Clinical trial NCT04188301
Conditions: Onchocerciasis
Keywords: ophthalmology
Sponsor: Washington University School of Medicine
Start date: 2019-12-06; Completion date: 2022-06-01
Enrollment: 154 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This DOLF study will investigate the safety and effectiveness of IDA treatment in persons with onchocerciasis when it is administered after pre-treatment with ivermectin to clear or greatly reduce microfilariae from the skin and eyes.

Detailed description:
This study will provide preliminary data on the safety of IDA treatment in persons with onchocerciasis when it is administered after pre-treatment with IVM to clear or greatly reduce microfilariae from the skin and eyes. Widespread use of IDA following IVM pretreatment (I/IDA) has the potential to greatly accelerate elimination of lymphatic filariasis (LF) in African countries that are co-endemic for LF and onchocerciasis. study later.

This study will also assess the efficacy of IDA for killing and sterilizing adult filarial worms. An improved macrofilaricidal treatment would be a major advance for the global program to eliminate onchocerciasis. Since the safety and efficacy objectives are both very important, we have included dual primary objectives for the study.

Primary objectives:

* Safety: To compare rates and types of severe adverse events (grade 3 or higher) that occur within 7 days following 1 day or 3 days of treatment with triple drug treatment ("IDA" = diethylcarbamazine (DEC) with ivermectin (IVM) and albendazole (ALB)) with the comparator regimen of 1 day of treatment with ivermectin and albendazole (IA) in persons with active Onchocerca volvulus infections after pretreatment with ivermectin alone.
* Efficacy: To compare the effect of three treatment regimens (1 day of IDA, 3 days of IDA, or IA) for killing or sterilizing adult female O. volvulus worms based on the percentage of all adult female worms in nodules that are alive with embryos in the uterus 18 months after treatment.

This is an open label, randomized clinical trial.

Arms: arm 1: Single dose of oral IVM (150 µg/kg) plus ALB (400 mg) arm 2: Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg) arm 3: Once daily for 3 days oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Interventions: intervention 1: IVM w/ ALB intervention 2: Single dose of IDA intervention 3: Three daily doses of IDA
Intervention descriptions: intervention 1: Participants will be given a single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB) intervention 2: Participants will be given a single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg) intervention 3: Participants will be given one daily dose for 3 days of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)

Protocol documents:
Prot_SAP_001.pdf: 
DOLF_IDA Oncho Safety_Ghana_Protocol v3.1 20 May 2020 
Page 1 of 49 
 
 
Safety and efficacy of combination therapy with ivermectin, 
diethylcarbamazine, and albendazole (IDA) for individuals with 
onchocerciasis 
 
Protocol Identifier: DOLF_IDA Oncho Safety_Ghana 
 
Type: Open label randomized clinical trial 
 
Protocol number: 201910085 
 
NCT #: NCT04188301 
 
 
Principal Investigator: 
Nicholas Opoku, MB, CHB, MSC 1 
 
Co-Principal Investigators: 
Christopher L. King, MD, PhD 2 
Gary J. Weil, MD 3 
Co-Investigators: 
Peter U. Fischer, PhD3 
Catherine Bjerum, MD, MPH2 
Felix Doe, MD, MPH4 
Michael E. Gyasi, MD, MSC 5 
Augustine R. Hong, MD 3 
Eric Kanza, MD6 
Philip J. Budge MD, PhD 3 
 
1 School of Public Health, University of Health and Allied Sciences, Hohoe, Ghana 
2 Center for Global Health & Diseases, Case Western Reserve University, USA 
3 Washington University School of Medicine, St Louis, USA 
4 Municipal Health Directorate, Hohoe, Ghana 
5 St. Thomas Eye Hospital, Accra, Ghana 
6 Université Catholique du Graben 
 
Initial Protocol: v3.0, 28 JUNE 2019 
Current Protocol: v3.1, 21 MAY 2020 


DOLF_IDA Oncho Safety_Ghana_Protocol v3.1 20 May 2020 
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Summary of Changes from Previous Version: 
 
Affected Section (s) 
Summary of Revisions Made 
Rationale 
5.5 
Section was added to describe 
modified procedures and 
potential risks to participants 
in conducting trial during 
COVID-19 pandemic 
These additions to the protocol 
describe in detail the 
modifications being made to 
protect participant safety 
during the COVID-19 
pandemic. No changes are 
being made to the actual study 
design of the trial. 


DOLF_IDA Oncho Safety_Ghana_Protocol v3.1 20 May 2020 
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Version: 3.1 Statement of Compliance 
Safety and efficacy of combination therapy with ivermectin, diethylcarbamazine, and 
albendazole (IDA) for individuals with onchocerciasis 
 
DOLF_IDA Oncho Safety_Ghana v[3.1] [20/MAY/2020] 
 
PACTR Registration Number: PACTR201906665550709 
 
This study will be carried out in accordance with Good Clinical Practice (GCP) as required by the: 
• U.S. Code of Federal Regulations applicable to clinical studies (45 CFR 46) 
https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46 
• ICH GCP E6 Completion of Human Subjects Protection Training 
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-148.html 
• Guidelines for Good Clinical Practice in Ghana 
https://fdaghana.gov.gh/index.php/clinical-trials-department/ 
• Bill and Melinda Gates Foundation “grant agreement” terms and conditions 
 
SIGNATURES 
I have read the protocol, including the appendices, and I agree that it contains all necessary details 
for me and my staff to conduct this study as described. I agree that this study will be conducted 
according to all stipulations of the protocol, including all statements regarding confidentiality and 
according to local legal and regulatory requirements and to the principles outlined in applicable 
U.S. federal regulations, Ghanaian and ICH guidelines. 
 
I will provide all study personnel participating in the study under my supervision copies of the 
protocol and access to all study related information provided by the DOLF project. I will discuss 
with them to ensure they are fully informed about the study procedures. 
 
 
 
 
 
Principal Investigator:  
Name/Title (Print/Type) 
Signed: 
Date: 
 
 
 
NOTE: The PI and co-PIs should have signed investigator agreements on file. 


DOLF_IDA Oncho Safety_Ghana_Protocol v3.1 20 May 2020 
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Table of Contents 
Key Study Contacts ..................................................................................................................................... 7 
List of Abbreviations .................................................................................................................................. 9 
1 
PROTOCOL SUMMARY .................................................................................................................... 11 
2 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ............................................ 12 
2.1 
Background .............................................................................................................................................. 12 
Ocular disease associated onchocerciasis and exacerbation with treatment ............................................ 12 
2.2 
Literature Review .................................................................................................................................. 13 
Prior treatments for onchocerciasis using diethylcarbamazine and ivermectin ..................................... 14 
2.3 Problem Statement ....................................................................................................................................... 15 
Better treatment is needed to eliminate Onchocerciasis ................................................................................... 15 
Triple drug treatment for elimination of Lymphatic Filariasis in Africa ..................................................... 16 
Gaps in knowledge about onchocercal eye disease .............................................................................................. 16 
New technology to better understand onchocercal ocular disease ............................................................... 16 
3 
HYPOTHESES ...................................................................................................................................... 17 
4 
STUDY OBJECTIVES AND PURPOSE ............................................................................................ 17 
4.1 
Study Design ............................................................................................................................................ 19 
4.2 
Inclusion and Exclusion Criteria ....................................................................................................... 19 
Inclusion Criteria ................................................................................................................................................................ 19 
Exclusion Criteria..................................................................................................................................... 20 
4.3 
Participant Exclusion from Routine MDA ...................................................................................... 21 
4.4 
Randomization ........................................................................................................................................ 21 
4.5 
Treatment masking ............................................................................................................................... 22 
4.6 
Study Procedures ................................................................................................................................... 22 
Parasitological Evaluations ............................................................................................................................................ 23 
Nodulectomies .......................................................................................................................................... 23 
Wound treatment for Nodulectomy ........................................................................................................................... 24 
Ocular Examinations: ........................................................................................................................................................ 24 
General health examination and skin evaluation. ................................................................................................. 25 
4.7 
Participant Treatment .......................................................................................................................... 25 
4.7.1 
Plan for Re-dosing .............................................................................................................................................. 26 
4.7.2 
Concomitant Medications ............................................................................................................................... 26 
4.8 
Assessment of Adult Filarial Worms ............................................................................................... 26 
4.9 
Study Duration and Timeline ............................................................................................................. 27 
4.10 
Investigational Product Supply and Storage ................................................................................ 28 
5 
POTENTIAL RISKS AND BENEFITS .............................................................................................. 28 
5.1 
Risks of Skin Snips: ................................................................................................................................ 28 
5.2 
Risk of ocular exams ............................................................................................................................. 28 
5.3 
Risk of study medications: .................................................................................................................. 29 
5.4 
Risks of nodulectomy ............................................................................................................................ 30 
5.5 Conducting the trial during the Covid-19 pandemic ........................................................................ 30 
5.6 
Study Benefits .......................................................................................................................................... 31 
Benefits to Individuals ..................................................................................................................................................... 31 
Public health benefit ......................................................................................................................................................... 31 
5.7 
Study Compensation ............................................................................................................................. 32 
Compensation for Loss of Earnings ............................................................................................................................ 32 


DOLF_IDA Oncho Safety_Ghana_Protocol v3.1 20 May 2020 
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Compensation for Research Related Injuries.......................................................................................................... 32 
6 
INSTRUCTIONS FOR SPECIMEN PREPARATION, HANDLING, AND STORAGE ............... 32 
6.1 
Specimen and Sample Handling ........................................................................................................ 32 
6.2 
Specimen Shipment ............................................................................................................................... 32 
7 
SAFETY REPORTING AND SAFETY MONITORING .................................................................. 33 
7.1 
Definitions ................................................................................................................................................ 33 
Adverse Events (AEs) ....................................................................................................................................................... 33 
Ocular Adverse Events (OAEs) ..................................................................................................................................... 33 
Serious Adverse Event (SAE) ........................................................................................................................................ 34 
Ocular SAEs ........................................................................................................................................................................... 34 
Unexpected ........................................................................................................................................................................... 34 
Expedited Safety Report .................................................................................................................................................. 34 
7.2 
Assessment of Adverse Events .......................................................................................................... 34 
7.3 
Serious Adverse Event (SAE) Assessment and Management .................................................. 35 
7.4 
Reporting of Pregnancy ....................................................................................................................... 35 
7.5 
Data Safety Monitoring Board ........................................................................................................... 36 
7.6 
Interim Analyses .................................................................................................................................... 36 
7.7 
Procedures for Pausing the Trial ..................................................................................................... 36 
8 
STATISTICAL CONSIDERATIONS .................................................................................................. 37 
8.1 
Sample Size Determination (Power calculation) ........................................................................ 37 
8.2 
Data Analysis Plan ................................................................................................................................. 37 
Efficacy analysis for primary outcome ...................................................................................................................... 37 
Efficacy analysis for secondary outcomes ................................................................................................................ 38 
Safety ....................................................................................................................................................................................... 38 
8.3 
Interim and Final Reports ................................................................................................................... 38 
9 
DATA HANDLING ............................................................................................................................... 39 
9.1 
Types of Data Collected ........................................................................................................................ 39 
Enrollment Data .................................................................................................................................................................. 39 
Laboratory Results ............................................................................................................................................................ 39 
Participant Monitoring and Follow-up ...................................................................................................................... 40 
Adverse Event Evaluation ............................................................................................................................................... 40 
9.2 
Study Records Retention ..................................................................................................................... 40 
9.3 
Participant Key/Participant List ....................................................................................................... 40 
9.4 
Source Documents ................................................................................................................................. 40 
10 FUTURE USE OF STORED SPECIMENS ........................................................................................ 41 
11 ETHICAL ISSUES ................................................................................................................................ 41 
11.1 
Informed Consent Process .................................................................................................................. 41 
11.2 
Comprehension of Informed Consent ............................................................................................. 41 
11.3 
Provisions for Subjects from Vulnerable Populations .............................................................. 42 
Plan to avoid treating pregnant women. .................................................................................................................. 42 
Plan for Inclusion of Illiterate Subjects ..................................................................................................................... 42 
Plan for Inclusion of Non-English Speaking Individuals .................................................................................... 42 
Minors ..................................................................................................................................................................................... 43 
11.4 
Alternatives to participation .............................................................................................................. 43 
11.5 
Withdrawal ............................................................................................................................................... 43 
11.6 
Participant Privacy ................................................................................................................................ 43 
11.7 
Plan for Subjects at the End of the Protocol .................................................................................. 44 


DOLF_IDA Oncho Safety_Ghana_Protocol v3.1 20 May 2020 
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12 RESPONSIBILITIES ............................................................................................................................ 44 
12.1 
Good Clinical Practice ........................................................................................................................... 44 
12.2 
Clinical Trial Monitoring ..................................................................................................................... 44 
12.3 
Institutional Review Board (IRB)/Ethics Review Committee (ERC) .................................... 44 
12.4 
Data Ownership ...................................................................................................................................... 45 
12.5 
Financial Disclosure .............................................................................................................................. 45 
12.6 DOLF Team Technical Support .............................................................................................................. 45 
13 LITERATURE REFERENCES ............................................................................................................ 45 
14 APPENDICES ....................................................................................................................................... 49 


DOLF_IDA Oncho Safety_Ghana_Protocol v3.1 20 May 2020 
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Key Study Contacts 
Principal Investigator: 
Nicholas Opoku, MB, CHB, MSC 
University of Health and Allied Sciences 
Hohoe, Ghana 
+233 244776668 
noopoku@uhas.edu.gh 
 
Co-Principal Investigators: 
Christopher L. King, MD, PhD 
Case Western Reserve University 
Center for Global Health and Diseases 
10900 Euclid Ave LC: 4983 
Cleveland, OH 44106 
+1 216-368-4817 
cxk21@case.edu 
 
Gary J. Weil, MD 
Washington University School of Medicine 
4444 Forest Park, Ste. 2212 
St. Louis, MO 63110 
+1 314-454-7787 
gary.j.weil@wustl.edu 
 
Co-Investigators: 
Peter U. Fischer, PhD 
Washington University School of Medicine 
4444 Forest Park, Ste. 2212 
St. Louis, MO 63110 
+1 314-454-7876 
pufischer@wustl.edu 
 
Catherine Bjerum, MD, MPH 
Case Western Reserve University 
Center for Global Health and Diseases 
10900 Euclid Ave LC: 4983 
Cleveland, OH 44106 
+1 602-828-1669 
cmbjerum@msn.com 
 
 
 
Felix Doe, MD, MPH 
Municipal Health Directorate 
PO Box 27 
Hohoe, Ghana 
+233 2445118342 
felixdoe@yahoo.co.uk 
 
Michael Gyasi, MD, MSC 
St. Thomas Eye Hospital, 
Accra, Ghana 
+233 246866580 
mikegyasi67@gmail.com 
 
Augustine R. Hong, MD 
660 South Euclid Avenue 
Campus Box 8096 
Saint Louis, MO 63110 
+1 314-362-3937 
ahong22@wustl.edu 
 
Eric Kanza, MD 
Centre de Recherche Clinique de Butembo 
(CRCB) 
Université Catholique du Graben (UCG) 
Butembo, Democratic Republic of the Congo 
+243 998 30 93 53 / +243 81 21 12 695 
kanzaeric@gmail.com 
 
 
Philip J. Budge MD, PhD 
Washington University School of Medicine 
4444 Forest Park, Ste. 2212 
St. Louis, MO 63110 
+1 314-747-5532 
pbudge@dom.wustl.edu 
 
Pharmacists: 
Lipe Johnson Gavu 
Hohoe Municipal Hospital 
Hohoe, Ghana 
+233 (20) 1230177 LipeGavu@GMail.com. 
 
Local Medical Monitor 


DOLF_IDA Oncho Safety_Ghana_Protocol v3.1 20 May 2020 
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Emmanuel Senyo Kasu, MB ChB, MPH, 
Head, Public Health Dept. 
Volta Regional Hospital, Ho, Ghana 
+233 244087676 
eskasu@uhas.edu.gh 
 
Local Study Monitor 
Margaret Williams 
Margan Clinical Research Organization 
67 Eastern Bypass 
Aburi, Ghana 
+233 249 333 809 
mwilliams@margancro.org; 
mywilliams015@gmail.com 
 
Study Sponsor: 
Washington University School of Medicine 
Jennifer Klenke (Contact) 
 
4444 Forest Park, Ste. 2212 
St. Louis, MO 63110 
+1 (314) 286-2112 
jklenke@wustl.edu 
 
 
 
Laboratory: 
Weil Lab 
Washington University in St. Louis 
4444 Forest Park Blvd 
St. Louis MO 63110 
+1(314) 454-7783 


DOLF_IDA Oncho Safety_Ghana_Protocol v3.1 20 May 2020 
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List of Abbreviations 
 
AE 
Adverse Event 
ALB 
Albendazole 
CFR 
Code of Federal Regulations 
CTCAE 
Common Terminology Criteria for Adverse Events 
DEC 
Diethylcarbamazine 
DOLF 
Death to Onchocerciasis and Lymphatic Filariasis 
DSMB 
Data Safety Monitoring Board 
EDC 
Electronic Data Capture System 
ERC 
Ethics Review Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GHS 
Ghana Health Service 
IATA 
International Air Transport Association 
ICH 
International Conference on Harmonisation 
IDA 
Ivermectin, Diethylcarbamazine, and Albendazole 
I/IDA 
IDA following ivermectin pre-treatment 
IRB 
Institutional Review Board 
IVM 
Ivermectin 
LF 
Lymphatic Filariasis 
MDA 
Mass Drug Administration 
Mf 
Microfilaria(e) 
OCRC 
Onchocerciasis Chemotherapy Research Centre 
OCT 
Optical Coherence Tomography 
PI 
Principal Investigator 
POC 
Point of Care 
RPE 
Retinal Pigment Epithelium 


DOLF_IDA Oncho Safety_Ghana_Protocol v3.1 20 May 2020 
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SAE 
Serious Adverse Event 
UHAS 
University of Health and Allied Sciences 
UNID 
Unique Study Identification Number 
VF 
Visual Field 
WHO 
World Health Organization 


DOLF_IDA Oncho Safety_Ghana_Protocol v3.1 20 May 2020 
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1 PROTOCOL SUMMARY 
 
 
 
 
Study Title: 
Safety and efficacy of triple drug therapy for individuals 
infected with Onchocerca volvulus 
Type of Study: 
Open label, randomized clinical trial 
Study Drugs: 
Diethylcarbamazine citrate (DEC) tablets - C16H29N3O8 
Ivermectin tablets - C48H74O14 
Albendazole tablets - C12H15N3O2S 
Population: 
Participants from the study ‘Microfilarial Clearance from the 
Eye and Ocular Changes Associated with Ivermectin Treatment 
in Individuals with Onchocerciasis’ will be invited to participate 
in the study described in this protocol. These participants were 
recruited from the Nkwanta North District in the Volta region of 
Ghana located at the northeastern part of Ghana. The population 
of Nkwanta North District, according to the 2010 Population 
and Housing Census, is 64,553. 
Number of 
Participants: 
Up to 300 eligible participants 
Study Duration 
24 months 
Duration of Participant 
Participation 
Participants will be followed for 18 months after their first 
treatment. 
Primary Objectives: 
Safety: To compare rates and types of severe adverse 
events (grade 3 or higher) that occur within 7 days 
following 1 day or 3 days of triple drug treatment (DEC 
with ivermectin and albendazole; “IDA”) with the 
comparator regimen of 1 day of treatment with 
ivermectin and albendazole in persons with 
onchocerciasis at least six months after pretreatment 
with ivermectin alone (in a preceding study). 
Efficacy: To compare the effect of three treatment 
regimens for killing or sterilizing adult female O. 
volvulus worms based on the percentage of all adult 
female worms in nodules that are alive with embryos in 
the uterus 18 months after treatment. 


DOLF_IDA Oncho Safety_Ghana_Protocol v3.1 20 May 2020 
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Secondary Objectives: 
Safety: 
1. To compare rates of adverse events grade 3 or higher by 
treatment group that occur within 7 days of treatment in 
the subset of participants who have intraocular 
microfilariae just prior to treatment with IDA 
2. To compare rates of ocular adverse events (any grade) 
by treatment group that occur within 3 months of 
treatment with IDA 
Efficacy 
1. To compare the effect of three treatment regimens for 
killing adult female O. volvulus worms based on the 
percentage of all adult female worms in nodules that are 
alive 18 months after treatment with IDA 
2. To compare the effects of three treatment regimens for 
complete clearance of microfilariae from the skin. 3, 12 
and 18 months after treatment with IDA 
3. To compare the effects of three treatment regimens for 
preventing reappearance of microfilariae in the skin at 
12, and 18 months after treatment with IDA. 
 
 
 
2 BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
 
2.1 Background 
 
Ocular disease associated onchocerciasis and exacerbation with treatment 
Onchocerciasis is caused by the filarial nematode Onchocerca volvulus and transmitted by the bite 
of Simulium blackflies that breed in rivers. Larval parasites (Mf) migrate through the skin and can 
cause severe skin and ocular diseases (“river blindness”). The World Health Organization (WHO) 
estimates that at least 25 million people are infected worldwide, affecting mainly 31 countries in 
sub-Saharan Africa, including Ghana 1, 2. Onchocerciasis is the world’s second leading infectious 
cause of blindness. An estimated one million people have been blinded or have severe visual 
impairment due to onchocerciasis 1, 2. Mass drug administration (MDA) with ivermectin for 
onchocerciasis has significantly reduced the burden of infection and associated ocular disease to the 
point where ocular disease is now uncommon in most endemic areas 2, 3. Improved treatments that 
kill or sterilize adult O. volvulus worms would accelerate elimination of the infection. 


DOLF_IDA Oncho Safety_Ghana_Protocol v3.1 20 May 2020 
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2.2 Literature Review 
Ocular pathology related to onchocerciasis was previously more common in savannah areas of West 
Africa and in Central America, and this has been attributed to various factors, such as localization of 
nodules in the upper part of the body, vector species, Mf burden, and parasite strains 4, 5. 
Onchocerciasis is a parasitic worm infection transmitted by Simulium black flies. The flies breed 
near rivers/streams, and biting rates are highest near the breeding sites. The infection is common in 
forested and savannah areas in West Africa that are drained by fast flowing rivers and streams. 
Ocular pathology (including blindness) was previously more common in savannah areas. Reasons 
for this are not fully understood, but we provided two references in the text to demonstrate what is 
known 4, 5. 
The actual route of entry of Mf into the eyes is not known, but proposed routes include the sheaths 
of the posterior ciliary arteries and nerves, the blood stream, the bulbar conjunctiva with entry 
through the limbus, and along the orbital septum and the cheek ligaments 6, 7, 8. The most common 
ocular lesion involves the cornea, that begins with “fluffy” or “snow-flake” stromal opacities (i.e., 
punctate keratitis), which later coalesce with fibrosis (i.e., sclerosing keratitis). The anterior 
chamber can be invaded by Mf, and death of Mf can be associated with uveitis with formation of 
synechiae, cataract and glaucoma. The lesions in the posterior segment of the eye include atrophy of 
the retinal pigment epithelium (RPE), choroidoretinal scarring, subretinal fibrosis and optical 
neuritis and post-neuritic optical atrophy which can be associated with permanent visual loss 9, 10. 
The main pathological changes seen in the posterior chamber of the eye are related to local invasion 
and host reactions to death of Mf within the retinal tissue. Some researchers have hypothesized that 
cross-reactive antibodies induced by O. volvulus antigens (Ov39) and the RPE antigen (hr44) may 
contribute to posterior segment diseases 11, 12, 13, 14, 15, 16. Indeed there is evidence of persistent ocular 
deterioration in subjects even following clearance of Mf from the anterior chamber of the eye 17, or 
after years of repeated IVM treatment 18. Whether these late ocular changes are a) the result of 
autoimmune responses, b) persistence of Mf or their products in the posterior chamber, or c) a 
parasite-independent disease progression is unknown. This is partly due to limitations in technology 
available to assess the retina when these studies were performed. New methods are now available 
to better assess the posterior chamber of the eye. Such techniques have not been previously used to 
study ocular pathology in subjects with onchocerciasis (see below). 
Onchocercal ocular disease has decreased dramatically with widespread use of IVM. Because IVM 
alone has no permanent effect on the adult worms and adult worms can live up to 15 years, the use 
of IVM alone for onchocerciasis elimination has only been successful in areas with low 
transmission, and/or in geographically isolated areas such as in the Americas 19, Senegal and Mali 20 
or Northern Sudan 21. However, there also examples where 15 or more rounds of IVM were not 
sufficient to interrupt transmission 22, 23, 24. There is an urgent need to find new drugs or novel 
combinations of existing drugs that can partially or completely sterilize/kill adult worms for 
elimination of onchocerciasis in Africa to occur 25, 26. Studies of new treatments should use the best 
available methods to assess potential ocular adverse events following treatment. 
The prevalence of Mf in the eye is correlated with microfiladermia levels and overall community 
prevalence of onchocerciasis 6, 7, 8, 27. Intraocular Mf are uncommon in persons who live in areas 
with microfiladermia rates below 20%, and they are uncommon in persons with <10 Mf/mg skin. 
Additionally, high intraocular Mf counts are not always associated with high rates of eye disease. 
For example, 44% of examined individuals in a hyper-endemic focus in Western Uganda had Mf in 
the anterior chamber, but sclerosing keratitis and vision loss were uncommon5. 


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Prior treatments for onchocerciasis using diethylcarbamazine and ivermectin 
The use of DEC and its associated adverse events in individuals with heavy infections with 
oncherciasis was recently reviewed by the study team26. The discussion below summarizes some 
key points from that publication. Prior to 1987, an 8 to 14 day course of diethylcarbamazine (DEC) 
was commonly used to treat onchocerciasis. DEC was an effective microfilaricide, but it 
occasionally was associated with the development of severe inflammatory responses—both 
systemic and dermal—caused by the death of Mf. This is referred to as a Mazzotti reaction. DEC 
also caused adverse events in the eye, with punctate and sclerosing keratitis, limbitis, anterior 
uveitis, and chorioretinitis. It sometimes caused optic neuritis with edema and visual impairment in 
individuals with heavy O. volvulus infection who received high doses of the drug for prolonged 
periods 9, 28. 
During the 1980’s a single dose of IVM was shown to be more effective than DEC for clearing the 
Mf from the skin with minimal ocular adverse effects 29, and it has been the treatment of choice 
since that time. IVM reduces O. volvulus Mf numbers in skin within a few days with a nadir of skin 
Mf between 1 and 3 months post-treatment. Mf may reappear in the skin as early as 3 months post- 
treatment 30. Mf clearance from the eye following IVM treatment is slower by several months than 
clearance observed in the skin 6, 31. The nadir of Mf clearance from the anterior chamber of the eye 
starts 6 months post-treatment based on unpublished results from heavily infected subjects in the 
Volta region of Ghana with ocular Mf (Table 1), and that reduction persisted out to 18 months after 
treatment 32. 
Table 1. Kinetics of Mf clearance from the anterior chamber of the eye following IVM treatment 
Visit 
(Days/months post 
IVM 150 mcg/kg 
treatment) 
Subjects with ≥ 1 Mf in the 
anterior chamber of both eyes 
before and following a single 
dose of IVM 
n/N (%) 
Day 0 (pretreatment) 
205/205 (100) 
Day 3 
145/174 (83.3) 
Day 4 
21/23 (91.3) 
Month 1 
90/201 (44.8) 
Month 6 
14/200 (7.0) 
Month 12 
16/195 (8.2) 
Month 18 
13/160 (8.1) 
 
The clearance of Mf from the posterior chamber of the eye is poorly understood because it is more 
difficult to visualize this part of the eye. Several studies have shown that anterior segment lesions 
such as punctuate keratitis, sclerosing keratitis, iridocyclitis improved after IVM 33, 34, but there are 
conflicting data about the effectiveness of IVM for improving vision or preventing visual loss 
related to posterior segment lesions. 
The Fischer et al. review also discussed the possibility for re-introducing DEC in combination with 
ivermectin and albendazole, referred to as IDA for treatment of onchocerciasis 26. The reason for 
this is that IDA has been found to be much more efficacious for treatment of lymphatic filariasis 
(LF) 35. This study along with a large multicenter safety study (manuscript development in progress) 
resulted in the World Health Organization changing its guidelines to recommend IDA for LF 
outside Africa 36. Based on this recommendation Merck Sharp & Dohme Inc agreed to increase 


DOLF_IDA Oncho Safety_Ghana_Protocol v3.1 20 May 2020 
Page 15 of 49 
 
their donation of ivermectin by 100 million doses per year for use of IDA in MDA programs for LF 
outside of sub-Saharan Africa 37. LF is often co-endemic with onchocerciasis in sub-Saharan 
Africa. This raises the important question of whether IDA can be safely used for LF elimination in 
coendemic areas. We hypothesize that IDA will be safe for use in persons with onchocericasis if 
dermal and ocular Mf are cleared or greatly reduced by pretreatment with ivermectin alone 
Many studies have examined Mf clearance from the skin after IVM treatment and these have been 
summarized in a meta-analysis 38. These results show microfilaridermia are reduced by half after 24 
h, by 85% after 72 h, by 94% after 1 week, and by 98-99% after 1-2 months . Mf reappear in the 
skin as early as 3 months post-treatment 38. 
Ocular Mf in the anterior chamber of the eye can be readily observed with a slit lamp. Using slit 
lamp examination Mf clearance from the eye following ivermectin treatment lags that observed in 
the skin by several months, but most treated subjects completely clear Mf from their eyes by three 
or six months after treatment 6, 33, 34. This was highlighted in a recent study where individuals with 
>10 Mf in the anterior chamber and treated with a single dose of 150 ug/kg of ivermectin and 
examined at 4 day, 1, 6, 12 and 18 months post-treatment show that Mf reached a nadir in mean Mf 
numbers in the anterior chamber at 6 months with little increase at 12 and 18 months 39. Mean 
percent reduction in Mf in the anterior chamber was 97±12%, N=74 at 12 months 39. Among the 
few individuals that failed to clear ocular Mf in anterior chamber, almost all ocular Mf were 
immobile and probably dead. 
A few older studies describe lesions associated with Mf in the posterior segment of the eye 9, 33, 40, 
41, which are though to cause most of the irreversible causes of visual loss. These changes primarily 
involved optic nerve disease and choroido-retinal changes, particularly retinal atrophy. However, 
Mf were rarely observed in the posterior segment of eye, even among individuals with high levels 
of microfiladermia. Several studies have shown that IVM may improve anterior segment lesions 
such as punctuate keratitis, sclerosing keratitis, iridocyclitis 33, but there are conflicting data about 
the effectiveness in preventing visual loss from posterior segment lesions 18. The current study will 
examine whether IDA, which includes DEC, can be safetly used following a pretreatment dose of 
IVM to reduce Mf in the eye. 
 
2.3 Problem Statement 
 
Better treatment is needed to eliminate Onchocerciasis 
Programs for control of onchocerciasis through community directed treatment with IVM as a form 
of MDA have been in place for almost 30 years. IVM is effective for clearing Mf and it temporarily 
sterilizes adult female worms, but it is not a microfilaricide and does not kill adult worms. For that 
reason, MDA with ivermectin must be repeated for the reproductive life of the adult worms, which 
is 10-15 years. Thus, there is a widely recognized need for drug(s) that can kill or permanently 
sterilize adult worms. A new, safe, short-course treatment that kills or sterilizes adult worms would 
be a breakthrough that could accelerate onchocerciasis elimination in Africa. 
The enhanced activity of IDA against filarial worms that cause LF suggests that this combination 
should be tested against O. volvulus. However, a single dose of IDA may be insufficient to 
kill/sterilize adult O. volvulus. Therefore, it is important to initially test the impact of a short multi- 
dose regimen of IDA. Three days of treatment would approach the practical limit for an MDA 
regimen. 


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Triple drug treatment for elimination of Lymphatic Filariasis in Africa 
Recent studies have shown that a single co-administered dose of IVM, DEC and ALB (IDA) is far 
superior for long-term reduction and elimination of blood Mf of human lymphatic filariasis (LF) 
compared to the standard treatment of a) IVM and ALB or b) DEC and ALB, indicating permanent 
sterilization of adult worms. This combination therapy should require only one or two annual rounds 
of MDA to interrupt transmission (with high compliance) in areas with moderate endemicity, while 
five or more rounds are required with prior 2-drug regimens. WHO has recently recommended use 
of IDA for LF elimination in regions that are not coendemic for onchocerciasis or loiasis and that 
are not currently on track to eliminate LF by 2020 (e.g. Madagascar, Zimbabwe). However, these 
countries represent only 10% of the population at risk for LF in the AFRO region. If IDA can be 
safely used in persons with onchocerciasis after pretreatment with IVM, it could be very useful for 
eliminating LF in countries that are coendemic for LF and onchocerciasis even if the combination is 
not effective for killing or sterilizing adult O. volvulus worms. While this study is not powered to 
demonstrate safety of IDA in persons with onchocerciasis, it will provide preliminary safety data 
that could lead to larger safety studies later. 
The WHO does not currently recommend use of IDA in areas with co-endemic LF and 
onchocerciasis. That is because one of the medicines in the IDA combination (diethylcarbamazine, 
also known as DEC) can cause severe/serious ocular adverse events in persons with high intensity 
infections with Mf in the eyes. Ivermectin pre-treatment (required for inclusion in this study) will 
reduce or completely clear Mf from the eyes of participants before they are treated with IDA in this 
study. Thus, pre-treatment should make it safe for participants to be treated with IDA. That would 
lead to accelerated elimination of LF in Africa, and IDA may also be better than currently available 
treatments used for elimination of onchocerciasis. 
 
Gaps in knowledge about onchocercal eye disease 
Although O. volvulus Mf can be readily observed in the anterior segment of eye using a slit lamp, it 
is challenging to visualize them in the posterior segment by previously used methods such as fundus 
photography, fluorescein angiography or indirect ophthalmoscopy. It is very uncommon for Mf to 
be in the posterior segment if the anterior chamber is clear. It is widely accepted among 
onchocerciasis researchers that the risk of ocular adverse events following DEC treatment is 
believed to be related to the number of Mf in the eye prior to treatment. Ophthalmologists believe 
that significant ocular adverse events (AEs) are very unlikely to occur if few Mf are present in the 
anterior chamber (Todd Margolis, Department Chairman of Ophthalmology at Washington 
University in St. Louis; Hugh Taylor, onchocerciasis expert and Professor of Ophthalmology, 
University of Melbourne, Australia; Yankum Dadzie, a retired Ghanaian ophthalmologist and 
former Director of the WHO Onchocerciasis Control Programme). 
 
New technology to better understand onchocercal ocular disease 
The methods currently available to evaluate ocular disease in patients with onchocerciasis include 
slit lamp, direct and indirect ophthalmoscopy, fundus photography, and fluorescein angiography. 
The latter test requires intravenous injection of a dye that sometimes causes acute adverse events (1 
– 9%) that can include nausea, vomiting, allergic reactions, and (rarely) hypertensive crisis or 
myocardial infarction. Slit lamp examination is useful for demonstrating the presence of Mf in the 
anterior segment of the eye, including the cornea and anterior chamber, and in the vitreous, and for 
evaluating the presence and severity of intraocular lesions. Optical coherence tomography (OCT) is 


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the current method of choice for detailed assessment of the posterior segment and retina for many 
ocular diseases. It is a rapid, simple, precise and non-invasive imaging method that uses low 
intensity laser light to capture three-dimensional images of both the anterior and posterior segments 
of the eye with micrometer-resolution 42. OCT examinations are safe and they only require a few 
minutes. OCT has not been used previously in patients with onchocerciasis. It should allow 
examiners to visualize Mf in eye in the visual axis of the eye, particularly the posterior segment, and 
to evaluate retinal anatomy in a way that is superior to fluorescein angiography with no risk of 
adverse events. 
OCT is not a new technology. It has been used to evaluate the posterior segment of the eye for more 
than 20 years, and several centers in Ghana have OCT machines. However, since most 
ophthalmological studies of onchocerciasis were performed prior to development of OCT, this will 
be the first study to use of OCT in patients with onchocerciasis. OCT is less invasive and provides a 
more detailed assessment of retinal anatomy than fluorescein angiography, which was used in past 
studies of posterior segment disease related to onchocerciasis. OCT is the state of the art, and it is 
appropriate that we use it in this study to carefully assess potential adverse events following 
treatment. 
The slit lamp is better for assessing the anterior segment of the eye, and OCT is superior for the 
posterior segment. These are complementary tools, and both will be used in this study for every eye 
examination. Ocular exams will occur the day prior to treatment, on Day 3 after treatment (during 
the 7 day observation period), and on Day 7 of the observation period. 
 
3 HYPOTHESES 
1. Triple drug therapy with ivermectin, diethylcarbamazine and albendazole (IDA) (following 
ivermectin pretreatment) is more effective for killing or sterilizing adult female O. volvulus 
worms than ivermectin plus albendazole. 
2. Triple drug therapy with ivermectin, diethylcarbamazine, and albendazole (following 
ivermectin pretreatment) is as safe as IVM/ALB alone in persons with onchocerciasis. 
 
4 STUDY OBJECTIVES AND PURPOSE 
This study will provide preliminary data on the safety of IDA treatment in persons with 
onchocerciasis when it is administered after pre-treatment with IVM to clear or greatly reduce 
microfilariae from the skin and eyes. Widespread use of IDA following IVM pretreatment (I/IDA) 
has the potential to greatly accelerate elimination of LF in African countries that are coendemic for 
LF and onchocerciasis. 
 
Note that the sample sizes per treatment group in this study are not sufficient to conclusively 
demonstrate that IDA after IVM pretreatment is safe enough for widespread use in communities. 
Therefore, the safety study should be considered to be exploratory, and larger studies would be 
needed to formally establish safety of a pretreat/treat strategy with ivermectin followed by IDA 
(“I/IDA”). Having said that, a small exploratory safety study like this is an appropriate first step, 
because it should generate sufficient data to justify (or rule out) performance of a larger safety 
study later. 


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This study will also assess the efficacy of IDA for killing and sterilizing adult filarial worms. An 
improved macrofilaricidal treatment would be a major advance for the global program to eliminate 
onchocerciasis. Since the safety and efficacy objectives are both very important, we have included 
dual primary objectives for the study. 
 
 
Primary Objectives: 
Safety: To compare rates and types of severe adverse events 
(grade 3 or higher) that occur within 7 days following 1 day or 3 
days of treatment with triple drug treatment (“IDA” = DEC with 
ivermectin and albendazole) with the comparator regimen of 1 
day of treatment with ivermectin and albendazole (IA) in 
persons with active Onchocerca volvulus infections after 
pretreatment with ivermectin alone. 
Efficacy: To compare the effect of three treatment regimens (1 
day of IDA, 3 days of IDA, or IA) for killing or sterilizing adult 
female O. volvulus worms based on the percentage of all adult 
female worms in nodules that are alive with embryos in the 
uterus 18 months after treatment. 
Secondary Objectives: 
Safety: 
1. To compare rates of adverse events grade 3 or higher by 
treatment group that occur within 7 days of treatment in 
the subset of participants who have intraocular 
microfilariae just prior to treatment with IDA to those 
who do not have intraocular microfilariae 
2. To compare rates of ocular adverse events (any grade) 
by treatment group that occur within 3 months of 
treatment with IDA 
Efficacy 
1. To compare the effect of three treatment regimens for 
killing adult female O. volvulus worms based on the 
percentage of all adult female worms in nodules that are 
alive 18 months after treatment. 
2. To compare the effects of three treatment regimens for 
complete clearance of microfilariae from skin snips 3, 12 
and 18 months after treatment with IDA. 
3. To compare the effects of three treatment regimens for 
preventing reappearance of microfilariae in the skin at 
12, and 18 months after treatment with IDA. 


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4.1 Study Design 
This is an open label, randomized clinical trial will be conducted in Ghana. The goal will be to 
enroll up to 300 eligible participants with microfiladermia. Some participants who have met the 
inclusion criteria (see Study Enrollment, below) will have intraocular Mf visible by slit lamp at 
baseline prior to IVM pre-treatment. Participants will be recruited from an on-going related study 
that is evaluating the kinetics of Mf clearance from the eye and skin after treatment with IVM. 
Participants will be treated with ivermectin at baseline in this study and then randomized into three 
treatment arms 6 months (with a window of 5.5 months to 12 months) after treatment with IVM: 
1. IVM with albendazole (the comparator) 
2. Asingle dose of IDA 
3. Three daily doses of IDA 
Each arm will be stratified with respect to the presence ocular Mf six months after their first IVM 
pre-treatment (i.e. in “Part I”, a precedingstudy) or at the baseline assessment in the Part II study. 
Participants will be closely monitored to determine whether the treatments are safe. Efficacy will be 
assessed by performing skin snips for detection of Mf and by histological examination of adult 
worms in onchocercal nodules surgically removed 18 months after treatment with IDA. 
All participants will be treated again with ivermectin at the time of consenting for the Part II study 
to further ensure that they have low skin and ocular Mf counts at the time of enrollment and 
randomization to treatment arms. Treatment with ivermectin is widely accepted as a standard of care 
for MDA programs, and should not present undo risk. 
Study Enrollment 
Participants will be recruited from an on-going related study of the kinetics of Mf clearance from 
skin and eyes after ivermectin treatment (Part I). Participants from that study with baseline skin Mf 
counts > 3 Mf/mg will be invited to participate in this “Part II” study. 
Study Population - Participants will be recruited from the Nkwanta North and South Districts in the 
Volta region of Ghana. Most participants will be recruited from Kpassa town or villages in Kpassa 
sub-district along the Kpassa river basin that are endemic for onchocerciasis. Residents are mainly 
of the Konkomba ethnic group. The local language is Konkomba, however most residents also 
speak and understand the Twi language. Bi-annual MDA with IVM in the area started in October 
2017. The target number of participants for the study will be up to 300. 
 
4.2 Inclusion and Exclusion Criteria 
 
Inclusion Criteria 
1. Men and women 16 – 70 years (at the time of enrollment; ±2 years) of age previously 
enrolled in the Part 1 study and residing in the area of the study. 
2. Participants must have at least 1 palpable subcutaneous nodule (onchocercoma). 
3. Participants with baseline skin Mf counts ≥ 3Mf/mg at the time of enrollment into the Part 1 
study (Part I, see above). 


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Exclusion Criteria 
1. Pregnant and breastfeeding mothers within 1 month of giving birth 
2. Severe eye disease at baseline including uveitis, severe glaucoma, , severe keratitis, and/or 
cataracts that interfere with visualization of the posterior segment of the eye as well as the 
list of ocular diseases as outlined below Individuals who are excluded with significant 
ocular disease will be referred to appropriate ophthalmological care in a health facility (the 
district hospital) or the any other health facility in Ghana, where affected subjects will obtain 
appropriate care (University hospital or private ophthalmologist). All ocular disease 
exclusion criteria apply to either eye. Bilateral disease is not necessary to exclude a 
participant. A participant will be excluded if any of the criteria are met for one eye. 
a. Any cataract of any type preventing clear visualization of fundus or imaging on 
Optical Coherence Tomography (OCT). 
b. Severe retinal nerve fiber layer thinning in the superior and inferior quadrant analysis 
on Ocular Coherence Tomography of the optic nerve with a corresponding visual 
field defect of grade 2 or worse on the same eye. 
i. If Ocular Coherence Tomography is not available, the following exclusion 
criteria will apply: vertical Cup/disc ratio on fundoscopy (not by OCT 
reading) greater than or equal to 0.80. 
c. Intraocular pressure (IOP) greater than or equal to 25 by Goldmann tonometry .12 
d. Retinal Detachment or Retinal Break 
e. Acute ocular infection (i.e., Viral conjunctivitis, corneal ulcer, endophthalmitis) 
f. Optic Atrophy with visual field defect reproducible on confrontation visual field 
testing.. 
g. Exam consistent with Herpes Simplex Virus eye infection 
h. Homonymous hemianopsia, quadrantopsia, bitemporal hemianopsia, or central 
scotoma related to cerebral vascular disease by Automated Visual Field testing and 
confrontation visual field testing. 
i. Acute Angle Closure Glaucoma 
j. Gonioscopy grade 0 (slit) limiting ability to safely dilate patient 
k. Severe Tremor, blepharospasm, or other voluntary or involuntary motor condition 
that prevents ability to examine patient with slit lamp, OCT, gonioscopy, IOP 
measurement, fundus photography, and Frequency doubling technology perimetry. 
l. Cognitive impairment sufficient to prevent ability to understand and perform Visual 
Acuity Test with Tumbling E chart, confrontation visual field, slit lamp exam, or any 
other ocular exam component. 
m. Optic nerve edema 
n. Active retinopathy or retinitis not attributable to onchocercal disease 
o. History of uveitis not associated with onchocercal disease 
p. Any pre-existing chorioretinal scar or retinal degeneration and other significant 
retinal pathologies (foveomacular schisis, dystrophies, arterial macroaneurysms etc) 
involving the macula. 
q. Severe ocular pain, that patient rates as 9 or 10 out of 10 pain. 
r. Best corrected or pinhole visual acuity worse than 6/60 (20/200) 
s. Age related macular degeneration (AMD) 
3. Significant comorbidities such as renal insufficiency, liver failure, or any other acute or 
chronic illness identified by study clinicians and investigators that interferes with the 
participant’s ability to go to school or work or perform routine household chores. 


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4. Prior allergic / hypersensitivity reactions or intolerance to IVM, albendazole, or DEC. 
5. Treatment with IVM outside of the study after the pre-treatment clearing dose provided in 
the Part I study. 
6. >5 motile Mf in the anterior chamber in either eye at the time of enrollment (after pre- 
treatment with IVM). 
Note: The cut-off of 5 Mf was suggested by external reviewers of our proposal to the Gates 
Foundation. These are experts in onchocerciasis selected by the Foundation. The reviews 
were anonymous, so we do not know their names. They also suggested that we exclude 
persons with any Mf in the posterior segment of the eye, and we have added that exclusion 
criteria that in the protocol. 
7. Any Mf identified in the posterior segment of the eye at the time of enrollment (six months 
after pre-treatment with IVM). 
8. Any other condition identified by study clinicians or investigators that may preclude 
participation in the study. 
 
4.3 Participant Exclusion from Routine MDA 
Participants will be informed that they should not participate in MDA distributed by the Ghana 
Health Service in their communities during this study period. Participants will receive a laminated 
card to identify them as participants in the study (Appendix A). Participants will present these cards 
to community drug distributors. Study investigators will communicate with local health officials 
responsible for MDA to inform them of the study and ensure that they are aware that there are study 
participants who should be excluded from routine MDA for the duration of the study. 
 
4.4 Randomization 
At least six months after treatment with ivermectin (-5.5 months or +12 months) in the preceding 
Part I trial, participants will first be split into two strata – those without ocular Mf detected six 
months after ivermectin pretreatment in the Part I preceding study AND without ocular Mf detected 
at baseline in the part II study will be in stratum 1. Those participants with ocular Mf detected 6 
months after ivermectin pretreatment in the preceding study OR with ocular Mf detected at the 
baseline exam for this study will be in stratum 2. Stratum 1 will be enrolled first, followed by 
stratum 2. This is a safety precaution that will ensure that participants with any Mf in either eye 6 
months after ivermectin pretreatment in the previous study will be the last to be dosed with 
combination drug treatments in this study. The decision to stratify so that persons who might be at 
higher risk are dosed last was based on recommendations from external expert reviewers of our 
grant proposal. 
Members of each stratum will be evenly randomized into one of three treatment arms: 
Stratum 1: Ocular Mf negative by slit lamp six months after ivermectin pretreatment (in 
Part I) AND ocular Mf negative by slit lamp at baseline enrollment 
1. IVM + ALB - Single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB) 
2. IDA x 1 dose - Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg) 
3. IDA x 3 doses -Once daily for 3 days oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB 
(400 mg) 


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Stratum 2: Oular Mf positive 6 months after ivermectin pre-treatment (in Part I) OR ocular 
Mf positive at baseline enrollment (ocular Mf counts by slit lamp greater than 0 but < 5 in 
either eye) 
1. IVM + ALB - Single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB) 
2. IDA x 1 dose - Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg) 
3. IDA x 3 doses -Once daily for 3 days oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB 
(400 mg) 
 
4.5 Treatment masking 
While this is an open label study and there is no placebo treatment group, all efforts will be made to 
ensure that that medical/technical staff assessing skin Mf, AEs and ophthalmological findings will 
be unaware of initial baseline skin and ocular Mf findings and treatment arm as best as possible. 
This is especially important for those performing AE assessments and for persons reviewing nodule 
slides, because the primary objectives depend on those evaluations. A study pharmacist will be 
responsible for managing the randomization assignment list and treating patients accordingly. The 
pharmacist should be the only person at the study site who will know treatment assignments. 
Treatment information will be kept separate from the rest of the participant case report form and 
shared only if required for medical purposes. Efforts will also be made to assure baseline infection 
status is not shared with examiners unless required for medical purposes in the case of severe or 
serious AEs. 
The histologists reading the nodule histology slides will only be provided with histology slides 
identified by a patient number and nodule number. The histologist will have no other information 
about the patient. 
Treatment and baseline infection status will be available to the study sponsor, data analysts, and 
DSMB. The data manager will un-mask the treatment assignment after the last participant has had 
their 3 month post-treatment evaluation. The safety data will then be compared by study arm. That 
will complete the safety study, which is separate from the efficacy study. Persons evaluating nodules 
will be masked regarding Mf counts and treatment assignment to avoid bias. Nodule data will be 
analyzed after the nodule evaluations have been completed. That part of the study is focused on the 
issue of whether IDA is superior to IVM and albendazole alone for killing or sterilizing adult 
worms. 
 
4.6 Study Procedures 
The six-month follow-up parasitological, general health, skin, and ocular examination from the 
preceding Part I study will serve as the baseline for this Part II study. Participants will be housed in 
dormitory-like wards of the University of Health and Allied Sciences School of Public Health 
Research Centre on the Hohoe Municipal Hospital grounds for 7 days following treatment with 
medical supervision. Participants will be fed three times daily. Accommodation, feeding, laundry 
and entertainment will be provided at no cost to participants. 
Participants will be dosed with study medications in the dormitory-like wards of the University of 
Health and Allied Sciences School of Public Health Research Centre on the Hohoe Municipal 
Hospital grounds. Medications will be administered by Study Pharmacist assisted by the study head 
nurse. 


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After treatment participants will be examined daily in the center for any adverse events for 7 days 
before being discharged to their communities. Full ocular examinations will be performed before 
treatment, on day 7 and at 3 months after treatment. Physicians will also obtain medical histories 
and perform physical examinations before treatment and on day 7 after treatment. In addition, any 
participant who reports any change in vision or ocular symptoms between day 7 and 3 months will 
be transported back to the clinical facility for a full ocular examination. Participants will be told to 
report to the study village coordinator if they develop any symptoms. In the event that some 
individuals fail to clear ocular Mf after IVM pretreatment (see Table 1), they will still be eligible for 
enrollment in the study if the number of motile Mf in the anterior chamber of each eye is ≤ 5. 
Individuals with >5 motile Mf in the anterior segment or any Mf observed in the posterior segment 
of the eye will be excluded from the study, and they will be referred for routine treatment with IVM, 
and adult worms will be assessed by standard histological methods for viability and fertility. 
Samples will be collected for later studies of biomarkers of Onchocerca infection. 5ml of peripheral 
venous blood and 10 ml of first void morning urine will be obtained prior to the Part II treatment 
and at 3, 12, and 18 months after treatment. Post-treatment samples will be compared with samples 
collected prior to the Part I IVM clearing dose and with samples collected just prior to treatment in 
this study (Part II). Samples will be stored at the UHAS study site until they are shipped to the USA 
for analysis (see paragraph 6.1). Analysis of samples will take place at the Weil Lab at Washington 
University in St. Louis. Samples will be stored for up to 35 years and then destroyed according to 
regulatory guidelines. 
 
Parasitological Evaluations 
Palpation for subcutaneous Onchocerca nodules: This baseline information will be available from 
the preceding related study, but nodule palpation will also be performed at the time of nodulectomy 
Skin snip testing to detect microfilaria in skin 
Skin snip testing for Mf will be performed at 3, 12 and 18 months. We will obtain four (4) skin snips 
using a corneoscleral punch. Each snip will be weighed on an analytical balance and incubated for 
at least 8 hours in isotonic saline in a well of a flat-bottomed micro-titre plate at ambient 
temperature. Microfilariae will be counted by microscopy. Mf number and skin snip weight will be 
recorded. The mean skin microfilarial density will be calculated and recorded as mf/mg. Skin snips 
will also be preserved for later PCR testing to detect parasite DNA (more sensitive than 
microscopy). 
 
Nodulectomies 
Nodulectomies will be performed at 18 months after IDA treatment. Nodules will be surgically 
excised by Ghanaian study medical officers, under local anesthesia (1% xylocaine) in a specially 
designated room at the University of Health and Allied Sciences School of Public Health Research 
Centre using aseptic procedures. At the final visit at 18 months post-treatment participants will be 
brought to the centre in Hohoe for 2 days for nodulectomies. After the procedure they will then be 
returned to their communities where a study nurse and will be stationed to continue wound 
management. 


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Wound treatment for Nodulectomy 
Wound management will begin with the nodulectomy incision and continued till all wounds are healed. 
Subjects will usually be detained on the ward after surgery for two days or longer. During this period, 
wounds are examined for bleeding, hematoma formation and dehiscence. Subjects will advised to stay 
off work for the first week post surgery to assist in wound healing. Compensation will be paid for loss 
of earnings for the seven (7) days if appropriate. The first change of dressing is done on the first day 
after nodulectomy. On day 10 post-nodulectomy, sutures will be removed. Subsequent dressing 
changes will occur on alternate days until wound is completely healed. Nurses will assist with wound 
care management in the community. This study draws participants from 5 communities, but at any one 
time there will only be participants from 1 or 2 communities who require care for nodulectomy 
wounds. Additionally, cohorts of participants receiving nodulectomies are staggered so that there are 
not more than 20 participants requiring wound care at one time. Two nurses will be available in the 
communities to monitor wound healing and provide wound management and dressing changes as 
needed. 
 
Ocular Examinations: 
The following ocular examinations will be performed by qualified medical personnel at the 
University of Health and Allied Sciences School of Public Health Research Centre in Hohoe: 
1. Visual acuity exam: using a standard Snellen or E chart, individuals will stand or sit 20 feet 
(6 meters) from the chart with both eyes open. They will be asked to cover one eye with the 
palm of the hand (or a small paddle) and read out loud the smallest line of letters that can be 
seen. The test is done in each eye, one at a time. 
2. Visual fields: We will assess visual fields either by confrontational testing and/or by 
automated VF perimetry testing. Both tests are widely used and non-invasive. 
3. Pupillary reflex response testing: This will involve shining a light in one eye and then 
examine pupillary response and the degree of constriction in the illuminated pupil as well 
and consensual response, or the response in the opposite pupil. This test can suggest 
asymmetric optic nerve or retinal disease. 
4. Applanation tonometry: this test measures intraocular pressure. We will apply local 
anesthetic drops approved for use in Ghana in each eye to numb the surface of the eye and 
then apply a fine fluorescein strip to tear film of each eye. The slit lamp is placed in front of 
the individual and the Goldmann tonometer will measure the intraocular pressure. 
5. Slit lamp examination: using a slit lamp, we will evaluate each participant for Mf in the 
anterior chamber of eye (after having the subject position their face downwards for at least 2 
minutes). We will look for the presence of anterior segment and posterior segment disease, 
including but not limited to uveitis, limbitis, cataracts, corneal scarring, optic nerve disease, 
and retinal disease. A 90 Diopter and 78 Diopter lens will be used in conjunction with the slit 
lamp to visualize the fundus (fundoscopy). 
6. Indirect ophthalmoscopy: this fundoscopy examination technique will be optionally 
performed at the discretion of study ophthalmologists and optometrists to evaluate the 
fundus of the eye (posterior segment) particularly for suspected retinal detachment Prior to 
the test, the examiner will apply eye drops approved for use in Ghana to dilate the pupil and 
then use the indirect ophthalmoscope to visualize the different structures in the posterior 
segment of the eye after the pupil is dilated. 


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7. Retinal photography: Flash photography of the retina and optic nerve will be taken to 
document anatomical findings. Black and white and color images will be recorded. Retinal 
photography will be taken with the pupils dilated. Pupils will already have been dilated for 
fundoscopy (see above), and therefore, retinal photography will not require re-dilation of the 
pupil. Faces will not be included in these photographs. 
8. Slit-lamp Photography. Photography of the anterior chamber will be taken whenever 
possible to record presence of microfilariae and anterior segment findings. Short videos will 
also be taken to be record microfilarial motility or immotility. This can be performed prior to 
dilation, and will not require re-dilation of the pupil. Faces will not be included in these 
photographs. 
9. Optical coherence tomography (OCT): this is a non-invasive method that uses low intensity 
laser light to capture micrometer-resolution, three-dimensional images of both the anterior 
and posterior segment of eye. It can visualize the full thickness cross-section of cornea, 
conjunctiva, anterior chamber, iris and retina and optic nerve head. Prior to the test we will 
apply eye drops (1% tropicamide) to dilate the pupil, which will already have been dilated 
for fundoscopy. Then the subject will be positioned in front of the OCT scan, resting the 
head on a support to keep it motionless. The equipment scans the eyes without touching 
them. Scanning takes 5-10 minutes. Because this technology utilizes light waves, media 
opacities such as vitreous hemorrhages, dense cataracts or corneal opacities may interfere 
with an optimal imaging. 
 
General health examination and skin evaluation. 
Each participant will undergo a routine history and physical examination as part of the screening 
process for eligibility that will include vital signs, height, and weight. We will also collect history 
of any past and current medications with a focus on onchocerciasis related skin and/or eye disease 
and any prior treatment for onchocerciasis over the past 6 months 
Skin evaluations will include a careful examination of the skin by a study physician; significant 
abnormalities (grade 2 or higher) present during the baseline examination will be documented by 
photography. Skin survey and records of baseline skin disease with photographs in persons with 
significant abnormalities will be collected in the case report form. Faces will not be included in 
photographs. 
 
4.7 Participant Treatment 
At baseline, participants will be given ivermectin (150 µg/kg) pretreatment. This pretreatment will 
be provided the participants’ villages near their homes following their consenting to participate in 
the study. *Please note, all participants will be treated with ivermectin at baseline to ensure that 
they have low skin and ocular Mf counts at the time of enrollment. (This treatment is in addition to 
the pretreatment with ivermectin given in the Part I study). 
After the baseline treatment with ivermectin alone, participants will be randomly assigned to one of 
the following treatment arms (all oral medications)*: 
I. Ivermectin 150µg/kg plus albendazole (400 mg) 
II. IDA single oral dose 
a. Ivermectin, 150µg/kg 


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b. Diethylcarbamazine citrate, 6 mg/kg 
c. Albendazole, 400 mg 
III. IDA three one time daily oral doses 
a. Ivermectin, 150µg/kg 
b. Diethylcarbamazine citrate, 6 mg/kg 
c. Albendazole, 400 mg 
 
Randomized treatment to one of the three treatment arms will occur in cohorts of up to 20 
individuals. This is based on the project’s capacity for transport, examination, and housing of 
participants. Initial participants will be individuals who had zero Mf in the eyes six months after 
pre-treatment with IVM in Part I and zero Mf in the eyes at baseline for Part II. If IDA proves safe 
in all of these participants,(i.e. if there are no serious or severe adverse events in any participant in 
the first 7 days) the study will continue with participants who had Mf in the anterior chamber in 
either eye six months after IVM pre-treatment in the Part I study or at the baseline exams for this 
study. Study investigators will monitor the safety of the participants in each treatment cohort for 7 
days before dosing the next cohort, and they will suspend the study if any treatment-related serious 
or severe adverse events occur. If SAEs are reported, the DSMB will be asked to review the cases 
and to implement study stopping and pausing guidelines if the SAEs are found to be related to study 
treatments. 
 
4.7.1 Plan for Re-dosing 
Participants who vomit within 30 minutes after dosing will be redosed the same day at least two hours 
after the first attempt. If they vomit the second dose, they will be excluded from the study and 
provided treatment with ivermectin alone the next day. 
 
4.7.2 Concomitant Medications 
Participants will be told to continue to take their regular medications. Additionally, each participant 
will be instructed and provided a study ID card during consenting that indicates that they are 
participants in a clinical trial and should not take ivermectin/Mectizan MDA given by mass drug 
administration (MDA) program or other groups until nodulectomies have been performed at 18 
months.. Each participant will be instructed and provided a study ID card during consenting that 
indicates that they are participants in a clinical trial and should not take ivermectin (or Mectizan) 
provided by a government program or other group until nodulectomies have been performed 18 
months after the Part II treatment. 
 
4.8 Assessment of Adult Filarial Worms 
Some of the primary and some secondary efficacy endpoints for this will be based on histology 
results from examination of nodules collected from participants at the end of the study. 
Nodulectomies will be performed at UHAS School of Public Health Research Centre in Hohoe. The 
nodules will be preserved before being sent to a histology laboratory (location to be decided) for 
embedding, slide preparation, and histological staining. This will include H&E for general 
morphology, APR-immunostain for differentiating dead and life worms43, and Gomori iron stain for 


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worm age assessment. The stained nodule sections will be read by two independent readers. The 
readers will not have access to each other’s results until after they have entered their results. The 
two results will be compared, and the two readers will work together to reconcile any discrepancies. 
A third reader can be used to reconcile discrepancies if the two readers cannot agree. The reconciled 
result will be considered to be the final result. 
 
4.9 Study Duration and Timeline 
Participants will be followed for 18 months after treatment. Participants will be transported to the 
study site at the University of Health and Allied Sciences (UHAS) School of Public Health 
Research Centre in Hohoe, Ghana to complete enrollment and treatment procedures and for 
assessment of adverse events. Participants will be housed at a clinical facility on the municipal 
hospital grounds for 7 days after treatment. Participants will be brought back to the clinical research 
facility in Hohoe 3 months after treatment for 2 days in order to complete ocular re-examinations 
and skin snip testing. Skin snips will be collected 12 months after treatment in the participants’ 
home village. The final visit will occur at 18 months ±60 days when participants are once again 
brought to the clinical facility in Hohoe for 2 days to have skin snip testing and nodulectomies. 
The on-study period per participant is approximately 20 months and it is anticipated that the 
duration of the study will be up to 24 months, including 4 months for recruitment. 
 
 
 
Figure 1. Study overview. Part I examines the kinetics of clearance of Mf from skin and eye 
following IVM treatment as well as Mazzotti reactions and ocular safety of IVM for treatment of 
onchocerciasis (now in progress). Part II examines the safety and efficacy of IDA (current protocol). 
Participants will be recruited from the Part I study into the Part II study, and given a second pre- 
treatment dose of ivermectin, skin snip and eye examinations will be conducted prior to randomization 
and dosing with the investigational combination therapies. 
 
 
The following tolerances will be allowed for flexibility in scheduling participant visits: 
• Day 7 visit ±1 day 
• Month 3 visit ±14 days 


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• Month 12 visits ±30 days 
• Month 18 visit ±60 days 
 
4.10 Investigational Product Supply and Storage 
Drugs used for this protocol will be purchased from manufacturers who donate their product for use 
in the Global Program to Eliminate Lymphatic Filariasis. Alternatively, WHO approved generic 
versions may be purchased. If necessary, import approvals will be requested from the government 
of Ghana. 
Albendazole and IVM are approved for use and widely used in Ghana for lymphatic filariasis and/or 
onchocerciasis control and elimination. However, DEC is a not approved for use in people with 
lymphatic filariasis or onchocerciasis. Thus use of DEC in this study will require approval by 
ethical review committees and by the Ghana FDA. 
Detailed information for each drug is available from the manufacturers and the package inserts are 
included an an appendix to this protocol (Appendix B). 
Investigational products should stored in a secure, locked pharmacy room. In this study all drugs 
will be stored at no greater than 30°C per the package insert. Documentation of tempature logs will 
be done per the study site SOPs. 
 
5 POTENTIAL RISKS AND BENEFITS 
 
5.1 Risks of Skin Snips: 
This procedure is associated with a small risk of bleeding and infection. The skin will be disinfected 
before a snip is taken with a sterile scleral punch. The snip (about 2 mg) will cause a superficial 
wound of the skin at the iliac crests and calves, which will be covered with a plaster for one day. 
These procedures are routine and designed to minimize risks of infection or bleeding. The scar will 
be 2 mm or less in size. 
 
5.2 Risk of ocular exams 
The ophthalmological procedures are routine and associated with minimal risk. The possible risks 
are related to the ocular medications administered during these tests. To perform applanation 
tonometry and slit lamp examinations investigators will apply local anesthetic eye drops approved 
for use in Ghana (e.g lidocaine, proparacaine or tetracaine), which may cause mild local reactions 
such as conjunctival hyperemia and ocular irritation/burning. 
To perform indirect ophthalmoscopy, retinal photography and OCT, investigators will apply eye 
drops to dilate the pupil (e.g. generic tropicamide) which may cause transient blurred vision, 
photophobia, ocular stinging. These eye drops are routinely used in persons undergoing 
ophthalmology examinations. Dilation eye drops will only need to be applied once, and the pupils 
will remain dilated for the remainder of the examination. Rare adverse events include increases in 
intraocular pressure and superficial punctuate keratitis; other uncommon systemic side effects 
include xerostomia, tachycardia, headache, nauseas and vomiting. 


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5.3 Risk of study medications: 
The combinations of IVM plus albendazole or DEC plus albendazole are widely used in MDA 
programs. There also have been 3 clinical trials and extensive safety trials of IDA in 5 countries. A 
published study demonstrated no significant interactions between the three IDA drugs35. The WHO 
has recently recommended use of IDA for LF elimination programs in areas without co-endemic 
onchocerciasis or loiasis that are not currently on track to meet the 2020 deadline 
(http://www.who.int/neglected_diseases/news/WHO_recommends_triple_medicine_therapy_for_LF 
_elimination/en/). Potential risks for each drug separately, with some indication of how likely these 
are to occur, are summarized below. 
Risks of Diethylcarbamazine (DEC): This drug is known to be safe for treatment of LF 
and hundreds of millions of people are treated each year by MDA programs in areas without 
coendemic onchocerciasis or loiasis. Mild to moderate adverse events are seen in persons 
with microfilaremia. The most adverse events are headache, fever, joint pain, unusual 
tiredness or weakness. Less common are dizziness, nausea or vomiting. Persons with 
onchocerciasis often experience pruitis and dermal edema. Ocular AEs in onchocerciasis 
patients that have not received a clearing dose of IVM are described above (see 
Background). 
Risks of Albendazole (ALB): This medication is safe and is provided as MDA to hundreds 
of millions of persons in Africa each year by programs to eliminate LF and onchocerciasis 
and to children in school-based deworming programs. Headache, nausea, stomach pain 
and/or vomiting sometimes occur after treatment, and this tends to be more common in 
persons with heavy STH infections. Severe allergic reactions occur rarely, and these can 
include rash, hives, itching, difficulty breathing, tightness in the chest, swelling of the 
mouth, face, lips, or tongue. Stevens-Johnson syndrome has been reported, but this is very 
rare. Mild, transient elevation in liver transaminases rarely occurs after single dose ALB 
treatment. More severe liver toxicity and leukopenia sometimes occur in persons treated 
with long courses of ALB with doses of 800 mg per day or more. 
Risks of Ivermectin (IVM): This medication is safe and is provided as MDA to more than 
100 million persons in Africa each year by programs to eliminate LF and onchocerciasis. 
The most common side effects are diarrhea, dizziness and nausea. Persons with 
onchocerciasis sometimes experience rash, hives, itching (see Mazzotti reactions, below), 
difficulty breathing, tightness in the chest, swelling of the mouth, face, lips, or tongue; eye 
pain, swelling, or redness. Seizures, fainting, mild decrease in leukocyte counts, elevated 
liver function tests, and cardiovascular effects that included tachycardia and orthostatic 
hypotension have been reported, but these adverse events are rare and not necessarily related 
to IVM treatment. 
Mazzotti Reactions: These AEs are caused by inflammatory and immune reactions to 
microfilariae that are killed by IVM or DEC as described above. Mazzotti reactions need to 
be differentiated from any coincidental illnesses that may occur in temporal relationship 
with IVM treatment. Common systemic clinical manifestations of the Mazzotti reaction 
include pruritus, rash, lymphadenitis, headache, myalgia, arthralgia, hypotension, fever, and 
swelling of the face and limbs. Ocular events include epiphora, photophobia, and 
conjunctival injection. The factors that govern the Mazzotti reaction include the intensity of 
infection, the dose regimen, and the microfilaricide used. These reactions usually resolve 
spontaneously, although treatment with ordinary analgesics (e.g. acetaminophen; aspirin, 


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ibuprofen) and antihistamines (e.g. diphenhydramine) are often provided in clinical trials. 
Most AEs resolve within 3- 4 days after treatment. 
The DEC is manufactured by Pfizer and will purchased through Amtrex Enterprises. Ivermectin and 
albendazole will be obtained from Merck and GlaxoSmithKline respectively. Each drug purchased, 
will have certificates of analysis which will be retained in the study trial master files and will be 
provided to the Ghana Health Service and FDA if required. 
 
5.4 Risks of nodulectomy 
Nodulectomies are a standard procedure to treat onchocerciasis in endemic countries since current 
approved medications cannot kill the adult worms in nodules. Nodulectomies will be performed in 
an operating room under sterile conditions. Onchocercomata will be removed under local anesthesia 
by an experienced physician. There is a risk of blood loss or infection at the incision site however, 
careful sterile techniques should mitigate this risk. Subjects will be required to stay from normal 
work for 1 week after nodulectomy to facilitate wound healing and will be paid for their loss of 
earnings. 
 
 
 
5.5 Conducting the trial during the Covid-19 pandemic 
 
Potential Risks to Participants 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 also known as COVID-19) is 
a virus that was first reported in China in late December 2019, but has since spread to most 
countries in the world, including the presence of some cases in Ghana. COVID-19 is spread 
from person-to-person contact through respiratory droplets of an infected individual (eg. 
from coughing, sneezing, breathing). In the current clinical trial, patients will be in contact 
with other patients and staff during transport to the study site and during their stay at the 
health center for enrollment and follow-up exams. 
 
Mitigation Procedures 
The following measures will be put in place during the trial to prevent the transmission of 
SARS-CoV-2: 
• The Research team will follow the Ghana Health Service Ethics Review Committee 
(GHS-ERC) Guidelines for conducting research during the COVID-19 pandemic 
• Participants will be educated on the COVID-19 pandemic with the emphasis on how 
COVID-19 is now being transmitted from human to human, adequate protection by 
practicing good personal hygiene, maintaining physical distancing, hand washing with 
soap and running water, and the use sanitizers and wearing of facemasks. 
• Participants will be triaged in their communities by asking whether they have 
symptoms of cough, catarrh, and/or fever and will also have their temperatures 
checked. All participants with suspected symptoms of COVID-19 will be referred to 
the Nkwanta South District COVID-19 team. 


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• Participants who leave the study site after a visit will be encouraged to share any covid- 
19 test that they have been made to take as soon as they do so and the results of the test 
as soon as they become available. 
• Physical distancing will be maintained in project vehicles during transportation to and 
from participants’ communities and participants will be required to wash their hands 
with soap and water, sanitise their hands with alcohol-based sanitisers and wear 
facemasks during all transportations. 
• On arrival at the center, participants will be required to wash their hands with soap 
and running water and to sanitise their hands with alcohol based sanitisers. 
• To ensure proper physical distancing, fewer participants will be housed in the center at 
one time (no more than 14 instead of 20). 
• The researchers will follow all preventive protocols as advised by WHO and the 
national directives on COVID-19 including adequate protection by practicing good 
personal hygiene through regular hand washing with soap and running water, the use 
of sanitizers, protective gloves and wearing of facemasks. Social/physical distancing 
will be observed at all times. 
• Staff and participants will wear facemasks in examination rooms. Hand sanitizer will 
be in the exam rooms, and staff will sanitize all instruments such as slit lamps and OCT 
that contact patient’s skin after each examination. 
5.6 Study Benefits 
Benefits to Individuals 
All participants in the study have onchocerciasis, and participants will benefit from the study 
treatments. Treatment with IDA may sterilize or kill adult worms better than treatment with the 
comparator regimen IVM/ALB. Participants will also benefit by having onchocercal nodules 
surgically removed. Drugs used in this study (ALB and IVM) are also active against intestinal 
nematode worms. 
 
Public health benefit 
If IDA is more effective for achieving sustain clearance of Mf than the comparator (IVM/ALB), this 
could lead to accelerated elimination of onchocerciasis in many areas in Africa. If IDA (after IVM 
pretreatment) is well tolerated in persons with onchocerciasis, this strategy might be used to 
accelerate LF elimination in Africa in areas with co-endemic LF and onchocerciasis even if the 
regimen is not effective for onchocerciasis. However, additional larger safety studies would be 
needed before I/IDA could be accepted as a MDA regimen for use in areas with onchocerciasis. 
Cost to Subjects 
There will be no cost to study participants, and study medications will be provided free of charge. 
All costs related to parasitological, ophthalmological and clinical monitoring and nodulectomies 
will be covered by the study. Study participants will be provided free transportation to Hohoe and 
back to their home communities, and they will be provided with food and accommodation in 
Hohoe. Participants will be visited and examined for follow-ups in their communities by the 
research team. All visits and examinations including wound dressings will free to participants. 


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5.7 Study Compensation 
Compensation for Loss of Earnings 
Subjects will not be paid for participation in this study. Subjects will be compensated for the loss of 
earnings for the participating in the study. The compensation will be based on the number of days 
spent participating in protocol related activity at the village/clinic facility in Hohoe. For each day of 
participation, each participant will be compensated forty Ghana Cedis (GH¢ 40:00) per day. Minors 
participating in the study will be compensated at the same rate. Compensation will be paid at the 
end of enrollment and at the conclusion of each follow-up visit. 
 
 
 
Compensation for Research Related Injuries 
Commercial clinical trial insurance will be purchased for this study. In the event that a subject 
experiences an AE attributable to treatment, the project will help support any medical treatment and 
hospitalization required. Participants (or their families) will be compensated if any participant dies 
or is disabled because of participation in the study according to procedures followed for clinical 
research projects in Ghana. 
The study will comply with Ghanaian government guidelines that require insurance to cover all 
participants, investigators and the institution in the clinical trial in case of damage to health due to 
participation in the clinical trial. The risk for the current trial is very low since the study 
medications are widely used and considered to be safe. The clinical evaluation procedures (skin 
snips, ophthalmological examinations, and nodulectomies) are standard of care, low risk procedures 
that are unlikely to damage health. 
 
 
 
6 INSTRUCTIONS FOR SPECIMEN PREPARATION, 
HANDLING, AND STORAGE 
 
6.1 Specimen and Sample Handling 
Specimens will be tested in clinical laboratories at Kpassa (skin snips) and at the UHAS School of 
Public Health Research Centre in Hohoe, Ghana (blood, urine, skin snips). Onchocercal nodules 
will be fixed in preservative and processed for histology at a histology laboratory with CAP 
(College of Amercian Pathologists) or an equivalent international certification. 
Samples (serum, urine, skin snips, nodules) sent outside of Ghana for testing or storage will be 
completely de-identified (study ID number only). De-identified samples will be sent to Washington 
University in St. Louis and/or Case Western Reserve University (USA). Samples may be stored at 
one or more of these sites. These samples will be used for onchocerciasis related studies only. 
 
6.2 Specimen Shipment 
Nodule histology slides will be read in two independent sites. One site will be the DOLF project 
reference laboratory (Weil Lab) at the Washington University in St. Louis. Shipments of nodules 
and slides ill comply with Ghanaian and United States federal rules and with IATA regulations. The 
Weil Lab at Washington University in St. Louis is located at 4444 Forest Park Blvd, St. Louis MO 


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63110. Samples will be stored for up to 35 years and then destroyed according to regulatory 
guidance. 
 
7 SAFETY REPORTING AND SAFETY MONITORING 
Most treatment related adverse events (cutaneous or ocular) result from the death of microfilariae in 
the skin and/or the eye are related to death of parasites and are not due to direct toxic effects of the 
drugs in humans. Other adverse events such as nausea and abdominal pain sometimes occur after 
treatment with IVM, ALB, or DEC. These may be related to local physical effects of the tablets or 
to effects of these drugs on intestinal worms. AEs related to death of O. volvulus Mf typically occur 
following the initial (first time) treatment when the burden of Mf in the skin and eye is greatest. 
These AEs typically start 1 or 2 days after treatment and they may occur up to 7 days after 
treatment. After treatment, participants will be assessed daily in the center for adverse events for 7 
days before being discharged to their communities. 
If participants develop severe AEs (grade 3, events that interfere with activities of daily living) or 
serious AEs for any reason after they return to the Kpassa area, they will be transported to Kpassa 
Health Centre, Nkwanta District Hospital, or UHAS School of Public Health Research Centre at 
Hohoe hospital for evaluation and management. SAEs will be reported to the Ghana Food and Drug 
Administration (FDA), UHAS Research Ethics Committee, Ghana Health Service Ethics Review 
Committee (GHS-ERC), to manufacturers of study medications, and to other institutional review 
boards per Good Clinical Practice (GCP) guidelines and timelines. 
More detail on Safety Reporting can be found in the Safety Plan corresponding to this study. 
 
7.1 Definitions 
 
Adverse Events (AEs) 
Adverse events (AEs) are any untoward medical occurrence in a clinical investigation participant 
who has received a study product intervention. AEs do not necessarily have to be causally related to 
treatment with the study product. An AE can, therefore, be any unfavorable and unintended 
symptom, sign (including an abnormal laboratory finding) or other disease temporally associated 
with the use of a study medicinal product, whether or not the AE is considered to be related to the 
study medicinal product. 
An AE does not include: 
• Medical or surgical procedures (e.g. surgery, tooth extraction, transfusion). The condition 
that leads to the procedure is an adverse event 
• Pre-existing diseases or conditions or laboratory abnormalities present or detected prior 
to the screening visit that do not worsen. 
 
Ocular Adverse Events (OAEs) 
Ocular adverse events are adverse events in the Guide for Assigning Adverse Events, or any other 
adverse event pertaining to the eye resulting in symptomatic, visual or functional disturbance. 


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Serious Adverse Event (SAE) 
Any adverse event that results in any of the following outcomes: 
• Death 
• Life-threatening (immediate risk of death) 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability or incapacity 
• Congenital anomaly/birth defect 
• Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered a serious adverse event when, based upon appropriate 
medical judgment, they may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
Ocular SAEs 
An ocular severe adverse event will be defined as: 
• An AE causing severe visual loss, defined as a decrease in VA of > or = 6 lines compared 
with baseline VA or a decrease in VA to level of 6/60 or worse 
• An AE requiring medical or surgical intervention to prevent permanent loss of vision; 
• An AE associated with severe intraocular inflammation; 
• Conjunctival or scleral necrosis 
• Corneal Edema or persistent corneal erosion 
• Retinal Detachment 
• Retinal Hemorrhage 
• Optic Atrophy 
• 
Increased IOP > 15 mmHg from baseline 
 
Unexpected 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g., Package Insert). 
 
Expedited Safety Report 
Documentation in appropriate form and format summarizing an SAE that meets expedited safety 
reporting criteria, submitted within the required reporting time frame of applicable regulatory 
authorities and/or institutional review boards (IRBs) or ERCs of participating countries. 
 
7.2 Assessment of Adverse Events 
Adverse event monitoring will be performed daily for 7 days following treatment with study 
medications. Participants will be kept at a the UHAS School of Public Health Research Centre 
clinical facility at the Hohoe municipal Hospital for 7 days after treatment so that they can be 


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closely monitored for adverse events and provided care if needed. See Appendix C for a sample AE 
assessment form. 
Adverse events will be defined using a modified Common Terminology Criteria for Adverse Events 
(CTCAE) grading table. Study ophthalmologists have added additional detail to the CTCAE tables 
for potential ocular adverse events related to this study (Appendix D). 
Evaluations will be documented on the case report forms (either paper or entered directly into an 
electronic CRF using a smart telephone or tablet computer). 
After 7 days participants will be returned to their homes. They will be instructed to contact the study 
village coordinators who are resident in their communities to inform the study investigators of any 
late adverse events and arrange transportation to the Kpassa Health Centre/Nkwanta District 
Hospital/ or UHAS School of Public Health Research Centre at Hohoe hospital medical care if 
required. 
 
7.3 Serious Adverse Event (SAE) Assessment and Management 
Project ophthalmologists will manage any significant ocular AEs with treatments such as topical or 
periocular injections of anti-inflammatory medications (e.g., steroids). Extra-ocular AEs such as 
Mazzotti reactions (fever with skin rash, pruritus, and malaise) will be managed by study personnel 
with medications such as anti-pyretics, anti-inflammatory drugs and anti-histamines, which are 
routine, approved medications and will be prescribed by the study clinician. Study participants with 
definite or suspected SAEs (any event ≥ grade 3) will be referred to a physician or appropriate 
health care professional for evaluation. The physician will determine whether the event qualifies as 
a serious adverse event (SAE). 
All SAEs will be reported to regulatory authorities and to the Ghana FDA within the stipulated 
timelimes (see Safety Plan). The report will specify whether the SAE was related, possibly related 
or unrelated to treatment and also specify whether the type of AE observed is unexpected based on 
the study drug’s package insert. (See Appendix C for a sample SAE report form.) 
All AEs and SAEs will be recorded in source documents. All AEs and SAEs will be recorded in the 
CRFs approved by GHS-ERC. SAEs and follow-up information will be reported to each IRB per 
their approved reporting policies. 
 
7.4 Reporting of Pregnancy 
Pregnancy is an exclusion criteria for this study. Although not AEs, pregnancies are reportable 
events. If a pregnant woman is inadvertently dosed, efforts will be made to follow-up and report the 
outcome of the pregnancy (e.g., healthy baby, miscarriage, etc.) Any pregnant woman inadvertently 
dosed who has a miscarriage or spontaneous abortion will be reported as an SAE. If a participant 
becomes pregnant after treatment they may remain in the study, but the study will not actively 
follow the outcome of the pregnancy. Pregnancy will be diagnosed by a urine human chorionic 
gonadotropin (urine HCG) test. If a pregnant woman is inadvertently dosed with study medications 
for either intervention arm, the baby delivered as a result of that pregnancy will be followed for one 
year after birth. 


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7.5 Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) will be formed consisting of at least 4 experts including: 
at least 2 physicians, one of which is an ophthalmologist; as well as one statistician, and at least one 
scientist or physician who is knowledgeable in onchocerciasis and neglected tropical diseases. At 
least one member of the DSMB will be a Ghanaian scientist or physician. Study investigators will 
send safety reports to the DSMB at least monthly, and the DSMB will meet when the first 30 
participants have been enrolled, at the midpoint of the study, and after the second stratum of 
participants is complete. Thereafter, meetings will take place quarterly until all participants have 
completed 3 month follow-ups. Ad hoc meetings will be held as needed and in the event that the PI 
or other study staff note safety concerns during enrollment. The DSMB will monitor the type and 
frequency of AEs and SAEs recorded by the teams and provide guidance to the PIs and the teams in 
the field. A draft of the DSMB charter is located in Appendix E. The final version of this charter will 
be submitted to all IRBs after members of the DSMB have confirmed their participation. 
 
7.6 Interim Analyses 
Data will be analyzed during the study for “go” or “no go” decisions for continuation of the study. 
Interim analyses will be performed after enrollment and 7 day follow-up is completed for 
participants in stratum 1 and then again at the end of stratum 2. A third interim analysis will be 
performed after the 3 month assessments have been completed for all participants. Among other 
things, the DSMB should consider whether severe AEs are significantly more common after IDA 
than after IVM/ALB treatment. The DSMB will review safety data on a regular basis, and they will 
review all severe or serious ocular AEs as and when they occur. The DSMB will consider stopping the 
study if one or more participant experiences a serious adverse event attributable to IDA treatment. At 
each review, the DSMB will make a “go” ahead with the study or “no go” decision based on their 
analyses and assessment. 
 
7.7 Procedures for Pausing the Trial 
Upon review of the safety data from the trial, the DSMB will make decisions regarding the 
continuation of the trial. The DSMB will conduct an initial review after study drugs are distributed 
to approximately 10 participants in each treatment arm and consider halting or stopping the study if 
1 or more participants in any treatment arm experiences an SAE by month 3 after treatment. The 
DSMB will pause to review data after any SAE then start again following the review and 
determination of the study’s safety. Because participants will be recruited as cohorts, safety 
evaluations will be held on an ongoing basis and include cumulative safety data of grade 1 and 2 
AEs and specific case information for grade 3 and above. 
The DSMB has been convened to look out for the safety of study participants; it has the right and 
responsibility to pause the study if any of the treatments is associated with an unacceptable frequency 
of serious or severe adverse events. The DSMB should consult with the study medical monitor and 
PI before making a final decision to suspend the study. If the DSMB recommends discontinuation or 
modification of the study, the Chair of the DSMB will meet or speak to the DOLF Project Team at 
the earliest opportunity to review the basis for the recommendation, and the DOLF Project team will 
notify the Principal Investigator. The DSMB will begin data review meetings after enrollment of 
participants in the investigational arms of this study. 
The DSMB and IRB/ERCs have the authority to stop the study at any point. The study may also be 
terminated by regulatory bodies if there is significant violation of GCP that compromises the ability 
to achieve the primary study objective or compromises subject safety. 


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However, as DSMB members are not on site, it is appropriate that they get input from the 
medical monitor and PI before making stopping or pausing decisions. The DSMB Chair will 
communicate the decision to discontinue or modify the study with the DOLF Project Team 
and the DOLF Project Team will immediately notify the PI of the DSMB’s decision. The 
DOLF Team is in a better position to communicate with the DSMB Chair (only 1 hour time 
zone difference, more reliable internet, etc.). 
 
8 STATISTICAL CONSIDERATIONS 
 
8.1 Sample Size Determination (Power calculation) 
The primary outcome variable used for our power analysis is the % fertile female worms (100 x 
fertile female worms/ total female worms) for each of the three drug treatments: (1) single-dose 
IVM (IVM alone); (2) single dose of IVM + DEC and albendazole (IDA1); (3) three daily doses of 
IVM + DEC and albendazole (IDA3). Power calculations for our primary treatment-group 
comparison (IVM /ALB vs IDA1) assumed that 30% of the total worms will be fertile females in 
IVM/ALB group and that 15% of the total worms will be fertile females in the IDA1 group. For our 
secondary treatment-group comparison (IVM/ALB vs IDA3), we assumed that 10% of the total 
worms were fertile females for the IDA3 group. On average, we assumed that there will be 6 total 
female worms to evaluate in 3 nodules per person after treatment. In our analysis we treated each 
worm within a subject as a Bernoulli trial (0=non-fertile female worm, 1=fertile female worm), and 
we used an intra-class correlation (ICC) of 30% to account for within subject correlation among the 
trials. The ICC and cluster size (# female worms/person) adjusts the sample-size estimate using the 
following formula: 1 + ICC x (Cluster size - 1) 44, 45. To achieve 80% power at a two-sided alpha- 
level of 0.05, we will need nodule histology data from 51 subjects in each treatment group for the 
primary treatment-group comparison (IVM/ALB vs IDA1). The expected % difference for our 
secondary treatment-group comparison (IVM/ALB vs IDA3) powered at 80% and an alpha of 0.05, 
would require 26 subjects/group. After accounting for a 20% drop-out rate, a sample size of at least 
61 subjects per treatment group will enable us to address both the primary (IVM/ALB vs IDA1) and 
secondary (IVM/ALB vs IDA3) treatment-group comparisons. Furthermore, we will attempt to 
enroll additional subjects beyond the target of 61 to provide some protection against other 
(unforeseen) factors that could decrease the power of this study (e.g., within village correlation, 
smaller effect size, higher drop-out rate than anticipated). The study will provide preliminary safety 
data, but a much larger study will be required to provide a precise safety comparison of IVM/ALB 
vs IDA. 
 
8.2 Data Analysis Plan 
 
Efficacy analysis for primary outcome 
Because of the within subject correlation for the primary outcome (% fertile female worms), we will 
use a generalized linear mixed model approach (PROC GLIMMIX, SAS) 46. Generalized linear 
mixed models (GLMM) permit modeling of non-normal outcomes while accounting for correlation 
among observations within a group. In the present study, the primary outcome is binary (0=non- 
fertile female worm, 1=fertile female worm) and worms within a person are not independent. To 
model these data we will use a GLMM assuming a binomial distribution with a logit link function, 


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and person will be treated as a random effect. Further, while we do not anticipate an effect of 
village on our outcomes, if subjects within village are correlated the GLMM can be extended to 
account for this correlation. A two-sided P-value ≤ 0.05 is considered significant for these analyses. 
 
Efficacy analysis for secondary outcomes 
Similar to the analysis of the primary outcome, percentage of all adult worms that are viable will be 
analyzed using a GLMM. Percent of persons with zero MF at 18 months will be analyzed using a 
generalized linear model assuming a binomial distribution and a logit link function. The difference 
between pre and post treatment MF counts (% reduction) will be analyzed using a paired t-test and 
will be transformed as necessary to meet the assumptions of this analysis. A P-value of 0.05 will be 
considered significant for all secondary outcomes. 
 
Safety 
The primary safety analysis will focus on AEs with severity grade 3 or greater. Secondary analyses 
will separately consider all AEs and ocular AEs. AEs will be assessed daily for 7 days after 
treatment and 3 months after treatment. This will include general assessments and detailed 
ophthalmological examinations on day 7 and 3 months after treatment. AE rates and severity will be 
compared across the three treatment groups using logistic regression analysis; with Student’s t-test 
will be used to assess differences for individual AEs. The data will also be examined using a 
generalized linear mixed model that as described below can model non-normal outcomes and 
examine correlations among the different events and how these change over time. In this model, we 
can also examine the impact of baseline Mf burdens prior to treatment and other potential risk 
factors (age, sex, location, etc.) on AEs. 
Note that the samples sizes per treatment group in this study are not sufficient to provide a robust 
safety profile (e.g., high confidence that the rate of SAEs after treatment is less than 0.1%). This 
proof of concept study will allow for initial safety assessments to be performed. Additional, larger 
studies will be required to establish a more complete safety profile. The safety assessments put in 
place for this study along with the frequent and ongoing review by the DSMB will provide a strong 
foundation to evaluate the participant’s safety throughout the study. 
Data from all participants in this study will be analyzed for safety and efficacy outcomes. The 
study population for the primary and secondary endpoints related to adult worm viability and 
fertility are persons who were enrolled and who have nodulectomies performed 18 months after 
treatment. The study population for secondary efficacy outcomes related to microfilariae in the 
skin are participants who were enrolled in the study who have follow-up microfilaria testing by 
skin snip examination at time points (12, 18 months) as indicated in the diagram on page 26 of 
the protocol. The study population for the early (7 day) safety analysis are participants who 
receive the study drugs who have safety assessments during the 7 days after dosing. A separate 
safety analysis will consider data from the follow-up examinations conducted 3 months after 
dosing. 
 
 
 
8.3 Interim and Final Reports 
An interim clinical trial report will be prepared and submitted to the Ghana FDA, IRB/ECs, and 
other relevant regulatory agencies after the 3-month safety assessments are complete. A final 


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report will be prepared and submitted to the same groups not later than 90 days after the 
completion of the trial (after the last patient, last visit for nodulectomy). Investigators will prepare 
these reports in accordance with the comprehensive formal report conforming to the ICH E3 
Guideline for the Structure and Content of Clinical Study Reports as per sub-section 3.6.4.1 of the 
FDA's Guidelines for Authorization of Clinical Trials. 
The biostatistician will generate tables, figures and listing during data analysis (after final 
follow-ups) during which time, they will review the data for missing, unused and spurious data. 
Study staff will report any major changes to the statistical analysis plan to the IRB at UHAS and 
the Ghana Health Service and to the DSMB. In addition, any major changes will be reported to the 
FDA prior to datalock. 
 
 
9 DATA HANDLING 
Data will be collected using a tablet-based system, pre-loaded with study templates. Study staff will 
be trained in the use of the instruments and data will be uploaded as entries are completed. 
Washington University in St. Louis will serve as the data coordinator for the study. The data will be 
owned by study investigators at UHAS School of Public Health Research Centre. The data will be 
compiled, validated and cleaned at UHAS School of Public Health Research Centre. Data will be 
accessible to Washington University in St. Louis for further validation checks and data cleaning. 
After data have been cleaned and finalized, the database will be locked, and the final dataset will be 
accessible to investigators at the University of Health and Allied Sciences School of Public Health 
Research Centre. Data analysis will be a collaborative effort between University of Health and 
Allied Sciences School of Public Health Research Centre and investigators at Case Western Reserve 
University and Washington University in St. Louis. 
 
9.1 Types of Data Collected 
 
Enrollment Data 
• 
Participant identifier 
• 
Informed consent date 
• 
Demographic information (date of birth, gender) 
• 
Pregnancy/breastfeeding status 
• 
Medical history 
• 
Presence of onchocercal nodules 
• 
History of prior MDA treatment 
• 
Physical exam 
• 
Skin exam (including photographs of skin lesions) 
• 
Ocular exam (including retinal and ocular coherence tomography photographs) 
 
Laboratory Results 
• 
Skin snip (including MF count) 
• 
Nodule histology results (number of live/dead female and male worms, etc.) 


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Participant Monitoring and Follow-up 
• 
Physical exam 
• 
Skin exam (including photographs of skin lesions) 
• 
Ocular exam (including retinal and ocular coherence tomography photographs) 
 
Adverse Event Evaluation 
• 
Adverse event assessment 
• 
Treatment assignment 
• 
Concomitant medication 
• 
Ae description 
• 
Start and stop date 
• 
Outcome 
• 
SAE evaluation and causality to MDA (definite, probable, possible, or unrelated) 
 
9.2 Study Records Retention 
Study documents will be retained for a minimum of seven (7) years after the study has been closed. 
These documents will be retained for a longer period if required by local regulations. No record will 
be destroyed without the written consent of DOLF and UHAS investigators. 
The principle investigator at the study site will maintain appropriate medical and research records 
for this trial, in compliance with ICH E6, Section 4.9, regulatory and institutional requirements for 
the protection of confidentiality of participants. The investigator will permit authorized 
representatives of the sponsor and regulatory agencies to examine (and when required by applicable 
law, copy) clinical records for the purposes of clinical site monitoring, quality assurance reviews, 
audits, and evaluation of the study safety and progress. 
 
9.3 Participant Key/Participant List 
The participant key linking the list of all study participants with their unique identifier will only be 
available to the Ghanaian PI and to study personnel who have been delegated authority to handle the 
participant key. The participant key may be paper or electronic. The participant key will not be 
shared with investigators outside of Ghana. 
 
9.4 Source Documents 
This study may use paper and/or electronic source records. An electronic data capture system (EDC) 
will be employed to record data either directly into electronic forms or entered into the EDC from 
paper forms. Paper data collection forms derived from the electronic case report forms (eCRFs) will 
available to study staff as a backup. The selected EDC vendor will be 21 CFR 11 compliant 
including audit trails, time stamps, and encryption with secure password protected access. 
Source documents will be stored for the duration of the study plus 7 years. The electronic database 
(study data) will be stored for 7 years by the Principle Investigators’ institution. Source documents 
may be stored longer if required by regulatory requirements. 


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10 FUTURE USE OF STORED SPECIMENS 
 
Samples collected in this study may be used for research related to onchocerciasis (diagnosis, 
parasite variability, treatment, or the pathogenesis of adverse events). Any other uses will require 
the prior approval of either the Washington University or University Hospitals Cleveland Medical 
Center (UHCMC) IRB, and the GHS-Ethical Review Committee and the UHAS Research Ethics 
Committee. Any use of samples outside of Ghana will require removal of any identifying 
information apart from study identification numbers. Subjects may still participate in this study 
even if they do not consent to use of their samples for future scientific studies. If the subject checks 
“no,” (in the informed consent document), then their samples will be stripped of its identification 
number in the database after the completion of this study and the samples will not be used. 
 
11 ETHICAL ISSUES 
 
11.1 Informed Consent Process 
Project investigators will consent eligible individuals in their own villages prior to the 6-month 
follow up of the Part I study. The Site PI or a co-investigator will inform the subjects of all aspects 
of the study covering all elements of informed consent. The study details will be explained in the 
local language Konkomba or Twi or in another language understood by the participant. 
Project investigators will consent eligible individuals in their communities prior to enrollment into 
the IDA study. The Site PI or a co-investigator will inform the subjects of all aspects of the study 
covering all elements of informed consent. The study details will be read and explained in the local 
language (Konkomba or Twi) to the participant. 
An informed consent document that is specific to the study will be available in English and the local 
language (Appendix F). The investigator must use an IRB/ERC approved informed consent 
document. Adequate time will then be allowed for the subjects to ask questions and make individual 
voluntary decisions. The form will be signed by the participant (or thumbprint) witnessed by an 
impartial community member and signed by an investigator (Dr. Opoku, Dr. Doe, Dr. Kanza, Dr. 
Gyasi). A copy of the information document and the consent will be given to the subject. A second 
copy of the consent will be stored in the Investigator’s file. Only individuals who have signed the 
consent form and meet eligibility criteria will be enrolled in the study. 
After the 18 month follow-up and nodulectomies, analysis will be done to determine the 
effectiveness of the drug therapies. All participants in less effective treatment arms will be offered 
the more effective treatment at no cost to the participant. 
 
11.2 Comprehension of Informed Consent 
To assess comprehension of informed consent and the study, the principal investigator and/or 
authorized consent study staff will ask the following questions: 
1. Do you understand why you are being asked to participate? 
2. Have you had the opportunity to ask questions and discuss the study? 
3. Do you voluntarily participate in this study? 


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4. Are you willing to take part in all the study procedures? 
5. Will we take blood from you during this study? 
6. How long will you be in this study? 
7. Do you understand you are free to stop being in the study at any time without having 
to give a reason? 
8. Is there any charge for being in the study? 
9. Do you understand that you will be compensated for lost wages? 
10. Do you understand that you are participating in research and not receiving treatment 
or cure? 
11. Do you know who to call if you have questions? 
 
 
The responses will be documented on the consent form, signed by the research staff or investigators, 
and a copy given to the study volunteer. Participants will not be enrolled unless they can correctly 
answer each of these questions. In the event a subject indicates a lack of understanding of the study, 
or any aspect of it, the Principal Investigators/co-investigators/study staff will invite questions and 
offer explanations of any particular point. If, in the judgment of the Principal Investigators, the 
subject’s response still does not reflect an understanding of the study, the subject will not be 
enrolled in the study. 
 
11.3 Provisions for Subjects from Vulnerable Populations 
 
Plan to avoid treating pregnant women. 
Pregnant women will not be eligible to participate in this study because of the unknown effects of 
the investigational products in pregnant women. Women of child-bearing age who wish to enroll in 
the study will have a pregnancy test prior to enrolment in the study to ensure they are not pregnant. 
Lactating women who had a delivery more than 1 (one) month prior to potential enrollment can be 
enrolled/treated. 
 
Plan for Inclusion of Illiterate Subjects 
Study participants, if illiterate, will have the consent form read to them in the local languages 
(Konkomba, or Twi). Their signature or mark (thumbprint) will be witnessed on the consent form. 
 
Plan for Inclusion of Non-English Speaking Individuals 
Subjects who do not speak or read English are neither specifically included nor excluded from this 
study. Informed consent documents will be translated into Konkomba and Twi languages since all 
the participants enrolled into the ocular microfilarial clearance study speak one or both languages. . 


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Minors 
Since minors can be affected by ocular onchocerciasis, participants aged 16-17 years will be included 
in this study. Younger children will not be included, because O. volvulus infections are generally less 
frequent and of lower intensity in that group and because younger children may not fully understand 
the potential risks and benefits of this first study of IDA in onchocerciasis. 
If a minor (16 or 17 years of age) wishes to participant in the study, he/she and a parent/legal guardian 
must participate in the informed consent process. The informed assent form will be signed or thumb- 
printed by the minor, by at least one parent or legal guardian, by an independent witness, and by the 
principal investigator or his designee. 
 
11.4 Alternatives to participation 
Study subjects may decline participation in this study with no consequences. Subjects with known 
Onchocerciasis will be advised to join MDA with IVM available in their communities. . 
Participants who are excluded from study due to severe eye disease or Mf in the posterior segment 
will be referred to the appropriate Ghana Health Service facility for management. 
 
11.5 Withdrawal 
Entry into the study and participation will be strictly voluntary. It will be made clear that refusal to 
participate or a decision to withdraw can occur at any time throughout the course of the study and 
will not influence their rights or the care they receive at local health facilities. 
In two of the three treatment arms the participants receive a single treatment. In the 3rd treatment 
arm the patients receive treatment on three consecutive days. While there is no dose titration in place 
the investigator has the discretion to discontinue treatment if the treatment appears to be creating 
distress to the participant. The study investigator would monitor these participants closely and assess 
any adverse events that have occurred. There is no plan in place for the study investigator to re- 
initiate treatment once it has been discontinued. 
Withdrawal from the study can be at the participant or investigator discretion at any time during the 
trial. All subjects that withdraw from the study will be encouraged to complete the safety follow-up 
visits (daily for 7 days after dosing and at 3 months). 
Data collected on the participant up to the point of withdrawal remainspart of the study database. If 
the participant withdraws from the interventional part of the study and agrees to continue being seen 
for the safety follow-up visits the associated clinical outcome information such as medical information 
and laboratory results will be part of the study database. 
There is no plan to replace withdrawn participants. 
Protocol deviations are collected through the electronic data capture system (i.e. visits out of window, 
in-appropriate dosing, etc.) and reviewed through the tables, figures, listings. Additionally, a Protocol 
Deviation Log has been put in place to address deviations not picked up by EDC. Participants who fail 
to report for follow-up examinations will not be considered to have withdrawn, and the study 
team will attempt to contact them for follow-up testing at later time points listed in the protocol. 
 
11.6 Participant Privacy 
Privacy of the study participants will be maintained by assigning a unique study identification 
number (UNID). All data, skin snip samples and results will be recorded and analyzed by UNID 


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with no personal identifiers. All information collected, including name, specific address, etc. that 
could identify subjects will be kept confidential and available only to the investigators and 
authorized study personnel. 
All written forms (i.e., consent and any paper data collection forms) will be stored in a designated 
locked area with limited access. All forms will be labelled and filed in cabinets with the study 
protocol number, PI’s names and collection dates. These cabinets will be metal and have 
functioning locks. Keys will be kept with the study site PI, Data Manager, or Study Coordinator. 
Any electronic devices used to enter or collect data will be password protected. PIs and/or Project 
Coordinator will authorize access. The paper forms will be stored for the duration of the study plus 
seven years per IRB protocol for primary data storage. 
Data will be entered into an electronic data capture system (EDC) that is 21 CFR 11 compliant. No 
participant names will be collected in the EDC. The database will be password protected and the 
Principal Investigators will authorize access to the password. For data transfer outside of the EDC 
data files will be exported as transfer files and, to ensure confidentiality, all files will be encrypted 
and password protected. 
 
11.7 Plan for Subjects at the End of the Protocol 
We will hold meetings at the end of the study in participating communities where the results of the 
study and significance of these results will be communicated to participants. At the end of the study 
participants will be informed to participate in MDA distributed in their communities. Results will 
also be shared with the Ghana Health Service. 
 
12 RESPONSIBILITIES 
 
12.1 Good Clinical Practice 
The investigator will ensure that the basic principles of Good Clinical Practice are followed along 
with the appropriate laws and regulations of Ghana. 
 
12.2 Clinical Trial Monitoring 
An independent person or group experienced in monitoring clinical trials will be employed to help 
with clinical monitoring. This will include a pre-study GCP training and site assessment and site 
initiation monitoring. Additional monitoring will include evaluation of the study at one year post- 
drug administration, and a close out assessment following nodulectomies. 
 
12.3 Institutional Review Board (IRB)/Ethics Review Committee (ERC) 
This protocol will reviewed by the following IRB/ERCs: 
• Research Ethics Committee of the University of Health and Allied Sciences (UHAS, Ho, 
Ghana) 
• Institutional Review Board of the University Hospitals (Cleveland, USA) 
• Washington University in St. Louis Institutional Review Board 
• Ghana Health Service Ethics Review Committee 
• 
Ghana Food and Drugs Authority (FDA) 


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The protocol and any accompanying material to be provided to the participants such as the informed 
consent will be submitted to the UHAS Research Ethics Committee, Ghana Health service Ethics 
Review Committee (GHS-ERC) and the Ghana FDA for review and approval. Approval from the 
committees must be obtained before starting the study and should be documented in correspondence 
to the investigator. 
Any modifications to the protocol after receipt of the IRB or ERC approval must be submitted to the 
UHAS Research Ethics Committee and Ghana Health service Ethics Review Committee (GHS- 
ERC) and the Ghana FDA for approval prior to implementation. 
 
12.4 Data Ownership 
Data will be owned by UHAS. However, it is understood that UHAS will share study data with 
Principal Investigators, Co-investigators and key personnel for use in publications, presentations at 
scientific meetings or as preliminary data for subsequent grant applications. Confidentiality of study 
participants will be maintained by not using names or personal identifiers. The project will be 
subject to the DOLF Project Data Sharing and Publication Policy (Appendix G). 
UHAS will permit access to all documents and records that may require inspection by the funding 
agencies, governmental regulatory agencies, institutional review boards (both UHCMC IRB and 
GHS-ERC) or its authorized representatives. 
 
12.5 Financial Disclosure 
The investigators listed in this protocol have no financial interests in the investigational products 
being researched in this study. This is an investigator-initiated study and the DOLF Project at 
Washington University in St. Louis Medical School is the sponsor of the study. The study is funded 
by a grant from the Bill and Melinda Gates Foundation. There is no financial agreement between 
the sponsor, funder, nor other investigators whereby the value of compensation would be influenced 
by the outcome of the study. 
 
12.6 DOLF Team Technical Support 
The DOLF Project Team conceived the idea of the study and obtained funding, DOLF developed 
the protocol with input from the P.I. DOLF provides technical support (e.g. data management, 
regulatory compliance support, statistical analysis, on-site training) and supplies for the conduct of 
the trial. The DOLF team will work with the P.I.s to analyze the data and publish results from the 
trial. 
 
 
 
 
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14 APPENDICES 
 
APPENDIX A: Sample Participant ID Card 
 
APPENDIX B: Investigational Product Package Inserts 
APPENDIX C: Sample Adverse Event Assessment Forms 
APPENDIX D: CTCAE Scoring Tables 
APPENDIX E: DSMB Charter 
 
APPENDIX F: Informed Consent Form 
APPENDIX G: Data Sharing Agreement