall Design for Part 2 - Alternative Scenario ...................................................... 38 
Figure 4. Overview of Study Periods in Part 1 ........................................................................ 61 
Figure 5. Overview of Study Periods in Part 2 ........................................................................ 61 
Figure 6. Graphical Approach to Multiplicity Control in Part 2 .............................................. 82 
 
 


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Protocol Amendment 1 rationale  
 
The Sponsor considers that with this amendment the overall risk-benefit assessment for the 
protocol remains unchanged. Also the changes below do not impact the determination of the 
sample size, nor the integrity of the trial design. In addition, there is no impact on subjects 
already enrolled in the study at the time of protocol amendment, nor consequences for the 
evaluation of the study results. 
  
The first participants were prescreened, screened and started treatment in May 2021. At the 
time of writing this amendment, a total of 272 participants were prescreened, 125 screened and 
57 randomised into the study. The screen failure rate was over 50% at the time of this 
amendment and the main reasons for screen failure were co-infection with other filarial species 
(Mansonella perstans and/or Wuchereria bancrofti) and the presence of THC in urine.  
 
The prevalence of other filarial species in the patient population was unknown prior to the start 
of the study due to lack of disease mapping. The consequences of killing intracellular 
endosymbionts (Wolbachia) using antibiotics has been very well described. Doxycycline, given 
at a dose of 200 mg daily for 4 to 6 weeks, has been shown to decrease the development, 
embryogenesis, fertility, and viability of filarial worms in species that harbor Wolbachia1. This 
is also the case for Wuchereria bancrofti2,3  and Mansonella perstans4,5  infection. Due to the 
indirect mode of action, i.e. killing of Wolbachia endobacteria, mf decline slowly over the 
course of approximately 12 months and thus no parasite-induced adverse events are expected 
in patients coinfected with other Wolbachia-harbouring filaria, as is the case for onchocerciasis. 
Therefore, we aim to include subjects with coinfections with Wuchereria bancrofti or 
Mansonella spp.   
 
Furthermore new criteria for re-screening have been added. These measures will give additional 
opportunities for subjects who already went through intensive screening procedures to 
participate, reduce the number of screen-failures, and to optimise recruitment.  
 
In addition, during the screening of the subjects, it was observed that the number of screening 
procedures was challenging within the allocated protocol window for the operational site team. 
Therefore, it was decided to allow more flexibility for the screening window. 
 
Some editorial changes were also implemented in this amendment to add clarity or correct some 
inconsistencies. Some administrative changes have also been made. 
 
Overall rationale for the amendment: 
1. 
Administrative and editorial changes 
2. 
Remove the exclusion criterion regarding the co-infection with Mansonella species 
and Wuchereria Bancrofti 
3. 
Add criteria for re-screening to optimise recruitment, without compromising safety  
4. 
Clarify that only abnormal and clinically significant ECGs and urine analyses would 
require re-test or further evaluations 
5. 
Remove non-critical tests/assessments to reduce burden for sites 
6. 
Clarify that future research could also be done on other parasites 


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7. 
Allow more time for repeat testing to avoid unnecessary blood draw after agreement 
from the sponsor 
8. 
Fix some inconsistencies or add clarification for some procedures 
 
Details about the changes and rationale are reported in below table. 
 
Section # and Name Description of Change 
Brief Rationale 
Title 
Page 
and 
Contact Details 
Update 
of 
DNDi’s 
Switzerland contact details at 
several places. 
 
The street name of DNDi’s office in Geneva has 
changed on 01Mar2021 due to a motion made to 
the Geneva Canton in 2019 accepting to change 
100 street names from masculine to feminine. 
 
Sponsor Signatures 
Removal of Medical Director 
(retain 
the 
Medical 
Responsible) as signatory and 
update of the Trial Statistician 
contact. 
 
Per DNDi SOP, the Medical Director is not 
required to sign in addition to the Medical 
Responsible. 
Change of Trial Statistician. 
1 Synopsis 
Correction of Kimpese’ site 
name 
Correct error 
Correction of typographical 
error in the inclusion criterion 
about body weight (should be 
≥ 40kg). 
 
This is a correction in the synopsis to be aligned 
with section 6.1 
1 
Synopsis 
and 
Section 
6.2 
Exclusion Criteria 
Clarification 
that 
only 
clinically significant abnormal 
physical 
examination 
or 
laboratory 
findings 
would 
exclude a subject from the 
study. 
 
All abnormal results are not necessarily 
clinically significant and therefore this criterion 
is clarified. 
Removal of co-infection with 
Mansonella 
species 
and 
Wuchereria 
bancrofti 
as 
exclusion criterion.  
 
Refer to Protocol amendment rationale section 
above. No risk is foreseen for subjects with co-
infection with other filarial worms.   
Clarification that exclusion 
criteria 7.viii regarding the 
presence of more than 50 
microfilariae in the anterior 
segment 
corresponds 
to 
number of microfilariae in  
one eye. 
 
Clarification only. 
Extension of the washout 
period for alcohol use (2 days 
versus 24 hours) and of drugs 
Alcohol use can be tested up to 48 hours before 
the first IMP administration as the participants 
will already be on site and this will allow more 


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of abuse (15 days versus 24 
hours)  
flexibility on the organizational aspects at the 
site.  
 
As re-screening will now be allowed in certain 
circumstances for participants screen-failing on 
drugs of abuse (see section 6.5.1 below), the 
washout period has been extended to avoid 
potential drug-drug interactions. 
 
3.5.4 
Risks 
Associated 
with 
Epidemics 
Clarification that COVID-19 
tests may be performed on site 
personnel 
and/or 
study 
subjects 
if 
required 
by 
standard clinical care. 
Protect the study subjects in case of suspicion of 
COVID-19 infection and apply standard of care.  
6.5.1 
Screening 
Failure 
Clarification that screening 
failures refer to subjects who 
discontinue 
study 
participation prematurely after 
they have signed the study 
main informed consent form 
(ICF) 
and 
undergone 
screening assessments and 
that subjects who re-enter the 
screening process must sign a 
new main ICF. 
 
Clarification only due to the use in the study of 
2 Informed Consents Forms: 1 pre-screening 
ICF and 1 main ICF.   
Clarification that up to 2 re-
screenings are allowed 
To give the opportunity to participants who 
already went through intensive screening 
procedures to be re-screened 
 
Allowance of re-screening for 
subjects who screen-failed 
due 
to 
blood 
donation/transfusion, 
vaccinations, recent alcohol or 
drugs consumption, if agreed 
by 
the 
investigator 
and 
sponsor. 
 
On a   case-by-case basis to give more 
possibility for  subjects who already went 
through screening to participate, and to optimise 
recruitment, whilst respecting the wash-out 
period required to ensure safety of participants. 
 
7.4.2 
Unblinding 
Measures 
Addition of more details about 
the procedure in event of 
emergency unblinding by the 
Investigator, including the 
precautions 
to 
prevent 
unnecessary unblinding of 
subjects, Sponsor personnel, 
and additional Site personnel. 
Clarification. 


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9.2.2 
Screening 
Period 
Clarification 
that 
initial 
screening procedures that are 
still 
within 
the 
protocol 
window do not need to be 
repeated 
in 
case 
of 
re-
screening. 
 
This amendment will avoid unnecessary 
repeated procedures such as additional blood 
draw for the participants. 
 
 
9.3.3.1.1 
Blood, 
Urine and Skin Snip 
Parasitology and 
Appendices 1 and 2 
(Tables 7 and 8) 
Removal 
of 
Schistosoma 
haematobium 
testing 
at 
screening.  
Change to symptom-directed assessment for 
Schistosoma haematobium at screening to avoid 
unnecessary procedures. Based on the mode of 
action, ABBV-4083 is not expected to be 
efficacious in patients with schistosomiasis.  
9.3.3.8 Standard 12-
lead ECG 
Clarification that clinically 
significant abnormality will 
be checked by repeat ECG. 
An abnormal ECG might not be clinically 
significant. 
This 
amendment 
will 
avoid 
unnecessary repeat testing. 
 
9.3.3.9.1 
Haematology, 
Biochemistry, 
Urinalysis and Urine 
Microscopy 
Requirement 
for 
urine 
microscopy to be conducted 
only if the abnormal urinalysis 
results 
were 
clinically 
significant.  
A urinalysis might be abnormal but this may not 
be clinically significant (e.g. red blood cells in 
the urine of a menstruating female). This has 
been amended to avoid unnecessary analysis and 
conduct urine microscopy only if clinically 
significant. 
9.3.3.9.3 Pregnancy 
Tests 
Specification that pregnancy 
test must be highly sensitive. 
 
Allowance 
for 
repeat 
pregnancy tests to be highly 
sensitive urine upon sponsor’s 
approval. 
 
To add precision. 
 
To avoid unnecessary blood draw. 
9.3.4.4 
Eliciting 
Adverse 
Event 
Information 
Addition that end date will 
also be recorded in the eCRF 
for non-serious AEs. 
Addition that the adverse 
event start and stop times are 
to be recorded when available 
during the In-house period  
 
This was omitted previously 
 
 
This would allow to more easily identify and 
capture Treatment Emergent Adverse Event 
(TEAE). 
9.3.4.5 
Adverse 
Event 
Reporting 
Period 
Added 
the 
precision 
‘treatment 
emergent’ 
AE 
regarding the AE reporting 
period. 
 
Clarification. 
9.3.4.6 Grading of 
Adverse 
Event 
Severity 
Removed bicarbonate, and 
lactate dehydrogenase (LDH). 
Correction for consistency with Appendix 5. 
Laboratory analyses. These 2 parameters are not 
required in the study for safety monitoring and 
were not present in the list of laboratory 
analyses, nor in the study operational manual.  


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9.3.4.10 
Adverse 
Event Follow-up 
Removal of the categories 
needed to document outcome 
of an AE. 
Information that need to be recorded in the 
eCRF for AEs is detailed in section 9.3.4.4. No 
need to have further details as the lists of 
possible action taken and outcome are present 
on the SAE form and AE eCRF page.  
10.2 Analysis Sets 
Clarification 
added: 
per 
protocol population includes 
ITT subjects who had live 
female adult worms at the 
Month 6 nodulectomy. 
 
This change was implemented to align with the 
SAP 
10.10 
Interim 
Analysis of Part 2 
and 
DSMB 
Recommendation for 
Phase III 
Correction that details on the 
analysis 
and 
method 
are 
described in the SAP and not 
in the DSMB charter 
This correction was implemented to align with 
the SAP/DSMB charter. 
Appendices 1 and 2 
(Tables 7and 8) 
Allowance of a longer period 
for repeat testing at screening 
in exceptional circumstances 
upon 
sponsor’s 
approval. 
With 
the 
exception 
of 
pregnancy testing which must 
be repeated within 2 days and 
can be a highly sensitive urine 
test if serum test was already 
done. 
 
The repeat testing 2-day window was initially 
only set for organizational purposes, however it 
was noted that this window is too short for the 
site personnel and agree to extend it to 3 days 
(and 
more, 
if 
required, 
in 
exceptional 
circumstances, upon approval from the sponsor) 
to avoid another blood draw, as this has no 
impact on the safety of the participants and data 
analysis. 
 
Change 
from 
‘urinary 
cannabis screen’ to ‘urinary  
drug screen. 
 
For consistency with section below: Appendix 5 
Laboratory analyses, Parameters of laboratory 
analyses 
 
Clarifications 
provided 
in 
some of the footnotes 
 
For better clarity and alignment with changes 
done in the protocol. 
Appendices 
5. 
Laboratory analyses- 
Parameters 
of 
laboratory analyses 
Removal 
of 
creatinine 
clearance as eGFR only is 
being used. 
 
Correction only. Creatinine clearance was not 
listed in the laboratory parameters elsewhere in 
the protocol. 
Revision of the Urine Drugs 
Screen section to specify 
Drugs of Abuse Screen. 
For consistency of wording with the exclusion 
criteria regarding drugs of abuse, and reflecting 
the RDT in use. 
 
 
 
 


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References used in the Protocol Amendment 1 rationale:  
 
1. 
Hoerauf, A., et al., Wolbachia endobacteria depletion by doxycycline as antifilarial therapy has 
macrofilaricidal activity in onchocerciasis: a randomized placebo-controlled study. Med 
Microbiol Immunol, 2008. 197(3): p. 295-311. 
2. 
Taylor, M.J., et al., Macrofilaricidal activity after doxycycline treatment of Wuchereria 
bancrofti: adouble-blind, randomised placebo-controlled trial. Lancet, 2005. 365(9477): p. 
2116-21. 
3. 
Taylor, M.J., et al., Anti-Wolbachia drug discovery and development: safe macrofilaricides for 
onchocerciasis and lymphatic filariasis. Parasitology, 2013: p. 1-9. 
4. 
Coulibaly, Y.I., et al., A randomized trial of doxycycline for Mansonella perstans infection. N 
Engl J Med, 2009. 361(15): p. 1448-58. 
5. 
Batsa Debrah, L., et al., The Efficacy of Doxycycline Treatment on Mansonella perstans 
Infection: An Open-Label, Randomized Trial in Ghana. Am J Trop Med Hyg, 2019. 101(1): p. 
84-92. 
 
 
 


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1 Synopsis 
Title 
A Phase-II, Randomised, Double-blind, Parallel-group, Proof-of-concept 
Trial to Investigate ABBV-4083 given for 7 or 14 Days or in Combination 
with Albendazole in Subjects with Onchocerca volvulus Infection, 
comprising: 
Part 1 to Investigate Safety, Tolerability, Efficacy for Dose-Ranging and 
Pharmacokinetics; 
Part 2 to Investigate Efficacy of Selected Doses, Safety, Tolerability and 
Pharmacokinetics 
Short Title 
Tylamac phase-II trial for treatment of onchocerciasis 
Protocol number 
DNDi-TYL-01/ AbbVie Protocol B18-894 
Clinical Study Phase 
Phase II 
Investigational Centres 
Hôpital Général de Référence de Masi-Manimba, Kwilu, Democratic 
Republic of Congo 
Centre de Santé de Référence de Kimpese, Kongo central, Democratic 
Republic of Congo 
Additional centres may be included. 
Study Design 
Multicentre, randomised, active and/or placebo-controlled, double-blind, 
parallel-group, adaptive Phase-II study in two parts: 
Part 1 will use a surrogate endpoint of Wolbachia depletion in adult 
female worms to:  
• establish proof-of-concept for ABBV-4083 in onchocerciasis by 
demonstrating superiority of the regimens of ABBV-4083 alone over 
the control regimen, albendazole alone, which has been shown to have 
little or no activity in onchocerciasis, 
• establish the activity of ABBV-4083 and albendazole in combination 
by demonstrating superiority of a regimen of ABBV-4083 plus 
albendazole over regimens of ABBV-4083 and albendazole alone of 
equal duration, and 
• establish up to two preferred regimens of ABBV-4083 and/or ABBV-
4083 + albendazole to progress into Part 2 of the study. 
 
Part 2 will use a clinically relevant endpoint of depletion of skin microfilaria 
at Month 24 to: 
• identify the preferred regimen of ABBV-4083 or ABBV-4083 + 
albendazole to progress into Phase III trials.  
• evaluate the effect of a dose of ivermectin 6 months after ABBV-4083 or 
ABBV-4083 + albendazole on skin microfilarial density at Months 12, 18 
and 24. 
If the superiority of ABBV-4083 + albendazole over ABBV-4083 alone is 
not demonstrated in Part 1, surrogate endpoint data from Part 2 (i.e. 
Wolbachia depletion in adult worms at Month 6) from Arms with ABBV-
4083 + albendazole and ABBV-4083 alone will be combined with data from 
Part 1 to assess the superiority of ABBV-4083 + albendazole to ABBV-4083 
alone (Part 2 Alternate Scenario). 
Study Objectives 
Primary Objectives  
Part 1:  
• To determine whether treatment with ABBV-4083 or ABBV-
4083 + albendazole effectively depletes Wolbachia bacteria in adult female 
worms at Month 6 by immunohistology;  
• To establish the superiority of ABBV-4083 + albendazole to each drug alone 


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according to the depletion of Wolbachia bacteria in adult female worms at 
Month 6 by immunohistology. 
Part 2:  
• To determine whether treatment with ABBV-4083 or ABBV-
4083 + albendazole effectively eliminates microfilariae from the skin at 24 
months;  
• If superiority of 7-day treatment with ABBV-4083 + albendazole to 7 days 
of ABBV-4083 is not established in Part 1, the Alternate Scenario of Part 2 
(see Section 3.3) has the additional objective to establish that a combination 
of ABBV-4083 + albendazole is superior to ABBV-4083 alone by 
combining data from Parts 1 and 2. 
 Key Secondary Objectives 
Part 2:  
• To determine whether ABBV-4083 or ABBV-4083 + albendazole 
demonstrates a macrofilaricidal effect at 24 months;  
• To determine whether ABBV-4083 or ABBV-4083 + albendazole inhibits 
embryogenesis in adult female worms at 24 months. 
 
Investigational Medicinal 
Products 
Part 1 
Names of active substances: 
ABBV-4083 (Tylamac) 
 
 Albendazole (Zentel) 
Dose and Duration of Treatment: 
 
• Arm A (N = 30): 7 days of ABBV-4083 400 mg + albendazole 
matching placebo followed by 7 days of ABBV-4083 matching 
placebo  
• Arm B (N = 30): 7 days of ABBV-4083 400 mg + albendazole 
matching placebo followed by 7 days of ABBV-4083 400 mg 
• Arm C (N = 30): 7 days of ABBV-4083 400 mg + albendazole 400 
mg followed by 7 days of ABBV-4083 matching placebo  
• Arm D (N = 30): 3 days of ABBV-4083 400 mg + albendazole 400 
mg followed by 4 days of ABBV-4083 400 mg + albendazole 
matching placebo followed by 7 days of ABBV-4083 matching 
placebo  
• Arm E (N = 30): 7 days of ABBV-4083 matching placebo + 
albendazole 400 mg followed by 7 days of ABBV-4083 matching 
placebo  
Route of Administration: Oral 
 
Part 2 
Names of active substances: 
ABBV-4083 (Tylamac) 
 
 Albendazole (Zentel) 
 
 Ivermectin (Stromectol) 
Dose and Duration of Treatment: 
 
• Arm K (n = 84): initial treatment with an active regimen selected from 
Part 1, followed by ivermectin at Month 6; 
• Arm L (n = 84): initial treatment with the same active regimen selected 
from Part 1 as Arm K, followed by ivermectin matching placebo at 
Month 6; 
• Arm M (n = 84): initial treatment with a second active regimen 
selected from Part 1, followed by either ivermectin or ivermectin 
matching placebo at Month 6; 
• Base scenario - Arm N1 (n = 42): initial treatment with ABBV-4083 
matching placebo and albendazole matching placebo, followed by 
ivermectin at Month 6. 
• Alternate scenario - Arm N2 (n = 84): 7 days of ABBV-4083 400  


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mg plus appropriate duration of albendazole matching placebo and 
ABBV-4083 matching placebo followed by either ivermectin or 
ivermectin matching placebo at Month 6. 
Ivermectin at Month 6 will be administered at the standard single oral dose 
of 150 µg/kg body weight.  
 
Route of Administration: Oral 
 
Indication 
Onchocerciasis 
Inclusion and Exclusion 
Criteria 
The Inclusion and Exclusion Criteria are the same for Parts 1 and 2. 
Inclusion Criteria 
1. Written, signed (or thumb-printed) and dated informed consent, after 
having the opportunity to discuss the study with the Investigator or a 
delegate. 
2. Men and women with Onchocerca volvulus infection, 18 to 65 years of age 
inclusive at time of Screening: 
i. Presence of at least one excisable subcutaneous nodule/ onchocercoma 
detected on palpation; 
ii. O. volvulus infection diagnosed by skin snip method: documented mf-
positivity on skin assessment on at least 2 out of 4 skin snips. 
3. Body weight > 40 kg at Screening. 
4. For women of child-bearing potential, acceptance of the requirement to use 
a highly effective form of birth control from Day 0 until at least 1 month 
after the final intake of IMP (Part 1: day 43; Part 2: 1 month after the 
administration of ivermectin or matching placebo at the Month 6 visit). 
Choice of birth control method must be clearly documented. 
Exclusion Criteria 
1. Participation in any studies other than purely observational studies within 
3 months prior to Screening, or during the trial, or within 5 times the half-
life of the drug tested in the previous clinical trial or is currently in the 
follow-up period for any clinical trial. 
2. Any vaccination within 4 weeks prior to IMP administration. 
3. Acute infection and/or febrile illness requiring therapy within 14 days prior 
to IMP administration. 
4. Administration of medication or herbal preparations as follows: 
i. Administration of any medication (with the exception of diclofenac, 
paracetamol, ibuprofen and aspirin) or herbal preparation within 14 days 
prior to IMP administration; 
ii. Use of strong CYP3A inhibitors or inducers including but not limited to 
ritonavir, 
ketoconazole, 
rifampicin, 
phenytoin, 
phenobarbital, 
carbamazepine, cimetidine within 14 days or 10 half-lives, whichever is 
longer, prior to IMP administration; 
iii. Use of other drugs known to interact with albendazole i.e. praziquantel, 
theophylline or dexamethasone, within 14 days or 10 half-lives, 
whichever is longer, prior to IMP administration; 
iv. The following antifilarial therapies, or medication that may have an 
antifilarial effect: 
o ivermectin; ≤ 6 months prior to IMP administration; and/or 
o doxycycline, ≤ 1 year prior to IMP administration: more than 2-week 
course; and/or 
o any other anti-Wolbachia treatments i.e. minocycline, rifapentine or 
rifampicin, ≤ 1 year prior to IMP administration: more than 2-week 
course; and/or 
o moxidectin, ≤ 2 years prior to IMP administration. 


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v. Other preventive chemotherapy, e.g. as part of an MDA programme, 
within 14 days prior to IMP administration 
5. Requirement for and inability to avoid ivermectin during the first 6 months 
after IMP administration. Requirement for albendazole during the first 28 
days after IMP administration or more than one dose per year thereafter 
given in MDA. 
6. Presence of any of the following at Screening, that could interfere with the 
objectives of the trial or the safety of the subject, in the opinion of the 
Investigator: 
i. Clinically significant abnormal physical examination or laboratory 
findings; 
ii. Any clinically significant medical condition, including, but not limited 
to significant acute or chronic liver or kidney condition or cardiovascular 
disease, active infection, current or previous epilepsy, known human 
immunodeficiency virus infection, disclosed by review of medical 
history or concomitant medication. 
7. Ophthalmological history or conditions that could interfere with the 
objectives of the trial or compromise the safety of the subject in the opinion 
of the Investigator, assessed at Screening, including the following (subject 
will be excluded if any of the criteria are met for either eye): 
i. 
Inflammatory eye disease, glaucoma, severe uveitis; evidence of 
retinal cysticercosis; 
ii. History of surgery for glaucoma; 
iii. Severe keratitis, and/or cataracts that interfere with visualisation of the 
posterior segment of the eye; 
iv. Evidence of an increased risk of acute glaucoma, based on examination 
of anterior chamber; 
v. Evidence of ocular media opacity, including lens opacity and vitreous 
opacities, that make difficult ocular examination in the opinion of the 
investigator; 
vi. Evidence of retinal or optic nerve pathology, including age-related 
macular degeneration; 
vii. Severe visual impairment (best corrected or pinhole visual acuity worse 
than 6/60 metres), severe reduction of peripheral visual fields (greater 
than grade 3 on Frequency Doubling Technology) or blindness; 
viii. Any microfilariae identified in the posterior segment of the eye or more 
than 50 microfilariae in the anterior segment of one eye. 
8. History of drug or alcohol abuse within 6 months prior to IMP 
administration. 
9. Use of alcohol within 48 hours and/or use of drugs of abuse within 15 days 
before IMP administration. 
10. Clinically significant history of cardiac abnormality, and/or relevant 
pathological abnormalities in the ECG in the screening period, such 
as atrioventricular block (PR interval > 240 msec), or prolongation of the 
QRS complex > 120 msec or QTcF interval > 450 msec. 
11. Abnormal laboratory test results at Screening, defined as: 
i. Aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
and/or alanine aminotransferase/serum glutamic pyruvic transaminase 
> 2 x upper limit of normal (ULN) and/or total bilirubin > 1.5 x ULN; 
ii. Serum potassium < lower limit of normal; 
iii. Serum creatinine > ULN and estimated glomerular filtration rate < 60 
mL/min (using the Modification of Diet in Renal Disease equation) 
12. History of severe drug allergy, non-allergic drug reactions, severe adverse 
reaction to any drug, or multiple drug allergies. 


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13. Known hypersensitivity to any ingredient of the IMPs, including the 
active ingredient of ABBV-4083, macrolides, albendazole or to 
ivermectin or to any medication used during the study (e.g. for eye 
examination). 
14. Blood donation within 8 weeks prior to Screening or blood transfusion 
received within 1 year prior to Screening. 
15. Coincidental infection with high Loa loa load (> 8000 microfilariae/mL) 
at Screening. 
16. Current hyperreactive onchodermatitis or severe manifestation due to 
onchocerciasis. 
17. Any other past or current condition that the Investigator feels would 
exclude the subject from the study or place the subject at undue risk. 
18. For women of child-bearing potential: pregnant, based on date of last 
menstrual period, and pregnancy test prior to first intake of IMP, or 
breastfeeding. 
19. Unwilling or unable to comply with the requirements of the study protocol 
for the entire duration of the study, in the opinion of the Investigator. 
20. Unable to participate in the study as per local law, if applicable. 
Type of Control 
In part 1: active control: albendazole  
In Part 2, base scenario: placebo control  
In Part 2, alternate scenario: active control: ABBV-4083  
Study Duration 
In Part 1: each subject’s participation will last approximately 6½ months, 
excluding the screening period, which may be up to 8 weeks. 
In Part 2: each subject’s participation will last approximately 24½ months, 
excluding the screening period, which may be up to 8 weeks. 
Data and Safety Monitoring 
Board 
An independent Data and Safety Monitoring Board will be established by the 
Sponsor in accordance with ICH guidelines. The composition, roles and 
responsibilities of the DSMB will be described in detail in the DSMB charter. 
Number of Subjects 
150 subjects in Part 1 
294 subjects (base scenario) or 336 subjects (alternative scenario) in Part 2 
Primary Endpoints and Time-
points for Measurement of 
Primary Endpoints 
The primary efficacy endpoints are: 
Part 1: 
• the status of each live female adult worm as without Wolbachia endobacteria 
or not, as assessed by immunohistology of nodules collected after 
nodulectomy at 6 months; 
Part 2: 
• the status of each subject as without skin microfilariae or not at 24 months, 
assessed across all skin snips in each subject. 
Sample Size Calculation 
Part 1: 
For the primary hypothesis in Part 1 that compares the proportion of live 
female adult worms without Wolbachia at Month 6 between a single-drug 
ABBV-4083 arm and the albendazole arm, an alternating logistic regression 
will be used to compare the endpoint between two arms, taking into 
account the clustering of this worm-level endpoint by subject. 17 subjects per 
arm will provide 88% power to detect the difference between a single-drug 
ABBV-4083 arm where 70% of worms are without Wolbachia and the 
albendazole arm where 30% of worms are without Wolbachia (2-sided α 
=0.10). 
For the primary hypothesis in Part 1 that compares the proportion of live 
female adult worms without Wolbachia at Month 6 between the combination 
arm of ABBV-4083 + albendazole for 7 days and the single-drug ABBV-
4083 arm, 25 subjects per arm will provide 81% power to detect the 
difference between the combination arm, where 90% of worms are without 
Wolbachia, 


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and the single-drug arm, where 70% of worms are without Wolbachia, with 
a 2-sided α-level of 0.10 using alternating logistic regression. 30 subjects will 
be enrolled per arm to account for 17% drop out by Month 6. 
 
Part 2: 
For the Part 2 primary hypothesis in the base scenario that compares the 
proportion of subjects without skin microfilariae at Month 24 between an 
active arm (Arm K, L or M) and the placebo arm (Arm N1), 62 subjects in 
the active arm and 31 subjects in the placebo arm will provide 91% power to 
detect the difference between an active arm (Arm K, L or M) where 70% of 
subjects are without skin microfilariae at Month 24 and the placebo arm (Arm 
N1) where 30% of subjects are without microfilariae at Month 24, using a 
logistic regression with 2-sided α=0.017 accounting for multiplicity 
adjustment. Assuming a 25% drop-out rate by Month 24, 84 subjects in each 
active arm and 42 subjects in the placebo arm are planned to be enrolled. 
Statistical Analyses 
All safety analyses will be performed on the Safety Population, which 
consists of all subjects who received at least one dose of IMP. Safety will be 
assessed by AEs, laboratory tests, vital signs, and ECG variables. This will 
be descriptive.  
 
Part 1:  
The Part 1 primary and combination endpoints, the proportion of adult female 
worms without Wolbachia endobacteria assessed by immunohistology at 6 
months, will be summarised among the PP for ND6M population, and the 
odds ratio for each of the treatment arm comparisons of interest (Arm A vs E 
and Arm B vs E; Arm C vs E, Arm C vs A, Arm D vs E, Arm D vs A) will 
be calculated using contrasts within an alternating logistic regression model 
with treatment arm as factor and also accounting for within-subject 
correlation, each at 2-sided α = 0.10. 
 
Part 2:  
The Part 2 primary endpoint of the percentage of subjects without skin 
microfilariae at Month 24 will be summarised across the PP for microfilariae 
population, and the adjusted odds ratio for each of the 3 active treatment arms 
will be compared to the comparator arm (Arm K vs N1 or N2, Arm L vs N1 
or N2, and Arm M vs N1 or N2) using contrasts within a logistic regression 
model with treatment arm as factor and number of sites per subject (1, > 1) 
and mean baseline mf (≤ 5, > 5) as covariates at 2-sided α = 0.017 Supportive 
subgroup analyses for the primary endpoint will also be performed for at least 
the following subgroups: number of sites per subject (1, > 1) and mean 
baseline mf (≤ 5, > 5). 
 
 


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List of Abbreviations 
ADME 
absorption, distribution, metabolism, and excretion 
AE 
adverse event 
ALCOA 
attributable, legible, contemporaneous, original, accurate 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
APOC 
African Program for Onchocerciasis Control 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AWOL 
Anti-Wolbachia Consortium 
BCRP 
breast cancer resistance protein 
bw 
body weight 
CD1 
cluster of differentiation 1 
CL 
clearance 
Cl– 
chloride 
Cmax 
maximum concentration in blood 
Cmin 
minimum concentration in blood 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DALY 
disability-adjusted life years 
DCF 
data clarification form 
DNA 
deoxyribonucleic acid 
DNDi 
Drug for Neglected Diseases initiative 
DSMB 
Data and Safety Monitoring Board 
EC50 
half maximal effective concentration 
EC90 
90% effective concentration 
ECG 
electrocardiogram/electrocardiography 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
FE 
food effect 
FIH 
first in human 
GABA 
gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 


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hERG 
human ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 
IC50 
concentration required to inhibit 50% of organisms 
ICC 
intraclass correlation coefficient 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IMP 
investigational medicinal product 
IR 
immediate release 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intention to treat 
IVM 
ivermectin 
LSF 
liquid service formulation 
M 
metabolite 
MAD 
multiple ascending dose 
MATE 
multidrug and toxin extrusion protein 
MDA 
mass drug administration 
MDCK 
Madin-Darby canine kidney 
MedDRA 
Medical Dictionary for Regulatory Activities 
mf 
microfilaria/microfilariae 
mRNA 
messenger ribonucleic acid 
NCI 
National Cancer Institute  
ND24M 
nodulectomy at 24 months 
ND6M 
nodulectomy at 6 months 
NK1 
neurokinin 1 
NOAEL 
no observed adverse effect level 
NOEL 
no observed effect level 
OATP 
organic anion transporting polypeptide 
OCP 
Onchocerciasis Control Program 
OCT 
organic cation transporter 
P-gp 
glycoprotein P 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic 
PIG-a 
phosphatidyl inositolglycan class A gene 
PK 
pharmacokinetic 
PoC 
proof of concept 
PP 
per protocol 
QD 
once daily 


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RDT 
rapid diagnostic test 
SAD 
single ascending dose 
SAE 
serious adverse event 
SmPC 
Summary of Product Characteristics 
SOP 
standard operating procedure 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
TaNT 
test-and-not-treat 
TEAE 
treatment-emergent adverse event 
tmax 
time to reach maximum concentration in blood 
TNT 
test and treat 
TylA 
tylosin A 
ULN 
upper limit of normal 
WHO 
World Health Organization 
WOCBP 
women of child-bearing potential 
 
 


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2 Introduction 
2.1 Background Information on Onchocerciasis 
Onchocerciasis represents a major public health problem in affected countries with up to 1.34 
million disability adjusted life years lost in 2017.1 This disproportionately high number is 
driven by disease-induced disability, and overall loss of economic productivity. The challenge 
for mass drug administration (MDA) programs is to eliminate transmission by periodic 
treatment of vulnerable populations with ivermectin. This removes microfilariae (mf) from the 
skin and temporarily prevents the release of mf by the adult female worm. However, mf return 
within 6-8 months, and control strategies delivering ivermectin on a six or 12 monthly cycle 
must be maintained over a 10 to 15-year period to reach elimination. Notably, MDA requires 
extensive logistical efforts and financial commitments. Treating entire populations requires 
ethical discussions and evaluations of cost-effectiveness. Success in MDA is dependent on the 
sustained coordination of supply logistics to ensure that treatment reaches all target recipients. 
Because of these challenges, interruption of transmission and disease elimination worldwide 
has proven more difficult than initially projected. In addition, MDA given for long periods 
carries the risk of resistance, described for ivermectin use in animal-health applications, 
together with sub-optimal response in humans.2 Clearly other options are needed. According to 
a number of recent studies and simulations,3–5 with the current strategies, elimination of 
onchocerciasis will not be feasible within the timelines of the United Nations Sustainable 
Development Goals,6 i.e. 90% reduction in the number of people requiring intervention by 
2030, or the previous goals set by the World Health Organization (WHO) to eliminate 
onchocerciasis in 80% of African countries by 2025.7 
New treatments are needed to improve individual clinical care for patients, reduce human 
suffering, achieve cure and ensure advancement toward the WHO’s goal of elimination by 
providing additional tools to shorten the timelines for elimination. 
Ivermectin, the current treatment of onchocerciasis used in MDA programs, is microfilaricidal, 
killing only the larvae (mf). Although ivermectin is effective in reducing transmission cycles, 
therapy must be repeated at regular intervals (6 or 12 months) for 10-15 years, making 
implementation of a sustainable MDA program challenging and extremely difficult in some 
endemic countries. In addition, there are limitations with the use of ivermectin in zones where 
Loa loa is co-endemic. It has become clear that elimination may not be feasible by 2025 and 
success highly depends on local pre-control endemicity, past and future (therapeutic) coverage 
patterns, and geographic coverage. If MDA coverage is lower or the fraction of systematic non-
adherers is higher than assumed in the simulations, the effectiveness of interventions will likely 
deviate from the model predictions and further delay the timeline to elimination. Recent 
modelling using ONCHOSIM predicts there will be around 10 million infected individuals with 
positive skin microfilaria in the areas covered by African Program for Onchocerciasis Control 
(APOC) in 2025,8 with > 6 million manifesting clinical symptoms.9 The total population at risk 
will be approximately 200 million in the countries formerly covered by APOC. Modelling 
activities have begun to assess the impact of a macrofilaricidal drug complementing or 
replacing current elimination activities. Preliminary results show that the timelines would 
shorten by 40-50% under both MDA and test-and-treat (TNT) strategies.  
In summary, while MDA is effective in reducing transmission and morbidity in some settings, 
a drug that kills the adult worm or has a long-term inhibition of embryogenesis, offers the 
advantage of reducing the need for multiple cycles of MDA and would be an essential addition 


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to the global strategy to eliminate onchocerciasis. A new macrofilaricide or long-term treatment 
would be useful for:  
• MDA, if the safety and tolerability profile and the duration of treatment are suitable, in 
order to drastically reduce the number of MDA cycles from 10-15 years as currently 
required. 
• TNT strategies, for treatment of patients in endemic areas outside MDA campaigns when 
diagnostic tools are available, especially in “mop up” campaigns after the disease burden 
has been reduced by MDA programs rendering them no longer cost effective, or in areas 
where regular ivermectin distribution is difficult.  
• Test-and-not-treat (TaNT) campaigns in areas where Loa loa is co-endemic, if the 
macrofilaricidal drug also has rapid microfilaricidal activity. 
• Appropriate medical care .  
2.2 Summary of Non-clinical Data 
2.2.1 Summary of Non-clinical Efficacy 
ABBV-4083 is a novel macrolide antibacterial that is highly potent against Wolbachia, the 
symbiotic endobacteria present in the filarial nematodes responsible for onchocerciasis. It is 
chemically derived from the common veterinary macrolide antibiotic tylosin and has a spectrum 
of activity across a panel of pathogenic bacteria similar to that of other macrolides. ABBV-
4083 is uniquely potent against Wolbachia, with EC50 values of 0.022 and 0.75 nM in insect 
cells and cultured Brugia malayi microfilariae, respectively.10 ABBV-4083 is not directly -cidal 
to filarial worms,11 but only elicits its effects indirectly through depletion of Wolbachia. 
ABBV-4083 was shown to effectively deplete Wolbachia in several in vivo models of filarial 
nematode infection. Following oral administration in mouse or jird (Mongolian gerbil) hosts 
implanted with either larval or adult stages of Brugia malayi, treatment with ABBV-4083 
resulted in > 95% depletion of Wolbachia.12,13 Similarly, ABBV-4083 depleted > 95% of 
Wolbachia within Onchocerca ochengi adult worms implanted into jirds,14 and within 
Litomosoides sigmodontis in naturally infected jirds.15,16 ABBV-4083 treatment also resulted in 
the sterilisation of Brugia malayi and Litomosoides sigmodontis female adult worms, as 
evidenced by a > 90% decline in microfilariae after several weeks.13,15,16 ABBV-4083 also 
demonstrated additivity/synergy in association with albendazole, as evidenced by a > 99% 
decline in microfilariae at doses of each agent that were ineffective when dosed alone.19 Finally, 
up to four non-consecutive daily treatments within a 14-dose regimen did not significantly 
erode Wolbachia depletion in Litomosoides sigmodontis female adult worms.20 
ABBV-4083 has also recently been shown to be additive/synergistic with albendazole in 
preclinical filarial models. The addition of albendazole has been shown to be beneficial for the 
depletion of Wolbachia with doxycycline in preclinical models,17 as well as in a recent clinical 
trial.18 In contrast, albendazole itself has shown very low anti-Wolbachia activity in preclinical 
studies. 
2.2.2 Summary of Safety Pharmacology Data 
ABBV-4083 was tested in safety pharmacology studies including assessing effects on the CNS, 
cardiovascular, and respiratory systems. In a panel of off-target binding assays, ABBV-4083 
displaced control-specific binding by > 50% in the NK1 (IC50 0.22 μM) and GABA-gated Cl– 
channel (IC50 9.1 μM) assays.21,22 ABBV-4083 produced no neurobehavioral effects in a GLP 


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functional observation batter in rat through the highest dose of 300 mg/kg (maximum blood 
concentration [Cmax] 1.86 µg/mL).23,24 ABBV-4083 decreased hERG tail current in vitro by 
30% at the highest concentration of 26.0 µg/mL (IC50 > 26.0 µg/mL).25 In a telemetry-
instrumented GLP dog study, ABBV-4083 had no effect on mean arterial pressure, heart rate 
or the electrocardiogram (ECG; QRS, RR, PR, and QT intervals) through the highest oral dose 
of 60 mg/kg (Cmax 2.73 µg/mL).26,27 In a GLP study, ABBV-4083 produced no effect on 
respiratory function through the highest dose of 300 mg/kg (Cmax 1.86 µg/mL).28,24 
2.2.3 Summary of Non-clinical Pharmacokinetic and Drug Metabolism Data 
The ABBV-4083 pharmacokinetic profile in CD-1 mice, Sprague-Dawley rats, beagle dogs and 
cynomolgus monkeys was characterised by high plasma clearance, high volumes of distribution 
(Vss > 2 L/kg) and short to moderate plasma elimination half-lives (t1/2 0.8 – 4.7 hr) following 
single intravenous doses.29 ABBV-4083 oral bioavailability was low in mice, rats, and monkeys 
(3.2%, 6.5%, 2.8%, respectively), with higher values in dog (17.4%). At steady state, there were 
no apparent sex differences in rats or dogs. ABBV-4083 exposures on Day 28 trended higher 
or were comparable to Day 1 following once daily dosing in rats and dogs.24,27 
ABBV-4083 has moderate plasma protein binding across species, with a mean unbound fraction 
at 1 µM of 0.071, 0.081, 0.11 and 0.076 for mice, dogs, monkeys and humans, respectively.30 
Mean total recovery of excreted radioactivity from the bile duct cannulated rats was 90.4% after 
the 6 mg/kg intravenous dose or 92.5% after a 100 mg/kg oral dose.31 Drug-related radioactivity 
was mainly eliminated via the biliary route (60.6% of the intravenous dose). Renal elimination 
was minor (8.0% of the intravenous dose). Of the radioactivity recovered in the bile, 18.4% 
was unchanged parent drug (19.3% of the dose). Cysteine conjugate M5 accounted for about 
32% of dose recovered in the bile, urine and faeces. Other metabolites were present at low or 
trace levels, each less than 10% of dose. M10 (hydrate) and co-eluting metabolites M11x 
(hydrate)/M5 (cysteine conjugation) were the major circulating components accounting for 
39.7% and 34.6% of the radioactivity in plasma, respectively; unchanged parent drug accounted 
for 25.6% of plasma radioactivity.31 
In human liver microsomes, ABBV-4083 is a direct inhibitor of CYP3A4 (midazolam as a 
substrate) with an IC50 of 26 µM, with all other isoforms exhibiting IC50 values greater than 
30 µM.32 No time-dependent inhibition was observed at ABBV-4083 concentrations up to 
50 µM. ABBV-4083 inhibited UGT1A1 in human liver microsomes, with an IC50 of 3.4 µM. 
ABBV-4083 does not increase CYP1A2, 2B6 or 3A4 mRNA expression at concentrations up 
to 20 µM in human hepatocyte incubations.33 At the projected therapeutic dose, i.e. 400 mg 
once daily (QD), ABBV-4083 is predicted to have no perpetrator drug interaction (AUCR < 2) 
with CYPs using the United States Food and Drug Administration (FDA)’s mechanistic static 
model.34 In vitro, ABBV-4083 is metabolised primarily by CYP3A; co-administration with 
CYP3A inhibitors or inducers is likely to modulate the ABBV-4083 concentrations. 
In vesicles, ABBV-4083 inhibited P-gp and BCRP with IC50 values of 0.98 and 4.1 µM, 
respectively; the IC50 values for P-gp and BCRP in MDCK cells were markedly higher (60 and 
11 µM, respectively), likely due to the low cellular permeability of the compound.35 ABBV-
4083 inhibited the uptake transporters OATP1B1 and OATP1B3 with IC50 values of 2.5 and 
1.1 µM, respectively. IC50 values for OCT1, OCT2, OAT1, OAT3, MATE1, and MATE2K 
were estimated to be > 30 µM. Based on the transporter inhibition decision trees,34 inhibition 
of P-gp, BCRP and OATP1B1/3 are expected at the 400 mg clinical dose. 
ABBV-4083 is a substrate for P-gp but not for BCRP.35 


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2.2.4 Summary of Toxicology Data 
The toxicity profile of ABBV-4083 has been characterised in 4-week GLP-compliant repeat 
dose studies in rats and dogs.24,27 These toxicity studies have identified the dog as the most 
sensitive species. All haematology, coagulation, and clinical chemistry effects in the rat were 
considered non-adverse and wholly reversed following the 4-week recovery period, with the 
exception of globulin. In the dog, hepatocellular and hepatobiliary findings were seen and 
considered adverse only at the high dose of 60 mg; these findings were resolved or partially 
resolved at the end of the recovery period. Microscopic findings were associated with elevated 
hepatic enzyme activities (ALP, GGT, ALT, AST) and total bilirubin concentration at the end 
of the dosing period; the minimal bile ductule hyperplasia present at the end of the recovery 
period was consistent with the partial resolution of adverse biliary effects and was reflected in 
the corresponding temporal changes in liver-related serum chemistries. There were no effects 
on the liver among animals at 5 or 15 mg/kg/day at the end of the dosing period. The NOAEL 
in the dog was established as the mid dose, 15 mg/kg/day, and was associated with a Cmax of 
0.849 µg/mL and whole blood exposure (AUC0-24) of 2.26 µg•hr/mL.  
ABBV-4083 presents no genetic toxicity risk to healthy subjects in the Phase-I study. A 
potential for direct mutation was not detected in the in vitro bacterial reverse mutation, mouse 
lymphoma or the in vivo PIG-a mutation assays.36,37,38 The in vivo rat micronucleus study (bone 
marrow), including an evaluation of liver, stomach, and blood for DNA strand breaks (comet 
assay), was negative.39 ABBV-4083 was evaluated in GLP-compliant embryo-foetal 
development studies in the rat,40 as well as the mouse41 and is not teratogenic or fetotoxic. 
In support of the Phase-II trial, a GLP-compliant 7-day toxicity study was conducted in dogs to 
examine the effects of ABBV-4083 when dosed in combination with albendazole.42 The 
ABBV-4083 doses (5 and 15 mg/kg/day) were selected to provide exposures comparable to 
those obtained from a 400 mg clinical dose and a small multiple. The albendazole dose (50 
mg/kg/day) targeted exposures of the albendazole sulfoxide metabolite comparable to a 
literature average of values obtained from a 400 mg albendazole dose. All study findings were 
non-adverse and reversible by the end of the 28-day recovery period. The primary microscopic 
effect observed was in the liver (non-adverse minimal increased cellularity of bile ductular 
epithelium and minimal periductular mixed cell infiltrates) at 15 mg/kg/day with or without 
50 mg/kg/day albendazole. The NOAEL in this GLP study was the highest combination dose 
tested, 15/50 mg/kg/day. 
A summary of all toxicology studies conducted with ABBV-4083 is presented in the 
Investigator Brochure. 
2.3 Summary of Clinical Data 
2.3.1 Phase-I Study in Healthy Subjects 
Study M16-710 was a Phase-I first-in-human (FIH) study in 3 parts.43 Part 1 was a randomised, 
double-blind, placebo-controlled single ascending dose (SAD) study. Part 2 was a randomised, 
single-dose, open-label, two-period cross-over food effect (FE) study. Part 3 was a randomised, 
double-blind, placebo-controlled multiple ascending dose (MAD) study. 
In the FIH study, single (40 mg up to 1000 mg [n=48 subjects]) and multiple (100, 200 or 400 
mg once daily for 7 days [n=18] and 200 or 400 mg once daily for 14 days [n=12]) doses were 


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administered. A total of 78 healthy subjects have been exposed to ABBV-4083 (36 in Part 1, 
12 in Part 2, and 30 in Part 3) and 22 received a placebo.  
In Part 1 (SAD), each of Groups 1 through 6 consisted of 6 subjects treated with ABBV-4083 
40 mg, 100 mg, 200 mg, 400 mg or 1000 mg, and 2 subjects treated with placebo.  
In Part 2 (FE), 12 subjects in Group 7 received ABBV-4083 1000 mg under either fasting or 
fed conditions.  
In Part 3 (MAD), each dose group, numbered 8 through 12, consisted of 6 subjects who received 
ABBV4083 100, 200 or 400 mg QD × 7 days; or 200 or 400 mg QD × 14 days and 2 subjects 
who received placebo. 
2.3.1.1 Summary of Phase-I Safety Information 
In Part 1, treatment-emergent adverse events (TEAEs) were reported in 16.7% of ABBV-4083-
treated subjects and 0% of placebo-treated subjects. The most common (≥ 5%) TEAEs for 
ABBV-4083-treated subjects were nausea (8.3%) and headache (5.6%). A single subject in the 
100-mg group experienced Grade-1 elevated alanine aminotransferase (ALT) on Study Day 3, 
resolving on Study Day 14. 
In Part 2, TEAEs were reported in 58.3% of ABBV-4083-treated subjects (66.7% in fasting 
subjects and 50.0% in fed subjects). The most common (≥ 10%) TEAEs for ABBV-4083-
treated subjects were nausea (25.0%), diarrhoea (16.7%), headache (16.7%), hepatic enzyme 
increased (16.7%) and vomiting (16.7%). During the fasting period, 2 subjects experienced 
asymptomatic and reversible elevated ALT and/or aspartate aminotransferase (AST) values at 
Grade 1. In the fed period, 2 subjects experienced mild adverse events (AEs) of elevated serum 
liver enzymes leading to discontinuation of study drug: one subject experienced asymptomatic 
and reversible Grade-2 elevated ALT and/or AST 6 days after receiving a single 1000 mg dose 
of ABBV-4083, and 1 subject experienced asymptomatic and reversible Grade-4 elevated ALT 
and/or AST 3 days after receiving a single 1000 mg dose of ABBV-4083. No accompanying 
total, direct, or indirect bilirubin elevations were observed. The Investigator considered the AEs 
to have a reasonable possibility of being related to ABBV-4083. The effect of food on exposure 
parameters, i.e. Cmax or area under the blood concentration-time curve (AUC), was minimal. 
Independent internal and external drug-induced liver injury experts were consulted. In 
accordance with their advice, the single dose of 400 mg was tested again in Part 1 Group 6 
(n = 6 subjects) with extended monitoring from 3 to 10 days. No above normal transaminase 
levels were observed. This was followed by the MAD portions of the study (Part 3) with the 
same extended monitoring period.  
In Part 3, three subjects experienced Grade-1 elevated ALT and/or AST in the dose group 
receiving 100 mg QD × 7 days. No elevated transaminase levels were observed in the dose 
groups receiving 200 or 400 mg × 7 days or 200 or 400mg QD × 14 days. All transaminase 
elevations were asymptomatic and reversible, and none were accompanied by elevated bilirubin 
levels. TEAEs were reported in 33.3% of ABBV-4083-treated subjects and 30.0% of placebo-
treated subjects. The most common (≥ 5%) TEAEs for ABBV-4083-treated subjects were 
headache (6.7%), nausea (6.7%), palpitations (6.7%) and medical device site reaction (6.7%).  
In this FIH study, one serious adverse event (SAE), which was of fatal outcome, was reported 
and was assessed as not related to ABBV-4083: the subject, who received a single 1000 mg 
dose of ABBV-4083 on Day 1 under fed conditions in Period 1 of Part 2, experienced an SAE 
of unconfirmed pulmonary embolus, which resulted in death on Day 9 post-dosing. The 


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Investigator considered the death to be not related to the study, and more likely related to the 
subject’s hypercoagulable state at baseline, i.e. underlying risk factor for thrombocytosis and 
hypercholesterolemia. 
2.3.1.2 Summary of Phase-I Pharmacokinetic Information 
All 78 subjects, i.e. 36 subjects from Part 1, 12 subjects from Part 2, and 30 subjects from Part 
3, who received ABBV-4083 were included in the pharmacokinetic analyses. 
Pharmacokinetic (PK) results from Parts 1 and 3 of Study M16-710 suggested that maximum 
concentrations of ABBV-4083 were achieved around 1.5 to 2 hours with a half-life less than 4 
hours at doses ≤ 400 mg. Cmax and AUC increased in a slightly more than dose-proportional 
and predictable manner. Following multiple dose administration, the concentrations on Day 1 
and Day 14 appeared to be similar. There did not appear to be a relationship between ABBV-
4083 concentrations and QTcF from baseline, suggesting that ABBV-4083 has no clinically 
relevant effects on QTc prolongation. The effect of food on exposure parameters, i.e. Cmax and 
AUC, was minimal. 
2.3.2 Conclusion on Clinical Data to Date 
In summary, no safety concerns have been identified to date for ABBV-4083 in doses up to 400 
mg/day QD for 14 days based on the FIH study. There was only one serious adverse event 
(SAE), of fatal outcome and assessed as not-related to ABBV-4083, reported after 
administration of a single dose of 1000 mg, in the FIH study. Elevated liver enzymes were seen 
after a 1000 mg single dose of ABBV-4083, but no hepatotoxicity was seen with multiple doses 
of ABBV-4083 up to 400 mg QD for 14 days. 
Taking into consideration the non-clinical data (see Section 2.2) and first data in human (see 
Section 2.3.1), one potential safety effect is currently under consideration: “alterations in liver 
tests”. Therefore, monitoring of biochemistry laboratory tests, including liver tests, is required 
to further assess this potential safety effect during the upcoming clinical trials. 
The results from the Phase-I study in healthy male and female subjects support continuation of 
the clinical development programme of ABBV-4083 as treatment for onchocerciasis. 
Further details can be found in the Investigator Brochure, which contains comprehensive 
information on ABBV-4083. 
2.4 Design and Rationale for Study 
2.4.1 Overview of Study Design 
This phase-II study in subjects with onchocerciasis will be an adaptive study with two parts. In 
Part 1 (proof-of-concept [PoC]), four regimens of ABBV-4083 ± albendazole will be assessed 
in comparison to albendazole alone with the aim of selecting two regimens having optimal 
activity and safety to continue into Part 2 Regimen Selection. Part 1 will end at 6 months follow-
up, and the study will be paused to evaluate nodules to determine whether the ABBV-
4083 + albendazole combinations are superior to both ABBV-4083 and albendazole alone, and 
to select the optimal arms to continue into Part 2 (see Figure 1, Figure 2 and Figure 3). Based 
on earlier studies, albendazole alone is not expected to affect Wolbachia levels18 or to 
substantially interfere with embryogenesis in female worms.44 The albendazole arm is therefore 
considered largely equivalent to an untreated control arm for efficacy. Selection of the regimens 


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for Part 2 will take into consideration the balance of efficacy, i.e. analysis of Wolbachia 
depletion in adult worms as surrogate marker, supported by effects on embryogenesis in female 
worms, as well as safety and convenience, i.e. the number and duration of drugs taken. The 
target efficacy for Part 1 will be based on comparison to studies using doxycycline, which 
produces ≥ 90% Wolbachia depletion at 6 months.18,45 This level of Wolbachia depletion at 
Month 6 has been correlated with the absence of skin mf at longer-term time-points.45 
Part 2 is a 24-month study designed to select the optimal regimen for progression to Phase III. 
The primary endpoint is the absence of skin mf at Month 24, which is the accepted endpoint 
for registration and was confirmed by US FDA. Positive results in Part 1 of the study (PoC), 
based on all safety, tolerability and efficacy available data, will initiate continuation of the study 
into Part 2 (Regimen Selection). Up to two regimens will be chosen from Part 1 and additional 
subjects will be enrolled. Provided that the combination rule has been satisfied based on data 
on Wolbachia depletion in Part 1, i.e. that ABBV-4083 + albendazole is superior to either agent 
alone of equal duration, the active arms in Part 2 will be compared to placebo. If the 
combination rule has not been satisfied in Part 1, the comparator arm will be ABBV-4083 400 
mg QD for 7 days, (based on the assumption that the superiority of a combination arm to 
albendazole alone (Arm E) will have been achieved), and the combined Month 6 data from 
Parts 1 and 2 will be used to satisfy the combination rule. 
2.4.2 Rationale for the Study 
Adult filarial worms causing onchocerciasis carry an obligate symbiotic endobacterium, 
Wolbachia, which is essential for development, fecundity, and ultimate survival.46,47 Clinical 
studies with the antibiotic doxycycline, which depletes endobacterium populations but has no 
direct effect on the host worms, have demonstrated the death of adult worms over time after 
antibacterial therapy.18,48–51 This indirect, anti-Wolbachia approach to the treatment of 
onchocerciasis brings several advantages that are considered particularly desirable for a new 
antifilarial agent, for the following reasons. 
• It may avoid the side effects caused by the rapid death of microfilariae. Treatment with 
ivermectin is rapidly microfilaricidal and can produce a systemic inflammatory reaction 
associated with the release of both microfilarial and Wolbachia antigens from dying 
microfilariae, called Mazzotti reaction. Treatment with an anti-Wolbachia agent only 
interrupts the production of microfilariae, resulting in a slow decline in microfilarial 
levels. Adult worm death also occurs, but very slowly i.e. ≥ 2 years after treatment, 
avoiding the potential for inflammation due to rapid death of the adult worms.49 
• It produces long-term sterilisation of adult female worms. In contrast to treatment with 
ivermectin, which primarily affects the late stages of microfilarial development and 
produces only temporary worm sterilisation, treatment with an anti-Wolbachia agent has 
been shown to interfere with embryogenesis for at least 24 months.49,50 
• It has the potential to interrupt transmission shortly after treatment, even before 
microfilarial levels decline. Rapid depletion of Wolbachia within microfilariae has been 
shown to retard the development of larvae within the insect vector following ingestion.54 
• It has the potential to modulate disease pathology. While live O. volvulus microfilariae 
are relatively benign, the release of Wolbachia endotoxin-like products from degenerating 
microfilariae creates a proinflammatory stimulus that has been shown to produce keratitis 
(corneal inflammation) in a mouse model.55 Depletion of Wolbachia by antibacterial 
therapy may thus reduce ocular and possibly also skin pathology. 


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• It is expected to be especially beneficial in regions co-endemic with Loa loa, where anti-
microfilarial treatment is challenging, due to potential severe AEs related to the rapid 
death of Loa loa microfilariae in the blood. Loa loa worms do not carry the Wolbachia 
endosymbiont and a microfilaricidal effect on Loa loa is not expected.51 
• Finally, it has also been shown to be effective in lowering microfilariae in regions with 
suboptimal response to ivermectin.48 
Although doxycycline is effective as a macrofilaricide via its anti-Wolbachia activity, it is 
contraindicated in pregnant women and children through the age of 8 years due to 
developmental toxicities. Furthermore, 4 to 6 weeks of daily therapy with doxycycline is 
required to lower the Wolbachia population sufficiently to produce a -cidal effect in the adult 
worm. Consequently, doxycycline is unsuitable for MDA and far from ideal for subject 
management. Therefore, agents with better safety profiles and more rapid onset of action are 
needed. The Wolbachia endobacterium is not susceptible to many traditional classes of 
antibacterials and screening for novel anti-Wolbachia agents was conducted with support from 
the Bill & Melinda Gates Foundation and the Global Health Innovative Technology Fund.56 
In conjunction with the Anti-Wolbachia Consortium (AWOL) based at the Liverpool School 
of Tropical Medicine, screening of a collection of antibacterials supplied by AbbVie led to the 
identification of tylosin A (TylA), a known veterinary antibacterial, as a promising lead. 
Preliminary studies with TylA suggested that it could effectively clear the Wolbachia bacterium 
in a mouse model of filariasis when delivered intraperitoneally to a greater extent than 
doxycycline and at shorter dosing regimens. However, the PK profile of TylA appears to be 
permeability limited, and oral administration produced only a marginal effect. This was 
corroborated by PK studies in mice suggesting that the oral bioavailability of TylA is ≤ 1%. 
Analogues of TylA with improved permeability were subsequently identified, leading to 
markedly enhanced drug exposure upon oral dosing. A subset of these PK-improved analogues, 
including ABBV-4083, also demonstrated superior anti-Wolbachia potency in vitro. This 
combination of properties greatly improves its ability to deplete the endosymbiont as an orally 
delivered drug. 
ABBV-4083 is a promising candidate to kill and/or provide long-term sterilisation of the 
sexually mature adult O. volvulus. ABBV-4083 could be considered as an alternative to 
doxycycline if a clear advantage with a shorter regimen duration, i.e. ≤ 14 days, and a better 
safety profile is demonstrated. ABBV-4083 has also recently been shown to be additive/ 
synergistic with albendazole in preclinical filarial models, similar to results with doxycycline 
plus albendazole in preclinical models,51 as well as in a recent clinical trial.18 In contrast, 
albendazole alone has shown very low anti-Wolbachia activity in preclinical studies. The study 
will therefore investigate the efficacy of ABBV-4083 both alone and in combination with 
albendazole for 7 or 14 days. 
2.4.3 Rationale for Dose Selection 
ABBV-4083, albendazole, and ivermectin or matching placebo will be administered orally. 
The 400 mg QD dose of ABBV-4083 administered for 7 or 14 days was tested in the FIH study 
(Study M16-710) and was considered safe and well tolerated. This dose maintains mean free 
plasma concentrations of ABBV-4083 in excess of the estimated in vitro EC90 for a similar 
period of time as a dose in jirds (50 mg/kg) that is effective following 7 or 14 days of dosing in 
Litomosoides sigmodontis infected jirds. This dose also produces a similar mean free Cmax and 
longer time in excess of the in vitro EC90 compared to a dose in jirds (20 mg/kg) that is effective 


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following 7 days of dosing in combination with albendazole in Litomosoides sigmodontis 
infected jirds. 
The oral dose of albendazole over-encapsulated tablets to be administered to subjects in Arms 
C, D and E is 400 mg QD for 7 days, 3 days and 7 days, respectively. Albendazole is given at 
400 mg QD for 1 to 3 days for intestinal worms and skin nematodes such as cutaneous larva 
migrans, and at 400 mg BID for 1 to 3 days for liver flukes.57 
Higher daily doses (400 mg BID) for prolonged periods up to 84 days total are indicated for 
more disseminated systemic infections such as echinococcosis and neurocysticercosis.58 Since 
mild to moderate elevations of liver enzymes have been reported with the higher/more 
prolonged dose,58 and the 400 mg QD dose produces plasma exposure of the active metabolite 
(albendazole sulfoxide) roughly equivalent to the exposure shown to be active in combination 
with ABBV-4083 in preclinical efficacy studies, this dose was selected for combination with 
ABBV-4083. In the preclinical Litomosoides sigmodontis model in jirds, as few as 3 days of 
albendazole combined with 7 days of ABBV-4083 produced strong signals of Wolbachia 
depletion and female adult worm sterilisation,59 providing the basis for the duration of dosing 
in Arm D. Plasma concentrations of albendazole sulfoxide are increased by administration with 
food,60,61 therefore albendazole will be administered with food in this study. 
Ivermectin over-encapsulated tablets will be given at the standard MDA dose as a single oral 
dose of 150 µg/kg body weight at Month 6 in Part 2 of the study to subjects who receive ABBV-
4083 matching placebo plus albendazole matching placebo.65,68 Some subjects receiving 
ABBV-4083  albendazole regimens in Part 2 will also receive over-encapsulated ivermectin 
at Month 6 while the remainder of subjects will receive ivermectin matching placebo, in order 
to assess the effect of a dose of ivermectin at Month 6 on efficacy at Month 24. No subjects 
receiving active ABBV-4083  albendazole in Part 2 are deemed at significant risk of ocular or 
other clinical progression without a dose of ivermectin at Month 6, since regimens will only be 
advanced into Part 2 on the basis of a strong signal of Wolbachia depletion in Part 1. Active 
anti-Wolbachia treatment is expected to produce a slow decline in skin microfilariae over time 
due to the sterilisation of adult female worms, lowering the likelihood of the appearance of 
ocular microfilariae. In addition, studies have shown that ocular disease progression is slow and 
is highly associated with microfilarial invasion into the eyes. Frequent ophthalmological 
examinations will be conducted, and unblinded ivermectin will be provided as rescue therapy 
at the discretion of the Investigator. Therefore, the study plan provides adequate measures to 
ensure the safety of all subjects in Part 2 who do not receive ivermectin at Month 6. 
3 Study Design 
3.1 Overall Study Design 
DNDi-TYL-01 will be a multicentre, randomised, active and/or placebo-controlled, double-
blind, parallel-group, adaptive Phase-II study in two parts. It will be conducted in at least two 
investigational centres, with competitive recruitment. Additional centres may be included. All 
centres must however have access to appropriate medical facilities to treat severe AEs. 
Part 1 will use a surrogate endpoint of Wolbachia depletion in adult female worms to: 
• establish proof of concept for ABBV-4083 in onchocerciasis by demonstrating 
superiority of the regimens of ABBV-4083 alone over the control regimen, albendazole 
alone, which has been shown to have little or no activity in onchocerciasis,62,44  


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• establish the activity of ABBV-4083 and albendazole in combination by demonstrating 
superiority of a regimen of ABBV-4083 + albendazole over regimens of ABBV-4083 and 
albendazole alone of equal duration, and 
• establish up to two preferred regimens of ABBV-4083 and/or ABBV-4083 + albendazole 
to progress into Part 2 of the study. 
Each subject’s participation in Part 1 of the trial will last approximately 6½ months, excluding 
the screening period, which may be up to 8 weeks. At Month 6, Part 1 will end, and the study 
will be paused to evaluate the nodules and skin mf. Part 1 data will be unblinded to the Sponsor 
and analysed to allow for finalisation of the study design in Part 2. Enrolment will then resume 
in Part 2. 
Part 2 will use a clinically relevant endpoint of depletion of skin microfilariae at Month 24 to: 
• identify the preferred regimen of ABBV-4083 or ABBV-4083 + albendazole to progress 
into Phase-III studies, and 
• evaluate the effect of a dose of ivermectin 6 months after ABBV-4083 or ABBV-4083 + 
albendazole on skin microfilarial density at Months 12, 18 and 24. 
If the superiority of ABBV-4083 + albendazole over ABBV-4083 alone is not demonstrated in 
Part 1, surrogate endpoint data from Part 2 (i.e. Wolbachia depletion in adult worms at Month 
6) from Arms with ABBV-4083 + albendazole and ABBV-4083 alone will be combined with 
data from Part 1 to assess the superiority of ABBV-4083 + albendazole to ABBV-4083 alone 
(Part 2 Alternate Scenario). 
Each subject’s participation in Part 2 of the trial will last approximately 24½ months, excluding 
the screening period, which may be up to 8 weeks. The set of subjects in Part 2 is fully 
independent from the set of subjects in Part 1. The final analysis will be conducted at the end 
of Part 2. 
A Safety Review Committee (SRC) and an independent Data and Safety Monitoring Board 
(DSMB) will be appointed (See Sections 13.2 and 13.3). 
3.2 Study Design - Part 1 
In Part 1, a total of 150 subjects will be recruited, and will be randomised continuously 1:1:1:1:1 
into one of five parallel treatment arms until group size is achieved. Within each treatment arm, 
participants will be stratified by the number of operable sites with onchocercomata. There will 
be two strata, i.e. one site and more than one site. 
The five treatment arms are defined as follows: 
• Arm A (N = 30): 7 days of ABBV-4083 400 mg + albendazole matching placebo followed 
by 7 days of ABBV-4083 matching placebo 
• Arm B (N = 30): 7 days of ABBV-4083 400 mg + albendazole matching placebo followed 
by 7 days of ABBV-4083 400 mg 
• Arm C (N = 30): 7 days of ABBV-4083 400 mg + albendazole 400 mg followed by 7 
days of ABBV-4083 matching placebo 
• Arm D (N = 30): 3 days of ABBV-4083 400 mg + albendazole 400 mg followed by 4 
days of ABBV-4083 400 mg + albendazole matching placebo followed by 7 days of 
ABBV-4083 matching placebo 
• Arm E (N = 30): 7 days of ABBV-4083 matching placebo + albendazole 400 mg followed 
by 7 days of ABBV-4083 matching placebo  


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Details of timing and sequence of investigations and measures are provided in the Schedule of 
Events (see Appendix 1). The overall design for Part 1 is presented in Figure 1.
Post-study ivermectin will be given to all participants after nodulectomy at 6 months.
Figure 1. Overall Design for Part 1
4083 = ABBV-4083; Alb = albendazole; d = days; D = (study) day; IVM = ivermectin; M = month; Pbo = 
placebo
3.3
Study Design - Part 2
For Part 2, up to two treatment arms from Part 1 that are likely to demonstrate high efficacy at 
Month 24 (based on Part 1 efficacy data and historical studies with doxycycline) and safety will 
be selected as treatment arms in Part 2. The choice will take into consideration feasibility to use
the regimen as potential future treatment.
In order also to assess the effect of a dose of ivermectin at Month 6, participants will be 
randomised into four treatment arms, with the best candidate based on Part 1 results 
administered with ivermectin and with ivermectin placebo at Month 6. 
Within each treatment arm, subjects will be stratified by the number of operable sites with 
onchocercomata and by mean screening skin mf. There will be four strata, i.e. 1 site and less 
than or equal to 5 mf/mg, more than 1 site and less than or equal to 5 mf/mg, 1 site and more 
than 5 mf/mg, more than 1 site and more than 5 mf/mg.
A total of either 294 subjects (Base Scenario) or 336 subjects (Alternative Scenario) will be 
recruited. The Base Scenario will be employed:
•
if neither Arm C nor Arm D from Part 1 is selected for continued enrolment in Part 2, or 
•
if either Arm C and/or Arm D in Part 1 is selected for continued enrolment in Part 2 and 
Arm C and/or Arm D has demonstrated superiority over both Arm E and Arm A in Part 
1. 


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The Alternative Scenario will be employed if either Arm C and/or Arm D in Part 1 is selected 
for continued enrolment in Part 2, but Arm C or Arm D in Part 1 has not demonstrated statistical 
superiority over both Arm E and Arm A.
In the Base Scenario, subjects will be randomised continuously 2:2:2:1 into one of four parallel 
treatment arms until group size is achieved:
•
Arm K (n = 84): initial treatment with an active regimen selected from Part 1, followed 
by ivermectin at Month 6;
•
Arm L (n = 84): initial treatment with the same active regimen selected from Part 1 as 
Arm K, followed by ivermectin matching placebo at Month 6;
•
Arm M (n = 84): initial treatment with a second active regimen selected from Part 1, 
followed by either ivermectin or ivermectin matching placebo at Month 6 (decision to be 
made prior to Part 2);
•
Arm N1 (n = 42): initial treatment with ABBV-4083 matching placebo and albendazole 
matching placebo, followed by ivermectin at Month 6.
Details of timing and sequence of investigations and measures are provided in the Schedule of 
Events (see Appendix 2). The overall design for Part 2 Base Scenario is presented in Figure 2.
Figure 2. Overall Design for Part 2 - Base Scenario
4083 = ABBV-4083; Alb = albendazole; d = days; D = (study) day; IVM = ivermectin; M = month; Pbo = placebo
In the Alternate Scenario, subjects will be randomised continuously 1:1:1:1 into one of four 
parallel treatment arms until group size is achieved:
•
Arm K (n = 84): initial treatment with an active regimen selected from Part 1, followed 
by ivermectin at Month 6;
•
Arm L (n = 84): initial treatment with the same active regimen selected from Part 1 as 
Arm K, followed by ivermectin matching placebo at Month 6;
•
Arm M (n = 84): initial treatment with a second active regimen selected from Part 1, 
followed by either ivermectin or ivermectin matching placebo at Month 6 (decision to be 
made prior to Part 2);


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•
Arm N2 (n = 84): 7 days of ABBV-4083 400 mg plus appropriate duration of albendazole 
matching placebo and ABBV-4083 matching placebo followed by either ivermectin or 
ivermectin matching placebo at Month 6 (decision to be made prior to Part 2).
In the Alternate Scenario, a minimum of 84 subjects with two or more operable sites will be 
enrolled to allow for approximately 21 subjects per arm to undergo a single-site nodulectomy 
at Month 6 for the evaluation of Wolbachia depletion but still have remaining onchocercomata
for evaluation of skin microfilariae and other endpoints at Month 24. The overall design for 
Part 2 Alternative Scenario is presented in Figure 3.
Figure 3. Overall Design for Part 2 - Alternative Scenario
4083 = ABBV-4083; Alb = albendazole; d = days; D = (study) day; IVM = ivermectin; M = month; Pbo = placebo
Rescue treatment with ivermectin will be offered at the investigator discretion to subjects with 
clinically significant worsening of symptoms and / or signs related to onchocerciasis at any 
time during the study or to subjects with increased mean number of microfilariae in the skin at 
Month 18, compared to the mean number at Month 12.
Post-study ivermectin will be provided after nodulectomy at 24 months to any subject with 
positive skin and/or eye microfilariae.
3.4
End of Study 
The end of study for an individual subject is his or her “last visit” defined as the latest of the 
following:
•
screening failure, or
•
the End of Study visit (see Schedules of Events in Appendix 1 and Appendix 2), or
•
early termination visit, or
•
for subjects lost to follow-up or withdrawn, the last visit the subject attended.
The overall end of the study is defined as the last visit, as defined above, of the last subject.


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If a decision is taken to terminate the study early, the study will end when the Sponsor notifies 
the Investigator, the regulatory authorities and ethics committee(s) in writing that the study has 
been stopped, or when the “last visit” as defined above occurs for the last subject, whichever is 
later. 
3.5 Assessment and Management of Risks 
3.5.1 Risks associated with the IMPs 
This section provides information on the main risks identified for the subjects who will take 
part in the trial, based on protocol design. This list is not exhaustive. Refer also to the ABBV-
4083 Investigator Brochure and albendazole or ivermectin reference safety information.57,58,63–
65,68  
3.5.1.1 Potential and Identified Risks of ABBV-4083 
At this stage of development, there is no risk management plan for ABBV-4083. In the Phase-
I study, elevated liver enzymes were seen after single doses of 1000 mg ABBV-4083, but no 
liver toxicity was seen with multiple doses of ABBV-4083 up to 400 mg QD for 14 days. In 
addition, no clinically significant haematological laboratory abnormalities associated with AEs 
or discontinuation from the study were observed (see also Section 2.3.1.1 and Summary of data 
and guidance to the investigator in the Investigator Brochure). Based on data from preclinical 
and Phase I studies, a potential risk associated with ABBV-4083 administration is under 
consideration: “alteration in liver tests”. Therefore, monitoring of biochemistry laboratory tests, 
including liver tests, is required to further assess this potential safety effect during this Phase-
II study. 
In vitro, ABBV‑4083 is metabolised primarily by CYP3A and by cysteine conjugation; co-
dosing with CYP3A inhibitors or inducers may affect ABBV-4083 concentrations. At the 400 
mg dose, ABBV-4083 may inhibit P-gp and BCRP. 
3.5.1.2 Potential and Identified Risks of Albendazole  
Treatment with albendazole has been associated with mild to moderate elevations on hepatic 
enzymes that usually normalize upon discontinuation of therapy. Cases of acute liver failure of 
uncertain causality and hepatitis have also been reported. Subjects with abnormal transaminases 
before starting albendazole therapy should be carefully monitored during treatment. Liver tests 
should be obtained before the start of therapy and on regular basis for long duration treatment 
courses.  
Treatment with albendazole has been shown to occasionally cause myelosuppression and 
therefore blood counts should be performed at the start of therapy and regularly for long 
duration treatment courses. Subjects with liver disease appear to be more susceptible to 
myelosuppression and warrant closer monitoring.  
Treatment with albendazole for neurocysticercosis may cause symptoms associated with an 
inflammatory reaction following the death of the parasite (e.g. seizures, increased intracranial 
pressure and focal signs). Pre-existing neurocysticercosis may be also uncovered in patients 
treated with albendazole for other conditions, especially in areas with high taeniasis infection.  
Treatment with albendazole has been shown to be teratogenic and embryotoxic in animal 
studies. Therefore, women of childbearing age should initiate treatment only after a negative 


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pregnancy test and should be advised to use highly effective method of contraception up to 1 
month after last intake of albendazole. See in addition the albendazole package inserts for 
further information.57,64 
3.5.1.3 Potential and Identified Risks of the Combination of ABBV-4083 and 
Albendazole  
Results of a GLP-compliant 7-day toxicity study conducted in dogs to examine the effects of 
ABBV-4083 when dosed in combination with albendazole at exposures comparable to those 
expected in this clinical trial, no additive effects were seen with the combination. All study 
findings were non-adverse and reversible by the end of the 28-day recovery period (see Section 
2.2.4).  However, due to potential risk of alteration of liver tests both with ABBV-4083 or 
albendazole, the proposed safety monitoring in the study includes transaminases and total 
bilirubin levels at treatment initiation and frequent monitoring during treatment. Furthermore, 
the proposed adaptive design of the study, allowing for arms with lower doses of ABBV-4083 
if toxicity is observed in initial arms, will mitigate the potential risk of effects on the liver with 
co-administration of ABBV-4083 + albendazole (see Section 3.5.2.2). 
3.5.1.4 Potential and Identified Risks of Ivermectin 
Treatment with microfilaricidal drugs such as ivermectin can produce a systemic inflammatory 
reaction associated with release of both microfilarial and Wolbachia antigens from dying mf. 
The so-called Mazzotti reaction is characterised by fever, ocular symptoms, arthralgia, 
synovitis, 
oedema, 
urticarial 
rash, 
pruritus, 
lymphadenitis, 
headache, 
myalgia, 
lymphadenopathy, weakness, tachycardia, nausea, conjunctivitis, diarrhoea and vomiting.52,53 
When ivermectin is administered in this study, a Mazzotti reaction may occur. Transient 
symptoms are likely to occur within 3 days of treatment and are usually mild requiring no more 
than simple reassurance. In addition, the following possible side effects have been reported with 
the use of ivermectin:63,65 allergic reaction, difficulty breathing, acute hepatitis, elevated liver 
enzymes, elevated blood bilirubin, elevated haemoglobin or elevated eosinophil levels or 
presence of blood in the urine. When used for treatment of onchocerciasis, worsening of asthma 
have also been identified. Rarely, transient postural hypotension occurs within 12-24 hours, 
which responds to rest and oral administration of fluids.68 These symptoms can be managed by 
the study personnel.  
Mazzotti reactions are not expected with ABBV-4083: treatment with an anti-wolbachial agent 
only interrupts the production of mf, resulting in a slow decline in mf levels. Adult worm death 
also occurs very slowly (≥ 2 years after treatment), avoiding the potential for inflammation 
from rapid death of the adult worms.50 
After administration of repeated doses of ivermectin close to or equal to maternotoxic doses, 
foetal abnormalities were observed in several animal species. Based on these studies, it is 
difficult to assess the risk of a single low dose. In clinical studies, no malformations or fetotoxic 
effects have been attributed to ivermectin. However, follow-up data of exposure to ivermectin 
during pregnancies is not sufficient to rule out any risk.69 Therefore, as a precaution, ivermectin 
should not be given to pregnant women. Ivermectin is excreted in human milk at low 
concentrations. Treatment of breastfeeding women should only be undertaken when the risk of 
delayed treatment to the mother outweighs the possible risk for the newborn.65 


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3.5.2 Adverse Event and Toxicity Management 
3.5.2.1 General Management 
The following measures will be implemented to minimise the risks: 
• 
Subjects with certain abnormalities on physical or neurological examination or 
laboratory tests that could interfere with the objectives of the trial or the safety of the 
subject, in the opinion of the Investigator will be excluded (see Section 6.2), as well as 
subjects with certain ophthalmological history or conditions; 
• 
Physical examinations, neurological examinations and ophthalmological examinations 
will be conducted regularly throughout the In-house Periods, and at follow-up visits; 
• 
Blood counts and liver tests including transaminase and bilirubin levels will be 
monitored regularly during treatment. 
• 
Medications or herbal preparations are prohibited within 14 days prior to IMP intake 
(see Sections 6.2) and for 24 hours post last intake of the IMP (see Section 8.1) with 
certain specific exceptions. 
3.5.2.2 Toxicity Management and Dose Adjustment 
Once at least 15 subjects have been treated in each of the five arms in Part 1, the SRC will 
review safety results separately for each arm in a blinded way every 2 weeks and evaluate 
causality. The study unblinded statistician will inform the SRC before their review if > 10% of 
the subjects in any arm meet any of the toxicity criteria listed below, without disclosing the 
arm(s). In case this criterion is met, the SRC will refer to the DSMB. The DSMB may 
recommend halting enrolment into arms of the same or longer duration with or without 
albendazole added and continuing enrolment in those arm(s) of the shorter duration, as shown 
in Table 1. The enrolment of the closed arms may be reopened using a lower dose of ABBV-
4083 at 300 mg QD with the same duration and same combination (with or without albendazole) 
as the original arm, in which case enrolment will continue until 30 subjects have been enrolled 
at that dose. However, subjects who have already started to receive 400 mg QD ABBV-4083 
in the halted arm and who have not experienced dose-limiting toxicity will remain on that dose 
until treatment completion. 
When albendazole is used in mass drug administration programs, adverse events are commonly 
encountered in areas where gastrointestinal helminth infection occurs.70 It is usually well 
tolerated and the liver injury reported with its use has been mild and self-limited in 
course.62,66,67,44 The proposed safety monitoring in the study includes blood counts and liver 
tests including transaminases and total bilirubin levels at treatment initiation and frequent 
monitoring during treatment. Furthermore, the proposed adaptive design of the study, allowing 
for arms with lower doses of ABBV-4083 if toxicity is observed in initial arms, will mitigate 
the potential risk of effects on the liver with co-administration of ABBV-4083 + albendazole. 
The end of exposure is defined as one day after the last dose of IMP, which is at least five half-
lives (t1/2) after the last intake of IMP, i.e. ABBV-4083 or albendazole. The half-life of ABBV-
4083 is less than 4 hours and the half-life of albendazole sulfoxide is 8-12 hours but active 
albendazole is administered up to Day 6 at the longest duration. 
A subject will be considered to have a toxicity if they have: 




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superficial corneal stroma. Long-standing and high-intensity infections, as measured by high 
levels of skin and ocular mf, can result in massive invasion of the cornea and other anterior 
regions, leading to later-stage disease including sclerosing keratitis, a progressive irreversible 
scarring of the cornea. 71,72 Sclerosing keratitis usually follows several years of high-intensity 
infection, and blindness due to this and accompanying conditions in the anterior segment, e.g. 
anterior uveitis, iris atrophy, anterior and posterior synechiae, secondary cataract and glaucoma, 
usually develop after the second decade.72 
Subjects with mf in the posterior segment with certain ophthalmological history or conditions 
predisposing them to greater risk of ocular pathology progression, will be excluded from the 
study, as well as those with current hyperreactive onchodermatitis. Moreover, subjects with 
severe manifestations of onchocerciasis will be excluded from the study.  
In order to avoid progression of ocular disease during the study, ivermectin may be used as 
rescue medication at any time at the discretion of the Investigator. Ophthalmological 
examinations will be performed at the visits at Month 3, 6, 12, 18 and 24, providing frequent 
opportunities to detect any ocular disease and introduce rescue medication (see Section 2.4.3). 
In addition, any subject with increasing microfiladermia at Month 18 compared to Month 12 
will be administered ivermectin.  
To minimize the risk of progression of onchocerciasis, ivermectin will be administered:  
• 
at any time, at the Investigator’s discretion if clinical symptoms and/or signs worsen. 
The most important goal of therapy is the continuous reduction of disease burden, i.e. 
mf levels (rescue medication). 
• 
to all subjects when they reach the end of Part 1 at Month 6 (post-study IVM).  
• 
to subjects in Part 2 with increased skin microfilariae at Month 18 compared to the 
number at Month 12 (rescue medication). In addition, at the 24-Month follow-up visit, 
ivermectin will be administered to subjects positive for microfilariae in the skin and/or 
eye after nodulectomy (post-study IVM).  
3.5.4 Risks Associated with Epidemics 
The presence of an epidemic, including for example COVID-19 or Ebola, could have an impact 
on the trial, trial subjects and personnel. This could potentially include subjects being in self-
isolation/quarantine, limited access to public places, including hospitals, due to the risk of 
spreading infection, impact on the clinical trial itself and healthcare professionals being 
reassigned to critical tasks. Furthermore, subjects may be exposed to infection during screening 
activities in the communities or while they are at the investigational centre. In addition, there is 
the risk of study personnel transmitting infection to communities from which subjects will be 
recruited. 
Mitigation steps to be taken include: 
• Prior to initiation of recruitment, and during the trial, the Investigator and the Sponsor 
will assess the current potential risks associated with each aspect of the trial, based on the 
incidence of infections in the area of recruitment, the centre and national directives. The 
start of recruitment may be delayed if necessary or mitigation measures taken to protect 
study personnel and subjects. 
• National and international guidelines will be followed during the trial to prevent the 
spread of infection (including testing site personnel and/or study subjects for COVID-19 
when required by standard clinical care), and protective equipment will be provided in 


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accordance with the guidelines. Training will be provided to study personnel on standard 
precautions. 
• Specific risk communication and education activities on national preventive directives on 
COVID-19 will be implemented for subjects as well as study personnel.  
• If travel to and from the centre is blocked, the trained community contact persons in each 
recruitment area will ensure basic follow-up of subjects including supporting access to 
local medical assistance while keeping remote contact with the investigational centres. 
Subjects with significant co-morbidities will not be included in the trial. The In-House Periods 
will also ensure that subjects will not be discharged back to their communities after the 
treatment period unless they are healthy. These measures will minimise the safety risks to 
subjects during follow-up, if visits are interrupted due to travel restrictions. 
4 Study Objectives 
4.1 Primary Objectives 
The primary objectives are to: 
Part 1: 
• determine whether treatment with ABBV-4083 or ABBV-4083 + albendazole effectively 
depletes Wolbachia bacteria in adult female worms at Month 6 by immunohistology; 
• establish the superiority of ABBV-4083 + albendazole to each drug alone according to 
the depletion of Wolbachia bacteria in adult female worms at Month 6 by 
immunohistology 
Part 2: 
• determine whether treatment with ABBV-4083 or ABBV-4083 + albendazole effectively 
eliminates microfilariae from the skin at 24 months. 
• if superiority of 7-day treatment with ABBV-4083 + albendazole to 7 days of ABBV-
4083 is not established in Part 1, the Alternate Scenario of Part 2 (see Section 3.3) has the 
additional objective to establish that a combination of ABBV-4083 + albendazole is 
superior to ABBV-4083 alone by combining data from Parts 1 and 2. 
4.2 Secondary Objectives 
4.2.1 Key Secondary Objectives for Part 2 
The key secondary objectives for Part 2 are to determine: 
• whether ABBV-4083 or ABBV-4083 + albendazole demonstrates a macrofilaricidal 
effect at 24 months; 
• whether ABBV-4083 or ABBV-4083 + albendazole inhibits embryogenesis in adult 
female worms at 24 months. 
4.2.2 Other Secondary Objectives 
The other secondary objectives are to assess: 
Part 1: 
• the safety and tolerability of ABBV-4083 or ABBV-4083 + albendazole in subjects with 
O. volvulus; 


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• whether ABBV-4083 or ABBV-4083 + albendazole will sterilise the adult female worm 
and/or have a macrofilaricidal effect at Month 6; 
• the effects of ABBV-4083 or ABBV-4083 + albendazole on skin microfilariae at all time-
points; 
• the effects of ABBV-4083 or ABBV-4083 + albendazole on microfilariae in nodular 
tissue at Month 6; 
• whether ABBV-4083 or ABBV-4083 + albendazole depletes Wolbachia bacteria in adult 
worms assessed by PCR at Month 6. 
Part 2: 
• the safety and tolerability of ABBV-4083 or ABBV-4083 + albendazole in subjects with 
O. volvulus; 
• the effects of ABBV-4083 or ABBV-4083 + albendazole with or without ivermectin at 
Month 6 on skin microfilariae at all applicable timepoints; 
• the effects of ABBV-4083 or ABBV-4083 + albendazole with or without ivermectin at 
Month 6 on microfilariae in nodular tissue at 24 months; 
• whether ABBV-4083 or ABBV-4083 + albendazole depletes Wolbachia bacteria in adult 
worms assessed by immunohistology and PCR at 24 months. 
4.3 Exploratory Objectives for Parts 1 and 2 
The exploratory objectives for both Parts 1 and 2 are to assess: 
• whether ABBV-4083 or ABBV-4083 + albendazole depletes Wolbachia bacteria in 
microfilariae; 
• the effects of ABBV-4083 or ABBV-4083 + albendazole on eye microfilariae; 
• the pharmacokinetic (PK) parameters of ABBV-4083 and albendazole sulfoxide (the 
active metabolite of albendazole) in subjects; 
• the relationship of PK parameters of ABBV-4083 and albendazole sulfoxide and efficacy 
and/or safety; 
• the effects of ABBV-4083 or ABBV-4083 + albendazole on clinical outcomes: 
o itching and skin disease; 
o ocular onchocercal disease. 
5 Study Endpoints 
5.1 Primary Efficacy Endpoints 
The primary efficacy endpoints are: 
Part 1: 
• the status of each live female adult worm as without Wolbachia endobacteria or not, as 
assessed by immunohistology of nodules collected after nodulectomy at 6 months; 
Part 2: 
• the status of each subject as without skin microfilariae or not at 24 months, assessed 
across all skin snips in each subject. 


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5.2 Secondary Efficacy Endpoints 
5.2.1 Key Secondary Efficacy Endpoints in Part 2 
The key secondary efficacy endpoints in Part 2 are: 
• the proportion of live female adult worms per subject assessed by histological 
examination of all nodules collected after nodulectomy at Month 24; 
• the proportion of live female adult worms with only degenerated embryos in uterus per 
subject as assessed by histological examination of nodules collected after nodulectomy at 
Month 24 out of all judgeable worms with embryos in uterus (normal or degenerated). 
5.2.2 Other Secondary Efficacy Endpoints 
The other secondary efficacy endpoints are: 
Part 1: 
• the proportion of live female adult worms with only degenerated embryos in the uterus 
per subject after nodulectomy at Month 6; 
• the proportion of live female adult worms out of all female adult worms per subject after 
nodulectomy at Month 6; 
• the absence of microfilariae in nodular tissue per subject after nodulectomy at Month 6; 
• the status of each subject as without skin microfilariae or not at Months 3 and 6; 
• the reduction in skin microfilarial density (defined as the mean number of 
microfilariae/mg per subject) at Months 3 and 6 compared to baseline; 
• the status of each live adult worm as without Wolbachia endobacteria or not, as assessed 
by PCR at Month 6. 
Part 2: 
• the status of each subject as without skin microfilariae or not at all time-points other than 
Month 24; 
• the reduction in skin microfilarial density (defined as the mean number of 
microfilariae/mg per subject) at all time-points compared to baseline; 
• the absence of microfilariae in nodular tissue per subject after nodulectomy at Month 24; 
• the status of each live adult female worm as without Wolbachia endobacteria or not, 
assessed by immunohistology at Month 24; 
• the status of each live adult worm as without Wolbachia endobacteria or not, as assessed 
by PCR at Month 24. 
5.3 Exploratory Endpoints in Parts 1 and 2 
The exploratory endpoints are: 
• the absence of Wolbachia in skin microfilariae per subject by PCR at all timepoints; 
• the decline in number of Wolbachia (assessed by PCR) in skin microfilariae per subject 
at all timepoints compared to baseline; 
• microfilaria levels in the cornea and anterior chamber per subject, at all timepoints when 
ophthalmological assessments are performed; 


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• the presence, severity and clinical evolution of onchocerciasis ocular disease and 
onchocerciasis skin disease in each subject at all time-points when ophthalmological or 
skin examinations are performed. 
5.4 Additional Endpoint in Alternative Scenario in Part 2 
The additional combination rule endpoint in Alternative scenario in Part 2 is: 
• the proportion of live female adult worms without Wolbachia endobacteria assessed by 
immunohistology of nodules collected after nodulectomy at 6 months to compare ABBV-
4083 + albendazole to 7 days of ABBV-4083. 
5.5 Safety and Tolerability Endpoints in Parts 1 and 2 
The safety and tolerability endpoints are: 
• AE assessment (all reported AEs); 
• physical and skin examination findings; 
• vital signs; 
• 12-lead ECG; 
• clinical laboratory parameters: haematology, biochemistry, urine analysis; 
• ophthalmological examination findings. 
5.6 PK and PK/PD Endpoints in Parts 1 and 2 
The PK and PK/PD endpoints are: 
• ABBV-4083 and albendazole sulfoxide AUCtau, Cmax, Cmin, CL and t½. Time above given 
concentrations may also be estimated; 
• the relationship between the presence or absence of Wolbachia in female adult worms in 
each subject at Month 6 with respect to ABBV-4083 and albendazole sulfoxide 
pharmacokinetic parameters; 
• the relationship between the status of adult female worms at Month 24 with respect to 
ABBV-4083 and albendazole sulfoxide pharmacokinetic parameters; 
• the relationship between the presence or absence of skin microfilariae at Month 24 with 
respect to ABBV-4083 and albendazole sulfoxide pharmacokinetic parameters; 
• The relationship between the reduction in skin microfilarial density over time and ABBV-
4083 and albendazole sulfoxide concentrations may be explored. 
Additional relationships between the efficacy and safety endpoints and ABBV-4083 and 
albendazole sulfoxide concentrations may be explored. 
 
6 Study Population 
The inclusion and exclusion criteria are the same for Parts 1 and 2. 
6.1 Inclusion Criteria 
To be eligible for the study, subjects must satisfy all of the following inclusion criteria. 
1. Written, signed (or thumb-printed) and dated informed consent, after having the 
opportunity to discuss the study with the Investigator or a delegate. 


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2. Men and women with Onchocerca volvulus infection, 18 to 65 years of age inclusive at 
time of Screening: 
i. 
Presence of at least one excisable subcutaneous nodule/onchocercoma detected on 
palpation; 
ii. 
O. volvulus infection diagnosed by skin snip method: documented mf-positivity on 
skin assessment on at least 2 out of 4 skin snips. 
3. Body weight > 40 kg at Screening. 
4. For women of child-bearing potential (WOCBP), (see Section 8.2), acceptance of the 
requirement to use a highly effective form of birth control (see Section 8.2 and Appendix 
7) effective from Day 0 until at least 1 month after the final intake of IMP (Part 1: day 
43; Part 2: 1 month after the administration of ivermectin or matching placebo at the 
Month 6 visit). Choice of birth control method must be clearly documented. 
6.2 Exclusion Criteria 
Subjects must not satisfy any of the following exclusion criteria. 
1. Participation in any studies other than purely observational studies within 3 months prior 
to Screening, or during the trial, or within 5 times the half-life of the drug tested in the 
previous clinical trial* or is currently in the follow-up period for any clinical trial. 
2. Any vaccination within 4 weeks prior to IMP administration. 
3. Acute infection and/or febrile illness requiring therapy within 14 days prior to IMP 
administration. 
4. Administration of medication or herbal preparations as follows: 
i. 
Administration of any medication (with the exception of diclofenac, paracetamol, 
ibuprofen and aspirin) or herbal preparation within 14 days prior to IMP 
administration;  
ii. 
Use of strong CYP3A inhibitors or inducers including but not limited to ritonavir, 
ketoconazole, rifampicin, phenytoin, phenobarbital, carbamazepine, cimetidine 
within 14 days or 10 half-lives, whichever is longer, prior to IMP administration. 
iii. 
Use of other drugs known to interact with albendazole i.e. praziquantel, theophylline 
or dexamethasone, within 14 days or 10 half-lives, whichever is longer, prior to IMP 
administration; 
iv. 
The following antifilarial therapies, or medication that may have an antifilarial effect: 
o ivermectin; ≤ 6 months prior to IMP administration; 
and / or 
o doxycycline, ≤ 1 year prior to IMP administration: more than 2-week course; 
and / or 
o any other anti-Wolbachia treatments i.e. minocycline, rifapentine or rifampicin, 
≤ 1 year prior to IMP administration: more than 2-week course; 
 
 
 
 
* Whichever is longer (time calculated relative to the last intake in the previous clinical trial. 


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and / or 
o moxidectin, ≤ 2 years prior to IMP administration; 
v. 
Other preventive chemotherapy, e.g. as part of an MDA program, within 14 days 
prior to IMP administration; 
5. Requirement for and inability to avoid ivermectin during the first 6 months after IMP 
administration. Requirement for albendazole during the first 28 days after IMP 
administration or more than one dose per year thereafter given in MDA; 
6. Presence of any of the following at Screening, that could interfere with the objectives of 
the trial or the safety of the subject, in the opinion of the Investigator: 
i. 
Clinically significant abnormal physical and/or neurological examination or 
laboratory findings; 
ii. 
Any clinically significant medical condition, including, but not limited to significant 
acute or chronic liver or kidney condition or cardiovascular disease, active infection, 
current or previous epilepsy, known human immunodeficiency virus (HIV) infection, 
disclosed by review of medical history or concomitant medication; 
7. Ophthalmological history or conditions that could interfere with the objectives of the trial 
or compromise the safety of the subject in the opinion of the Investigator, assessed at 
Screening, including the following (subject will be excluded if any of the criteria are met 
for either eye): 
i. 
Inflammatory eye disease, glaucoma, severe uveitis; evidence of retinal 
cysticercosis; 
ii. 
History of surgery for glaucoma; 
iii. 
Severe keratitis, and/or cataracts that interfere with visualisation of the posterior 
segment of the eye; 
iv. 
Evidence of an increased risk of acute glaucoma, based on examination of anterior 
chamber; 
v. 
Evidence of ocular media opacity, including lens opacity and vitreous opacities, 
that make difficult ocular examination in the opinion of the investigator; 
vi. 
Evidence of retinal or optic nerve pathology, including age-related macular 
degeneration; 
vii. 
Severe visual impairment (best corrected or pinhole visual acuity worse than 6/60 
metres), severe reduction of peripheral visual fields (greater than grade 3 on 
Frequency Doubling Technology) or blindness; 
viii. 
Any microfilariae identified in the posterior segment of the eye or more than 50 
microfilariae in the anterior segment of one eye. 
8. History of drug or alcohol abuse within 6 months prior to IMP administration.  
9. Use of alcohol within 48 hours and/or use of drugs of abuse within 15 days before IMP 
administration. 
10. Clinically significant history of cardiac abnormality, and/or relevant pathological 
abnormalities in the ECG in the screening period, such as atrioventricular block (PR 
interval > 240 msec), or prolongation of the QRS complex > 120 msec or QTcF interval 
> 450 msec. 


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11. Abnormal laboratory test results at Screening, defined as: 
i. 
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) 
and/or alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT 
> 2  upper limit of normal (ULN*) and/or total bilirubin > 1.5 x ULN*; 
ii. 
Serum potassium < lower limit of normal*; 
iii. 
Serum creatinine > ULN* and estimated glomerular filtration rate (using the 
Modification of Diet in Renal Disease equation73) < 60 mL/min. 
12. History of severe drug allergy, non-allergic drug reactions, severe adverse reaction to 
any drug, or multiple drug allergies. 
13. Known hypersensitivity to any ingredient of the IMPs, including the active ingredient of 
ABBV-4083, macrolides, albendazole or to ivermectin or to any medication used during 
the study (e.g. for eye examination). 
14. Blood donation within 8 weeks prior to Screening or blood transfusion received within 
1 year prior to Screening. 
15. Coincidental infection with high Loa loa load (> 8000 microfilariae/mL) at Screening. 
16. Current hyperreactive onchodermatitis or severe manifestation due to onchocerciasis. 
17. Any other past or current condition that the Investigator feels would exclude the subject 
from the study or place the subject at undue risk. 
18. For women of child-bearing potential (WOCBP): pregnant (based on date of last 
menstrual period, and pregnancy test prior to first intake of IMP) or breastfeeding. 
19. Unwilling or unable to comply with the requirements of the study protocol for the entire 
duration of the study, in the opinion of the Investigator. 
20. Unable to participate in the study as per local law, if applicable. 
6.3 Rationale for Study Population 
Since the aim of the study is to assess the safety, tolerability, PK and efficacy of ABBV-4083 
and ABBV-4083 + albendazole in subjects with onchocerciasis, it will be performed in an adult 
Sub-Saharan subject population infected with O. volvulus with detectable skin microfiladermia 
and palpable onchocercomata (nodules), which constitutes the future target population. 
6.4 Subject Identification 
All subjects will be assigned a unique identification number by the interactive response 
technology (IRT) system at the Screening visit. For subjects who rescreen, the Screening 
number assigned by the IRT at the initial Screening visit should be used. For subjects who 
comply with the entry criteria and are randomised, the IRT will assign a randomisation number 
that will encode the subject’s treatment group assignment according to the randomisation 
 
 
 
 
* Using the laboratory reference ranges defined for the study. 


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schedule generated by the Sponsor or Designee. It will be used only to determine the treatment 
assignment for each subject upon unblinding. 
6.5 Discontinuation and Withdrawal Criteria 
 As a general principle, all subjects who receive at least one dose of IMP should continue 
participation in the trial, unless they withdraw consent. This is also to ensure follow-up of any 
adverse event, including documentation of its outcome. 
The Investigator must consult with the Sponsor in all cases of interruption or discontinuation 
of the IMP, or withdrawal from the trial. 
6.5.1 Screening Failure 
A subject who discontinues study participation prematurely for any reason after s/he has signed 
the study main informed consent and undergone screening assessments, but before 
randomisation, is regarded as a “screening failure”. 
Subjects regarded as screening failures are not permitted to re-enter the screening process at a 
later time-point, except under the circumstances listed below. 
• The inclusion and/or exclusion criteria preventing the subject’s initial attempt to 
participate have been changed via protocol amendment; 
• The subject failed the initial screening because the required wash-out period (as described 
in the exclusion criteria) had not been completed after prior treatment, or the required 
period after excluded procedures or substance use had not been completed, on a case-by-
case basis, if agreed by the sponsor;  
• The subject had successfully passed the initial screening, but the 8-week screening period 
expired before s/he could receive the IMP; 
Subjects who re-enter the screening process must sign a new main informed consent form (ICF) 
and will keep the same screening number. Up to two re-screenings are allowed. 
6.5.2 Interruption or Discontinuation of IMP 
If treatment with the IMP is interrupted for any reason, the decision to resume treatment will 
be taken by the Investigator. The aim is to complete the treatment course, assuming it is safe to 
do so.  
The IMP must be permanently discontinued if any of the following occurs:  
• at subject’s request. At any time during the study and without giving reasons, a subject 
may decline to take the IMP. The subject will not suffer any disadvantage as a result; 
• positive pregnancy test 
The IMP may be discontinued if any of the following occurs: 
• if continuation of the IMP would be harmful to the subject’s well-being, in the opinion of 
the Investigator; 
• at the specific request of the Sponsor and in liaison with the Investigator, for example in 
the event of safety concerns; 
• if the subject develops conditions that would have prevented his/her inclusion in the study 
according to the in-/exclusion criteria. The Investigator will decide in consultation with 


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the Sponsor, taking into account safety, and whether this is a conflict with the study 
objectives. 
The reason and date for IMP discontinuation will be recorded in the source documents and 
electronic case report form (eCRF). Subjects who discontinue the IMP should continue 
participating in the study off the IMP with continued assessments as per the Schedule of Events. 
6.5.3 Withdrawal from the Trial 
Subjects must be withdrawn from the trial if any of the following occurs:  
• 
at subject’s request (withdrawal of consent). At any time during the study and without 
giving reasons, a subject may decline to participate further. The subject will not suffer 
any disadvantage as a result. 
Subjects may be withdrawn from the study if any of the following occurs: 
• 
if continuation of the study would be harmful to the subject’s well-being, in the opinion 
of the Investigator; 
• 
at the specific request of the Investigator, or the Sponsor in only very exceptional 
circumstances and in liaison with the Investigator, for example in the event of safety 
concerns for the subject or others; 
• 
in the event of premature termination of the study (see Section 12). 
If a subject withdraws consent, no further evaluations should be performed, and no attempts 
should be made to collect additional data, with the exception of safety data, which should be 
collected if possible and only with the subject’s consent. The Sponsor may retain and continue 
to use any data collected before withdrawal of consent. However, if the subject consents to 
follow-up but asks the Investigator to destroy all identifiable samples taken from the subject 
and/or not enter in the eCRF results of the follow-up examinations, the Investigator will comply 
with the subject’s requests. 
If a subject withdraws from the study, the reason and date must be noted in the source 
documents and in the eCRF. 
The Investigator should inquire about the reason for withdrawal, and conduct an Early 
Termination visit as soon as possible, if the subject agrees (see Schedules of Events in Appendix 
1 and Appendix 2). 
If a subject withdraws from the study due to an AE, all measures must be taken to clearly 
document the outcome of the AE. 
6.5.4 Lost to Follow-up 
A subject will be considered lost to follow-up if s/he can no longer be contacted by the study 
personnel (see also the Study Operations Manual). 
Before the subject can be considered as lost to follow-up, the study personnel must make every 
effort to re-establish contact with the subject as soon as possible to advise him/her of the 
importance of continuing in the study and to ascertain whether or not s/he wishes to and/or 
should continue in the study. In addition, every effort should be made to document subject 
status. The contact attempts should be recorded in the source documents and in a note in the 
Investigator Site File. If a subject is finally considered lost to follow-up, this must be noted in 
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7.2 IMP Supply and Storage 
ABBV-4083 and matching placebo, over-encapsulated albendazole and matching placebo will 
be supplied by AbbVie. The clinical supplies will be packaged and labelled by AbbVie. Final 
assembly of subject treatments, packaging, labelling and batch release will be performed by 
AbbVie.  
In Part 2, Month 6 over-encapsulated intact commercially available ivermectin tablets and 
visually-matched placebo capsules containing inactive excipients will be supplied and 
packaged by AMATSI Group. Final assembly of subject treatments, packaging, labelling and 
batch release will also be performed by AMATSI Group. 
All IMPs will be labelled in accordance with the requirements of local laws and regulations. 
The labelling text will be approved according to the Sponsor’s agreed procedures, and a copy 
of the labels will be made available to the regulatory authorities and investigational centre upon 
request. 
Packaging, labelling and storage conditions of the IMPs, as well as supply of the IMPs to the 
investigational centre will be described in the Pharmacy Manual. 
At the investigational centre the IMPs will be stored in a locked cabinet, inaccessible to 
unauthorised personnel. 
ABBV-4083 and matching placebo are to be stored protected from light, at a temperature 
between 2 °C and 30 °C and should not be frozen. 
Albendazole and matching placebo are to be stored at a temperature between 2 °C and 30 °C 
and should not be frozen. 
Over-encapsulated ivermectin tablets and matching placebo are to be stored at a temperature 
not exceeding 30 °C. 
The supplies of ABBV-4083, albendazole and ivermectin for the study must not be used for 
purposes other than the present protocol. The Investigator and the study personnel staff may 
not, under any circumstances, provide other healthcare workers or services with the IMPs, or 
allow the IMPs to be used other than as described in this protocol without prior written approval 
from the Sponsor. 
A system of numbering in accordance with the requirements of Good Manufacturing Practice 
(GMP) will be used for the IMPs, ensuring that each dose of IMP can be traced back to the 
respective bulk batch of the ingredients. Lists linking all numbering levels will be maintained 
by the Sponsor’s suppliers for the IMPs. 
A complete record of batch numbers and expiry dates of all IMPs as well as the labels will be 
maintained in the Sponsor’s study file. 
7.3 IMP Assignment and Administration 
7.3.1 IMP Assignment and Administration in Part 1 
7.3.1.1 IMP Assignment in Part 1 
In Part 1, the IMP will be randomly assigned. A total of 150 subjects will be recruited and 
centrally and continuously randomised under double blind 1:1:1:1:1 into one of five parallel 
groups (Arms A, B, C, D and E), based on dosing regimen, until group size is achieved. Subjects 


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will be stratified by the number of operable sites with onchocercomata. There will be two strata, 
i.e. one site and more than one site. 
7.3.1.2 IMP Administration in Part 1 
The IMP ABBV-4083 will be administered as 100-mg capsules or matching placebo capsules. 
The IMP albendazole will be administered as over-encapsulated 400-mg tablets or matching 
over-encapsulated placebo . 
Subjects will receive a maximum of 5 capsules per day for 14 days. Depending on the treatment 
arm allocation, subjects will receive four ABBV-4083 capsules (400 mg) or matching placebo 
+ one over-encapsulated albendazole tablet (400 mg) or matching placebo, once a day, from 
Day 0 to Day 6, followed by four ABBV-4083 capsules (400 mg) or matching placebo, once a 
day, from Day 7 to Day 13. 
The IMPs will be administered once daily by the oral route and are to be taken with food (see 
Section 9.2.8 for details). 
The IMP will be administered at the investigational centre at approximately the same time each 
morning, and intake of the IMP will be directly observed by the study personnel. 
7.3.2 IMP Assignment and Administration in Part 2 
7.3.2.1 IMP Assignment in Part 2 
In Part 2, there will be four treatment arms. The two study arms of the shortest treatment 
duration in Part 1 that are likely to demonstrate high efficacy at Month 24 (based on Part 1 
efficacy results and historical studies with doxycycline) and safety will be selected as active 
arms for Part 2. In order also to assess an additional effect of a dose of ivermectin at Month 6, 
participants will be into four groups stratified by the number of operable sites with 
onchocercomata (one site, > 1 site) and by mean skin mf (≤ 5 mf/mg, > 5 mf/mg) at Screening, 
with two arms receiving the same ABBV-4083 or ABBV-4083 + albendazole regimen but one 
receiving ivermectin at Month 6 and the other receiving ivermectin matching placebo.  
In the Base Scenario, subjects will be randomly assigned 2:2:2:1 under double blind to Arms 
K, L, M and N1. 
In the Alternative Scenario, subjects will be randomly assigned 1:1:1:1 under double blind to 
Arms K, L, M and N2. 
7.3.2.2 IMP Administration in Part 2 
The IMP ABBV-4083 will be administered as 100-mg capsules or matching placebo capsules. 
The IMP albendazole will be administered as over-encapsulated 400-mg tablets or matching 
over-encapsulated placebo . 
The IMPs ABBV-4083, albendazole and both matching placebo will be administered once daily 
by the oral route and are to be taken with food (See Section 9.2.8 for details). 
The IMP ivermectin or matching placebo will be administered at the approved single oral dose 
of 150 µg/kg body weight per Table 5 as a single administration at Month 6. It will be 
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All IMPs will be administered at the investigational centre at approximately the same time each 
morning, and intake of the IMP will be directly observed by the study personnel. 
7.4 Blinding 
7.4.1 Blinding Measures 
In both parts of the study, the IMPs will be administered under double-blind conditions. To that 
end, ABBV-4083 and matching placebo capsules, as well as albendazole over-encapsulated 
tablets or matching placebo capsules will be identical in appearance, i.e. size, shape and colour, 
taste and smell. In Part 2, over-encapsulated ivermectin tablets and matching placebo capsules 
will be identical in appearance, taste and smell. The packaging and labelling will be designed 
to maintain blinding to the Sponsor and study personnel, as well as to subjects. The study data 
will remain blinded until each planned database locks of the study, and authorisation of data 
release according to standard operating procedures. 
The Investigator, as well as clinical, pharmacy, and laboratory personnel, and the Sponsor, 
including statistics and data management personnel and the study monitor, will remain blinded 
during the study, excluding those individuals, intentionally designated as unblinded and 
described below, so as not to potentially introduce bias, unless safety concerns necessitate 
unblinding by the Investigator, i.e. if knowledge of the IMP administered is useful for the best 
medical care of an SAE (see Section 7.4.2). 
A copy of the randomisation codes in each part of the study will be kept under the management 
of dedicated unblinded personnel designated by the Sponsor, and access strictly limited to those 
minimally designated unblinded staff directly involved in activities requiring access to the 
randomisation code, e.g. staff directly involved in pharmacovigilance for expedited safety 
reporting only, bioanalytical processes and PK evaluation, packaging and labelling service 
providers, etc., plus quality control activities (by independent personnel) related to these 
activities.  
The emergency procedures for revealing medication codes are specified in Section 7.4.2. 
7.4.2 Unblinding Measures 
If emergency unblinding is required in the interest of the safety of a subject, an Investigator 
will discuss the matter with the Sponsor before contacting IRT to break the blind for that 
subject, unless, in a medical emergency, when the Principal Investigator or delegate may 
contact IRT to break the blind for that subject without prior consultation with the Sponsor. 
Designated Sponsor personnel will be notified via IRT that unblinding occurred but with no 
information on the treatment allocation. In the event of emergency unblinding by the Principal 
Investigator or delegate, there will be a process in place to prevent unnecessary unblinding 
of others to the treatment allocation. This will include documenting the circumstances together 
with justification and the actions taken following the unblinding, using a specific form with 
restricted access. 
In compliance with applicable regulations, in the event of unblinding for safety reporting by 
the Sponsor to the regulatory authorities and ethics committee(s), a process will be in place via 
the IRT system to prevent unblinding of the clinical team. 
If the randomisation code is broken by the Investigator, the reason and date will be fully 
documented and entered in the source documents and eCRF (in a blinded manner). 


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The DSMB may exceptionally request unblinding of certain subject(s), e.g. in case of a major 
safety concern, but only if absolutely necessary, and always in accordance with the DSMB 
Charter.  
The study data will be unblinded after database lock in Part 1 and in Part 2. 
7.5 IMP Logistics and Accountability 
All IMPs will be stored at the investigational centres in accordance with GCP and GMP 
requirements and the instructions given by the Sponsor and will be inaccessible to unauthorised 
personnel. Special storage conditions and a complete record of batch numbers and expiry dates 
can be found in the Sponsor’s study file; the centre-specific elements of this information will 
be available in the Investigator Site File. On the day of receipt, the responsible study personnel 
will confirm receipt of the IMPs per the instructions supplied. The personnel will use the IMPs 
only within the framework of this clinical study and in accordance with this protocol. Receipt, 
distribution, return and destruction (if any) of the IMPs must be properly documented according 
to the Sponsor’s agreed and specified processes and procedures. 
Written instructions on IMP destruction will be made available to affected parties as applicable, 
and in accordance with any requirements of the regulatory authority. 
7.6 Treatment Compliance 
The IMPs will be administered by the study personnel. Treatment compliance will therefore be 
ensured by direct observation. Treatment intake will be recorded in the eCRF. In addition, in 
both parts of the study, ABBV-4083 and albendazole levels will be measured in the blood at 
regular time-points (see Schedules of Events in Appendix 1 and Appendix 2). 
8 Non-study Medication 
8.1 Prior and Concomitant Medication 
The prior medication listed below will be recorded in the source documents and eCRF. See 
Section 6.2 for exclusion criteria based on concomitant medication. 
• 
All prior anthelminthic treatments or medication given for onchocerciasis including 
ivermectin or albendazole alone or in combination, doxycycline, minocycline, 
rifampicin, rifapentine, moxidectin, praziquantel or mebendazole, including date of last 
intake.  
• 
Doxycycline for other indications, within 1 year prior to IMP administration 
• 
Vaccinations, within 4 weeks prior to IMP administration 
• 
All other prior medication, including contraceptives, and preventive chemotherapy, 
herbal preparations or food supplements taken within 1 month before the start of 
Screening at the investigational centre 
• 
Other currently effective contraceptive medication or devices, including long-acting 
depot or implantable preparations containing sex hormones or intra-uterine devices, (see 
also Section 8.2) 
From signature of ICF onwards, subjects will be instructed not to take any medications, 
traditional medicines or herbal preparations by themselves at any time during the study (with 
the exception, where relevant, of contraceptives allowed by protocol). 


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During the study, if the subject requires treatment, the Investigator should be informed and 
approve the proposed medication in line with the following instructions: 
Throughout the entire study, the use of medication that may have an impact on the study 
objectives is not permitted.  
• In addition, up to 24 hours after the final dose of IMP, no medication, including herbal 
remedies or food supplements and preventive chemotherapy (MDA), other than the IMPs, 
rescue medication and permitted medication described in this section is allowed unless 
absolutely necessary for treatment of AEs or the symptoms of onchocerciasis (see Appendix 
8 for the list of prohibited medication during the trial). 
• Permitted medications, as an exception, include: 
• 
diclofenac, paracetamol, ibuprofen, and aspirin 
• 
contraceptives (see Section 8.2) for WOCBP 
• 
topical drugs required for the eye examinations (e.g. mydriatic eye drops, anaesthetic 
drops) 
The following information will be recorded (along with the details as specified in Section 
9.3.1.3): 
• Medications taken between signature of ICF and the end of study participation (see Section 
3.4) must be recorded in the source documents and eCRF.  
• Any medication used to treat an SAE at any time in the study must be recorded in the source 
document, eCRF and SAE reporting form. 
8.2 Contraception/Birth Control 
Women of child-bearing potential (WOCBP) must agree to use or continue to use a highly 
effective birth control method as defined by the EU Clinical Trial Facilitation Group and 
detailed in Appendix 7 until at least 1 month after the last intake of IMP (Part 1: day 43; Part 
2: 1 month after the administration of ivermectin or matching placebo at the Month 6 visit).  
Contraceptives permitted by local regulations will be used. The most recent depot injection or 
implant or hormonal intra-uterine device or oral contraceptives should have been administered 
at least 14 days prior to Day 0. If required, the Investigator can arrange for suitable highly 
effective contraception to cover the required period. 
For WOCBP, details of the contraceptives used will be documented in the source documents.  
The definition of WOCBP according to the Clinical Trial Facilitation Group will be used in the 
trial as follows: a woman is considered of childbearing potential, i.e. fertile, following menarche 
and until becoming post-menopausal unless permanently sterile. Permanent sterilisation 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A post-
menopausal state is defined as no menses for 12 months with no alternative medical cause.74  
Contraception is not required for male subjects participating in the trial. 
8.3 Ivermectin: Rescue Medication, Post-Study, Screening Failures 
Ivermectin used as described in this section for rescue medication or post-study will be provided 
as a single oral administration at the approved dose of 150 µg/kg bw and is not an IMP, i.e. will 
not be presented as over-encapsulated tablets. 


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When ivermectin is administered at a follow-up or early termination visit, it must be 
administered only after completion of the procedures scheduled at that visit, and after 
confirmation of last menstrual period and a negative pregnancy test. Ivermectin will be 
administered to subjects under fasting conditions. 
Subjects who fail screening in the communities or at the investigational centre will be referred 
to the National Program PNLMTN-CTP for MDA with ivermectin.  
8.3.1 Rescue Medication in Part 1 
In Part 1, ivermectin will be administered as rescue medication at any time during the study, at 
the investigator’s discretion, to subjects with clinically significant worsening of symptoms 
and/or signs related to onchocerciasis.  
8.3.2 Rescue Medication in Part 2 
In Part 2, ivermectin will be proposed as rescue medication to all subjects with clinically 
significant worsening of symptoms and/or signs related to onchocerciasis at any time during 
the study and/or to subjects with increased mean number of skin microfilariae at Month 18, 
compared to the mean number at Month 12. 
8.4 Post-study Ivermectin 
In Part 1, ivermectin will be administered to all subjects at the 6-month follow-up visit. 
In Part 2, ivermectin will be administered to any subjects positive for microfilariae in the skin 
or eye at the 24-month follow-up visit. In addition, all subjects will be advised to continue to 
participate in MDA in their communities. 
In all parts of the trial, in the event of early termination, subjects will be offered ivermectin at 
the Investigator’s discretion. 
9 Study Procedures and Assessments 
9.1 Conduct of Study Procedures and Assessments 
The Schedule of Events for Part 1 is presented in Appendix 1. 
The Schedule of Events for Part 2 is presented in Appendix 2. Schedule of Events in Part 2 
Every effort should be made to ensure that protocol-required procedures and assessments are 
performed as described. 
Permitted time windows related to days of scheduled visits are detailed in the Schedules of 
Events. 
Examinations may be repeated in the event of a technical failure. This may require an additional 
out-patient visit if absolutely necessary. 
In the event of certain AEs considered to be associated with the IMP, additional examinations 
to better interpret the AE may be conducted, including safety laboratory, PK, ophthalmological, 
physical, neurological and parasitological examinations.  
However, it is anticipated that from time to time there may be circumstances outside the control 
of the Investigator that may make it unfeasible to perform the test. In those cases, the 




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Additional information can be found in the Schedule of Events (see Appendix 1 Error! 
Reference source not found.and Appendix 2. Schedule of Events in Part 2). 
9.2.2 Screening Period 
Informed consent will be collected before any study-specific procedures are performed. The 
procedure for obtaining informed consent is described in the Study Operations Manual. 
Screening procedures will be performed, and the results will be assessed within 8 weeks prior 
to the first IMP administration. 
Screening is likely to take place in two parts. 
Pre-screening will usually take place in the subjects’ communities to confirm the diagnosis of 
onchocerciasis and eligibility to participate in the study and will be performed by trained study 
personnel authorised by the investigator. A specific pre-screening ICF will be used to review 
and explain to the subjects the procedures that will be performed during the pre-screening 
phase. Subjects who are eligible based on the pre-screening will be invited to participate in the 
study. A separate ICF will be used to collect the subject’s consent to participate in the main 
study. After signature of the ICF for the main study, the subject will be invited for further 
screening at the investigational centre.  
The remaining procedures and assessments not performed during the initial screening in the 
community or which are out of window, as specified in the Schedule of Events, will be 
performed at the investigational centre 
Screening procedures may be performed the same day as signing of the ICF or a few days later, 
however, no screening procedures will be performed until the corresponding ICF has been 
signed. However, in case of re-screening, the procedures that were performed during the 
previous screenings, which didn’t lead to the exclusion of the subject and which are still within 
the allowed window as per the Schedules of Events for Part 1 and Part 2 (see Appendix 1 and 
Appendix 2) won’t be repeated, unless deemed necessary by the investigator. If the initial 
screening procedures start on the same day as the subject signs the ICF, the time of the subject’s 
signature will be recorded on the subject’s ICF and medical file. Some initial screening 
procedures may be performed during that visit. This will depend on the centre-specific 
recruitment procedures and logistic capacity (see Study Operations Manual for centre-specific 
information). 
9.2.3 Randomisation 
Eligible subjects will be centrally randomised using an IRT system after checking inclusion and 
exclusion criteria and before the first intake of the IMP. Randomisation may take place on 
Day -1, provided all the required examination results are available to assess subject eligibility 
in relation to the inclusion and exclusion criteria. 
Randomisation in the trial is described in the Study Operations Manual. 
9.2.4 Treatment Period  
The procedures to be performed each day during the treatment period are presented in the 
Schedules of Events for Part 1 and Part 2 (see Appendix 1 and Appendix 2) and a flow-chart is 
provided in the Study Operations Manual, with a day-to-day description of the various visits. 


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It is important that each procedure for an individual subject is performed at around the same 
time each day throughout the treatment period. 
Some procedures are to be performed before IMP administration and others after IMP 
administration (see below for details).  
Note that not all procedures are to be performed at each study visit (see the Schedule of Events 
for information on which ones to perform). 
9.2.4.1 Procedures routinely to be performed before IMP administration  
• Collection of pre-dose AEs (see Section 9.3.4).  
• Collection of pre-dose concomitant medications (see Section 8.1 and 9.3.1.3) 
• Laboratory safety, including haematology, biochemistry and urinalysis (see Section 
9.3.3.9.1) 
• Pregnancy test in WOCBP (see Section 9.3.3.9.3) 
• Collection of exploratory samples 
• Pre-dose PK blood sampling (see Section 9.3.2) 
• Vital signs (see Section 9.3.3.6) 
The IMP must be administered to subjects with food (see Section 9.2.8), except for ivermectin 
or matching placebo at Month 6 in Part 2, which must be administered in the fasting state. 
9.2.4.2 Procedures routinely to be performed after IMP administration 
• Full or shortened symptom-directed physical examination (see Section 9.3.3.3) 
• Brief neurological examination (see Section 9.3.3.4) 
• Collection of post-dose AEs (see Section 9.3.4)  
• Collection of post-dose concomitant medications (see Section 8.1 and 9.3.1.3)  
• 12-lead safety ECG (see Section 9.3.3.8) 
• Post-dose PK blood sampling (see Section 9.3.2) 
• Ophthalmological examination (see Section 9.3.3.7) 
• Skin snip (see Section 9.3.3.1.1) 
9.2.5 Follow-up Period 
All the procedures that need to be performed at every follow-up visits are listed in the Schedules 
of Events for Part 1 and Part 2 (see Appendix 1 and Appendix 2) and a flow-chart will be 
provided in the Study Operations Manual to indicate a description of the different visits. 
9.2.6 Early Termination Visit 
See also Section 6.5. 
All of the procedures to be performed at the early termination visit (unless the subject withdraws 
consent for some or all, as described in Section 6.5) are listed in the Schedules of Events for 
Part 1 and Part 2 (see Appendix 1 and Appendix 2) and a flow-chart will be provided in the 
Study Operations Manual to describe the visit. 




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• Sex; 
• Ethnic origin; 
• Body weight; 
• Height. 
• Town and/or district of residence. 
9.3.1.2 Medical History 
The following medical history items will be recorded: 
• Relevant past medical history, including prior diseases with start and end dates, prior 
treatment with start and end dates (see Section 8.1); 
• Surgical history, including indications and dates; 
• Current medical history, including start date and grade of on-going conditions; 
• Symptoms of onchocerciasis disease (ocular, skin, other). 
9.3.1.3 Concomitant Medication 
The following items for concomitant medication will be recorded: 
• International non-proprietary name (i.e. generic name); dose, frequency, route of 
administration and indication; 
• Start and stop dates  
9.3.2 Pharmacokinetics and Pharmacodynamics 
Blood samples for PK analyses of ABBV-4083 and albendazole sulfoxide, i.e. the active 
metabolite of albendazole, will be collected in Parts 1 and 2 at the time-points indicated in the 
Schedule of Events (see Appendix 1 and Appendix 2). A dry blood spot collection method will 
be used, for which detailed instructions will be included in the Laboratory Manual. The PK 
analyses will be performed using validated analytical methods. Since the PK calculations will 
be based on actual sampling, dosing times, and content of the meal provided with dosing, the 
data must be thoroughly documented in the subject’s medical file and/or eCRF. 
The PD effect of ABBV-4083 and of albendazole sulfoxide, the active metabolite of 
albendazole, on Wolbachia levels in female adult worms, status of female adult worm and skin 
microfilariae will be assessed in Parts 1 and 2 with regard to the PK parameters of ABBV-4083 
and albendazole (see also Section 9.3.3.1). 
9.3.3 Efficacy and Safety 
9.3.3.1 Parasitology 
9.3.3.1.1 Blood, Urine and Skin Snip Parasitology 
The following assessments will be performed at Screening: 
• In blood, testing for Wuchereria bancrofti, Mansonella perstans and Loa loa; 
• 
In skin snips, testing for Mansonella streptocerca, and O. volvulus. 


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9.3.3.1.2 Microfilaria Levels in the Skin 
A total of four skin snips will be taken at each time-point indicated in the Schedules of Events 
(see Appendix 1 and Appendix 2) to test for O. volvulus microfilariae and calculate skin 
microfilarial density. The presence of any microfilariae from other species, such as Mansonella 
streptocerca, will also be recorded. 
The specimens will be collected from the iliac crests and calves using a corneoscleral punch. 
One punch will be used per subject, and punches will be sterilised between subjects. Each snip 
will be incubated overnight, then weighed. The microfilariae that have emerged from the skin 
snips in the wells during incubation will then be counted. 
PCR will be used to assess the effect of the IMPs on Wolbachia bacteria in skin microfilaria. 
Processing of samples will be in accordance with the laboratory’s standard operating 
procedures, and additional information will be provided in the Laboratory Manual/Study 
Operations Manual. 
9.3.3.1.3 Microfilaria Counts in the Cornea and Anterior and Posterior Segments 
of the Eyes 
Microfilaria counts in the cornea and anterior and posterior segments will be assessed as part 
of the ophthalmological evaluations (see Section 9.3.3.7) in accordance with the procedures 
described in the Study Operations Manual. 
9.3.3.1.4 Nodulectomy and Histological Assessment of Nodules 
Nodulectomy will be performed under local anaesthesia using aseptic and standard surgical 
procedures. 
The subjects will be scheduled for an operation date and will be transported from their 
community either the evening before or early in the morning. Following surgery, the subjects 
will usually stay overnight in the investigational centre, or longer for logistic reasons or if 
medically indicated, and the subjects will then return to their communities where a nurse will 
continue wound management for up to approximately 2 weeks. 
Wound management will begin following the incision and continue until the wounds are 
completely healed. Subjects will be advised to stay off work for the first week post-surgery to 
promote wound healing. Sutures will be removed approximately 8 days post-nodulectomy. 
Evidence of an effect on the macrofilariae and microfilariae will be obtained from histological 
examination of nodules excised at the time-points indicated in the Schedule of Events (see 
Appendix 1 and Appendix 2).  
PCR will be used to assess the effect of the IMPs on Wolbachia bacteria  in adult worms. 
Removal of nodules and judgement of the adult worms will be performed according to 
published procedures.75,76 Detailed instructions on processing and assessment of the nodules 
including PCR assessments will be included in the Laboratory Manual/Study Operations 
manual/standard operating procedures (SOPs). 
9.3.3.2 Clinical Outcomes 
In Parts 1 and 2, clinical outcomes of onchocerciasis ocular disease, onchocerciasis skin 
disease, and itching will be assessed at the time-points indicated in the Schedule of Events (see 


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Appendix 1 and Appendix 2) The assessments will take place during ophthalmological 
examinations (see Section 9.3.3.7) and skin examinations (see Section 9.3.3.5).  
9.3.3.3 Physical Examination 
A full physical examination, including height and weight (only at Screening) and a complete 
review of body systems will be performed at the time-points specified in the Schedule of Events 
(see Appendix 1 and Appendix 2). At some time-points, a shortened symptom-directed physical 
examination will be performed. Detailed instructions for the physical examination will be 
provided in the Study Operations Manual/SOPs. 
9.3.3.4 Neurological Examination 
A brief neurological examination will be performed at various time-points specified in the 
Schedules of Events (see Appendix 1 and Appendix 2). Detailed instructions for the short 
neurological examination will be provided in the Study Operations Manual/SOPs. 
9.3.3.5 Skin Examination and Nodule Palpation 
Specific onchocerciasis examinations will be performed at the time-points specified in the 
Schedules of Events (see Appendix 1 and Appendix 2).  
Nodule Palpation will be conducted, with documentation of Onchocerca nodules. 
Skin examinations will be conducted to document manifestations of onchocercal skin disease 
and itching, to assess clinical outcomes (see Section 9.3.3.2). The clinical classification and 
grading system of the cutaneous changes in onchocerciasis scale (modified) will be used.77 
Detailed instructions for the skin examination will be provided in the Study Operations 
Manual/SOPs.  
9.3.3.6 Vital Signs 
The following parameters will be assessed for vital signs with one measurement at each 
specified time-point (see Appendix 1 and Appendix 2). 
• Supine systolic BP; 
• Supine diastolic BP; 
• Supine heart rate; 
• Resting respiratory rate; 
• Temperature. 
Measurements will be repeated if values are outside of the ranges defined in the Study 
Operational Manual. If the result of the repeat measurement is still out of range, it will be 
assessed for clinical significance and, in accordance with the instructions in Section 9.3.4.2, 
may be reported as an AE. 
9.3.3.7 Ophthalmological Examination 
Ophthalmological assessments will be performed by a specialist at the time-points specified in 
the Schedule of Events (see Appendix 1 and Appendix 2). The assessments will include past 
ocular history, ocular symptoms, ocular examinations including ocular alignment and mobility 


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and pupillary response, visual function (visual acuity, visual field, colour vision), slit lamp 
examination of anterior and posterior segments and intraocular pressure measurement and 
fundus photography. 
Motile and non-motile microfilariae in the cornea, and the anterior and posterior segments, and 
onchocercal corneal punctate opacities will be counted. 
Subjects will be informed that they will need to bring their distance glasses (if applicable) and 
their near vision will be blurred for approximately 2 hours (due to the use of mydriatic eye 
drops) following the eye-testing procedures,  
Detailed instructions for the ophthalmological assessments will be provided in the Study 
Operations Manual/SOPs. 
9.3.3.8 Standard 12-lead ECG 
A complete standard 12-lead ECG will be recorded in the supine position using a computerised 
ECG device at the time-points specified in the Schedule of Events (see Appendix 1 and 
Appendix 2). 
The following parameters will be calculated: 
• heart rate, 
• PR interval, 
• QRS-interval, 
• QT/ QTcF interval (uncorrected and corrected QT interval according to Fridericia’s 
formulae). 
All ECGs recorded will be read by a physician experienced in evaluating ECGs, providing an 
ECG diagnosis and overall assessment, including clinical significance and changes compare to 
screening. The data from this central reading will be used for the statistical analysis. 
Any clinically significant abnormality on ECG will be checked by repeat ECG. Any clinically 
significant ECG abnormality that is confirmed by repeat ECG will be assessed in accordance 
with the instructions in Section 9.3.4 and may be considered to be an AE. 
The triplicate ECG recordings at Screening for the purposes of assessing eligibility may be 
repeated only once. Triplicate ECGs will be performed at all time points, except at Day 3 in 
Part 1 when single ECGs will be performed. 
Detailed instructions for recording and handling of the ECGs will be provided in the Study 
Operations Manual/SOPs. 
9.3.3.9 Laboratory Assessments 
9.3.3.9.1 Haematology, Biochemistry, Urinalysis and Urine Microscopy 
Blood and urine samples will be collected at the time-points specified in the Schedule of Events 
(see Appendix 1 and Appendix 2) for assessment of haematology, biochemistry, urinalysis by 
dipstick, and urine microscopy (only in the event of abnormal and clinically significant results 
with dipstick). For the parameters to be assayed, see Appendix 5.  
On days when the IMP is administered, blood samples must be collected prior to administration 
of the IMP, and as far as possible at the same time each day during the treatment period. 


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Detailed instructions for blood and urine sample collection will be provided in the Study 
Operations Manual/SOPs. 
9.3.3.9.2 Alcohol Breath Test and Urinary Cannabis Screen 
Breath and urine samples will be tested for alcohol concentration and presence of cannabis, 
respectively, at Screening to ensure compliance with the Inclusion and Exclusion Criteria (see 
Sections 6.1 and 6.2). 
9.3.3.9.3 Pregnancy Tests 
A highly sensitive pregnancy test, i.e. beta human chorionic gonadotropin level, and the 
verification of the date of the last menstrual period will be performed in WOCBP at the time-
points specified in the Schedule of Events (see Appendix 1 and Appendix 2).  
The test performed at baseline closest to and before the first IMP administration and at the Day 
13 visit (at least 24 hours after the last IMP intake) or Early Termination visit if done before 
Day 13 visit, must be a serum test. In case a repeat test is needed during screening at the site, it 
can be a urine test providing the initial testing was serum and that the repeat is approved by the 
sponsor. 
Tests at other time points may be urine or serum, however serum is preferred where feasible, 
i.e. when blood collection for another purpose is already scheduled at that time-point. 
Any positive pregnancy test after the first IMP administration up to and including the Day 13 
visit or Early Termination Visit, if done before Day 13 visit, must be confirmed by a serum test. 
If the menstrual period is delayed, with over one month between menstruations, confirmation 
of absence of pregnancy with a pregnancy test is mandatory. This recommendation also applies 
to WOCBP with infrequent or irregular menstrual cycles. 
9.3.3.9.4 Remainder and Exploratory Samples, and Future Use 
Where feasible, remainder tissue samples collected from study procedures, e.g. skin, 
microfilariae and nodules will be retained for possible future research. In addition, specific 
exploratory samples of plasma and urine will be collected at the time-points specified in the 
Schedules of Events (see Appendix 1 and Appendix 2). 
The samples may be used in the future for research on onchocerciasis and other parasitic 
diseases, including identification of biomarkers of molecular, immunological or genetic origin 
to develop diagnostic tools for onchocerciasis and increase the knowledge on the disease and 
response to the IMPs. 
Preparation and storage of the samples will be described in the Study Operations Manual/SOPs. 
The samples may be stored indefinitely after the end of the study. The coded samples will only 
be transferred providing the relevant documents (e.g., Materials Transfer Agreement) have been 
submitted to the regulatory authorities and ethics committee(s) if required. 
These samples are optional, and subjects may still participate in this study if they do not consent 
to the collection of exploratory samples and use of their samples for future scientific studies via 
the informed consent document. If consent is not given, the remainder samples will be discarded 
after completion of the study and specific exploratory samples will not be collected. All samples 
transferred for future research will be anonymised. 


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9.3.4 Safety - Adverse Event Definitions and reporting 
In this section, the term “reporting” refers to data collection on AEs in source documents, as 
well as to informing the Sponsor via the eCRF. The term “safety reporting” refers to time-
limited additional reporting of individual case safety reports (SAE, pregnancy, child) to the 
Sponsor, and where required to ethics committee(s) and regulatory authorities. 
9.3.4.1 Definition of Adverse Event 
An adverse event (AE) is defined as: 
“Any untoward medical occurrence in a clinical trial subject administered a medicinal product, 
and which does not necessarily have a causal relationship with that treatment. 
It can therefore be any unfavourable and unintended sign, symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.”78 
The definition of an AE includes worsening in severity or frequency of pre-existing conditions 
(medical history) before the first IMP administration and abnormalities of procedures (e.g. 
ECG, x-ray, physical or ophthalmological examination) or laboratory results that are assessed 
as “clinically significant”. 
What is not an AE, and not captured on the AE page: 
• 
Medical conditions present at the initial study visit that do not worsen in severity or 
frequency during the study are not considered as AEs; 
• 
Lack of efficacy of the IMP is not considered as AE.  
9.3.4.2 Assessment of Abnormalities from Laboratory Tests or Other Procedures  
For every laboratory test/procedure, the Investigator will evaluate if the result of the laboratory 
test/procedure is normal or abnormal. If abnormal (after repeat testing, if indicated), the 
Investigator will assess whether the finding is “clinically significant” or not. An abnormal result 
on a laboratory test/procedure must be compared with the previous value taking into account 
normal values in the studied population/country. 
If the result of a laboratory test/procedure is abnormal and the abnormality assessed as clinically 
significant, it should be reported as an AE. 
Abnormalities on laboratory tests/procedures (e.g. ECG) or worsening in severity or frequency 
of pre-existing abnormalities should be assessed as “clinically significant” and therefore must 
be reported as AE if they meet at least one of the following conditions: 
• The abnormality suggests a disease and/or organ toxicity and this abnormality was not 
present at the screening visit or is assessed as having progressed since the screening visit; 
• The abnormality results in discontinuation of the IMP; 
• The abnormality requires medical intervention or concomitant therapy. 
When reporting an abnormal result on laboratory test/procedure as an AE, a clinical diagnosis 
should be recorded rather than the abnormal value itself, if available (e.g. acute pancreatitis 
instead of each finding separately: high levels of amylase, high levels of lipase, abdominal pain 


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and vomiting; e.g. “hypokalaemia” rather than “decreased potassium levels”; “anaemia” rather 
than “decreased red blood cell count). 
An event that occurs after signature of the ICF and prior to the first IMP administration is not 
considered an AE per se but as an “event” that could be due to the disease or specific 
circumstances in which the subject has been placed (e.g. “protocol related” which may be 
caused by the participation to the trial). 
9.3.4.3 Serious Adverse Event 
An AE is defined as serious if it: 
• Results in death, 
i.e. causes or contributes to death; 
• Is life-threatening, 
In this context refers to an AE in which the subject was at risk of death at the time of the 
AE; it does not refer to an AE that hypothetically might have caused death if it had been 
more severe; 
• Requires in-patient hospitalisation or prolongation of existing hospitalisation, 
i.e. the AE requires at least an overnight admission or prolongs hospitalisation beyond 
the expected length of stay. Hospital admissions for surgery planned before study entry, 
for social reasons, for any elective surgery (i.e. plastic surgery), for uncomplicated 
delivery or per protocol or for normal disease management (including treatment 
adjustment) are not to be considered as SAE according to this criterion (i.e. if the protocol 
requires planned hospitalisation); 
• Results in persistent or significant disability or incapacity, 
i.e. the AE results in a substantial disruption of the subject’s ability to conduct normal 
activities; 
• Is a congenital anomaly or birth defect, 
i.e. an AE outcome in a child or foetus of a subject exposed to the IMP before conception 
or during pregnancy; 
• Is an important medical event, i.e. is medically significant, 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious events/reactions, such as important medical events that 
might not be immediately life-threatening or result in death or hospitalisation but might 
jeopardise the subject or might require intervention to prevent one of the other outcomes 
listed above. Examples of such events include, but are not limited to, intensive treatment 
in an emergency room or at home for allergic bronchospasm, potential drug induced liver 
injury, blood dyscrasias or convulsions that do not result in hospitalisation. Any suspected 
transmission via a medicinal product of an infectious agent is also considered as a serious 
AE.78  
For the purposes of the study, stillbirth and spontaneous or induced abortion will also be 
considered as an SAE. 
Although exposure during pregnancy and overdose are not always associated with an AE, these 
events must be handled as defined in Sections 9.3.4.9 and 9.3.4.11). 


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For the purpose of this study, prolongation of hospitalisation that is not related to a medical 
event but related to any social and/or financial reasons or logistical reasons, will not be 
considered as an SAE. 
SAE onset/start date: Start date of SAE or date when the AE becomes serious (see seriousness 
criteria of an SAE). 
SAE end/stop date: SAE end date is the date of AE recovery. 
9.3.4.4 Eliciting Adverse Event Information  
The Investigator is required to report all directly observed AEs and all AEs spontaneously 
reported by subjects using concise medical terminology. 
In addition, to avoid bias in eliciting AEs, subjects will be questioned about the occurrence of 
AEs at the time-points indicated in the Schedules of Events (see Appendix 1. and Appendix 2. 
Schedule of Events in Part 2), with general non-leading questions such as “Since xxx (e.g. last 
visit) have you had any health problem?” or “How are you feeling?”. 
All AEs (serious and non-serious) must be recorded on the source documents and AE pages of 
the eCRF regardless of the assumption of a causal relationship with the IMP. The definition, 
reporting, and recording requirements for AEs are described in Section 9.3.4. 
Information on AEs must be evaluated by a physician.  
Each AE is to be classified by the Investigator as serious or non-serious (see definition of a 
SAE in Section 9.3.4.3). This classification will determine the reporting procedure for the event. 
In addition, the frequency, seriousness, severity (see Section 9.3.4.6) and causality (see Section 
9.3.4.7) assessment of AEs will be described.  
Non-serious AEs are to be recorded in the eCRF, including description of the event, onset date, 
end date, severity, seriousness, relationship to all study drugs, actions taken and outcome. Start 
and stop times are to be recorded when available during the in-house period in order to capture 
Treatment Emergent Adverse Event (TEAE). 
Only one AE and the maximum severity will be recorded in the eCRF for each separate event. 
If the AE resolves but then recurs, each will be recorded as a separate AE, with the appropriate 
start and stop times. 
SAEs will be reported both on the AE page of the eCRF and the SAE forms. 
9.3.4.5 Adverse Event Reporting Period 
In this protocol, the reporting period is different for AEs and for SAEs: 
• Non-serious AEs: all non-serious AEs will be reported from administration of the first 
intake of IMP until the subject’s end of study participation (see Section 3.4). 
Furthermore, non-serious events that occur in the screening period (from signature of the 
ICF) until before the first intake of the IMP and that are judged as related to study 
participation (e.g. haematoma due to venipuncture, wound infection due to skin snips), 
will be recorded on the AE page of the eCRF. 
• SAEs: all SAEs must be reported after signature of the ICF during the screening period 
until the subject’s end of study participation (as defined in Section 3.4) on the AE page 
of the eCRF and the SAE form. 


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All treatment emergent AEs that occur during the AE reporting period as defined in this section 
must be reported, whether or not the event is considered treatment related. 
In addition, any SAE that occurs after the end of the AE reporting period and that the 
Investigator assesses as possibly, probably or definitely related to the IMP or to participation 
in the study may also be reported as an SAE. 
Screening failure: beyond the date of screening failure (to be recorded), only serious study-
related events will be reported. 
9.3.4.6 Grading of Adverse Event Severity 
For each serious and non-serious AE, the Investigator is required to assess the severity of each 
AE.  
It is to be noted the distinction between severity and seriousness of AEs. A severe AE is not 
necessarily a SAE. 
The severity for an AE should be graded using the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 (see Appendix 6), as a guide in 
the grading of the severity of AEs. Certain grading definitions have been adapted to ensure they 
are appropriate for the IMP, the disease and patient population. 
The exceptions are:  
• The Vaccine Trial Grading Scale 2007, from the U.S. FDA Center for Biologics Evaluation 
and Research,79 will be used for: 
o haemoglobin  
o eosinophils  
o blood urea nitrogen 
o total protein 
o urine glucose 
 
• For values in the urinalysis with no grading available in either CTCAE version 5.0 or 
Vaccine Trial Grading 2007, the Investigator will use the terminology mild, moderate, 
severe, life-threatening or death described below. 
• In case of AEs that are not described in the CTCAE version 5.0 AE severity grading system, 
nor in the exceptions listed above the Investigator will use the terminology mild, moderate, 
severe, life-threatening or death to describe the maximum severity of the AE as follows: 
o Mild: The subject is aware of the event or symptom, but the event or symptom is easily 
tolerated, (e.g. no reduction in daily activities is required); 
o Moderate: The subject experiences sufficient discomfort to interfere with or reduces his 
or her usual level of activity; 
o Severe: Significant impairment of functioning: the subject is unable to carry out usual 
activities and/or the subject’s life is at risk from the event. 
o Life-Threatening: The subject is at significant risk of life; it does not refer to an event 
which hypothetically might have caused death if it were more severe (life-threatening 
consequences, urgent intervention required). 
o Death: Death related to an event. 
This information will be entered on the AE page of the eCRF. 


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When the severity of an AE changes over time, each change in severity will be recorded in the 
source documents until the event resolves. However, only one AE and the maximum severity 
will be recorded in the eCRF for each separate event. If the AE resolves but then recurs, each 
recurrence will be recorded as a separate AE, with the appropriate start and stop times. 
9.3.4.7 Adverse Event Causality Assessment 
For each serious and non-serious AEs, the Investigator is required to assess the possible 
relationship between the AE and each IMP, i.e. to determine whether there exists a reasonable 
possibility that the IMP(s) caused or contributed to the AE(s). 
The following categories for relationship to treatment will be used during AE reporting: 
• Definitely related. The AE and administration of IMP are related in time, and a direct 
association can be demonstrated; 
• Probably related. The AE and administration of IMP are reasonably related in time, and 
the AE is more likely explained by the IMP than other causes; 
• Possibly related. The AE and administration of IMP are reasonably related in time, and 
the AE can be explained equally well by causes other than the IMP; 
• Probably not related. A potential relationship between IMP and the AE could exist (i.e. 
the possibility cannot be excluded), but the AE is most likely explained by causes other 
than the IMP; 
• Not related. The AE is clearly explained by another cause not related to the IMP. 
Note: for regulatory reporting purposes, when compared to binary classification, “not related” 
corresponds to “not related” and “probably not related” and “related” corresponds to “possibly”, 
“probably”, and “definitely related”. 
To help the Investigator with the decision binary tree (related/not related) in the evaluation of 
causality, the Council for International Organisations of Medical Sciences VI group 
recommends that the Investigator should consider the following before reaching a decision: 
• Medical history (including presence of risk factors); 
• Lack of treatment efficacy/Worsening of existing condition; 
• Trial medications; 
• Other medications (concomitant or previous); 
• Withdrawal of trial medication, especially following study discontinuation/end of 
treatment; 
• Erroneous treatment with trial medication (or concomitant); 
• Protocol-related procedure. 
In addition, for SAEs, the Sponsor will also perform a causality assessment in accordance with 
Sponsor’s standard operating procedures. 
9.3.4.8 Safety Reporting Requirements 
Each AE is to be classified by the Investigator as serious or non-serious. This classification will 
determine the reporting procedure for the event. 
All SAEs are to be reported immediately (within 24 hours of awareness of the SAE by the 
Investigator), to SAETYL01study@dndi.org, using the SAE report form. This includes a 


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description of the event, onset date and type, duration, severity, relationship to each of the IMPs, 
outcome, measures taken and all other relevant clinical and laboratory data. 
The initial report is to be followed by submission of additional information (follow-up SAE 
form) as it becomes available. Any follow-up reports should be submitted as soon as possible, 
and if possible within 5 working days from awareness of the information by the Investigator. 
SAEs should also be reported on the AE page of the eCRF. It should be noted that the form for 
reporting of SAE (SAE form) is not the same as the AE section of the eCRF. Where the same 
data are collected, the two forms must be completed in a consistent manner, and the same 
medical terminology should be used. 
In addition to immediately reporting SAEs to DNDi, the Investigator will immediately notify 
the regulatory authorities and ethics committee(s) of SAEs (and non-serious AE if required by 
the local regulatory requirements), and follow-up information, that occur during this trial, if 
applicable, in accordance with the standard operating procedures/guidelines/regulations issued 
by the regulatory authorities and ethics committee(s). 
A suspected unexpected serious adverse reaction (SUSAR) is a suspected AE related to an 
investigational medicinal product that is both unexpected and serious. 
DNDi, the Sponsor is responsible for determining the expectedness of the event for each IMP, 
using the reference safety information defined for the study, contained in the Investigator 
Brochure for ABBV-4083, and in the Prescribing Information for albendazole and 
ivermectin.57,63,65  
DNDi will notify the regulatory authorities and ethics committee(s) of all SUSARs (if 
applicable based on local requirements) in compliance with local safety reporting requirements.  
If unblinding is required for expedited reporting (as per local requirements), reporting of 
SUSARs to the regulatory authorities and ethics committee(s) will not involve any personnel 
at the investigational centre or other members of the Sponsor’s study team, to preserve the study 
blind. 
9.3.4.9 Exposure in utero 
If a trial subject becomes or is found to be pregnant (based on date start last menstruation 
period) while receiving any IMP or within 1 month of discontinuing the IMP, the Investigator 
must submit the event on a “Pregnancy Surveillance Form” in accordance with the same process 
and timelines as defined for SAEs (see Section 9.3.4.8). 
This must be done irrespective of whether an AE has occurred. The information submitted 
should include the start date of last menstruation period (or the best estimation) and the 
anticipated date of delivery. 
The Investigator will follow the subject until completion of the pregnancy or until pregnancy 
termination (i.e. induced / spontaneous abortion). The Investigator will provide pregnancy 
follow-up or outcome information on a “Pregnancy Surveillance Form”. 
In the case of a live birth, a medically qualified person (preferably a paediatrician) should assess 
the infant at the time of birth and submit a “Child Surveillance Form”. The Investigator will 
offer the parents follow-up on infants exposed to the study treatment in utero until they reach 
24 months of age.  
A pregnancy is not a SAE. Any unfavourable outcome meeting at least one seriousness criteria 
i.e. in the case of unfavourable pregnancy outcome (spontaneous and induced abortion, still 


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birth) or congenital abnormality shall be reported using the “SAE form” (in addition to the 
Pregnancy/Child Surveillance Form). 
9.3.4.10 Adverse Event Follow-up 
All AEs should be followed until: 
• they are resolved; or 
• the Investigator assesses them as “chronic” or “stable”; or 
• the subject’s participation in the trial ends, i.e. as defined in Section 3.4. 
The Principal Investigator or Co-investigator may or will interrupt or suspend treatment due to 
serious safety issues in order to protect the subjects. In addition, all SAEs, whether related or 
not, must continue to be followed even after the subject’s end of study participation in order to 
collect the outcome. Such events should be followed until they resolve or until the Investigator 
assesses them as “chronic” or “stable.” Resolution of such events is to be documented on the 
AE page of the eCRF (up to the end of study participation) and SAE form (up to and after the 
end of study participation). 
For SAEs that occur after the subject’s end of study participation, see Section 9.3.4.8. 
9.3.4.11 Overdose 
All overdoses with the study treatment will be recorded in the eCRF. If the overdose is 
symptomatic and clinically significant, it will also be reported as an AE. 
In the event of an overdose with the study treatment, symptomatic and supportive therapy 
should be given as appropriate, and the Investigator should contact the Sponsor’s Medically 
Responsible Person.  
Medication errors with the study treatment committed by study personnel that result in a 
possible overdose, as well as all medication errors, must be documented as protocol deviations 
and reported to the Sponsor and the regulatory authorities and ethics committee(s) if required 
in accordance with the requirements of the local ethics committee(s) and regulatory authorities. 
9.3.4.12 Monitoring of AEs Outside the Investigational Centre 
To ensure appropriate and timely management of AEs, a process will be set up for reporting 
and communication of any AEs that occur when the subject is not at the investigational centre. 
The process will be described in the Study Operations Manual/SOPs. 
10 Statistical Analyses 
10.1 Statistical Hypotheses 
10.1.1 Primary Hypothesis in Part 1 
The primary hypothesis for the proof of concept in Part 1 is that more worms will have 
Wolbachia depletion at 6 months in the subjects who completed treatment with ABBV-4083 
for 7 days (Arm A), ABBV-4083 for 14 days (Arm B), ABBV-4083 + albendazole for 7 days 
(Arm C), or ABBV-4083 for 7 days + albendazole for 3 days (Arm D) than in subjects treated 


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with albendazole for 7 days (Arm E) among all subjects who completed treatment and who had 
live female worms from nodulectomies at 6 months. 
The primary hypothesis to satisfy the combination rule in Part 1 is that more worms will have 
Wolbachia depletion at 6 months in the subjects treated with ABBV-4083 + albendazole for 7 
days (Arm C) than in subjects treated with albendazole for 7 days (Arm E) or those treated with 
ABBV-4083 for 7 days (Arm A) among all subjects who completed treatment and had live 
female worms from nodulectomies at 6 months. If the combination arm of ABBV-4083 for 7 
days + albendazole for 3 days (Arm D) is to advance to Part 2 and ABBV-4038 for 7 days + 
albendazole for 7 days (Arm C) is not, then the combination rule will be tested for ABBV-4083 
for 7 days + albendazole for 3 days (Arm D) in Part 1. Of note, the possible substitution of 
ABBV-4083 for 7 days plus albendazole for 3 days in place of ABBV-4038 + albendazole for 
7 days will not be continuously noted below for brevity sake. 
10.1.2 Primary Hypotheses in Part 2 
The primary hypothesis for Part 2 is that more subjects treated with one or more of the active 
regimens selected from Part 1 (Arms K, L and M) will be without skin microfilariae at 24 
months as compared to subjects treated with placebo (Arm N1, base scenario) or ABBV-4083 
for 7 days (Arm N2, alternate scenario). 
Combination Rule Hypothesis for Part 2 Alternative Scenario 
If the primary hypothesis to satisfy the combination rule in Part 1 is not satisfied and ABBV-
4083 + albendazole for 7 days (Arm C in Part 1) is to be carried forward to Part 2 (as either 
Arm K with ivermectin and Arm L without ivermectin, or as Arm M with or without 
ivermectin), an additional hypothesis using appropriate subjects from both Part 1 and Part 2 
will be that more worms will have Wolbachia depletion at 6 months in subjects treated with 
ABBV-4083 + albendazole for 7 days (Arm C for Part 1 and Arm K plus Arm L [or alternately 
Arm M if appropriate] for Part 2) than in subjects treated with ABBV-4083 for 7 days (Arm A 
for Part 1 and Arm N2 for Part 2) among all subjects who completed treatment and who had 
live female worms from nodulectomies at 6 months.  
In the case that ABBV-4083 for 7 days + albendazole for 3 days (Arm D in Part 1) is selected 
for Part 2 and ABBV-4083 + albendazole for 7 days (Arm C in Part 1) is not selected, and the 
primary hypotheses for satisfying the combination rule in Part 1 are not satisfied, then the arm 
or arms containing ABBV-4083 for 7 days + albendazole for 3 days will be treated as described 
elsewhere in this document for ABBV-4083 + albendazole for 7 days in the Alternate Scenario, 
and the data combined with Arm D in Part 1 for analysis. 
10.1.3 Key Secondary Hypotheses in Part 2 
The key secondary hypotheses in Part 2 are as follows: 
• 
The first secondary hypotheses for Part 2 (Endpoint 2a) are that a smaller mean 
percentage of female adult worms per subject will be alive at 24 months among the 
subjects who completed treatment with one or more of three assigned regimens selected 
from Part 1 (Arms K, L and M) compared to either placebo (Arm N1) or ABBV-4083 
for 7 days (Arm N2).  
• 
The second secondary hypotheses for Part 2 (Endpoint 2b) are that a larger mean 
percentage of live female adult worms will have only degenerated embryos in their uteri 


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per subject at 24 months among the subjects who completed treatment with one or more 
of three regimens selected from Part 1 (Arms K, L and M) compared to either placebo 
(Arm N1) or ABBV-4083 for 7 days (Arm N2). 
10.2 Analysis Sets 
The analysis sets are: 
• Intention-to-treat (ITT) population: all randomised subjects who received at least one 
dose of IMP.  
• Primary population for Part 1 primary endpoint and Part 2 combination rule endpoint for 
Alternative Scenario: Per protocol (PP) for nodulectomy at 6 months (ND6M), i.e. all 
ITT subjects who had Month 6 nodulectomy with live female adult worms, who 
completed treatment and who did not take prohibited medication during the study (see 
Appendix 8 - Sections II and IV).  
• Primary population for Part 2 proportion of subjects with microfilaria depletion at Month 
24 endpoint: PP population for microfilaria, defined as all subjects in the ITT population 
who had microfilaria-positive skin-snips at baseline, who completed treatment, had skin 
snips at Month 24 or received ivermectin rescue before Month 24, and who did not take 
prohibited medication during the study (see Appendix 8 - Sections II and IV). 
• Primary population for Part 2 secondary endpoints 2a: PP population for nodulectomy at 
24 months (ND24M), i.e. all ITT subjects who had Month 24 nodulectomy with female 
adult worms, who completed treatment and who did not take prohibited medication 
during the study. 
• Primary population for Part 2 secondary endpoints 2b: PP population for nodulectomy at 
24 months (ND24M) with live female adult worms, i.e. all ITT subjects who had Month 
24 nodulectomy with live female adult worms, who completed treatment and who did not 
take prohibited medication during the study. 
• Safety population: all randomised subjects who received at least one dose of IMP. 
Subjects who take prohibited medications that may have an impact on the study objectives 
(Appendix 8- sections II and IV) are excluded from the PP populations. Specifically subjects 
who take medications with an anti-filarial or anti-Wolbachia effect at any time during the study 
(Appendix 8-section II) or strong CYP3A inducers or dexamethasone during the treatment 
period that may lower ABBV-4083 or albendazole exposures (see Appendix 8 - Section IV) are 
excluded from the PP population. 
Completed treatment for Part 1 is defined as taking at least 6 out of 7 days of randomised 
ABBV-4083, ABBV-4083 + albendazole or albendazole alone (Arms A, C or E, respectively), 
12 out of 14 days of randomised ABBV-4083 (Arm B) or 6 out of 7 days of randomised ABBV-
4083 and all of 3 days of randomised albendazole (Arm D). The same definitions of treatment 
completion will be applied to the similar arms in Part 2, except that subjects must also be 
administered ivermectin or matching placebo at Month 6 to be considered as having completed 
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10.3 Determination of Sample Size 
10.3.1 Determination of Sample Size in Part 1 
For the Part 1 primary hypothesis that compares the proportion of live female adult worms 
without Wolbachia at Month 6 between a single-drug ABBV-4083 arm (Arm A or Arm B) and 
the albendazole arm (Arm E), an alternating logistic regression will be used to compare the 
endpoint between two arms, taking into account the clustering of this worm-level endpoint by 
subject. Using simulations that add substantial clustering by subject to the endpoint values and 
assuming the number of worms in each subject varies from 1 to 10,54 following the multinomial 
distribution with probability = (0.20, 0.16, 0.16, 0.16, 0.08, 0.08, 0.08, 0.03, 0.03, 0.02) for 
values (1, 2, 3, 4, 5, 6, 7, 8, 9, 10), 17 subjects per arm will provide 88% power to detect the 
difference between a single-drug ABBV-4083 arm (Arm A or Arm B) where 70% of worms 
are without Wolbachia and the albendazole arm (Arm E) where 30% of worms are without 
Wolbachia (2-sided α =0.10). The clustering of the endpoint values by subject is provided by 
the Pearson intraclass correlation coefficient (ICC) for binary outcomes80 and was given as ICC 
= 0.54 for simulated arms where 70% or 30% of the worms are without Wolbachia. 
For the Part 1 primary hypothesis that compares the proportion of live female adult worms 
without Wolbachia at Month 6 between the combination arm of ABBV-4083 + albendazole for 
7 days (Arm C) and the single-drug ABBV-4083 arm (Arm A), 25 subjects per arm will provide 
81% power to detect the difference between the combination arm where 90% of worms are 
without Wolbachia and the single-drug arm where 70% of worms are without Wolbachia (2-
sided α =0.10 using alternating logistic regression). ICC = 0.54 was added to the simulated arm 
where 70% of the worms are without Wolbachia. Minimal clustering (ICC = 0.01) was added 
to the simulated arm where 90% of the worms are without Wolbachia because the difference 
between subjects would be negligible for such a high response rate. 30 subjects will be enrolled 
per arm to account for 17% drop out by Month 6. 
10.3.2 Determination of Sample Size in Part 2 
For the Part 2 primary hypothesis in the Base Scenario that compares the proportion of subjects 
without skin microfilariae at Month 24 between an active arm (Arm K, L or M) and the placebo 
arm (Arm N1), 62 subjects in the active arm and 31 subjects in the placebo arm will provide 
91% power to detect the difference between an active arm (Arm K, L or M) where 70% of 
subjects are without skin microfilariae at Month 24 and the placebo arm (Arm N1) where 30% 
of subjects are without microfilariae at Month 24, using a logistic regression with 2-sided 
α=0.017. In addition, 62 subjects per arm will provide 80% power to detect the difference 
between two active arms where 90% and 70% of subjects are without skin microfilariae 
at Month 24, respectively, using a logistic regression with nominal 2-sided α=0.05. Assuming 
a 25% drop-out rate by Month 24, 84 subjects in each active arm and 42 subjects in the placebo 
arm are planned to be enrolled. 
For the Part 2 primary hypothesis in the Alternate Scenario that compares the proportion of 
subjects without skin microfilariae at Month 24 between each active arm (Arm K, L or M) and 
the control arm (Arm N2: 7 days of ABBV-4083), 62 subjects per arm will provide 84% power 
to detect the difference between an active arm (Arm K, L or M) where 90% of subjects are 
without skin microfilariae at Month 24 and the control arm (Arm N2) where 65% of subjects 
are without microfilariae at Month 24 , using a logistic regression with 2-sided α=0.017. 


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For the Part 2 combination rule hypothesis in the Alternate Scenario that compares the 
proportion of live female adult worms without Wolbachia at Month 6 between the combination 
arms of ABBV-4083 + albendazole for 7 days (Arm K plus Arm L) and the ABBV-4083 single 
drug arm (Arm N2), 17 subjects per each of Arms K and L for a total of 34 subjects in Part 2 
in addition to the 25 subjects per arm in Part 1 will be able to provide an overall power of 96% 
to detect the difference between the combination arm where 90% of worms are without 
Wolbachia and the single drug arm where 70% of worms are without Wolbachia (2-sided α 
=0.10) in either Part 1 or Part 2, using an inverse normal combination test that combines the p-
values of alternating logistic regressions that use data from Part 1 only and Part 2 only. The 
assumption for the number of worms in each subject in Part 2 is adjusted to a multinomial 
distribution with probability = (0.22, 0.18, 0.17, 0.16, 0.08, 0.06, 0.06, 0.03, 0.02, 0.02) for 
values (1, 2, 3, 4, 5, 6, 7, 8, 9, 10) in order to account for the design that only worms from one 
nodule per subject in Part 2 will be used for this analysis. If Part 1 Arm B of ABBV-4083 for 
14 days is used for Arms K and L of Part 2, Arm M would be the 4083/albendazole combination 
that is compared to Arm N2. 17 subjects in Arm M Part 2 in addition to the 25 subjects per arm 
in Part 1 will be able to provide an overall power of 95% using the same method. Assuming 
17% of the subjects per arm drop out by Month 6, the enrolment in the alternate scenario will 
require at least 25% of subjects of those retained to Month 6 nodulectomy to have > 1 nodule 
site in the arms used to test this hypothesis to obtain the power shown above.  
10.4 Handling of Potential Intercurrent Events for the Primary and Key 
Secondary Endpoints 
Subjects who do not complete the treatment as defined above will be excluded from the PP 
populations (but will be included in the ITT analyses). Subjects in Part 2 with evidence of 
reinfection will be included in all analyses as it is not possible to distinguish between reinfection 
and a failure in this study. However, in sensitivity analyses, those subjects will be excluded 
from efficacy analysis. Subjects in Part 2 who do not have skin snips at Month 24 will be 
excluded from the PP for microfilaria population, except those who received ivermectin rescue 
before Month 24. Any subject who received ivermectin rescue before Month 24 as allowed per 
protocol will be counted as a failure in both the PP and ITT analyses of the Part 2 primary and 
key secondary endpoints. Subjects who do not have nodulectomy data at Month 6 (for Part 1 
and for Part 2 Alternate Scenario) or Month 24 (for Part 2) will be excluded from the PP for the 
ND6M or ND24M populations, respectively. Subjects who take prohibited medications (see 
Appendix 8-sections II and IV) will be excluded from the PP analyses; subjects who take 
medications with an anti-filarial or anti-Wolbachia effect at any time during the study (see 
Appendix 8 - Section II) will be counted as failures in the ITT analyses. 
In the ITT analysis of the primary and key secondary endpoints, if the result is missing for the 
assessment, the assessment of that outcome will be a failure if the absence of data is due to 
administration of prohibited medication or withdrawal due to efficacy or safety issue. In the 
event of withdrawal of informed consent, subject lost to follow-up or withdrawal for a reason 
independent from the treatment (e.g. moving, lethal accident), multiple imputation will be used 
to impute the missing data. 
10.5 Population Level Summary and Analysis for the Primary Endpoints 
The Part 1 primary and combination endpoints, the proportion of adult female worms without 
Wolbachia endobacteria assessed by immunohistology at 6 months, will be summarised among 


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the PP for ND6M population, and the odds ratio for each of the treatment arm comparisons of 
interest (Arm A vs E and Arm B vs E; Arm C vs E, Arm C vs A; Arm D vs E, Arm D vs A) 
will be calculated using contrasts within an alternating logistic regression model with treatment 
arm as factor and also accounting for within-subject correlation, each at 2-sided α = 0.10. 
The Part 2 primary endpoint of the percentage of subjects without skin microfilariae at Month 
24 will be summarised across the PP for microfilariae population, and the adjusted odds ratio 
for each of the 3 active treatment arms will be compared to the comparator arm (Arm K vs 
N1 or N2, Arm L vs N1 or N2, and Arm M vs N1 or N2) using contrasts within a logistic 
regression model with treatment arm as factor and number of sites per subject (1, > 1) and 
mean baseline mf (≤ 5, > 5) as covariates at 2-sided α = 0.017. Supportive subgroup analyses 
for the primary endpoint will also be performed for at least the following subgroups: number 
of sites per subject (1, > 1) and mean baseline mf (≤ 5, > 5). 
The Part 2 combination rule endpoint for the alternate scenario, the proportion of adult female 
worms without Wolbachia endobacteria assessed by immunohistology at 6 months across all 
subjects treated with the same regimens in Parts 1 and 2 will be summarised among the PP 
for ND6M population, and the odds ratio for the comparison of interest (Arm K plus Arm L 
vs N2 [or Arm M vs Arm N2 if ABBV-4083 for 14 days is chosen for Arms K and L]) will 
be calculated using contrasts within an alternating logistic regression model with treatment 
arm as factor. P-values for the odds ratio of Part 1 and Part 2 will be combined using an 
inverse normal combination test and tested at 2-sided α = 0.10. 
10.6 Population Level Summary and Analysis for the Key Secondary Endpoints 
The Part 2 secondary endpoint 2a, the mean percentage of live female adult worms per subject 
as assessed by histological examination of nodules collected during nodulectomy at 24 
months, will be summarised among the PP for ND24M population and the mean difference 
between each of the 3 active treatment arms and the comparator arm (Arm K vs N1 or N2, 
Arm L vs N1 or N2, and Arm M vs N1 or N2) will be calculated using a stratified Mann-
Whitney U test with number of sites per subject (1, > 1) and mean baseline mf (≤ 5, > 5) as 
strata, with α allotted according to the graphical approach in Figure 2. In the exploratory 
regimen/duration ranging, the percentage of live adult female worms per subject at Month 24 
will be similarly compared between the 3 active arms, each at nominal 2-sided α = 0.05.  
The Part 2 secondary endpoint 2b, the mean percentage of live female adult worms with 
degenerated embryos in uterus per subject as assessed by histological examination of 
nodules collected during nodulectomy at 24 months will be summarised among the PP for 
ND24M with life female adult worms and the mean difference between each of the 3 active 
treatment arms compared to placebo (Arm K vs N1 or N2, Arm L vs N1 or N2, and Arm M 
vs N1 or N2) will be calculated using a stratified Mann-Whitney U test with number of sites 
per subject (1, > 1) and mean baseline mf (≤ 5, > 5) as strata, with α allotted according to 
the graphical approach in Figure 2. In the exploratory regimen/duration ranging, the mean 
percentage of adult female worms with degenerated embryos per subject and per nodule 
will be similarly compared between the 3 active arms, each at nominal 2-sided α = 0.05.  
The primary and key secondary endpoints will also be analysed on the ITT population.  


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10.7 Multiplicity Adjustment
Since Part 1 is a Phase-II proof-of-concept study, no adjustment will be made for the multiple 
comparisons in the primary endpoint (Arm A vs Arm E, Arm B vs Arm E, Arm C vs Arm A,
Arm C vs Arm E, Arm D vs Arm A and Arm D vs Arm E). Each comparison will be controlled 
at 2-sided α = 0.10. 
In Part 2, the multiplicity adjustment to control the overall Type I error rate at 5% will include: 
(1) Bonferroni allocation of α = 0.017 to each primary endpoint comparison: Arm K vs Arm 
N1, Arm L vs Arm N1, and Arm M vs N1; (2) a graphical approach to multiplicity adjustment 
to control the family-wise error at 0.05 (see Figure 6). The same method will be used in the Part 
2 Alternate Scenario, with comparisons between Arms K-M and Arm N2.
Figure 6. Graphical Approach to Multiplicity Control in Part 2
Of note, the parallel graphical approach above shows how the α is passed to the next comparison 
if the null hypothesis is rejected.81
In the Alternate Scenario of Part 2, the primary endpoint for satisfying the combination rule in 
Part 1 continued in Part 2 (combination rule endpoint) is conducted at 2-sided α = 0.10 with no
need to adjust for multiplicity per Section 5.5.2 of the European Medicines Agency Guideline 
on Multiplicity Issues for Clinical Trials.82
10.8 Statistical Analysis of Safety
All safety analyses will be performed on the Safety Population, which consists of all subjects 
who received at least one dose of IMP. Safety will be assessed by AEs, laboratory tests, vital 
signs, and ECG variables. Details of the analyses will be provided in the Statistical Analysis 
Plan. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). A TEAE 
is defined as an AE with an onset date that is after the first intake of IMP and no more than 30 
days after the last intake of IMP. The number and percentage of subjects experiencing TEAEs 
will be tabulated using MedDRA system-organ class and preferred term, as well as by severity 
and by relationship to the IMP as assessed by the Investigator. Summaries of SAEs, deaths, 
AEs leading to discontinuation will also be provided.


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For laboratory test and vital signs variables, mean change from baseline and percentage of 
subjects with on-treatment laboratory values of CTCAE 5.0 adapted scale grade 3 or 4 will be 
summarised. 
10.9 Interim Analysis of Part 1 and DSMB Recommendation to Proceed to Part 2 
Once subjects in Part 1 have completed or prematurely discontinued the study, up to and 
including nodulectomy at 6 months, a database lock for Part 1 database and an interim analysis 
of data from Part 1 will be conducted by the Sponsor and the randomisation code unblinded. 
The unblinded data will be reviewed by the Sponsor and the DSMB (see Section 13.3), for 
futility and risk/benefit ratio. Taking into account the recommendations of the DSMB, 
especially regarding the safety assessment of the data, the Sponsor will decide whether or not 
to proceed to Part 2, and with which dose regimens. 
Selection of up to two acceptable/suitable doses / regimens for Part 2 will be based on analysis 
of all of available unblinded data from Part 1, including safety and tolerability of ABBV-4083 
and ABBV-4083 + albendazole, Wolbachia depletion, disruption of embryogenesis and an 
exploratory surrogate marker, microfilaria Wolbachia, observed at Months 3 and 6. 
10.10 Interim Analysis of Part 2 and DSMB Recommendation for Phase III 
After all subjects in Part 2 have performed the Month 18 visit or prematurely discontinued from 
the study, the safety and skin microfilaria data through Month 18 will be analysed by an 
independent unblinded statistician (not associated with the study team) for review by the 
DSMB. The study team, sponsor and patients will remain blinded to the randomization and 
results. Details of the analyses and methods of maintaining the blind will be described in a 
separate statistical analysis plan. Based on this analysis, the DSMB may recommend a 
regimen(s) for advancement into a subsequent Phase-III study in advance of the primary 
endpoint at Month 24. The recommendation will be based on safety, tolerability and efficacy 
within target limits provided by the Sponsor. If no recommendation is feasible based on data 
through Month 18, the DSMB will make a recommendation after Month 24 based on all 
unblinded study results including the Month 24 endpoints. 
11 Data Handling and Quality Assurance 
11.1 Data Collection 
11.1.1 Investigator Site File 
The Principal Investigator must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified. These 
records include the Investigator Site File, subject clinical source documents and the eCRF. The 
Investigator Site File will contain the logs of subjects screened and randomised, 
protocol/protocol amendments, SAE Reporting Forms and query forms, approval from ethics 
committee(s) and regulatory authorities with correspondence, sample of the approved study 
information document and ICF, completed ICFs, drug accountability records, staff curriculum 
vitae, training and authorisation forms, hard copies of eCRFs and queries (if applicable), 
records of maintenance and/or calibration of equipment, and other appropriate 
documents/correspondence etc. The Principal Investigator is responsible for storing the 


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Investigator’s Site File and other study documentation in a secure location and to archive them 
at the end of the clinical study. 
11.1.2 Case Report Forms 
After informed consent, data will be recorded in the source documents (see Section 11.1.3). 
The study eCRF will be filled out by authorised personnel at the investigational centre. The 
data include any updates or corrections to SAE Reporting Forms or Pregnancy or Child 
Surveillance Forms or data clarification forms (DCF) sent to the Sponsor’s pharmacovigilance 
team. Data entry in the eCRF will be supervised, and the eCRFs will be signed electronically 
by the Principal Investigator. 
Study-specific information will be entered into the eCRF/SAE forms/pregnancy or child 
surveillance forms according to the instructions for eCRF completion provided by the Sponsor. 
A master subject log containing identifying information (name, etc.) of all subjects screened 
for the study, together with their screening numbers, will be stored securely by the Investigator. 
A log will also be kept of all subjects randomised in the study. All eCRF data must be coded, 
i.e. identified by screening/randomisation number only. 
The Investigator will ensure the accuracy, completeness, legibility, and timeliness of all data 
reported to the Sponsor in the eCRFs/SAE forms/pregnancy or child surveillance forms/DCF 
and any other additional information that is required. The Investigator is responsible for keeping 
all consent forms, screening forms, eCRF/SAE forms/pregnancy or child surveillance 
forms/DCF and the completed master subject log in a secure location. 
At the end of the study, a copy of the data from the eCRF will be provided to investigator in an 
appropriate format, e.g. DVD or flash drive, for long-term archiving. 
11.1.3 Source Documents 
Source documents may include subject hospital/clinic records, physician’s and nurse’s notes, 
appointment book, original laboratory reports, ECG, X-ray, pathology and special assessment 
reports, signed ICFs, consultant letters, and logs of subjects screened/randomised. 
Source data should be attributable, legible, contemporaneous, original, accurate, and complete. 
The Investigator must maintain source documents for possible review and/or audit by the 
Sponsor and/or regulatory authorities. The Investigator or designee will record the date of each 
subject’s visit together with a summary of their status and progress in the study. 
11.1.4 Data from Screening Failures 
Data on screening failures will be recorded in the Screening Log, source documents and eCRF, 
for entry in the clinical database. Instructions will be provided in the Study Operations Manual. 
For screening failures with an SAE, an SAE Form will also be completed.  
11.2 Study Monitoring 
Study monitors will review on an ongoing basis the quality and the plausibility of the eCRF 
data. The monitors will perform regular monitoring – including both remote monitoring, and 
visits to the investigational centre to verify that the clinical study is conducted in accordance 


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with the study protocol, ICH GCP E6 and ALCOA guidelines, as well as local GCP guidelines 
and regulatory requirements. 
Monitoring will include checks that the data are authentic and accurate, by verifying eCRFs 
and study documents (including SAE/pregnancy or child surveillance forms /query forms) 
versus source documents, by direct inspection, and checking for consistency between them all. 
The frequency of the monitoring and data checks will be decided and adapted by the Sponsor 
and defined in the Monitoring Plan. 
Prior to the start of the study, the monitors will review with the study personnel the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and Sponsor’s 
requirements. When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items. 
The monitors will monitor the activity of the investigational centre to ensure that: 
• Data are authentic, accurate and complete. Supporting data may be requested, e.g. blood 
glucose readings to support a diagnosis of diabetes; 
• The safety and rights of subjects are being protected; 
• The study is being conducted in accordance with the currently approved protocol,  
including use of the IMP in accordance with the protocol; 
• Any other study agreements, GCP, and all applicable regulatory requirements are met. 
The Investigator and the head of the medical institution, if applicable, agrees to allow the 
monitors direct access to all study-related documents. 
11.3 Data Processing 
Processing of study data will be performed in accordance with applicable Sponsor’s standards 
and data cleaning procedures and study Data Management Plan, using a validated database. 
This is applicable for data recorded on eCRF as well as for data from other sources (e.g. 
pharmacokinetic laboratory). 
For data coding (e.g. AEs, medical history, medication), internationally recognised and 
accepted dictionaries will be used (e.g. MedDRA and WHODrug Global dictionary). This will 
be detailed in the Data Management Plan. 
11.4 Missing Data 
 Methods for handling missing data are described in Section 10.4. In addition, any deviation(s) 
from the original statistical analysis plan will be described in the final clinical study report. 
11.5 Audit and Inspection 
To ensure compliance with ICH GCP E6 and local GCP requirements if applicable, a member 
of the Sponsor’s quality assurance team, or a designated clinical research organisation, may 
arrange to perform an audit to assess the conduct of the study at the investigational centre and 
the handling of the study documents originating there. The Investigator/institution will be 
informed of the audit findings. 
In addition, inspections by regulatory authority and ethic committee representatives are 
possible. The Investigator should notify the Sponsor immediately of any such inspection. 
The Investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 


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discuss findings and any issues. Audits and inspections may occur at any time before, during 
or after completion of the study. 
11.6 Archiving of Essential Study Documents 
Essential study documents will be archived safely and securely in such a way that ensures that 
they are readily available upon request from the regulatory authorities. 
The essential documents, including Investigator Site File, subject files and source documents 
will be archived according to local regulations and in accordance with the maximum period of 
time permitted by the investigational centre. Where the archiving procedures do not meet the 
minimum timelines required by the Sponsor, i.e. 25 years, alternative arrangements must be 
made to ensure the availability of the essential documents for the required period. 
The Investigator/institution will notify the Sponsor of any change in the arrangements for 
archiving, e.g. relocation or transfer of ownership. 
The essential documents are not to be destroyed without the Sponsor’s approval. 
12 Premature Study Termination 
Both the Sponsor and the Investigator reserve the right to terminate the study at any time prior 
to inclusion of the intended number of subjects, however they intend to exercise this right only 
for valid scientific or administrative reasons. Should this be necessary, both parties will arrange 
the procedures on an individual study basis after review and consultation. In terminating the 
study, the Sponsor and the Investigator will ensure that adequate consideration is given to the 
protection of the subjects’ safety and well-being. 
Reasons for early termination by the Sponsor may include but not be limited to: 
• Insufficient rate of subject inclusions; 
• Protocol violations; 
• Inaccurate or incomplete data; 
• Unsafe or unethical practices; 
• Questionable safety of the IMP; 
• Suspected lack of efficacy of the IMP; 
• Recommendation from the DSMB, regulatory authorities or ethics committee(s); 
• Administrative decision. 
Reasons for early termination by the Investigator may include but not be limited to: 
• Insufficient time or resources to conduct the study; 
• Lack of eligible subjects. 
If the study is early terminated either by the Sponsor or by the Investigator, the Investigator is 
required to: 
• Complete all eCRFs to the greatest extent possible; 
• Return all IMPs and related study materials to the Sponsor; 
• Answer all questions from the Sponsor or its representatives related to data on subjects 
recruited at the investigational centre prior to study termination; 
• Ensure that subjects included in the study who have not yet completed the study are 
followed up with the necessary medical care; 
• Provide the national regulatory authorities and ethics committee(s) and the Sponsor with 
the reasons for the decision in writing. 


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13 Ethical and Legal Aspects 
13.1 Investigator and Other Study Personnel 
All study personnel not specifically referred to in this protocol are identified in a separate list 
of study personnel. The list will be updated as needed; an abbreviated version with personnel 
relevant for the centre will be available in the Investigator Site File of the investigational centre. 
Whenever the term ‘Investigator’ is used in the protocol text, it may refer to either the Principal 
Investigator at the investigational centre, or an appropriately qualified, trained and delegated 
individual in the investigational centre. 
The Principal Investigator must sign the protocol signature page and must receive all required 
external approvals (e.g. regulatory authorities, ethics committees, Sponsor) before subject 
recruitment may start at the investigational centre. Likewise, all amendments to the protocol 
must be signed by the Principal Investigator and must have received all required external 
approvals before coming into effect at the investigational centre. 
13.2 Safety Review Committee 
A Safety Review Committee (SRC) will be appointed with a minimum of three Sponsor 
representatives, including at least one medically qualified person, and the Investigators. The 
exact composition, roles and responsibilities of the SRC will be described in the SRC Charter.  
The SRC will review safety results regularly (see Section 3.5.2.2.). If > 10% of subjects in any 
of the arms meets any of the toxicity criteria the SRC will refer to the DSMB. Throughout the 
study, the SRC will keep the DSMB fully informed of their decisions, including reports from 
SRC meetings and may consult the DSMB for recommendations. 
13.3 Data and Safety Monitoring Board  
An independent Data and Safety Monitoring Board (DSMB) will be established by the Sponsor 
in accordance with ICH guidelines for GCP.83 
The composition, roles and responsibilities of the DSMB will be described in detail in the 
DSMB charter.  
The DSMB may recommend stopping enrolment in the event of a negative safety assessment. 
The DSMB will be comprised of a minimum of three persons, including at least one medically 
qualified disease expert, a statistician, and other persons, taking into account any requirements 
specified by the regulatory authorities. 
The DSMB will be informed by the SRC if > 10% of subjects in any of the arms meets any of 
the toxicity criteria (see Section 3.5.2.2). The DSMB will review the reports and make 
recommendations regarding halting enrolment into Arms A, B, C or D and opening enrolment 
in appropriate arms with a lower dose of ABBV-4083. 
The DSMB will also review and evaluate, at intervals and as defined in the DSMB charter, the 
progress, scientific validity and data integrity of the clinical trial, the safety data collected 
during the trial to recommend to the Sponsor to continue, modify or terminate the trial. The 
DSMB will assess reports on cumulative data about enrolment, subject discontinuation, subject 
demographic and safety data, including serious and non-serious AEs and other safety 


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parameters, cases of exposure during pregnancy and outcomes, PK results, concomitant 
treatments, as well as ad-hoc requests if deemed necessary by the Sponsor and in line with the 
DSMB charter. 
At the end of Part 1 the database from Part 1 will be locked, the randomisation codes broken, 
and the efficacy and safety results from that part will be prepared by the Sponsor or designee. 
The DSMB will review all the results to provide a recommendation whether to proceed or not 
to Part 2, and which dose regimens to include (see Section 10.10). 
After all subjects have reached Month 18 of Part 2 or prematurely discontinued from the study, 
the Part 2 database will be locked and an interim analysis of Part 2 will be performed. An 
independent unblinded statistician(s) not associated with the study team will prepare efficacy 
results based on microfilaria and subject discontinuation, subject demographic and safety 
results for review by the DSMB. Based on these results the DSMB will make recommendation 
to an unblinded senior management committee, separate from the study team, to review the 
interim analysis results and to start Phase III studies. All study team members, patients and 
investigators will remain blinded until lock of the database at Month 24. Further details on the 
Part 2 Month 18 interim analysis will be provided in a separate DSMB Charter. 
13.4 Funding and Financial Disclosure 
13.4.1 Funding of the Study 
The study will be funded by the Sponsor. 
13.4.2 Financial Disclosure 
The Investigator, including the Principal Investigator and/or any sub-Investigators, directly 
involved in the treatment or evaluation of subjects may be requested to provide a financial 
disclosure. All relevant documentation will be filed in the Study Master File. 
13.4.3 Costs for Subjects 
After the initial screening procedures in the community, the subjects’ travels costs will be 
covered depending on the particular practices in the investigational centre with regard to 
payment of taxi fares, use of a study-specific vehicle or reimbursement at a flat rate, etc. Missed 
days of work due to participation in the study may be compensated, depending on local 
procedures and if permitted by the regulatory authorities and/or ethics committee(s). 
Accommodation, meals, toiletries, laundry and entertainment (such as television) during the In-
house Period and any overnight stays at the investigational centre will also be provided free of 
charge to the subject. 
All examinations, medication, including contraception, and medical care are part of the study 
and will be paid for by the Sponsor. 


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13.5 Ethical and Legal Conduct of the Study 
The procedures set out in this protocol, pertaining to the conduct, evaluation and documentation 
of this study, are designed to ensure that the Sponsor and Investigator abide by GCP guidelines 
and the guiding principles detailed in the Declaration of Helsinki. The study will also be carried 
out in accordance with applicable local laws and regulations, including those regarding public 
health measures (e.g. COVID-19). 
Documented approval from the regulatory authorities and ethics committee(s) will be obtained 
before the start of the study, in accordance with GCP, local laws and regulations. When 
necessary, an extension, amendment or renewal of the approval from the regulatory authorities 
and ethics committee(s) will be obtained and forwarded to the Sponsor as well. The responsible 
unit (e.g. the ethics committee, head of the investigational centre/medical institution) must 
supply to the Sponsor, upon request, a list of the members of each ethics committee involved 
in the vote and a statement to confirm that the ethics committee is organised and operates 
according to GCP and applicable laws and regulations. 
Strict adherence to all specifications laid down in the protocol is required for all aspects of study 
conduct; the Investigator may not modify or alter the procedures described in this protocol.  
Modifications to the study protocol will not be implemented by either the Sponsor or the 
Investigator without agreement by both parties. However, the Investigator or the Sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard to 
the subjects without prior approval/favourable opinion from the Sponsor and/or the regulatory 
authorities. As soon as possible, the implemented deviation or change, the reasons for it and if 
appropriate the proposed protocol amendment should be submitted to the regulatory authorities 
and ethics committee(s)/head of medical institution/Sponsor. Any deviations from the protocol 
must be explained and documented by the Investigator. 
13.6 Subject Information and Informed Consent 
All relevant information on the study will be summarised in a comprehensive study information 
document and ICF, provided by the Sponsor or the investigational centre.  
The informed consent process will begin only after obtaining approval from the regulatory 
authorities and ethics committee(s) applicable for the investigational centre. It will be 
conducted before screening of subjects, and it will include both community and individual 
consent (see also Section 9.2.2). The informed consent process will be conducted as per the 
detailed procedure described in the Study Operations Manual/SOPs. 
13.7 Publication Policy and Use of Study Data 
The study will be registered with a recognised clinical study registry, e.g. 
www.clinicaltrials.gov, Pan African Clinical Trials Registry. 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the Sponsor who may utilise them in various ways, such as for 
submission to the regulatory authorities. 
The final clinical study report will be the responsibility of the Sponsor and will be submitted to 
the regulatory authorities and ethics committee(s), if required by these bodies, when available. 
The Sponsor encourages the communication and/or publication of the results, in accordance 
with the terms of the Clinical Trial Agreement. 


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13.8 Insurance 
The Sponsor will cover any claims made by a subject, or by a family member or legal 
representative on his/her behalf, for damage resulting directly from the study and will also 
indemnify the Investigator against any liability resulting from such claims. Coverage of the 
damage to the subject and indemnification of the Investigator by the Sponsor will not apply if 
the damages to the subject result from negligence or intentional misconduct on the part of 
employees or agents of the institution/the investigational centre(s). Such claims will be covered 
by insurance contracted by the institution/investigational centre(s). 
13.9 Confidentiality and Protection of Privacy 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and regulations, will not be made publicly available. 
Subject names will not be entered in the eCRF or any document or digital file supplied to the 
Sponsor. The screening number / randomisation number will be used as identification and, if 
the subject’s name appears on any other document or file, e.g. pathologist report, etc., it will be 
redacted before a copy of the document is supplied to the Sponsor. Images captured during the 
study according to this protocol, e.g. photographs of ocular fundi, parasitological images, 
photographs of abnormalities found during physical examination, including skin lesions, will 
be coded using screening number/randomisation number as described above, and no images 
from which a subject can be visually identified will be transmitted outside of the investigational 
centre. Study findings stored on a computer will be stored in accordance with local data 
protection laws. As part of the informed consent process, the subjects will be informed in 
writing that only authorised persons will have access to their information and that all personal 
information will be handled in strictest confidence and in accordance with data protection laws. 
Also that the Sponsor and their authorised representatives, the ethics committee(s) and 
regulatory authorities may inspect their medical records to verify the information collected. 
If the results of the study are published, the subject’s identity will remain confidential. 
The Investigator will maintain master subject log to enable subjects to be identified. 
 
 
 
 


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55. Saint Andre A, Blackwell NM, Hall LR, et al. The role of endosymbiotic Wolbachia 
bacteria in the pathogenesis of river blindness. Science. 2002;295(5561):1892-5. 
56. Taylor MJ, Hoerauf A, Townson S, et al. Anti-Wolbachia drug discovery and 
development: safe macrofilaricides for onchocerciasis and lymphatic filariasis. 
Parasitology. 2014;141(1):119-27. 
57. Zentel® (albendazole) [package insert]. Abbotsford, Australia: GlaxoSmithKline, 2011. 
58. Albenza® (albendazole) [package insert]. Horsham, PA: Amedra Pharmaceuticals LLC; 
2015. 
59. AbbVie. R&D/19/1306. Assessment of the in vivo activity of ABBV-4083 in 
combination with different regimens of albendazole in Litomosoides sigmodontis adult 
worms propagated in jirds. 2019. 
60. H. Lange, R. Eggers and J. Bircher. Increased systemic availability of albendazole when 
taken with a fatty meal. Eur J Clin Pharmacol. 1988;34:315-317. 
61. Mares SS, Jung CH, López AT and González‐Esquivel DF. Influence of a Mexican diet 
on the bioavailability of albendazole. Basic & Clinical Pharmacology & Toxicology, 
2005;97:122-124. doi:10.1111/j.1742-7843.2005.pto_172. 
62. Awadzi K, Hero M, Opoku O, et al. The chemotherapy of onchocerciasis. XV. Studies 
with albendazole. Trop Med Parasitol. 1991;42:356-60. 
63. Mectizan® (ivermectin). European Summary of Product Characteristics, Merck Sharp & 
Dohme 2007. 
64. Eskazole® (albendazole) [package insert]. Abbotsford, Australia: GlaxoSmithKline, 
2010. 
65. Stromectol® (ivermectin) [package insert] Merck & Co., Inc. 2010. 
66. Awadzi K, Hero M, Opoku O, et al. The chemotherapy of onchocerciasis XVII. A 
clinical evaluation of albendazole in patients with onchocerciasis; effects of food and 
pretreatment with ivermectin on drug response and pharmacokinetics. Trop Med 
Parasitol. 1994 Sep;45(3):203-8. 
67. Awadzi K, Opoku NO, Addy ET, Quartey BT. The chemotherapy of onchocerciasis. 
XIX: The clinical and laboratory tolerance of high dose ivermectin. Trop Med Parasitol. 
1995 Jun;46(2):131-7. 
68. WHO Model Prescribing Information: Drugs Used in Parasitic Diseases – 2nd edition, 
1995. https://apps.who.int/iris/handle/10665/41765 accessed 30th March 2020. 
69. Guide for Donation of Mectizan for IDA countries 2017. https://mectizan.org/wp-
content/uploads/2018/07/Guide-Mectizan-Application-for-IDA-countries_V1.pdf 
70. Horton, J. Albendazole: a review of anthelmintic efficacy and safety in humans. 
Parasitology, 2000. 121(S1), S113. doi:10.1017/s0031182000007290. 


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71. Nutman T.B. Onchocerciasis. In Magill AJ, Strickland GT, Maguire JH, Ryan ET, 
Solomon T. Hunter’s tropical medicine and emerging infectious disease. London: 
Elsevier Health Science. 2012;Chapter 116. 
72. Thylefors B. Ocular Onchocerciasis. Bulletin of the WHO 1978;56(1):63-73. 
73. Modification of Diet in Renal Disease (MDRD). National Institute of Diabetes and 
Digestive and Kidney Diseases Central Repository. 
https://repository.niddk.nih.gov/studies/mdrd/ accessed 30th March 2020 
74. Clinical Trial Facilitation Group. Recommendations related to contraception and 
pregnancy testing in clinical trials. Final version 15 September 2014. 
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
75. Specht S, Brattig N, Büttner M and Büttner DW. Criteria for the differentiation between 
young and old Onchocerca volvulus filariae. Parasitol Res. 2009 Nov;105(6):1531–1538. 
76. Specht S, Hoerauf A, Adjei O, Debrah A and Büttner DW. Newly acquired Onchocerca 
volvulus filariae after doxycycline treatment Parasitol Res. 2009 Dec;106(1): 23–31. 
Published online 2009 Sep 16. doi: 10.1007/s00436-009-1624-5 PMCID: PMC2780640. 
77. Murdoch, M, Hay, R, Mackenzie, C, Williams, J, Ghalib, H, Cousens, S, Abiose, A and 
Jones, B. (1993), A clinical classification and grading system of the cutaneous changes in 
onchocerciasis. British Journal of Dermatology, 129: 260-269. doi:10.1111/j.1365-
2133.1993.tb11844.x 
78. European Medicines Agency. ICH Topic E2A Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting. CPMP/ICH/377/95, June 1995. 
79. U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, 
Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. September 2007. 
80. Wu S, Crespi CM, Wong WK. Comparison of Methods for Estimating the Intraclass 
Correlation Coefficient for Binary Responses in Cancer Prevention Cluster Randomized 
Trials. Contemp Clin Trials. 2012;33(5):869-80. 
81. Bretz F, Maurer W, Brannath W. and Posch M. A graphical approach to sequentially 
rejective multiple test procedures. Statistics in Medicine. 2009;28:586-60. 
82. European Medicines Agency. Guideline on multiplicity issues in clinical trials. 
EMA/CHMP/44762/2017. 15 December 2016. 
83. International Council for Harmonisation. The Integrated Addendum to ICH E6 R1: 
Guidelines for Good Clinical Practice E6 R2. 9 November 2016 
 
 


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15 Appendices 
List of Appendices 
Appendix 1: Schedule of Events for Part 1 
Appendix 2: Schedule of Events for Part 2 
Appendix 3: Total Blood Volume to be Collected in Part 1 
Appendix 4: Total Blood Volume to be Collected in Part 2 
Appendix 5: Laboratory Analyses  
Appendix 6: Adverse Event Severity Grading Reporting for DNDi-TYL-01 Clinical Trial. 
Appendix 7: Permitted and non-permitted birth control methods in DNDi-TYL-01. 
Appendix 8. Prohibited medications in DNDi-TYL-01 


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Appendix 1. Schedule of Events for Part 1 
Table 7. Schedule of Events for Part 1 
All study days / times are calculated relative to the time of administration of IMP on Day 0, i.e. 0d00h00m. 
Time (and window if allowed) 
Screening1 
In-house 
 
Up to 8 weeks before 
first intake of IMP 
D02 
D12 
D32 
D62 
D132, 24 
Month 3 
(±1week)2 
Month 6 
(+1Month)2 
EOS 
Early 
Termination 
Subject information and 
informed consent, allocation of 
screening number3 
X 
 
 
 
 
 
 
 
 
 
Demographic data and medical 
history, including prior and 
current medication 
X 
 
 
 
 
 
 
 
 
 
Review of inclusion and 
exclusion criteria  
X 
X 
 
 
 
 
 
 
 
 
Skin snips4, 
X  
(repeat if >30 days 
before 1st intake of 
IMP*) 
 
 
 
 
 
X 
X 
 
X 
Parasitology5  
X (repeat if >3 days 
before 1st intake of 
IMP*) 
 
 
 
 
 
 
 
 
 
Nodule palpation6 
X 
 
 
 
 
 
 
X 
 
X 
Physical examination7 
X (repeat if >3 days 
before 1st intake of 
IMP*) 
X9 
 
X9 
X9 
X 
X 
X 
 
X 
Brief neurological 
examination8 
X (repeat if >3days 
before 1st intake of 
IMP*) 
X 
 
X 
X 
X 
X 
X 
 
X 
Pregnancy test (WOCBP 
only)10  
X  
(repeat if >2 days before 
1st intake of IMP) 
 
 
 
 
X 
X 
X 
 
X 
Check birth control and date of 
last menstrual period11 
X  
(repeat if >3 days before 
1st intake of IMP*) 
 
 
 
 
X 
X 
 
 
 


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Time (and window if allowed) 
Screening1 
In-house 
 
Up to 8 weeks before 
first intake of IMP 
D02 
D12 
D32 
D62 
D132, 24 
Month 3 
(±1week)2 
Month 6 
(+1Month)2 
EOS 
Early 
Termination 
Vital signs12  
X 
(repeat if >3 days before 
1st intake of IMP*) 
X 
 
X 
X 
X 
X 
 
 
X 
Ophthalmological 
examination,13  
X6  
(repeat if >30 days 
before 1st intake of IMP) 
 
 
 
 
X 
X 
X 
 
X 
Skin examination14 
X 
 
 
 
 
X 
X 
X 
 
X 
12-lead safety ECG 15 
X  
(repeat if >3 days before 
1st intake of IMP*) 
 
 
X 
X 
X 
 
 
 
X15 
Laboratory safety tests16 
X  
(repeat if >3 days before 
1st intake of IMP*) 
 
 
X 
X 
X 
X 
 
 
X 
Alcohol breath test and urinary 
drug screen 
X  
(repeat if >2 days before 
1st intake of IMP) 
 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
IMP administration17  
 
Every day – Direct Observed Treatment 
 
 
 
 
PK of IMPs in blood, 21  
 
X 
X 
X 
X 
X 
 
 
 
 
Ivermectin administration  
 
 
 
 
 
 
 
X18 
 
X18 
AE monitoring19,20  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory samples 22 
  
X 
 
 
 
X 
 
X 
 
X 
Nodulectomy23  
 
 
 
 
 
 
 
X23 
 
X23 
Post-nodulectomy wound care25  
 
 
 
 
 
 
 
X 
 
1. Some screening procedures will be conducted in the subjects’ communities.  
2. For each subject, a given procedure should as far as possible be performed at the same time of day every time it is scheduled throughout the study to minimise variability. 
Also note that on IMP administration days, some procedures must be performed pre-IMP intake and others post-IMP intake. See Section 9.2.4 for details, and other 
footnotes herein. 
3. Screening procedures will be performed only after obtaining the main written informed consent 
4. Skin snips will be used to assess O. volvulus skin microfilarial density and depletion of Wolbachia in the microfilaria at the indicated time-points. Four skin snips per time-
point (iliac crests and calves on both sides). 


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5. Blood sampling; including evaluation in blood of Wuchereria bancrofti, Mansonella perstans and Loa loa.  
6. Nodule palpation and documentation of Onchocerca nodules. 
7. Details of the physical examinations will be specified in the Study Operations Manual. To include height and weight at Screening, and within 2 days prior to first intake 
of IMP.  
8. A short symptom-directed neurological examination will be conducted. Details of the examination will be specified in the Study Operations Manual. 
9. At the time-points indicated, a shortened symptom-directed physical examination will be conducted. Details of the examination will be specified in the Study Operations 
Manual. 
10. Pregnancy testing may be urine or serum, except for test at screening at the site and at Day 13 visit (or Early Termination Visit if done before Day 13), which must be 
serum. In case a repeat is needed during screening at the site, test can be urine providing the initial testing was serum and this was approved by the sponsor. Test at the 
Day 13 visit will be done at least 24 hours after the last IMP intake. 
11. The Investigator will arrange for a highly effective form of birth control (as detailed in Section 8.2) if required. Must be discussed at screening and checked within 2 days 
prior to the first intake of IMP and checked at the time-points indicated and documented. In the event of delayed menstrual period for over one month between 
menstruations, confirmation of absence of pregnancy with a pregnancy test is mandatory. This recommendation also applies to WOCBP with infrequent or irregular 
menstrual cycles. 
12. Supine blood pressure (SBP, DBP), supine heart rate, respiratory rate and temperature. 
13. Ophthalmological findings from examinations including ocular symptoms, ocular examinations including ocular alignment, mobility and pupillary response, visual 
function (visual acuity, visual field, colour vision), retinal examination and fundus photography, slit lamp examination of anterior and posterior segment and intraocular 
pressure. Eye microfilarial count and data for clinical outcomes in the eye will be recorded during the ophthalmological examination. 
14. Assessments for clinical outcomes in the skin (see Study Operations Manual for details) to be performed during physical examinations where the time-points coincide. 
15. ECGs will be recorded in triplicate (with 1 minute between recordings) except at D3, which will be single. ECGs will be performed 1-2 hours after intake of the IMP.   
ECG at early termination is only applicable if early termination is before Month 3. 
16. Blood and urine samples for clinical laboratory safety tests (haematology, biochemistry, & urinalysis (plus urine microscopy where indicated if urinalysis is abnormal and 
clinically significant).  
17. IMPs will be administered daily from D0 to D13 on site. IMPs dispensation will be done on D0, D3 and D7 via the IRT system. 
18.Administration of ivermectin to all subjects. Only after completion of all the procedures of the 6-month follow-up visit, and after nodulectomy and negative pregnancy test. 
It can also be administered at the early termination visit at the discretion of the Investigator. Ivermectin will also be available for administration as Rescue Medication, at 
the Investigator’s discretion, in the event of clinically significant worsening of symptoms and/or signs related to onchocerciasis at any time during the study.18.AE 
monitoring will be performed as specified in Section 9.3.4 and will include scheduled questioning at the indicated time-points.  
19. AE collection from signature of Informed Consent onwards. AE monitoring will be performed as specified in Section 9.3.4 and will include scheduled questioning at the 
indicated time-points. 
20. In the event of certain AEs considered to be associated with the IMP, additional examinations may be conducted in order to better interpret the AE, including safety 
laboratory, PK, ophthalmological, physical, neurological, and parasitological (eye and skin) examinations. 
21. Blood samples for dry blood spot assay (PK) of ABBV-4083 and albendazole sulfoxide will be collected on Day 0: 0h (any time before dosing), 1h, 2h, 3h, 4h, 6h and 
12h (+/- 15 minutes for all) ; and Day 1 at 0h (up to 30 min prior dosing). Samples on Day 3, 6 and 13 will be collected between 2 and 4 hours after dosing. 
22. Blood and urine samples will be collected at the time-points indicated and stored for future analysis (for example: biomarkers, immunological markers testing). Note: in 
addition, where feasible, tissue samples collected from other procedures during the study (e.g. skin, nodules etc.) will also be stored after analysis. Subjects have the 
possibility to opt out of exploratory samples. 
23. Nodulectomy must be conducted only after completion of the procedures at the Month 6 visit. 
24. In-house Period will have one additional day on D13 for observation post last dose and to perform pregnancy test at the end of exposure period.  


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25. Post-nodulectomy wound care will continue for up to approx. 2 weeks. The subject may go back to the community or may stay at the investigational site for logistic reasons 
or if medically indicated. End of Study visit will be 2 weeks after nodulectomy +/- 2 weeks. The visit may be performed in the community. 
* Repeat period can be extended to 7 days in exceptional circumstances, with prior agreement of the Sponsor  (exception of pregnancy test which must be repeated within 2 
days and can be urine if serum test was already done) 






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1. Some screening procedures will be conducted in subjects’ communities. 
2. For each subject, a given procedure should as far as possible be performed at the same time of day every time it is scheduled throughout the study to minimise variability. Also note 
that on IMP administration days, some procedures must be performed pre-IMP intake and others post-IMP intake. See Section 9.2.4 for details and other footnotes herein. 
3. Screening procedures will be performed only after obtaining the main written informed consent 
4. Skin snips will be used to assess O. volvulus skin microfilarial density at the indicated time-points.. Four skin snips per time-point (iliac crests and calves on both sides). 
5. Blood sampling  including evaluation in blood of Wuchereria bancrofti, Mansonella perstans and Loa loa.  
6. Nodule palpation and documentation of onchocerca nodules. 
7. Details of the physical examinations will be specified in the Study Operations Manual. To include height and weight at Screening, and within 2 days prior to first intake of IMP.  
8. A short symptom-directed neurological examination will be conducted. Details of the examination will be specified in the Study Operations Manual.9. At the time-points indicated, 
a shortened symptom-directed physical examination will be conducted. Details of the examination will be specified in the Study Operations Manual. 
10. Pregnancy testing may be urine or serum, except for test at screening at the site and at Day 13 visit, (or Early Termination Visit if done before Day 13) which must be serum. In 
case a repeat is needed during screening at the site, test can be urine providing the initial testing was serum and this was approved by the sponsor. Test at the Day 13 visit will be 
done at least 24 hours after the last IMP intake.  
11. The Investigator will arrange for a highly effective form of birth control (as detailed in Section 8.2) if required. Must be discussed at Screening, checked within 2 days prior to 
first intake of IMP, checked at the time-points indicated and documented. In each case of delayed menstrual period (over one month between menstruations) confirmation of 
absence of pregnancy with a pregnancy test is mandatory. This recommendation also applies to WOCBP with infrequent or irregular menstrual cycles. 
12. Supine blood pressure (SBP, DBP), supine heart rate, respiratory rate and oral temperature 
13. Ophthalmological examinations: full ophthalmological examination includes ocular symptoms, ocular examinations including ocular alignment, mobility and pupillary response, 
visual function (visual acuity, visual field, colour vision), retinal examination and fundus photography, slit lamp examination of anterior and posterior segments and intraocular 
pressure. Eye microfilarial count and data for clinical outcomes in the eye will be recorded during the ophthalmological examination. 
14. Assessments for clinical outcomes (see Study Operations Manual for details) in the skin to be performed during physical examinations where the time-points coincide. 
15. 12-lead ECGs will be recorded in triplicate with 1 minute between recordings at all time-points. ECGs will be performed 1-2 h after intake of the IMP. ECG at early termination is 
only applicable if early termination is before Month 3. 
16. Blood and urine samples for clinical laboratory safety tests (haematology, biochemistry & urinalysis (plus urine microscopy where indicated if urinalysis is abnormal and clinically 
significant).  
17. IMPs will be administered daily on site and IMPs dispensation will be done via the IRT system. Treatment duration and IMPs dispensation scheme will be confirmed before start 
of the Part 2, depending on the regimen selected. 
18. Administration of ivermectin must be only after completion of the procedures scheduled at the visit (including nodulectomy where scheduled), and after a negative pregnancy test. 
Rescue medication (ivermectin) will be offered at the investigator discretion to administer if worsening symptoms and/or signs related to onchocerciasis at any time throughout the 
study and/or to patients with increased mean microfilaria in the skin at Month 18, compared to the Month 12 mean value. 
19. AE collection from signature of Informed Consent onwards. AE monitoring will be performed as specified in Section 9.3.4 and will include scheduled questioning at the indicated 
time-points.  
20. In the event of certain AEs considered to be associated with the IMP, additional examinations may be conducted in order to better interpret the AE, including safety laboratory, PK, 
ophthalmological, physical, neurological and parasitological (eye and skin) examinations. 
21. Blood samples for dry blood spot assay (PK) of ABBV-4083 and albendazole sulfoxide will be taken on Day 0: 0h (any time before dosing), 1h, 2h, 3h, 4h, 6h and 12h (+/- 15 
minutes for all); and Day 1 at 0h (up to 30 min prior dosing. Samples on Day 6 and 13 will be collected between 2 and 4 hours after dosing. Schedule to be confirmed based on data 
from Part 1  


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22. Blood and urine samples will be collected at the time-points indicated and stored for future analysis (for example: biomarkers, immunological markers testing). Note: in addition, 
where feasible, tissue samples collected from other procedures during the study (e.g. skin, nodules etc.) will also be stored after analysis. Subjects have the possibility to opt out of 
exploratory samples. 
23. Nodulectomy must be performed only after completion of the other procedures at the visit. 
24. In-house Period will have one additional day on D13 for observation post last dose and to perform pregnancy test at the end of exposure period. 
25. Post-nodulectomy wound care will continue for up to approx. 2 weeks. The subject may go back to the community or may stay at the investigational site for logistic reasons or if 
medically indicated. End of Study visit will be 2 weeks after nodulectomy. The visit may be performed in the community 
* Repeat period can be extended to 7 days in exceptional circumstances, with prior agreement with the Sponsor  (exception of pregnancy test which must be repeated within 
2 days and can be urine if serum test was already done) 
 
  
 
 
 
 


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Appendix 3. Total Blood Volume to be Collected in Part 1 
 
The blood volume planned to be collected from each subject during the Part 1 of this study is 
detailed in Table 9, rounded up to the nearest 1 mL. Additional samples may be required in the 
event of AEs. 
Table 9. Total Blood Volume in Part 1 
Test 
Planned number 
of tests 
Volume (mL) 
Total planned blood 
volume (mL) 
Pregnancy serum test 
2 
Screening and Day 13:0 
(on biochemistry tube) 
 
0 
Parasitology - microscopy 
Parasitology - RDT 
1 
4 
1 
 
5 
Haematology 
5 
4 
20 
Biochemistry 
5 
5 
25 
Pharmacokinetics 
11 
1 
11 
Exploratory samples 
3 
5 
15 
Cannula discard 
7 
1 
7 
Total blood volume to be collected in Part 1 per subject 
84 
RDT: rapid diagnostic test 
 
When using a cannula: after each blood sample, the cannula will be flushed with 3 to 5 mL 
normal saline, to keep it patent. In order to minimise dilution of each subsequent blood sample 
with normal saline, the following procedure will be used: about 1 mL will be drawn via the 
cannula into the sampling syringe and discarded. The definitive blood sample will then be 
collected. 
 
 
 


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Appendix 4. Total Blood Volume to be Collected in Part 2 
 
The blood volume planned to be collected from each subject during Part 2 of the study is 
detailed in Table 10, rounded up to the nearest 1 mL. Additional samples may be required in 
the event of AEs. The total blood volume to be taken during the study will be confirmed once 
the regimens for Part 2 have been selected. 
Table 10. Total Blood Volume in Part 2 - Phase II 
Test 
Planned 
number of tests 
Volume (mL) 
Total planned 
blood volume (mL) 
Pregnancy serum test 
2 
Screening and Day 
13:0 (on biochemistry 
tube) 
0 
Parasitology - microscopy 
Parasitology - RDT 
1 
4 
1 
5 
Haematology 
4 
4 
16 
Biochemistry 
4 
5 
20 
Pharmacokinetics 
10 
1 
10 
Exploratory samples 
5 
5 
25 
Cannula discard 
7 
1 
7 
Total blood volume to be collected in Part 2 per subject 
84 
RDT: rapid diagnostic test 
 
When using a cannula: after each blood sample, the cannula will be flushed with 3 to 5 mL 
normal saline, to keep it patent. In order to minimise dilution of each subsequent blood sample 
with normal saline, the following procedure will be used: about 1 mL will be drawn via the 
cannula into the sampling syringe and discarded. The definitive blood sample will then be 
collected. 
 
 
 


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Appendix 5. Laboratory Analyses 
 
Detailed information about the collection, processing, storage and shipment of the samples will 
be provided in the laboratory manual and/or Study Operations Manual. Information on the 
parameters to be analysed and the laboratories to be used is presented in Table 11. 
Table 11. Parameters of Laboratory Analyses 
Parameters (by category) 
Sample destination 
Haematology: 
haemoglobin, haematocrit, platelets, white blood cells 
(WBC) and differential, red blood cells (RBC). 
 
Study Investigational sites 
Biochemistry: 
aspartate transaminase (AST), alanine transaminase (ALT), 
alkaline phosphatase (AP), glucose, creatinine, eGFR, blood 
urea nitrogen (BUN), total bilirubin, albumin, total protein, 
chloride, sodium, potassium and calcium in serum. 
Study Investigational sites 
Urinalysis – dipstick, multistick and microscopy: 
glucose, ketone bodies, specific gravity, occult blood, pH, 
proteins, leucocytes, bilirubin, urobilinogen, nitrite 
Study Investigational sites 
Parasitological co-infections (microscopy): 
Blood: lymphatic filariasis, Mansonella perstans, and 
Loa loa 
 
Study Investigational sites 
Urine drug screen: 
Drugs of abuse screen 
Study Investigational sites 
Serum pregnancy test: 
Beta-HCG 
Study Investigational sites 
Urine pregnancy test: 
Beta-HCG 
Study Investigational sites and Participants’ 
communities 
Alcohol test: 
Breath test 
Study Investigational sites 
Pharmacokinetic analyses in blood: 
Parameters are specified in Section 5.6 
Attn: AbbVie Sample Receiving 
 
Delivery Services 
1150 S. Northpoint Blvd. 
Waukegan, IL 60085 
E-mail: sample.receiving@abbvie.com 
Microfilarial density from skin snips 
O. volvulus 
Mansonella streptocerca 
Study Investigational sites 
Nodule assessment 
Institute of Medical Microbiology, 
Immunology and Parasitology; University 
Hospital Bonn, Germany 
Exploratory samples 
Plasma 
Urine 
Remaining samples from those collected from scheduled 
protocol procedures 
Study Investigational sites 
May be transferred for logistical purposes 
(longer term storage) to another location with 
prior agreement of Ethical Committees and 
Regulatory Authority. 
Appendix 6. Adverse Event Severity Grading Reporting for DNDi-TYL-01 Clinical Trial 


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Please refer to most current document “Adverse Event Severity Grading Reporting for DNDi-
TYL-01” attached to the protocol. 
 


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Appendix 7. Permitted and non-permitted birth control methods in DNDi-TYL-01 
 
Permitted birth control methods in DNDI-TYL-01 
Methods which may be considered as “highly effective” (failure rate of less than 1% per year 
when used consistently and correctly): 
(based on the Clinical Trial Facilitation Group recommendations from The Medicines and 
Healthcare Products Regulatory Agency website related to contraception and pregnancy testing 
in clinical trials, dated 15 September 2014). 
• Combined (oestrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
• oral 
• intravaginal 
• transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
• oral 
• injectable 
• implantable  
- intrauterine device (IUD) 
- intrauterine hormone-releasing system (IUS) 
- bilateral tubal occlusion 
- vasectomised partner1 
- sexual abstinence2  
  
1 Vasectomised partner is a highly effective birth control method provided the partner is the sole sexual partner of 
the WOCBP and that the vasectomised partner has received medical assessment of the surgical success. 
2 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the subject. 
  
 
  
 
 


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Non-Permitted birth control methods in DNDI-TYL-01 
 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
- male or female condom with or without spermicide1 
- cap, diaphragm or sponge with spermicide1 
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods 
of contraception. Female condom and male condom should not be used together. 
 
1 A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods) 
are not considered highly effective birth control methods and therefore are not permitted in DNDI-TYL-01. 
 
 


Clinical Trial Protocol DNDI-TYL-01 
Final Version 2.0 dated 09 November 2021 
 
 
 
Confidential 
Page 111 of 112 
Appendix 8. Prohibited medications in DNDi-TYL-01 
 
I. 
Prohibited medication before starting the study (see also Section 6.2 ) 
• within 2 years prior to start of IMP administration: moxidectin; 
• within 1 year prior to start of IMP administration: more than 2-week course of anti-
Wolbachia treatments, i.e. doxycycline, minocycline, rifapentine or rifampicin; 
• within 6 months prior to start of IMP administration: ivermectin; 
• within 3 months prior to start of Screening (or within 5 times the half-life of the drug tested): 
any investigational drug;  
• within 4 weeks prior to start of IMP administration: any vaccination; 
• Within 14 days prior to start of IMP administration: 
o any medication (with the exception of diclofenac, paracetamol, ibuprofen and aspirin), 
herbal preparation or food supplement;  
o strong CYP3A inhibitors or inducers including but not limited to ritonavirc, 
ketoconazolec, rifampicin, phenytoin, phenobarbital, carbamazepine, cimetidinec (or 
within 10 half-lives, whichever is longer); 
o other drugs known to interact with albendazole such as praziquantelc, theophyllinec or 
dexamethasonec (or within 10 half-lives, whichever is longer);  
 
II. 
Prohibited medication throughout the entire studya  
Prohibited medication throughout the entire study include any medication that may have an 
impact on the study objective. Specifically, medication with anti-filarial or anti-Wolbachia 
effects are prohibited, including: 
• ivermectin, excluding post-study ivermectin or rescue ivermectin as detailed in Section 
8.3.  
• moxidectin,  
• doxycycline, 
• minocycline, 
• rifampicin,  
• rifapentine. 
  
III. 
Prohibited medications during the first 28 days after the last IMP administration  
• Albendazole (however it is permitted thereafter, one dose per year in MDA) 
 
IV. 
Prohibited medication during the treatment period 
Up to 24 hours after the final dose of IMP, medication, herbal remedies or food supplements, 
that could affect the PK and/or PD of ABBV-4083 and/or albendazole are prohibited. 


Clinical Trial Protocol DNDI-TYL-01 
Final Version 2.0 dated 09 November 2021 
 
 
 
Confidential 
Page 112 of 112 
• Any CYP3A and/or P-gp inhibitors or inducers, such as: 
o ritonavirc,  
o ketoconazolec,  
o rifampicinb,  
o phenytoinb,  
o phenobarbitalb,  
o carbamazepineb,  
o cimetidinec, 
o others known to interfere with the CYP3A and/or P-gp metabolic pathways (the 
US FDA tables of Substrates, Inhibitors and Inducersb will be used as a 
reference, and included in the Study Operations Manual for reference). 
 
• Drugs known to interact with albendazole, such as 
o praziquantelc,  
o dexamethasoneb 
o theophyllinec 
 
a. Subjects taking these medications during the study will not be included in the PP population for analysis and 
will be imputed as failures in analyses of the primary and secondary endpoints in the ITT population. 
b. Subjects taking these medications during the treatment period (or for 14 days before) will not be included the 
PP population for analysis but will not be imputed as failures in analyses of the primary and secondary endpoints 
in the ITT population. 
c. Subjects taking these medications during the treatment period (or for 14 days before) will be included in the PP 
population for analysis and will not be imputed as failures in analyses of the primary and secondary endpoints 
in the ITT population. 
 
 
 
 
 

SAP_001.pdf: 
ABBV-4083
B18-894/DNDi-TYL-01 – Statistical Analysis Plan
Version 2.0 – 24 March 2023
1
Statistical Analysis Plan 
for Study B18-894/DNDi-TYL-01
A Phase-II, Randomised, Double-blind, 
Parallel-group, Proof-of-concept Trial to Investigate 
ABBV-4083 given for 7 or 14 Days or in Combination 
with Albendazole in Subjects with 
Onchocerca volvulus Infection
Part 1 to Investigate Safety, Tolerability, Efficacy for 
Dose-Ranging and Pharmacokinetics
Date: 24 MAR 2023
Version 2.0
NCT04913610


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Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives, Hypotheses and Estimands .....................................................5
2.2
Study Design Overview .............................................................................7
2.3
Treatment Assignment and Blinding .........................................................7
2.4
Sample Size Determination........................................................................9
3.0
Endpoints................................................................................10
3.1
Primary Endpoint.....................................................................................10
3.2
Secondary Endpoints ...............................................................................10
3.3
Exploratory Endpoints .............................................................................11
3.4
Safety Endpoints ......................................................................................11
4.0
Analysis Populations .............................................................11
5.0
Subject Disposition................................................................12
6.0
Study Drug Duration and Compliance................................13
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................14
7.1
Demographics and Baseline Characteristics............................................14
7.2
Medical History .......................................................................................15
7.3
Prior and Concomitant Medications ........................................................15
8.0
Handling of Potential Intercurrent Events for the 
Primary Endpoint..................................................................16
9.0
Efficacy Analyses...................................................................17
9.1
General Considerations............................................................................17
9.2
Handling of Missing Data for the Primary Endpoint...............................17
9.3
Primary Efficacy Endpoint and Analyses................................................18
9.3.1
Primary Efficacy Endpoint ......................................................................18
9.3.2
Main Analysis of Primary Efficacy Endpoint..........................................18
9.3.3
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoint...................................................................................................21
9.4
Secondary Efficacy Endpoints and Analyses ..........................................21
9.4.1
Key Secondary Efficacy Endpoints and Analyses...................................21


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9.4.2
Supportive Secondary Efficacy Endpoints and Analyses........................21
9.5
Additional Efficacy Analyses ..................................................................23
9.6
Efficacy Subgroup Analyses....................................................................25
10.0
Safety Analyses ......................................................................26
10.1
General Considerations............................................................................26
10.2
Adverse Events ........................................................................................26
10.2.1
Treatment-Emergent Adverse Events ......................................................27
10.2.2
Adverse Event Overview .........................................................................27
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................28
10.2.4
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................28
10.3
Analysis of Laboratory Data....................................................................29
10.4
Analysis of Vital Signs ............................................................................31
10.5
Other Safety Analyses..............................................................................31
11.0
Interim Analyses....................................................................32
11.1
Data and Safety Monitoring Board..........................................................32
12.0
Overall Type-I Error Control ..............................................33
13.0
Version History......................................................................33
14.0
References...............................................................................36
15.0
SAP Approval ........................................................................37
List of Tables
Table 1.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint...................................................................................................20
Table 2.
SAP Version History Summary...............................................................33
List of Figures
Figure 1.
Study Schematic.........................................................................................7


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List of Appendices
Appendix A.
Protocol Deviations..................................................................................39
Appendix B.
List of Prohibited Medications.................................................................40
Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints ...............41


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses of Part 1 only for 
ABBV-4083 Study B18-894/DNDi-TYL-01 "A Phase-II, Randomised, Double-blind, 
Parallel-group, Proof-of-concept Trial to investigate ABBV-4083 given for 7 or 14 Days 
or in combination with Albendazole in Subjects with Onchocerca volvulus Infection." Part 
2 will have a separate clinical database with a separate SAP and database lock.
Part 1 of Study B18-894/DNDi-TYL-01 investigates the safety, tolerability, efficacy for 
duration-ranging and pharmacokinetics of ABBV-4083 with or without albendazole in 
subjects infected with Onchocerca volvulus.
The analyses of pharmacokinetic endpoints and their relationship to efficacy and safety 
endpoints will not be covered in this SAP.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 
(SAS Institute Inc., Cary, NC 27513) or later under the UNIX operating system.
All analyses in this SAP are consistent with what is described in the study protocol unless 
otherwise noted in Section 13.0.
2.0
Study Design and Objectives
2.1
Objectives, Hypotheses and Estimands
The primary objectives are to:
●
determine whether treatment with ABBV-4083 or ABBV-4083 + albendazole 
effectively depletes Wolbachia endobacteria in adult female worms at Month 6 
by immunohistology;


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●
establish the superiority of ABBV-4083 + albendazole to each drug alone 
according to the depletion of Wolbachia endobacteria in adult female worms at 
Month 6 by immunohistology.
The primary hypothesis for Part 1, proof-of-concept, is that more worms will have
Wolbachia endobacteria (hereafter only referred to as Wolbachia) depletion at Month 6 in 
subjects who completed treatment with ABBV-4083 for 7 days, ABBV-4083 for 14 days, 
ABBV-4083 for 7 days + albendazole for 7 days, or ABBV-4083 for 7 days + albendazole 
for 3 days than in subjects treated with albendazole for 7 days among all subjects who 
completed treatment and had live female worms from nodulectomies at Month 6. The 
associated estimand is the odds ratio of Wolbachia depletion in a live female adult worm 
between subjects treated with one of the active regimens (ABBV-4083 for 7 days, 
ABBV-4083 for 14 days, ABBV-4083 for 7 days + albendazole for 7 days, or 
ABBV-4083 for 7 days + albendazole for 3 days) and the control regimen (albendazole 
for 7 days) in the Per Protocol population (see Section 4.0). Subjects who did not 
complete treatment, did not have Month 6 nodulectomy data, or took prohibited 
medications will be excluded.
The primary hypothesis for the combination rule is that more worms will have Wolbachia
depletion at Month 6 in subjects treated with ABBV-4083 for 7 days + albendazole for 
7 days than in subjects treated with ABBV-4083 for 7 days or those treated with 
albendazole for 7 days among all subjects who completed treatment and had live female 
worms from nodulectomies at Month 6. If the combination arm of ABBV-4083 for 
7 days + albendazole for 3 days is to advance to Part 2 of Study B18-894/DNDi-TYL-01 
and ABBV-4038 for 7 days + albendazole for 7 days is not, the combination rule in Part 1 
will instead be tested for ABBV-4083 for 7 days + albendazole for 3 days. The associated 
estimand is the odds ratio of Wolbachia depletion in a live female adult worm between 
subjects treated with the combination regimen (ABBV-4083 for 7 days + albendazole for 
7 days, or ABBV-4083 for 7 days + albendazole for 3 days, depending on Part 2 as 
described before) and the single drug regimen (ABBV-4083 for 7 days, and albendazole 
for 7 days) in the Per Protocol population (see Section 4.0). Subjects who did not 


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complete treatment, did not have Month 6 nodulectomy data, or took prohibited 
medications will be excluded.
2.2
Study Design Overview
A total of 150 subjects will be enrolled into five treatment arms with 30 subjects for each 
arm. The treatment period will last for 14 days and the post-treatment period will follow 
till Month 6. Post-study ivermectin that kills microfilaria will be given to all participants 
after nodulectomy at Month 6.
The schematic of the study is shown in Figure 1.
Figure 1.
Study Schematic
4083 = ABBV-4083; Alb = albendazole; d = days; D = (study) day; IVM = ivermectin; M = month; Pbo = placebo
2.3
Treatment Assignment and Blinding
Subjects will be randomized continuously 1:1:1:1:1 into one of five parallel treatment 
arms through an Interactive Response Technology (IRT) system. Randomization will be 


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stratified by the number of operable sites with onchocercomata (one site vs. more than one 
site).
The five treatment arms are defined as follows:
●
Arm A: 7 days of ABBV-4083 400 mg + albendazole matching placebo 
followed by 7 days of ABBV-4083 matching placebo
●
Arm B: 7 days of ABBV-4083 400 mg + albendazole matching placebo 
followed by 7 days of ABBV-4083 400 mg
●
Arm C: 7 days of ABBV-4083 400 mg + albendazole 400 mg followed by 
7 days of ABBV-4083 matching placebo
●
Arm D: 3 days of ABBV-4083 400 mg + albendazole 400 mg followed by 
4 days of ABBV-4083 400 mg + albendazole matching placebo followed by 
7 days of ABBV-4083 matching placebo
●
Arm E: 7 days of ABBV-4083 matching placebo + albendazole 400 mg 
followed by 7 days of ABBV-4083 matching placebo 
The treatment assignment will remain blinded to the Investigator, as well as clinical,
pharmacy, and laboratory personnel, and the Sponsor, including statistics and data 
management personnel and the study monitor, until the final database lock, after all Part 1 
subjects are followed to Month 6 or have prematurely discontinued from follow-up.
Toxicity of the treatments will be monitored throughout the study. If > 10% of the 
subjects in any arm meet any of the protocol-specified toxicity criteria after 15 subjects 
are enrolled in each arm, the Data and Safety Monitoring Board (DSMB) may recommend 
halting enrolment into arms of the same or longer duration with or without albendazole 
and continuing enrolment in those arms of the shorter duration. The enrolment of the 
closed arms may be reopened using a lower dose of ABBV-4083 at 300 mg QD with the 
same duration and same combination (with or without albendazole) as the original arm, in 
which case enrolment will continue until 30 subjects have been enrolled at that dose.
However, subjects who have already received 400 mg QD ABBV-4083 in the halted arm 


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and have not experienced dose-limiting toxicity will be kept on the same dose until 
treatment completion.
If Arm A, B, C, or D is closed and then reopened using ABBV-4083 at 300 mg QD, the 
subjects previously given ABBV-4083 at 400 mg QD in the closed arm will be excluded 
from all efficacy analyses (Section 9.1). Throughout this SAP, Arm A, B, C, D will be 
used to denote treatment regimens using either ABBV-4083 at 400 mg or 300 mg QD. For 
the actual treatment assignment, Arm A, B, C, D will be renamed as Arm F, G, H, I, 
respectively, upon reopening. For safety analyses, all arms will be summarized separately, 
even if any of them is closed during the study (Section 10.0). If all of Arms A, B, C, and 
D are closed, and any of Arms F, G, H, I are opened, the control arm (albendazole alone), 
Arm E, will be replaced with Arm J which uses the same pill count as Arms F, G, H, I to 
maintain blinding of the control arm. For all analyses, subjects from Arm E and Arm J 
will be combined.
2.4
Sample Size Determination
To test the primary hypothesis for the proof of concept, an alternating logistic regression 
will be used to compare the proportion of live female adult worms without Wolbachia at 
Month 6 between each of the four active arms (Arm A, B, C, or D) and the control arm 
(Arm E), taking into account the clustering of this worm-level endpoint by subject. Using 
simulations that add substantial clustering by subject to the endpoint values and assuming 
the number of worms in each subject varies from 1 to 10, following the multinomial 
distribution with probability = (0.20, 0.16, 0.16, 0.16, 0.08, 0.08, 0.08, 0.03, 0.03, 0.02) 
for values (1, 2, 3, 4, 5, 6, 7, 8, 9, 10),1 17 subjects will provide 88% power to detect the 
difference between an active arm (Arm A, B, C, or D) where 70% of worms are without 
Wolbachia and the control arm (Arm E) where 30% of worms are without Wolbachia
(2-sided α =0.10). The clustering of the endpoint values by subject is provided by the 
Pearson intraclass correlation coefficient (ICC)2 for binary outcomes and was given as 
ICC = 0.54 for simulated arms where 70% or 30% of the worms are without Wolbachia.


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To test the primary hypothesis for the combination rule, an alternating logistic regression 
will be used to compare the proportion of live female adult worms without Wolbachia at 
Month 6 between the combination arm (Arm C or D) and the two single drug arms 
(Arm A and E) separately, 25 subjects per arm will provide 81% power to detect the 
difference between the combination arm where 90% of worms are without Wolbachia and 
the single drug arm where 70% of worms are without Wolbachia (2-sided α =0.10).
ICC = 0.54 was added to the simulated arm where 70% of the worms are without 
Wolbachia. Minimal clustering (ICC = 0.01) was added to the simulated arm where 90% 
of the worms are without Wolbachia because there would be little variation among 
subjects with an overall high response rate. 30 subjects will be enrolled per arm to account 
for 17% drop out by Month 6.
3.0
Endpoints
3.1
Primary Endpoint
The primary efficacy endpoint is the status of each live female adult worm as without 
Wolbachia, assessed by immunohistology of nodules collected after nodulectomy at 
Month 6.
3.2
Secondary Endpoints
There is no key secondary endpoint in Part 1 of Study B18-894/DNDi-TYL-01. The other 
secondary efficacy endpoints are:
●
the proportion of live female adult worms with only degenerated embryos in 
the uterus per subject after nodulectomy at Month 6;
●
the proportion of live female adult worms out of all female adult worms per 
subject after nodulectomy at Month 6;
●
the absence of microfilariae in nodular tissue per subject after nodulectomy at 
Month 6;
●
the status of each subject as without skin microfilariae at Months 3 and 6;


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●
the reduction from baseline in skin microfilarial density (defined as the mean 
number of microfilariae/mg per subject) at Months 3 and 6;
●
the status of each nodule that contains at least 1 live female adult worm as 
without Wolbachia assessed by PCR at Month 6.
3.3
Exploratory Endpoints
The exploratory efficacy endpoints are:
●
the absence of Wolbachia in skin microfilariae per subject by PCR at all 
timepoints;
●
the decline from baseline in number of Wolbachia (assessed by PCR) in skin 
microfilariae per subject at all timepoints;
●
microfilaria levels in the cornea and anterior chamber per subject, at all 
timepoints when ophthalmological assessments are performed;
●
the presence, severity and clinical evolution of onchocerciasis ocular disease 
and onchocerciasis skin disease in each subject at all timepoints when 
ophthalmological or skin examinations are performed.
3.4
Safety Endpoints
The safety endpoints are based on the following assessments:
●
Adverse Event (AE) assessment (all reported AEs);
●
Vital signs;
●
12-lead ECG;
●
Clinical laboratory parameters: hematology and biochemistry.
4.0
Analysis Populations
The following population sets will be used for the analyses.


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The Intention-to-Treat (ITT) population includes all randomised subjects who received at 
least one dose of study drug. The ITT population will be used for all non-primary efficacy 
estimands. Subjects will be included in the analysis according to the treatment arm to 
which they were randomised.
The Per-Protocol (PP) population will include all ITT subjects who had Month 6 
nodulectomy (ND6M) with live female adult worms, who completed treatment and did 
not take prohibited medication(s) during the study. Treatment completion is defined as 
taking at least 6 out of 7 days of ABBV-4083 in Arm A, 12 out of 14 days of ABBV-4083 
in Arm B, 6 out of 7 days of ABBV-4083 + albendazole in Arm C, 6 out of 7 days of 
ABBV-4083 and all 3 days of albendazole in Arm D, and 6 out of 7 days of albendazole 
in Arm E. Prohibited medications (Appendix B) include those with anti-filarial or 
anti-Wolbachia effect taken at any time during the study, or strong CYP3A inducers or 
dexamethasone taken during the treatment period. The PP population will be used as the 
primary population for testing the two primary hypotheses (Section 2.1).
The Safety population includes all randomized subjects who received at least one dose of 
study drug. Subjects will be included in the analysis according to treatment as 
randomized. The Safety population is the same as the ITT population. 
5.0
Subject Disposition
The number of subjects in each of the following categories will be summarized by site and 
overall for each treatment arm and overall:
●
Subjects who were screened;
●
Subjects who were randomized;
●
Subjects who took at least one dose of study drug;
●
Subjects who completed protocol-specified treatment (ABBV-4083, 
albendazole, and the overall regimen [i.e., both study drugs]);
●
Subjects who prematurely discontinued study drug (ABBV-4083, albendazole, 
and at least one of ABBV-4083 or albendazole);


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●
Subjects who completed the protocol-defined follow-up period;
●
Subjects who prematurely discontinued study follow-up;
●
Subjects in the PP population.
The number and percentage of subjects, overall and by treatment arm, who prematurely 
discontinued study drug (ABBV-4083, albendazole, and at least one of ABBV-4083 or 
albendazole) will be summarized by primary reason for discontinuing study drug 
(ABBV-4083 and albendazole) and overall for discontinuing at least one of ABBV-4083 
or albendazole. The number and percentage of subjects, overall and by treatment arm, 
who prematurely discontinued the study will also be provided.
The number and percentage of subjects, overall and by treatment arm, who interrupted 
study drug (ABBV-4083, albendazole, and at least one of ABBV-4083 or albendazole) 
will be summarized by primary reason for interrupting study drug (ABBV-4083 and 
albendazole) and overall for interrupting at least one of ABBV-4083 or albendazole.
6.0
Study Drug Duration and Compliance
For the Safety population, duration of treatment will be summarized by treatment arm and 
overall. Duration of treatment is defined for each subject as last dosing date minus first 
dosing date + 1 day. Duration of treatment will be summarized using the number of 
subjects treated, mean, standard deviation, median, Q1, Q3, minimum, and maximum. In 
addition, the number and percentage of subjects by each treatment duration interval (1 to 7 
days, 8 to 14 days, or > 14 days) will be summarized, and the number and percentage of 
subjects with duration long enough to meet the Per Protocol definition will also be 
summarized.
For the Safety population, treatment compliance will be summarized by treatment arm 
separately for ABBV-4083/matching placebo and albendazole/matching placebo.
Treatment compliance is defined as the number of capsules that were taken divided by the 
number of capsules that should have been taken (56 capsules for 14 days of 
ABBV-4083/matching placebo at 400 mg QD, 42 capsules for 14 days of 


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ABBV-4083/matching placebo at 300 mg QD, 7 capsules for 7 days of 
albendazole/matching placebo). The mean, median, standard deviation, Q1, Q3, 
minimum, and maximum of treatment compliance will be summarized. In addition, the 
number and percentage of subjects with treatment compliance between 80% and 120% 
will also be summarized, excluding subjects with missing values in the denominator. A 
listing of each subject's treatment compliance will also be provided.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline or disease characteristics, medical history, and prior and 
concomitant medications will be summarized for the PP and ITT populations by treatment 
arm as well as overall. Categorical variables will be summarized with the number and 
percentage of subjects; percentages will be calculated based on the number of 
non-missing observations. Continuous variables will be summarized with descriptive 
statistics (number of non-missing observations, mean and standard deviation, median, Q1, 
Q3, minimum and maximum).
7.1
Demographics and Baseline Characteristics
Continuous demographic variables include age, weight, height, and body mass index 
(BMI). Categorical demographic variables include sex, race, age (< 40, or ≥ 40 years), 
weight (< 60 or ≥ 60 kg), and BMI (< 18, 18 to < 25, or ≥ 25 kg/m2).
Baseline characteristics include symptoms of onchocerciasis disease (ocular or skin), 
number of operable sites with onchocercomata (continuous and categorical: 0, 1 or > 1), 
number of palpated nodules (continuous and categorical: 0, 1 or > 1), skin microfilarial 
density (continuous and categorical: ≤ 5 or > 5 mf/mg), district of residence (Kimpese, 
Masa, Masi-Manimba, Moanza, Nsonampangu, Pay Kongila, or Other), number of years 
resident in endemic area (continuous), number of previous ivermectin rounds (continuous 
and categorical 0, 1, or > 1), time since the last ivermectin administration (continuous and 
categorical, ≤ 1 year or > 1 year), parasitological co-infections (e.g., Loa loa or 
Schistosoma haematobium).


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Baseline continuous laboratory values include aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (AP), creatinine clearance, estimated 
glomerular filtration rate (eGFR), total bilirubin, and albumin.
"Baseline" refers to the last non-missing observation before the first administration of 
study drug.
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report. The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall and by treatment arm. The system organ class (SOC) will be 
presented in alphabetical order, and the preferred terms will be presented in alphabetical 
order within each SOC. Subjects reporting more than one condition/diagnosis will be 
counted only once in each row (SOC or preferred term).
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name. A prior 
medication is defined as any medication taken prior to the date of the first dose of study 
drug. A concomitant medication is defined as any medication that started prior to the date 
of the first dose of study drug and continued to be taken after the first dose of study drug 
or any medication that started on or after the date of the first dose of study drug, but not 
after the date of the last dose of study drug. The number and percentage of subjects taking 
medications will be summarized by generic drug name based on the World Health 
Organization (WHO) Drug Dictionary for both prior and concomitant medications.
Anthelmintic medications taken prior to the initiation of study drug will not be included in 
the summary of concomitant medications.


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8.0
Handling of Potential Intercurrent Events for the 
Primary Endpoint
The primary efficacy endpoint (defined in Section 3.1) will be analyzed in the PP and ITT 
populations and the following methods will be used to address potential intercurrent 
events:
●
Subjects who did not complete treatment will be excluded from the PP 
population (definition of completion in Section 4.0). They will be included in 
the ITT population.
●
Subjects who took prohibited medications (Appendix B) will be excluded from 
the PP population. They will be included in the ITT population, but subjects 
who took medications with an anti-filarial or anti-Wolbachia effect at any time 
during the study will be counted as failures in the ITT population 
(Section 9.2).
●
Subjects who withdrew due to a safety issue (premature discontinuation of 
study or study treatment due to an adverse event related to either study drug) 
will be excluded from both the PP population and the ITT population analyses 
if they have no count of live female adult worms (no ND6M results or no live 
female adult worms in the ND6M results). If the subjects had live female adult 
worms in the ND6M results, they will be included in both the PP population 
and the ITT population analyses with any missing Wolbachia depletion results 
imputed as failures (Section 9.2).
●
Subjects who prematurely discontinued from the study or study treatment for 
reasons independent of the treatment (for example, lost to follow-up, withdrew 
informed consent, or due to an adverse event not related to either study drug) 
will be excluded from both the PP population and the ITT population analyses 
if they have no count of live female adult worms (no ND6M results or no live 
female adult worms in the ND6M results). If the subjects had live female adult 
worms in the ND6M results, they will be included in the PP population 
analysis if not all Wolbachia depletion results were missing and they will be 
included in the ITT population analysis with any missing Wolbachia depletion 
results imputed through multiple imputation (Section 9.2).


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9.0
Efficacy Analyses
9.1
General Considerations
The analyses for the primary endpoint will be conducted in both the PP population and the 
ITT population. However, the PP population will be the population used for the primary 
estimand comparisons. All other efficacy analyses will be conducted in the ITT 
population. The testing of the two primary hypotheses will be 2-sided at an alpha level of 
0.10. No adjustment for multiple comparisons will be made. 
The Primary Analysis will be performed after all subjects have completed the Month 6 
Visit or have prematurely discontinued study follow-up. This will be the only and final 
analysis for the primary endpoint as well as all other efficacy endpoints.
If Arm A, B, C, or D is closed and then reopened using ABBV-4083 at 300 mg QD, only 
the new arm using 300 mg ABBV-4083 will be included in the efficacy analyses of this 
SAP. Efficacy summaries of the closed arms may be performed as ad hoc analyses.
9.2
Handling of Missing Data for the Primary Endpoint
First, subjects with no count of live female adult worms (no ND6M results or no live 
female adult worms in the ND6M results) will be excluded from the PP population and 
the ITT population analysis, because the primary endpoint is a worm-level endpoint about 
the Wolbachia status of a live female adult worm in the ND6M results.
Then, if a subject took prohibited medications with an anti-filarial or anti-Wolbachia
effect (Appendix B) at any time during the study, all live female adult worms in that 
subject will be counted as having Wolbachia for the ITT population analyses, regardless 
of the observed Wolbachia status. All worms in such subjects will be excluded according 
to the definition of the PP population (Section 4.0).
Then, if a subject withdrew due to a safety issue (Section 8.0), all the live female adult 
worms that have missing Wolbachia status will be imputed as having Wolbachia for both 


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the PP population and the ITT population analyses. Any live female adult worm that has 
the observed Wolbachia status will be analyzed as observed.
Finally, if any live female adult worm still has missing Wolbachia status, the Wolbachia 
status will be imputed for the worms of those subjects in the ITT population analyses 
using the multiple imputation described below, but those worms will be excluded from the 
analyses for the PP population.
For multiple imputation, the missing Wolbachia depletion results will be generated in 
30 datasets in SAS PROC MI (fully conditional specification). The logistic regression 
method will be used to impute the binary primary Wolbachia status for each live female 
adult worm with missing Wolbachia status. The imputation model will include treatment 
and the randomization stratification factor (Section 2.3) as covariates. The random seed 
for PROC MI will be the SAS numerical form of the first subject randomization date in 
the study. In case of non-convergence, the random seed will be updated by adding 
100,000 at each attempt until convergence of model occurs. If the model will not 
converge due to data sparsity issue, the randomization stratification factor will be 
removed from the imputation model. The primary endpoint data from the 30 datasets will 
then be separately analyzed using the method described in Section 9.3.1. The results will 
be combined using SAS PROC MIANALYZE to generate the final inference.
9.3
Primary Efficacy Endpoint and Analyses
9.3.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the status of each live female adult worm as without 
Wolbachia, assessed by immunohistology of nodules collected after nodulectomy at 
Month 6.
9.3.2
Main Analysis of Primary Efficacy Endpoint
The primary efficacy endpoint will be compared between the following pairs of treatment 
arms for the PP population in Part 1:


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●
For proof of concept: (1) A vs. E, (2) B vs. E, (3) C vs. E, (4) D vs. E;
●
For satisfying the combination rule: if Arm C is to advance to 
Study B18-894/DNDi-TYL-01 Part 2, then (1) C vs. A, (2) C vs. E; if Arm D 
is to advance to Part 2 but Arm C is not, then: (1) D vs. A, (2) D vs. E.
The comparisons will be conducted using contrasts from an alternating logistic regression 
model3 that includes all the five treatment arms as factors. The alternating logistic 
regression will account for within-subject association of the worm-level endpoint by 
estimating the pairwise log odds ratio (different than the odds ratio of the primary 
estimand) of a worm's Wolbachia status in relation to another worm's Wolbachia status 
within each subject. In this regression model, the within-subject association is estimated 
with one parameter. That is, the pairwise log odds ratios used to account for the 
within-subject association are assumed as equal for all pairs of worms within a subject, 
and the same log odds ratios are assumed for all subjects in the same treatment arm.
However, different log odds ratios/parameters are assumed in different treatment arms, 
allowing for arm-specific within-subject associations. If the model does not converge, the 
within-subject associations for the five treatment arms will be assumed as the same. If the 
model still does not converge, a generalized linear mixed model will be used instead of 
the alternating logistic regression model. The mixed model will assume the framework of 
a logistic regression using a random intercept for each subject to account for the 
within-subject association of the worm-level endpoint. The variance of the random 
intercepts will be assumed as different for the five treatment arms.
Odds ratios with p-values and 95% confidence intervals for each of the pairwise 
comparisons will be reported. In addition, the percentages of live female adult worms 
without Wolbachia out of all live female adult worms from subjects in the PP population 
will also be summarized by treatment arm with 95% Wilson's score confidence intervals 
for all the percentages. The numerator and denominator of the percentage will be a sum 
across all subjects in a treatment arm. The rules of Section 9.2 for imputing missing data 
in the PP population worms will be applied; any worms that still have missing Wolbachia 
status after that will be excluded from both the numerator and denominator.


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The attributes of the estimands corresponding to the primary efficacy endpoint are 
summarized in Table 1.
Table 1.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
Proof of 
concept
Arm A:
ABBV-4083 for 
7 days
Arm B: 
ABBV-4083 for 
14 days
Arm C:
ABBV-4083 for 
7 days + 
albendazole for 
7 days
Arm D: 
ABBV-4083 for 
7 days + 
albendazole for 
3 days
Arm E:
albendazole for 
7 days
Status of 
depletion 
of 
Wolbachia
in each 
live 
female 
adult 
worm, 
evaluated 
using 
nodules 
collected 
at 
Month 6
PP 
population: 
all subjects 
who 
completed 
treatment 
and did not 
take 
prohibited 
medication, 
who had 
Month 6 
nodulectomy 
with female 
worms
IE1: Subjects who did 
not complete treatment 
(6 out of 7 days for 
Arms A, C, E, 12 out of 
14 days for Arm B, 6 out 
of 7 days of 
ABBV-4083 and all 
3 days of albendazole 
for Arm D) will be 
excluded.
IE2: Subjects who did 
not have Month 6 
nodulectomy data will 
be excluded.
IE3: Subjects who took 
prohibited medications 
will be excluded.
Odds ratio 
of 
Wolbachia
depletion in 
live female 
adult worms 
in subjects 
taking 
active 
regimen vs. 
control 
regimen
Satisfying 
the 
combination 
rule
Arm A
Arm C (or D 
depending on 
Part 2 regimens)
Arm E
Same as 
above
Same as 
above
Same as above
Odds ratio 
of 
Wolbachia
depletion in 
live female 
adult worms 
in subjects 
taking the 
combination 
regimen vs. 
the single 
drug 
regimens


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9.3.3
Sensitivity and Supplementary Analyses of the Primary 
Efficacy Endpoint
As supplementary analyses of the primary endpoint, the same analyses listed in 
Section 9.3.2 will be repeated for the ITT population following the imputation rules for 
the missing Wolbachia depletion results at Month 6 (Section 9.2).
9.4
Secondary Efficacy Endpoints and Analyses
9.4.1
Key Secondary Efficacy Endpoints and Analyses
There is no key secondary efficacy endpoint in Study B18-894/DNDi-TYL-01 Part 1.
9.4.2
Supportive Secondary Efficacy Endpoints and Analyses
The supportive secondary efficacy endpoints include the following:
●
Proportion of live female adult worms with only degenerated embryos out of 
all live female adult worms with either normal embryos or only degenerated 
embryos in the uterus per subject at Month 6;
●
Proportion of live female adult worms out of all female adult worms per 
subject at Month 6;
●
The status of each subject as without microfilariae in nodular tissue at 
Month 6;
●
The status of each subject as without skin microfilariae at Months 3 and 6;
●
The reduction in skin microfilarial density (defined as the mean number of 
microfilariae/mg per subject) at Months 3 and 6 compared to baseline;
●
The status of each nodule that contains at least 1 live female adult worm as 
without Wolbachia, as assessed by PCR, at Month 6.
All supportive secondary efficacy endpoints will be analyzed in the ITT population using 
observed data. All summaries will be produced by treatment arm.
The proportion of live female adult worms out of all female adult worms in each subject 
at Month 6 will be calculated as a percentage per subject. The proportion of live female 


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adult worms with only degenerated embryos out of all live female adult worms with either 
normal embryos or only degenerated embryos in the uterus in each subject at Month 6 will 
also be calculated as a percentage per subject, excluding from the denominator any worm 
with an empty uterus, with oocytes only, or not evaluable. Subjects with no worm for the 
denominator will be excluded from this summary. The percentage per subject will be 
summarized with descriptive statistics (number of subjects, mean and standard deviation, 
median, Q1, Q3, minimum, and maximum). P-values for the pairwise comparison of each 
of Arms A, B, C, D with Arm E will be provided using the Mann Whitney U test for the 
percentage per subject.
The status of each subject as without microfilariae in nodular tissue at Month 6 will be 
summarized as the percentage of subjects without microfilariae in nodular tissue at Month 
6. The status of each subject as without skin microfilariae or not at Months 3 and 6 will be 
summarized in the same way. P-values for the pairwise comparison of each of Arms A, B, 
C, D with Arm E will be provided using the chi-square test for the binary response per 
subject.
The status of each nodule that contains at least 1 live adult female worm as without 
Wolbachia, as assessed by PCR at Month 6 will be summarized as the percentage of 
nodules without Wolbachia out of all nodules. The numerator and denominator of the 
percentage will be a sum across all subjects in a treatment arm. For the calculation of the 
percentages, nodules that do not contain live adult worms will be excluded from both the 
numerator and denominator. P-values for the pairwise comparison of each of Arms A, B, 
C, D with Arm E will be provided using the alternating logistic regression as detailed in 
Section 9.3.2 for the binary response per nodule clustered by subject.
The reduction in skin microfilarial density at Months 3 and 6 compared to baseline will be 
a mean change across all subjects summarized with descriptive statistics (number of 
subjects, mean and standard deviation, median, Q1, Q3, minimum, and maximum). The 
mean skin microfilarial density at baseline, Month 3 and 6 will also be summarized. P-
values for the pairwise comparison of each of Arms A, B, C, D with Arm E will be 
provided using the Mann Whitney U test for the change from baseline in skin microfilarial 


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density per subject. The skin microfilarial density of each subject at a given time point 
will be collected as the final mean density of all the available skin snips. A supplementary 
analysis will be performed for this endpoint including only the final mean density values 
from ≥ 2 skin snips.
9.5
Additional Efficacy Analyses
The additional efficacy endpoints include the following:
●
The status of each subject as without Wolbachia in skin microfilariae or not, as 
assessed by PCR, at baseline (screening), Month 3, Month 6, and end of study 
follow-up (including premature discontinuation);
●
The decline in number of Wolbachia (assessed by PCR) in skin microfilariae 
per subject at Month 3, Month 6 and end of study follow-up (including 
premature discontinuation) compared to baseline;
●
The microfilaria levels in the cornea and anterior chamber per subject, at 
baseline (screening), Day 13, Month 3, Month 6, and end of study follow-up 
(including premature discontinuation);
●
the presence, severity and clinical evolution of onchocerciasis ocular disease 
and onchocerciasis skin disease in each subject at baseline (screening), Day 13, 
Month 3, Month 6, and end of study follow-up (including premature 
discontinuation).
All additional efficacy endpoints will be analyzed in the ITT population using data as 
observed. All analyses will be descriptive summaries and will be produced by treatment 
arm. No statistical method will be used for any pairwise comparison between arms.
The status of each subject as without Wolbachia in skin microfilariae or not, as assessed 
by PCR, will be summarized as the percentage of subjects without Wolbachia in skin 
microfilariae for each time point.
The decline in number of Wolbachia (assessed by ratio of PCR copy number of 
Wolbachia signal to PCR copy number of worm signal, FtsZ/Actin ratio) in skin 


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microfilariae per subject will be a mean change from baseline across all subjects 
summarized for each post-baseline time point with descriptive statistics (number of 
subjects, mean and standard deviation, median, Q1, Q3, minimum, and maximum). The 
mean number of Wolbachia in skin microfilariae at baseline and post-baseline time points 
will also be summarized.
The microfilaria levels (motile, non-motile, and total) in the cornea and anterior chamber 
will both be summarized as continuous variables using descriptive statistics (number of 
subjects, mean and standard deviation, median, Q1, Q3, minimum and maximum) for 
each time point. The values from the left and the right eye will be summarized separately.
Onchocerciasis ocular disease at each time point will first be summarized as the 
percentage of subjects with "abnormal" results from the following examinations: 
frequency doubling technology perimetry; pupils, extraocular movement and eyelids 
(pen torch); intraocular pressure (Goldman tonometer); anterior segment (slit lamp); iris 
anterior chamber examination; lens/cataract examination; posterior segment (slit lamp); 
fundus photography; visual acuity for distance; and ocular symptoms.
Then for each of the following outcomes, the percentage of subjects will be summarized 
for each clinical grade at each time point: ocular itching, watering eyes, ocular pain, 
photophobia, eye redness, blurred vision, night blindness, conjunctivitis, limbitis, punctate 
opacities, sclerosing keratitis, phlyctenule-like kerato-conjunctival lesions, anterior uveitis 
(number of cell/field and flare), cataract, glaucoma, optic nerve edema, optic nerve 
atrophy, posterior uveitis, chorioretinal atrophy, eyelid, chemosis, and visual field defect.
The change of clinical grade from baseline will be summarized as improvement, no 
change, or worsening. The outcomes of the right eye and the left eye will be combined by 
using the higher grade of the two. The percentage of subjects will be summarized for each 
change category at each post-baseline time point, as well as the last post-baseline value.
The clinical grading collected by the eCRF all starts from 1 for subjects with the outcome 
at a visit, but for the sake of analyses, grade 0 will be applied to subjects without the 
outcome at that visit. Outcomes with a binary evaluation (normal/abnormal, no/yes) will 


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be analyzed as grade 0 and 1. If the result of a particular examination is normal, all 
outcomes in that examination will also be normal (grade 0).
For the outcome of visual acuity (uncorrected, corrected, and color vision), continuous 
measures will be collected. The mean change from baseline at each post-baseline time 
point will be summarized across all subjects with descriptive statistics (number of 
subjects, mean and standard deviation, median, Q1, Q3, minimum and maximum). The 
mean at baseline and each post-baseline time point will also be summarized. The values 
from the left and the right eye will be summarized separately.
Onchocerciasis skin disease at each time point will first be summarized as the percentage 
of subjects with each of the symptoms collected on the skin examination eCRF form, 
based on the "present/absent" question. Then for each of the symptoms, the percentage of 
subjects will be summarized for each clinical grade at each time point. The change of 
clinical grade from baseline will be summarized as improvement, no change, or 
worsening. The percentage of subjects will be summarized for each change category at 
each post-baseline time point, as well as the last post-baseline value. When applicable, 
"Sum (clinical grading)" on the eCRF form will be used as the clinical grade. Otherwise, 
the single grading variable will be used and will be interpreted as an ordinal scale as 
applicable. For each symptom, the clinical grade will start from 1, but for the sake of 
analyses, grade 0 will be applied to subjects without the symptom.
9.6
Efficacy Subgroup Analyses
The percentages of live female adult worms without Wolbachia out of all live female 
adult worms from subjects in the PP population will be summarized by treatment arm for 
each category of the following subgroup variables, after applying the rules of Section 9.2
for missing data. 95% Wilson's score confidence intervals will be provided for all the 
percentages if the denominator is ≥ 10. The rules of Section 9.2 for imputing missing data 
in the PP population worms will be applied; any worms that still have missing Wolbachia 
status after that will be excluded from both the numerator and denominator. The subgroup 
variables include:


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●
Operable sites with onchocercomata (0, 1, or > 1),
●
Baseline skin microfilarial density (≤ 5 or > 5 mf/mg),
●
Number of previous ivermectin rounds (0, 1, or > 1)
●
Time since the last ivermectin administration (≤ 1 year or > 1 year)
●
District of residence (Kimpese, Masa, Masi-Manimba, Moanza, 
Nsonampangu, Pay Kongila, or Other)
The different treatment effects across these subgroup variables will be further explored 
using the alternating logistic regression model detailed in Section 9.3.2. The continuous 
values of the subgroup variables will be used except for district of residence. Each 
subgroup variable will be added separately to the model as a factor in addition to the 
treatment arms. Then, the interaction term of the subgroup variable with the treatment 
arms will be included in addition to the main effect term and analyzed in a separate model 
to examine the effect of the subgroup variables on treatment efficacy.
10.0
Safety Analyses
10.1
General Considerations
Safety data will be summarized for the Safety population in Part 1. If any of 
Arms A B C, D was closed during the study and any of Arms F, G, H, I was opened, all 
individual treatment arms will be included in the safety analyses. All safety summaries 
will be presented by treatment arm, as well as for all subjects taking ABBV-4083 (i.e., 
combining Arms A, B, C, D, as well as, F, G, H, I, if applicable). For the safety analyses, 
a subject's treatment arm will be determined based on the treatment arm assigned at 
randomization.
10.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock. The actual version of the 
MedDRA coding dictionary used will be noted in the AE tables and in the clinical study 


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report. Specific PTs will be counted once for each subject for calculating percentages, 
unless stated otherwise. In addition, if the same PT occurs multiple times within a subject, 
the highest severity and level of relationship to investigational product will be reported.
10.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs are defined as any AE with the onset date that is after the first 
dose of study drug and no more than 30 days after the last dose. Events with the same 
onset date as the study drug start date are assumed to be treatment-emergent. All 
treatment-emergent AEs will be summarized overall, as well as by primary MedDRA 
SOC and Preferred Term. The SOCs will be presented in alphabetical order, and the PTs 
will be presented in alphabetical order within each SOC. The number and percentage of 
subjects experiencing treatment-emergent AEs will be summarized.
10.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any treatment-emergent AE;
●
Any treatment-emergent AE related to study drug (ABBV-4083, albendazole, 
ABBV-4083 and/or albendazole, and ABBV-4083 and albendazole) according 
to the investigator;
●
Any Grade 3 or higher treatment-emergent AE (or if an AE is not graded as 
such, using maximum severity instead and including AEs that are severe, 
life-threatening, or led to death);
●
Any serious treatment-emergent AE;
●
Any serious treatment-emergent AE related to study drug (ABBV-4083, 
albendazole, ABBV-4083 and/or albendazole, and ABBV-4083 and 
albendazole) according to the investigator;
●
Any treatment-emergent AE leading to discontinuation of study drug 
(ABBV-4083, albendazole, ABBV-4083 and/or albendazole, and ABBV-4083 
and albendazole);


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●
Any treatment-emergent AE leading to death;
●
All deaths during the study, deaths occurring prior to or at 30 days after the 
last dose, and deaths occurring > 30 days after the last dose.
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent AEs will be summarized by SOC and PT; by maximum relationship 
to study drug as assessed by the investigator and SOC and PT; by maximum 
grade/severity and SOC and PT; and by subject number and SOC and PT. Specific PTs 
will be counted once for each subject for calculating percentages, unless stated otherwise.
In addition, if the same PT occurs multiple times within a subject, the highest
grade/severity and level of relationship to investigational product will be reported. The 
relationship to study drug will be collected as "definitely related," "probably related," 
"possibly related," "probably not related" and "not related," but it will be summarized as 
"related" (combining "definitely related," "probably related," "possibly related") and "not 
related" (combining "probably not related" and "not related"). Summaries of treatment-
emergent AEs by maximum relationship to study drug, SOC and PT will be performed 
separately by relationship to ABBV-4083, relationship to albendazole, relationship to 
ABBV-4083 and albendazole, and relationship to ABBV-4083 and/or albendazole.
For the summary of treatment-emergent AEs, the maximum severity is determined by 
using reported per CRF severity as mild, moderate, severe, life-threatening, and death; 
CTCAE grades 1-5 as categories mild, moderate, severe, life-threatening, and death; or 
Vaccine Trial grades 1-4 as categories mild, moderate, severe, and life-threatening. 
In addition, treatment-emergent adverse events will be summarized by PT and sorted by 
decreasing frequency among all subjects taking ABBV-4083.
10.2.4
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
Treatment-emergent SAEs (including deaths) and AEs leading to study drug 
discontinuation (ABBV-4083, albendazole, ABBV-4083 and albendazole, and 


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ABBV-4083 and/or albendazole) will be summarized by SOC and PT and in listing 
format. Listings of all SAEs and all deaths during the study will also be provided.
10.3
Analysis of Laboratory Data
Haematology variables to be summarized include: haematocrit, haemoglobin, red blood 
cells (RBC), white blood cells (WBC), neutrophils, lymphocytes, monocytes, eosinophils, 
basophils, platelets.
Chemistry variables to be summarized include: aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (AP), glucose, creatinine, eGFR, blood 
urea nitrogen (BUN), total bilirubin, albumin, total protein, chloride, sodium, potassium 
and calcium.
Each laboratory variable will be summarized for all time points (Baseline, Day 3, Day 6, 
Day 13, Month 3, and end of study follow-up) with the number of non-missing 
observations, mean and standard deviation, median, Q1, Q3, minimum and maximum.
Mean change from baseline to each applicable post-baseline visit will be summarized for 
all laboratory variables, with the number of observations, baseline mean, and visit mean.
The change from baseline mean, standard error, and 95% confidence interval will be 
presented for the mean change from baseline within each treatment arm and difference 
between the active arms and the control arm (A, B, C, D vs. E) and between all active 
arms and the control arm (A – D vs. E) using separate ANOVA models.
Changes in chemistry and hematology laboratory parameters will be tabulated using shift 
tables, for laboratory parameters that have a normal range reported. Laboratory data 
values will be categorized as low, normal, or high based on the normal ranges of the 
laboratory used for each sample. Shift tables from baseline to the minimum and maximum 
values during the Treatment Period will be created. In these shift tables, the number and 
percentage of subjects with baseline values within or above the normal range (baseline 
high or normal) and a minimum value below the normal range (post-baseline low during 
treatment) and the number and percentage of subjects with baseline values within or 


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below the normal range (baseline low or normal) and a maximum value above the normal 
range (post-baseline high during treatment) will be summarized. Similar shift tables will 
be created for the shift from baseline to the final post-baseline value where the number 
and percentage of subjects with baseline values within or above the normal range 
(baseline high or normal) and the final post-baseline value below the normal range and the 
number and percentage of subjects with baseline values within or below the normal range 
(baseline low or normal) and the final post-baseline value above the normal range will be 
summarized.
The number and percentage of subjects with a maximum of Grade 3, a maximum of 
Grade 4, and a maximum of at least Grade 3 (CTCAE 5.0) for the laboratory parameters 
during treatment as defined in Appendix C will be summarized. The post-baseline value 
must be in a toxicity grade that is more extreme than the toxicity grade corresponding to 
the baseline value, if a baseline value is available, in order to be counted. A listing of all 
relevant laboratory parameters will be provided for each subject who had an increase to 
Grade 3 or higher.
The following criteria will be used to assess potential hepatotoxicity during treatment.
●
ALT > 3 × ULN, > 5 × ULN, > 10 × ULN, > 20 × ULN
●
AST > 3 × ULN, > 5 × ULN, > 10 × ULN, > 20 × ULN
●
bilirubin > 1.5 × ULN, > 2 × ULN
●
ALT and/or AST > 3 × ULN and bilirubin > 1.5 × ULN
●
ALT and/or AST > 3 × ULN and bilirubin > 2 × ULN
●
ALT > 3 × ULN and bilirubin > 1.5 × ULN
●
ALT > 3 × ULN and bilirubin > 2 × ULN
●
Alkaline phosphatase (ALP) > 1.5 × ULN
The number and percentage of subjects with laboratory values meeting the above criteria 
during treatment will be summarized. Listing of ALT, AST, total bilirubin, and alkaline 
phosphatase values will be provided for each subject who met one or more of the criteria 
defined above.


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An Evaluation of Drug Induced Serious Hepatotoxicity (eDISH) plot of the maximum 
post-baseline ALT value (as a multiple of the ULN) versus the maximum post-baseline 
bilirubin value (as a multiple of the ULN) during treatment, not necessarily concurrent, 
will also be utilized to assess for potential hepatotoxicity. A similar plot will be produced 
for AST versus bilirubin.
10.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, heart rate, resting 
respiratory rate and temperature will be summarized.
Each vital sign variable will be summarized for all time points (Baseline, Day 3, Day 6, 
Day 13, Month 3, and end of study follow-up) with the number of non-missing 
observations, mean and standard deviation, median, Q1, Q3, minimum, and maximum.
Mean change from baseline to each applicable post-baseline visit will be summarized for 
each vital sign variable, with the number of observations, baseline mean, and visit mean.
The change from baseline mean, standard error, and 95% confidence interval will be 
presented for the mean change from baseline within each treatment group and difference 
between treatment arms (A, B, C, D vs. E) and between all active arms and the control 
arm (A – D vs. E) using separate ANOVA models.
Vital signs variables will be evaluated based on potentially clinically important (PCI) 
criteria (Appendix C) using all post-baseline values. For each vital sign PCI criterion, the 
number and percentage of subjects who have a vital sign value meeting the criteria will be 
summarized. Listings will be provided to summarize subject-level vital sign data for 
subjects meeting PCI criteria. 
10.5
Other Safety Analyses
ECG findings will be summarized for all time points (Baseline, Day 3, Day 6, Day 13, 
and end of study follow-up) using the investigator interpretation. The summaries will 
include the number and percentage of patients in the following categories:


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●
Normal
●
Abnormal – Not Clinically Significant
●
Abnormal – Clinically Significant
Counts will be provided for the category "Interpretation not possible."
11.0
Interim Analyses
No interim analysis is planned for Study B18-894/DNDi-TYL-01 Part 1.
11.1
Data and Safety Monitoring Board
An independent Data and Safety Monitoring Board (DSMB) will be established by the 
Sponsor in accordance with ICH guidelines. The DSMB will be composed of a minimum 
of three members, including at least one medically qualified disease expert and a 
statistician, in accordance with any requirements specified by the regulatory authorities.
The composition, roles, and responsibilities of the DSMB will be described in detail in a 
separate DSMB charter.
During the study, the DSMB will review reports about enrolment, subject discontinuation, 
subject demographic, and safety data, including serious and non-serious AEs and other 
safety parameters, cases of exposure during pregnancy and outcomes, PK results (only 
drug concentration data), concomitant treatments, as well as ad-hoc requests if deemed 
necessary by the Sponsor and in line with the DSMB charter.
The DSMB will also review and evaluate, at intervals and as defined in the DSMB 
charter, the progress, scientific validity, data integrity, and the safety of the clinical trial, 
and make recommendations to the Sponsor about whether to continue, modify or 
terminate the trial. The DSMB may also request unblinding of certain subject(s), e.g., in 
case of a major safety concern, but only if absolutely necessary, and always in accordance 
with the DSMB Charter.


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In addition, a Safety Review Committee (SRC) will be appointed with a minimum of 
three Sponsor representatives, including at least one medically qualified person, and the 
Investigators. The exact composition, roles, and responsibilities of the SRC will be 
described in a separate SRC Charter.
Once at least 15 subjects have been treated in each of the five arms, the SRC will review 
safety results separately for each arm every 2 weeks and evaluate causality. If > 10% of 
the subjects in any arm meet any of the toxicity criteria, the SRC will inform the DSMB.
The DSMB will review the reports and make non-binding recommendations regarding 
halting enrolment into Arms A, B, C or D and opening enrolment in appropriate arms 
with the lower dose of ABBV-4083.
Both the Sponsor and the DSMB will review the final unblinded analyses of 
Study B18-894/DNDi-TYL-01 Part 1. The DSMB will provide a non-binding 
recommendation to the Sponsor about whether to proceed to Part 2 and with which dose 
regimens.
12.0
Overall Type-I Error Control
Since Study B18-894/DNDi-TYL-01 Part 1 is for proof of concept, no multiplicity 
adjustment for alpha spending will be used. 
13.0
Version History
Table 2.
SAP Version History Summary
Version
Date
Summary
1.0
02 Nov 2021
Original version
2.0
24 Mar 2023 
•
Section 1.0 Noted that analyses inconsistent with the
protocol are noted in Section 13.0.
•
Section 2.3 Administrative clarification of randomization
was made.


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Version
Date
Summary
•
Section 3.2 and Section 9.4.2 Secondary endpoint of 
status of each live female adult worm as without 
Wolbachia assessed by PCR at Month 6 has been 
changed to status of each nodule containing at least one 
live female adult worm as without Wolbachia assessed 
by PCR at Month 6 due to a change in PCR data 
availability. 
•
Section 3.4 For safety endpoints, removed physical, skin, 
and ophthalmological examination findings since they 
are summarized as the secondary efficacy endpoints. 
•
Section 3.4 For safety endpoints, removed urine analysis 
because only abnormal results are collected. 
•
Section 4.0 and Section 10.1 Updated safety analysis 
arms to be determined by the subject's randomized arm 
to align with treatment regimens under study. 
•
Section 5.0 Subject disposition summary for completed 
protocol-specified treatment, prematurely discontinued 
study drug, reason for discontinuation of study drug, 
interruption of study drug, and reason for interruption of 
study drug were clarified to include summaries by study 
drug. 
•
Section 6.0 Study drug duration categorical summary 
was updated to add the category of "> 14 days."
•
Q1, Q3 were added to all numerical summaries that 
included calculation of the median. 
•
Section 7.1 and Section 9.6 For demographics and 
baseline characteristics, categories for number of 
operable sites with onchocercomata, number of palpated 
nodules, and number of previous ivermectin rounds were
updated to be 0, 1, >1. Also, number of years resident in 
endemic area was added, and for summary of symptoms 
of onchocerciasis disease, "other" category was removed. 
•
Section 7.3 Summaries of prior and concomitant 
procedures were removed because they are collected as 
text fields. Anthelmintic medications taken prior to the 
start of study drug were removed from the summary of 
concomitant medications because by definition these 
medications were only taken prior to start of study drug.
•
Section 8.0 and Section 9.2 Clarified the conditions 
which lead to data imputation. 
•
Section 9.1 Clarified that no adjustment for multiple 
comparisons would be made. 


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Version
Date
Summary
•
Section 9.5 Clarified that the decline in number of 
Wolbachia, as assessed by PCR, would be assessed using 
the ratio of PCR copy number of Wolbachia signal to 
PCR copy number of worm signal. 
•
Section 9.5 For ophthalmological exam outcomes, added 
blurred vision and night blindness to summary of clinical 
grade and clarified that anterior uveitis would have 
separate grades for number of cell/field and flare). For 
summaries of change from baseline in ocular and skin 
exam, summary category of "similarity" was changed to 
"no change."
•
Section 10.2.2, Section 10.2.3, and Section 10.2.4
Clarified that summaries of treatment-emergent AEs 
based on relationship to study drug and of treatment-
emergent AEs leading to discontinuation of study drug 
would be performed with study drug defined in 4 ways: 
ABBV-4083, albendazole, ABBV-4083 and/or 
albendazole, and ABBV-4083 and albendazole. The 
description of the summary of all deaths was clarified to 
include time periods. 
•
Section 10.2.4 Added listings of all SAEs and all deaths.
•
Section 10.3 Deleted statement about including 
laboratory testing due to an SAE because SAE-related 
laboratory assessments are not collected in a format that 
can be summarized. Removed summary of creatinine 
clearance and added eGFR because eGFR is collected in 
the study and is more applicable to the study population. 
Removed summary of urinalysis data because only 
abnormal results are collected. Clarified that changes 
from baseline would be analyzed using ANOVA models. 
Provided more detail about the analyses related to 
normal range shift for laboratory parameters. Added 
separate summaries for a maximum of Grade 3 and a 
maximum of Grade 4 for graded laboratory parameters. 
Added an eDISH plot for AST versus bilirubin.
•
Section 10.4 Clarified that changes from baseline would 
be analyzed using ANOVA models. Clarified that 
evaluation of potentially clinically important criteria are 
to be assessed using all post-baseline values. 


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Version
Date
Summary
•
Section 10.5 Deleted Month 3 visit summary because 
ECG data are not collected at Month 3. Clarified that 
only investigator interpretation of ECG would be 
summarized and that percentages would be calculated 
using only interpretable tests. 
•
Appendix A Added the protocol deviation categories.
•
Appendix B Clarified that any subject taking a prohibited 
medication will be documented as a protocol deviation. 
•
Appendix C Removed creatinine clearance from table 
and added eGFR because eGFR is collected in the study 
and is more applicable to the study population. Revised 
albumin criteria to use units of g/dL. Updated grade 
definitions for ALT, AST, ALP, and bilirubin to match 
CTCAE v5.
14.0
References
1.
Albers A, Esum ME, Tendongfor N, et al. Retarded Onchocerca volvulus L1 to L3 
larval development in the Simulium damnosum vector after anti-wolbachial 
treatment of the human host. Parasit Vectors. 2012;5:12.
2.
Wu S, Crespi CM, Wong WK. Comparison of methods for estimating the intraclass 
correlation coefficient for binary responses in cancer prevention cluster randomized 
trials. Contemp Clin Trials. 2012;33(5):869-80.
3.
Carey V, Zeger SL, Diggle PJ. Modelling Multivariate Binary Data with 
Alternating Logistic Regressions. Biometrika. 1993;80(3):517-26.
4.
U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, 
Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. September 2007.


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15.0
SAP Approval
AbbVie Statistics
Signature
Date (DD-MMM-YYYY): 
AbbVie Statistics Director 
Signature
Date (DD-MMM-YYYY): 
AbbVie Statistical Programming
Signature
Date (DD-MMM-YYYY): 
AbbVie Medical Director
Signature
Date (DD-MMM-YYYY): 
AbbVie Group Medical Director
Signature:
Date (DD-MMM-YYYY): 
DNDi Head of Filarial Program
Signature:
Date (DD-MMM-YYYY): 
24-Mar-2023
24-Mar-2023
24-Mar-2023
24-Mar-2023
24-Mar-2023
24-Mar-2023


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DNDi Medical Manager
Signature
Date (DD-MMM-YYYY): 
DNDi Clinical Project Manager
Signature:
Date (DD-MMM-YYYY): 
24-Mar-2023
27-Mar-2023


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Appendix A.
Protocol Deviations
Protocol deviations include eligibility criteria violations, receipt of wrong treatment or 
incorrect dose of study treatment, development of withdrawal criteria without being 
withdrawn, use of prohibited concomitant medications, and Month 6 nodulectomy not
performed. A listing of subjects with protocol deviations will be provided. 


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Appendix B.
List of Prohibited Medications
The following medications are prohibited throughout the entire study because of their 
anti-filarial or anti-Wolbachia effects:
●
ivermectin (excluding protocol-defined, post-study ivermectin mentioned in 
Section 2.2)
●
moxidectin, 
●
doxycycline,
●
minocycline,
●
rifampicin, 
●
rifapentine.
The following medications are prohibited during the treatment period, up to 24 hours after 
the final dose.
●
Any CYP3A and/or P-gp inhibitors or inducers, such as:
○
rifampicin, 
○
phenytoin, 
○
phenobarbital, 
○
carbamazepine, 
○
others known to interfere with the CYP3A and/or P-gp metabolic pathways 
(the US FDA tables of Substrates, Inhibitors and Inducers will be used as a 
reference, and included in the Study Operations Manual for reference).
●
Dexamethasone is known to interact with albendazole and will also be 
prohibited during the treatment period, up to 24 hours after the final dose.
Any subject who takes a prohibited medication during the study will be documented via a 
protocol deviation, which will be used to determine eligibility for the per-protocol 
population. 


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Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints
Table C-1.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory Values
Test
Grade 1
Grade 2
Grade 3
Grade 4
ALT*
> ULN – 3 × ULN if 
baseline was normal or 
missing; 1.5 – 3 x baseline 
if baseline was abnormal 
> 3 – 5 × ULN*
> 5 – 20 × ULN*
> 20 × ULN*
AST*
> ULN – 3 × ULN if 
baseline was normal or 
missing; 1.5 – 3 x baseline 
if baseline was abnormal
> 3 – 5 × ULN*
> 5 – 20 × ULN*
> 20 × ULN*
ALP*
> ULN – 2.5 × ULN if 
baseline was normal or 
missing; 2 – 2.5 x baseline 
if baseline was abnormal
> 2.5 – 5 × 
ULN*
> 5 – 20 × ULN*
> 20 × ULN*
Bilirubin*
> ULN – 1.5 × ULN if 
baseline was normal or 
missing; 1- 1.5 x baseline 
if baseline was abnormal
> 1.5 – 3 × 
ULN*
> 3 – 10 × ULN*
> 10 × ULN*
Haemoglobin 
(female)+
11.0 – 12.0 g/dL
9.5 – 10.9 g/dL
8.0 – 9.4 g/dL
< 8.0 g/dL
Haemoglobin 
(male)+
12.5 – 13.5 g/dL
10.5 – 12.4 
g/dL
8.5 – 10.4 g/dL
< 8.5 g/dL
White blood 
cells
< LLN – 3.0 × 109/L
< 3.0 – 2.0 × 
109/L
< 2.0 – 1.0 × 
109/L
< 1.0 × 109/L
Platelets
< LLN – 75.0 × 109/L
< 75.0 – 50.0 × 
109/L
< 50.0 – 25.0 × 
109/L
< 25.0 × 109/L
Glucose 
(decreased)
< LLN – 3.0 mmol/L
< 3.0 – 2.2 
mmol/L
< 2.2 – 1.7 
mmol/L
< 1.7 mmol/L
Creatinine
> ULN – 1.5 × ULN
> 1.5 – 3 × 
ULN
> 3 – 6 × ULN
> 6 × ULN
eGFR
< 90 – 60 mL/min/1.73m2
< 60 – 30 
mL/min/1.73m2
< 30 – 15 
mL/min/1.73m2
< 15 
mL/min/1.73m2
Albumin
< LLN – 3 g/dL
< 3 – 2 g/dL
< 2 g/dL
--
*
ULN used as reference if baseline was normal or missing; if baseline was abnormal (> ULN), baseline should be 
used as reference, for example, > ULN – 3 × ULN should be changed to > baseline – 3 × baseline if baseline was 
abnormal, according to CTCAE v5.
+
Haemoglobin values are taken from the Vaccine Trial Grading Scale 2007.4


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Table C-2.
Criteria for Potentially Clinically Important Vital Sign Values
Test/Measurement
Low
High
Systolic Blood Pressure
≤ 90 mmHg and a decrease of
≥ 20 mmHg from baseline
≥ 180 mmHg and an increase of
≥ 20 mmHg from baseline
Diastolic Blood Pressure
≤ 50 mmHg and a decrease of
≥ 15 mmHg from baseline
≥ 105 mmHg and an increase of
≥ 15 mmHg from baseline
Heart Rate
≤ 50 bpm and a decrease of
≥ 15 bpm from baseline
≥ 120 bpm and an increase of
≥ 15 bpm from baseline
Body Temperature
> 38.3°C and an increase of
≥ 1.1°C from baseline