Repeat Ivermectin Mass Drug Administrations for Control of Malaria: a Pilot Safety and Efficacy Study
Phase: PHASE2
Conditions: Malaria, Lymphatic Filariasis
Sponsor: Colorado State University

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Title:  Repeat ivermectin mass drug administrations for control of malaria: a pilot 
safety and efficacy study 
Short Title: RIMDAMAL 
 
Trial Identifiers: 
Comité d’Ethique d’IRSS: A03-2015/CEIRES 
CSU IRB: 15-5796H 
ClinicalTrials.gov: NCT02509481 
 
Sponsor:  
Colorado State University, 2011 Campus Delivery, Fort Collins, CO, USA.  80523-2011 
Phone: 1-970-491-1553 
 
emails: Tammy.Felton-Noyle@colostate.edu; Cat.Bens@colostate.edu 
 
Principal Investigators:  
Brian Foy, PhD, Colorado State University, Arthropod-borne & Infectious Diseases Laboratory, Department of 
Microbiology, Immunology & Pathology, 1692 Campus Delivery, Fort Collins, CO, USA.  80523-1692 
Mobile in US: 1-970-443-5251 
Mobile in Burkina Faso: +226 62 75 34 22 
 
email:Brian.Foy@colostate.edu  
 
Rock Dabiré, PhD, Institute de Recherche en Sciences de la Santé, Direction Régionale de l’Ouest, Centre 
Muraz, 399 Ave de la Liberté, Bobo Dioulasso, Houet, Burkina Faso.  10400-000 
Mobile in Burkina Faso: +226 70 73 90 69 
 
email:dabire_roch@hotmail.com 
 
Co-Investigators:  see pg. 8 
 
Funder: The Bill and Melinda Gates Foundation (BMGF) 
 
Revision Chronology: 
7/30/2015; v1.3  
 
 
Confidentiality Statement: This document contains confidential information that must not be disclosed to 
anyone other than the sponsor, the investigator team, host institution, relevant ethics committees and 
regulatory authorities.  
 
 

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Contents 
1. Title of Research Protocol ......................................................................................................................... 8 
2. Investigators and Institutions..................................................................................................................... 8 
2.1. Principle Investigators’ ....................................................................................................................... 8 
2.2. Co-Investigators ................................................................................................................................. 8 
2.3. Non-engaged collaborators ................................................................................................................ 8 
2.4. Institutions ......................................................................................................................................... 8 
3. Protocol Summaries ................................................................................................................................. 9 
3.1. Trial Registration Data ....................................................................................................................... 9 
3.2. Narrative Protocol Summary ............................................................................................................ 10 
3.2.1. 
Background and Rationale ................................................................................................. 10 
3.2.2. 
Primary Objective ............................................................................................................... 10 
3.2.3. 
Hypothesis .......................................................................................................................... 10 
3.2.4. 
Overview Study Design ...................................................................................................... 11 
3.2.5. 
Sites ................................................................................................................................... 11 
3.2.6. 
Study Population ................................................................................................................ 11 
3.2.7. 
Study Interventions ............................................................................................................. 11 
3.2.8. 
Outcome Measures ............................................................................................................ 11 
3.2.9. 
Follow-up Procedures ......................................................................................................... 11 
3.2.10. Sample size ........................................................................................................................ 11 
3.2.11. Data analysis ...................................................................................................................... 11 
3.2.12. Partner institutions .............................................................................................................. 11 
3.2.13. Funding .............................................................................................................................. 11 
4. Introduction ............................................................................................................................................. 13 
4.1. Malaria Transmission and Disease in Southwestern Burkina Faso .................................................. 13 
4.2. Malaria control and treatment in Burkina Faso ................................................................................. 13 
4.3. Lymphatic Filariasis and its Control in Burkina Faso ........................................................................ 13 
4.4. Ivermectin and its efficacy against blood feeding Anopheles vectors ............................................... 13 
4.5. Efficacy of ivermectin MDA to interrupt malaria transmission ........................................................... 15 
4.6. Modeling of Repeated Ivermectin MDAs for sustained effects against malaria vectors, sporozoite 
transmission, and malaria prevalence and disease .......................................................................... 15 
4.7. Safety of ivermectin in humans ........................................................................................................ 16 
4.8. Integration of malaria and NTD control efforts globally and in Burkina Faso .................................... 17 
5. Justification for the study ........................................................................................................................ 18 
5.1. Why is this study needed now?  ....................................................................................................... 18 
5.2. Other relevant ongoing research ...................................................................................................... 18 
6. Hypothesis .............................................................................................................................................. 18 
7. Aim & Objectives .................................................................................................................................... 18 
7.1. Primary objective ............................................................................................................................. 19 
8. Design and Methodology ........................................................................................................................ 19 
8.1. Overview of Design .......................................................................................................................... 19 
8.2. Secondary Objectives ...................................................................................................................... 19 
8.2.1. 
To determine the effect of repeated IVM MDAs on the number of new Plasmodium clones 
acquired over time in treated patients.  ............................................................................... 19 
8.2.2. 
To determine the effect of repeated IVM MDAs on the prevalence and intensity (eggs/larvae 
per gram of feces) of soil transmitted helminth infections in a subset of treated patients 
between 6-10 years of age.  ............................................................................................... 19 
8.2.3. 
To determine the effect of repeated IVM MDAs on the indoor-resting Anopheles mosquito 
capture rate ........................................................................................................................ 19 
8.2.4. 
To determine the effect of repeated IVM MDAs on the outdoor-host seeking Anopheles 
mosquito capture rate ......................................................................................................... 19 
8.2.5. 
To determine the effect of repeated IVM MDAs on the adult mosquito age structure of 
captured mosquitoes. ......................................................................................................... 19 
8.2.6. 
To determine the effect of repeated IVM MDAs on the Plasmodium sporozoite 
rate/entomological inoculation rate in captured mosquitoes ................................................ 19 

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8.2.7. 
To determine the effect of repeated IVM MDAs on the rate of Wuchereria bancrofti in captured 
mosquitoes ......................................................................................................................... 19 
8.3. Design Considerations ..................................................................................................................... 19 
8.3.1. 
Malaria epidemiology in Burkina Faso ................................................................................ 19 
8.3.2. 
The focus on the village as the cluster unit ......................................................................... 20 
8.3.3. 
The focus on children ≤5 years of age as the patient population for measuring the primary 
outcome ............................................................................................................................. 20 
8.3.4. 
The intervention model - parallel assignment with 2 arms ................................................... 20 
8.4. Study setting .................................................................................................................................... 21 
8.4.1. 
Study areas ........................................................................................................................ 21 
8.5. Eligibility criteria ............................................................................................................................... 21 
8.5.1. 
Population of the study villages for receiving MDAs............................................................ 21 
8.5.1.1. Inclusion criteria ......................................................................................................... 21 
8.5.1.2. Exclusion criteria ........................................................................................................ 21 
8.5.2. 
Active case surveillance cohort ........................................................................................... 21 
8.5.2.1. Inclusion criteria ......................................................................................................... 21 
8.5.2.2. Exclusion criteria ........................................................................................................ 21 
8.6. Interventions .................................................................................................................................... 21 
8.6.1. 
Mass drug administrations .................................................................................................. 21 
8.6.1.1. Ivermectin (IVM)  .......................................................................................................... 21 
8.6.1.2. Albendazole (ALB)  ....................................................................................................... 22 
8.6.2. Procedures for Drug Import, Handling and Accountability ...................................................... 22 
8.6.3. Product Labelling and Storage .............................................................................................. 22 
8.6.4. Product Accountability ........................................................................................................... 22 
8.6.5. Removal of Patients from Treatment or Assessment ............................................................. 22 
8.6.6. Discontinue from storage of blood for future studies .............................................................. 23 
8.6.7. Adherence to study intervention protocol and strategies for retention .................................... 23 
8.6.7.1. 
Adherence to study protocol and MDA ....................................................................... 23 
8.6.7.2. 
Strategies for retention ............................................................................................... 23 
8.6.7.3. 
Prior and concomitant therapy ................................................................................... 23 
8.6.7.4. 
Permitted medications during active case surveillance .............................................. 23 
8.6.7.5. 
Self-medications ........................................................................................................ 23 
8.7. Endpoints/Outcome Measures ......................................................................................................... 24 
8.7.1. Primary efficacy outcomes ..................................................................................................... 24 
8.7.1.1. 
Cumulative incidence of uncomplicated malaria episodes in enrolled study village 
children ages 0-5 years. ............................................................................................. 24 
8.7.2. Secondary outcomes  
8.7.2.1. 
Incidence of new Plasmodium falciparum clones acquired in patients over the study 
period ......................................................................................................................... 24 
8.7.2.2. 
Prevalence and intensity (eggs/larvae per gram of feces) of soil transmitted helminth 
infections in a subset of treated patients between 6-10 years of age.......................... 24 
8.7.2.3. 
Indoor-resting Anopheles mosquito capture rate ........................................................ 24 
8.7.2.4. 
Outdoor-host seeking Anopheles mosquito capture rate ............................................ 24 
8.7.2.5. 
Adult mosquito age structure in captured mosquitoes as assessed by parity rate 
examination of mosquitoes and near-infrared spectroscopy scanning of mosquitoes . 24 
8.7.2.6. 
Plasmodium sporozoite rate/entomological inoculation rate in captured mosquitoes .. 24 
8.7.2.7. 
Rate of Wuchereria bancrofti in captured mosquitoes ................................................ 24 
8.7.3. Tolerability and safety endpoints ........................................................................................... 24 
8.7.3.1. 
Tolerability ................................................................................................................. 24 
8.7.3.2. 
Safety ........................................................................................................................ 24 
8.8. Participants Timeline ........................................................................................................................ 24 
8.8.1. Overview of Study Phases ..................................................................................................... 24 
8.8.2. Recruitment Phase ................................................................................................................ 24 
8.8.3. Enrollment ............................................................................................................................. 25 
8.8.3.1. Assignment of IDs ......................................................................................................... 25 
8.8.3.2. Clinical assessment of the MDA-eligible population ...................................................... 25 

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8.8.3.3. Pregnant Subjects ........................................................................................................ 25 
8.8.3.4. Breastfeeding subjects .................................................................................................. 25 
8.8.3.5. Enrollment and clinical assessment of the ACD cohort ................................................. 26 
8.8.4. Treatment Phase ................................................................................................................... 26 
8.8.4.1. Mass drug administration visits ..................................................................................... 26 
8.8.4.2. Active case detection and adverse events monitoring ................................................... 26 
8.8.4.3. Entomology sampling .................................................................................................... 26 
8.8.5. Post-treatment follow-up phase ............................................................................................. 26 
8.8.5.1. Post-treatment clinical assessment ............................................................................... 26 
8.8.6. Unscheduled visits................................................................................................................. 26 
8.9. Sample size ..................................................................................................................................... 27 
8.9.1. Primary endpoint sample size and recruitment strategy ......................................................... 27 
8.9.2. Secondary endpoints with parasite measures........................................................................ 27 
8.9.2.1. Molecular force-of-infection (number of new Plasmodium clones acquired over time)... 27 
8.9.2.2. Soil transmitted helminths (Prevalence and intensity of STHs in a subset of treated 
patients between 6-10 years of age)  ............................................................................ 27 
8.9.3. Secondary endpoints with entomological measures .............................................................. 27 
8.10. Assignment of Interventions ........................................................................................................ 28 
8.10.1. Allocation ............................................................................................................................... 28 
8.10.2. Blinding ................................................................................................................................. 28 
9. Data Collection, Management and Analysis ............................................................................................ 28 
9.1. Clinical procedures .......................................................................................................................... 28 
9.1.1. Malaria episode diagnosis in the ACD cohort ........................................................................ 28 
9.2. Laboratory procedures ..................................................................................................................... 28 
9.2.1. Thick and thin blood smears for malaria ................................................................................ 28 
9.2.2. Molecular force-of-infection ................................................................................................... 28 
9.2.3. Hemoglobin testing ................................................................................................................ 28 
9.2.4. Stool microscopy ................................................................................................................... 28 
9.2.5. Plasmodium sporozoites in the head+thorax of captured mosquitoes .................................... 28 
9.2.6. Squashed mosquito blood meal spots for detecting Wuchereria bancrofti ............................. 29 
9.2.7. Aging of captured Anopheles vectors .................................................................................... 29 
9.3. Data collection methods and storage ............................................................................................... 29 
9.4. Statistical methods ........................................................................................................................... 29 
9.4.1. Trial profile and flowchart....................................................................................................... 29 
9.4.2. Baseline characteristics ......................................................................................................... 29 
9.4.3. Analysis populations .............................................................................................................. 29 
9.4.3.1. Screening failures ......................................................................................................... 29 
9.4.3.1.1. Enrolled population in the clusters who receive the treatments ............................ 29 
9.4.3.1.2. ACD cohort .......................................................................................................... 29 
9.4.3.2. Primary endpoint analysis population – ACD cohort ..................................................... 29 
9.4.3.3. Safety population .......................................................................................................... 30 
9.4.3.4. Treated population ........................................................................................................ 30 
9.4.4. Missing data .......................................................................................................................... 30 
9.4.5. Assessment of efficacy .......................................................................................................... 30 
9.4.6. Analysis of adverse events .................................................................................................... 30 
9.5. Monitoring ........................................................................................................................................ 30 
9.5.1. Data monitoring ..................................................................................................................... 30 
9.5.2. Interim analysis and criteria for termination of the trial ........................................................... 30 
9.6. Safety Monitoring and Reporting ...................................................................................................... 31 
9.6.1. Definitions ............................................................................................................................. 31 
9.6.1.1. 
Adverse Event (AE)  .................................................................................................... 31 
9.6.1.2. 
Adverse Reaction (AR)  ............................................................................................... 31 
9.6.1.3. 
Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR)  ............................ 31 
9.6.1.4. 
Suspected Unexpected Severe Adverse Reaction (SUSAR) ....................................... 31 
9.6.1.5. 
Intensity ....................................................................................................................... 31 
9.6.2. Identifying, managing adverse events ................................................................................... 32 

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9.6.3. Assessment of causality ........................................................................................................ 32 
9.6.4. Reporting adverse event procedures ..................................................................................... 32 
9.6.4.1. Expedited reporting ....................................................................................................... 32 
9.6.4.2. Regular reporting .......................................................................................................... 32 
9.6.4.3. Recipients of reports ..................................................................................................... 32 
9.7. Quality Assurance ............................................................................................................................ 33 
9.7.1. Clinical monitoring ................................................................................................................. 33 
9.7.2. Auditing ................................................................................................................................. 34 
9.7.3. Training ................................................................................................................................. 34 
9.7.4. Quality assurance/control of laboratory tests ......................................................................... 34 
9.8. Mitigation and Risk Reduction Plan  ................................................................................................. 34 
10. Timeframe of the study ........................................................................................................................... 34 
11. Ethical Considerations and Regulatory Approvals ................................................................................... 35 
11.1. Declaration of Helsinki ................................................................................................................. 35 
11.2. Regulatory Approval and Trial Authorization ............................................................................... 35 
11.3. Research Ethics Approval ........................................................................................................... 35 
11.3.1. Review Process ..................................................................................................................... 35 
11.3.2. Protocol Amendments ........................................................................................................... 35 
11.4. Informed Consent Procedures ..................................................................................................... 36 
11.4.1. Consent Procedures .............................................................................................................. 36 
11.4.2. Consent forms ....................................................................................................................... 36 
11.5. Protection of Privacy and Confidentiality ..................................................................................... 36 
11.5.1. Privacy .................................................................................................................................. 36 
11.5.2. Privacy of individual ............................................................................................................... 37 
11.5.3. Confidentiality of data ............................................................................................................ 37 
11.6. Declaration of Interest ................................................................................................................. 37 
11.7. Access to source data/documents ............................................................................................... 37 
11.8. Risk and Benefits ........................................................................................................................ 37 
11.8.1. Risks to Study participants .................................................................................................... 37 
11.8.1.1. Ivermectin .................................................................................................................. 37 
11.8.1.2. Albendazole ............................................................................................................... 37 
11.8.1.3. Blood sampling by finger prick ................................................................................... 37 
11.8.2. Benefits to study participants ................................................................................................. 38 
11.8.2.1. Anticipated Benefits to study participants ................................................................... 38 
11.8.2.2. Benefit to the community ............................................................................................ 38 
11.9. Ancillary and Post-trial Care ........................................................................................................ 38 
11.9.1. Health care during the trial ..................................................................................................... 38 
11.9.2. Trial Insurance ....................................................................................................................... 38 
11.9.3. Post-trial care ........................................................................................................................ 38 
11.10. Expenses Reimbursement and Incentives ................................................................................... 38 
12. Dissemination and Application of the Results ......................................................................................... 39 
12.1. Result dissemination and publication policy ................................................................................ 39 
12.2. Impact ......................................................................................................................................... 39 
12.3. Training and capacity building ..................................................................................................... 39 
12.4. Authorship and publications ........................................................................................................ 39 
12.5. Data sharing statement ............................................................................................................... 39 
13. References ............................................................................................................................................. 40 
14. Financial Aspects and Conflicts of Interest .............................................................................................. 42 
14.1. Funding the trial .......................................................................................................................... 42 
14.2. Provision of the study drugs ........................................................................................................ 43 
15. Budget and Budget Justification .............................................................................................................. 43 
16. Appendices ............................................................................................................................................. 43 
16.1. Appendix I.  Role of Investigators ................................................................................................ 44 
16.1.1. Protocol development: authors’ contributions ........................................................................ 44 
16.1.2. Role of Investigators .............................................................................................................. 44 
16.1.3. Role of non-engaged collaborators ........................................................................................ 44 

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16.2. Appendix II: Terms of Reference Oversight Committees ............................................................. 45 
16.2.1. Trial Management Group (TMG)  ........................................................................................... 45 
16.2.1.1. Purpose ..................................................................................................................... 45 
16.2.1.2. Membership ............................................................................................................... 45 
16.2.1.3. Responsibilities .......................................................................................................... 45 
16.2.2. Data Monitoring  .................................................................................................................... 45 
16.2.2.1. Independent Safety Monitor/Clinical Trial Monitor (ISM/CTM) .................................... 45 
16.2.2.2. Roles ......................................................................................................................... 45 
16.2.2.3. Responsibilities .......................................................................................................... 45 
16.3. Appendix III: Budget and Budget Justification.............................................................................. 46 
16.3.1. Budget  .................................................................................................................................. 46 
16.3.2. Justification ........................................................................................................................... 46 
16.4. Appendix IV. SPIRIT 2013 Checklist ........................................................................................... 47 
16.5. Appendix VI. Product Characteristics .......................................................................................... 50 
16.6. Appendix VII.  Participant Information Sheets and Informed Consent Forms ............................... 51 
16.7. Appendix VIII.  Guidelines for study nurses managing AEs and SAEs following MDA ................. 57 
 
 
 

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Abbreviations 
 
95% CI  
 
95 percent Confidence Interval  
ACD 
Active Case Detection (cohort) 
ACT  
Artemisinin-based combination therapy  
AE  
Adverse event  
AL  
Artemether-Lumefantrine  
ALB 
Albendazole 
CHW  
Community Health Worker  
Cmax  
Maximum drug concentration  
CM 
Centre MURAZ 
CRF  
Case Record Form  
CSPS 
Centre de Santé et de Promotion 
Sociale (Health Center) 
CSU 
Colorado State University 
DDT 
Dichlorodiphenyltrichloroethane 
DEC 
Diethylcarbamazine 
DMC  
Data Monitoring and Ethics Committee  
DRS 
Direction Régionale de la Santé 
ERC  
Ethics Research Committee  
FDA  
Food and Drug Administration  
GCP  
Good Clinical Practice  
GPELF 
Global Programme for the Elimination 
of Lymphatic Filariasis 
GMP  
Good Manufacturer Practice  
Hb  
Hemoglobin  
ICH 
International Conference on 
Harmonization of Technical 
Requirements for Registration of 
Pharmaceuticals for Human Use 
IRB  
Institutional Review Board  
IRS 
Indoor Residual Spraying 
IRSS 
Institute de Recherche en Sciences de 
la Santé 
ITT  
Intention to Treat  
ISM 
Independent Safety Monitor 
IVM  
Ivermectin  
LF 
Lymphatic Filariasis 
LLIN  
Long-lasting Insecticide Treated Net(s)  
MCD 
Médecin Chef de District 
MDA  
Mass drug administration  
MoH  
Ministry of Health  
NMCP  
National Malaria Control Program  
NTD 
Neglected Tropical Disease(s) 
PCR  
Polymerase Chain Reaction  
RCT  
Randomized Controlled Trial  
RDT  
Rapid diagnostic test  
REC  
Research Ethics Committee  
SAE  
Serious adverse event  
SOP  
Standard Operating Procedure  
SSA 
Sub-Saharan Africa 
STH 
Soil Transmitted Helminth(s) 
TMG  
Trial Management Group  
WHO  
World Health Organization  
 
 
 
 

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1. Title of Research Protocol 
Repeat Ivermectin Mass Drug Administrations for Control of Malaria: a pilot safety and efficacy study 
Short Title: RIMDAMAL study 
 
2. Investigators and Institutions 
2.1. Principle Investigators: 
Dr. Brian D. Foy, PhD (CSU) 
Dr. Rock K. Dabiré, PhD (IRSS) 
2.2. Co-Investigators: 
 
Dr. Haoues Alout, PhD (CSU) 
 
Dr. Noël Rouamba, MD (IRSS) 
2.3. Non-engaged collaborators: 
 
Dr. Sangeeta Rao, PhD (CSU) 
Dr. Roland Bougma, MD (MoH) 
2.3. Institutions: 
CSU - Colorado State University, Fort Collins, CO, USA 
IRSS - Institute de Recherche en Sciences de la Santé, Bobo Dioulasso, Burkina Faso 
CM - Centre MURAZ, Bobo Dioulasso, Burkina Faso 
MoH – Ministry of Health, Ouagadougou, Burkina Faso 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3. Protocol Summaries 
3.1. Trial Registration Data 
Data Category 
Information 
Primary registry and trial 
identifying number 
ClinicialTrials.gov [NCT02509481] 
 
Date of registration 
29 / 07 / 2015 
Secondary identifying 
numbers 
CSU IRB: 15-5796H; Comite d’Ethique d’IRSS: A03-2015/CEIRES 
Source(s) of monetary or 
material support 
The Bill and Melinda Gates Foundation (BMGF) 
Burkina Faso Ministry of Health (MoH) 
Primary Sponsor 
Colorado State University (CSU) 
Secondary Sponsor(s) 
NA 
Contact for public queries 
Dr. Brian Foy, email: Brian.Foy@colostate.edu 
Contact for scientific queries 
Dr. Brian Foy, email: Brian.Foy@colostate.edu 
Public title 
Repeat ivermectin mass drug administrations for control of malaria: a pilot safety and efficacy study 
Scientific title 
Repeat ivermectin mass drug administrations for control of malaria: a pilot safety and efficacy study 
Countries of recruitment 
Burkina Faso 
Health condition(s) or 
problem(s) studied 
• 
Malaria 
• 
Lymphatic Filariasis 
Intervention(s) 
Active comparator (standard treatment): Single mass drug administration of ivermectin (150 µg/kg) + albendazole (400 
mg) performed after the start of the rainy season as part of public health efforts to eliminate lymphatic filariasis. 
Experimental: standard treatment, followed by five more mass drug administrations of ivermectin (150 µg/kg) every 
three weeks thereafter. 
Study type 
Interventional 
Allocation: cluster (village)-randomized control trial; Intervention model: Parallel assignment with 2 arms; Masking: 
Single Blind (Outcomes Assessor) 
Primary purpose: Prevention 
Phase 2/Phase 3 
Date of first enrollment 
17 / 06 / 2015 
Target sample size 
8 clusters (villages) will receive the treatments, ranging from population sizes of approximately 250-800 persons each, 
of which usually >70% meet the inclusion criteria for treatment.  Sample size of patients within each cluster who are ≤5 
years of age and who will be assessed for the primary outcome (clinical malaria incidence) is 69 per cluster or a total of 
552 patients. 
Recruitment status 
Not yet recruiting 
Primary objective 
To determine the efficacy of repeated ivermectin mass drug administrations (150 µg/kg), given to the population of 
eligible patients in enrolled villages, for reducing the cumulative incidence of uncomplicated malaria episodes in 
enrolled village children (≤ 5 years of age) over the course of the treatment    
Key inclusion criteria 
Patients receiving the mass drug administration(s) (MDA):   
• 
Residence in the study site  
• 
Able to understand the information and willing to give consent and assent (parent or guardian consent if 
study participant age is < 18 years) 
Patients monitored for malaria episodes through active case surveillance: 
• 
Children who are residents of the study villages and who are ≤ 5 years of age. 
• 
Parent or guardian consent  
Exclusion criteria 
Patients receiving the mass drug administration(s) (MDA):   
• 
Residence outside of in the study site  
• 
Height ≤ 90 cm 
• 
Permanent disability, serious medical illness that prevents or impedes study participation and/or 
comprehension 
• 
Pregnancy 
• 
Breast feeding if infant is within 1 week of birth 
• 
Known allergy to the study drugs 
 

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Patients monitored for malaria episodes through active case surveillance: 
• 
Permanent disability, serious medical illness that prevents or impedes study participation 
Primary outcome(s) 
• 
Cumulative incidence of uncomplicated malaria episodes in children ≤ 5 years of age (as assessed by active 
case surveillance in study villages 2X/week – malaria episode defined as ≥38.0°C fever or history of fever in 
the last 24 hours + positive rapid diagnostic test for Plasmodium falciparum). 
Key secondary outcomes 
• 
Incidence of new P. falciparum infections acquired (molecular force-of-infection) 
• 
Prevalence and intensity (eggs/larvae per gram of feces) of soil transmitted helminth infections in a subset of 
treated patients between 6-10 years of age. 
• 
Indoor-resting Anopheles mosquito capture rate 
• 
Outdoor-host seeking Anopheles mosquito capture rate 
• 
Adult mosquito age structure (parity rate) in captured mosquitoes 
• 
Plasmodium sporozoite rate/entomological inoculation rate in captured mosquitoes 
• 
Rate of Wuchereria bancrofti in captured mosquitoes 
Safety outcomes 
• 
Adverse events 
• 
Serious adverse events 
• 
Further criteria and monitoring for adverse events may be determined by the Independent Safety Monitor  
 
 
3.2. Narrative Protocol Summary 
3.2.1. Background and Rationale:  Malaria control efforts that have been implemented across SSA 
over the last 10 years have significantly curbed infections, morbidity and mortality (1).  Efforts 
towards vector control have primarily been through massive distribution of LLINs and to a lesser 
extent, increased IRS.  However, gains have stagnated in certain regions.  In many regions vector 
mosquitoes are avoiding LLIN and IRS by biting humans outside and in crepuscular hours when 
people are not in their homes or yet sleeping under LLINs.  Additionally, in Burkina Faso and other 
parts of West Africa, widespread malaria vector resistance to insecticides used on LLIN and for 
IRS are hampering control efforts (2, 3).  Novel tools are needed to circumvent these issues.  The 
implementation of new tools should integrate with existing public health interventions in the same 
communities for maximal cost savings and logistical benefits.  Malaria-endemic communities in 
Burkina Faso and in other parts of SSA and the world often concomitantly suffer from high rates of 
NTDs, including LF.  Integration of NTD and malaria control efforts, especially with tools that target 
both, would be ideal.  Current LF elimination efforts focus on IVM (150-200 µg/kg) + ALB (400 mg) 
MDA occurring once per year, but a more intense effort will be needed in places like the Sud-
Ouest administrative region of Burkina Faso where >13 rounds of MDA have not yet eliminated 
the disease (4, 5).  We and others have demonstrated that the standard dose of IVM is highly 
effective at killing malaria vectors that bite treated people for up to 1 week post treatment (6).  On 
a village scale, IVM MDA occurring during the rainy season significantly affects the survivorship 
and population structure of malaria vectors around treated villages, which significantly reduces 
their ability to transmit malaria parasites for approximately 2 weeks.  We will conduct a pilot trial to 
determine the safety and efficacy of repeated IVM MDA over the rainy season to sustainably 
reduce malaria transmission and clinical disease, while simultaneously integrating with and 
enhancing LF and other NTD control efforts. Such an affect would have profound implications for 
malaria control and elimination across SSA and the rest of the world.  We expect the results of our 
trial to advance integrated control efforts for these important diseases, and inform national, 
regional and international health authorities.     
 
3.2.2. Primary Objective: To determine the efficacy of repeated ivermectin mass drug administrations 
(150 µg/kg), given to the population of eligible patients in enrolled villages, for reducing the 
cumulative incidence of uncomplicated malaria episodes in enrolled village children (≤ 5 years of 
age) over the course of the treatment. 
 
3.2.3. Hypothesis: Repeated IVM MDA starting at the beginning of the rainy season will be well 
tolerated and safe, and will reduce clinical malaria episodes in children by significantly reducing 
malaria transmission among treated villages. 
  
3.2.4. Overview Study Design: Single-blind (outcomes assessor); parallel assignment with 2 arms; 
cluster-randomized control trial to determine the effect of repeated IVM MDA on malaria 

11 
 
transmission and clinical malaria episodes.  The unit of randomization will be the village (cluster).  
8 villages total will be enrolled in two arms. The active comparator arm (4 villages) will receive a 
single standard MDA (IVM; 150-200 µg/kg + ALB; 400 mg) soon after the start of the rainy season, 
while the experimental arm (4 villages) will receive the standard MDA on the same date, plus 5 
more IVM MDA at 3 week intervals thereafter.  The primary endpoint will be the cumulative 
incidence of clinical malaria episodes in children ≤5 year of age within each village.   
   
3.2.5. Sites: This study will be conducted in villages along the main east-west and north-south road 
corridors in the Sud-Ouest administrative region of Burkina Faso. 
 
3.2.6. Study Population: Indigenous Burkinabé from various ethnic groups (Dagara, Bobo, Lobi, 
Mossi, etc.).  The entire eligible population of each enrolled village will receive the MDAs, following 
the standard inclusion/exclusion criteria of MDA for control of microfilaremia caused by 
Wuchereria bancrofti (LF).  Clinical incidence of malaria will be assessed only in children living in 
enrolled villages who are 0-5 years of age, most of whom will not have received any treatment due 
to the standard MDA exclusion criteria of children < 90 cm.      
 
3.2.7. Study Interventions: 2 arms: 1) Active comparator arm – single standard MDA with IVM (150 
µg/kg) + ALB (400 mg) soon after the beginning of the rainy season; 2) Experimental arm, single 
standard MDA with IVM (150 µg/kg) + ALB (400 mg) plus 5 more MDA with IVM alone (150 µg/kg) 
at 3 week intervals thereafter.  CHW from the CSPS and trained by DRS authority of the Sud-
Ouest region will perform the first MDA in both arms with logistical assistance from the study 
investigators.  Repeated MDAs will only occur in the experimental-arm villages, and be performed 
by the study investigators.     
 
3.2.8. Outcome Measures: Primary efficacy outcome – cumulative incidence of uncomplicated 
clinical malaria episodes in children ≤5 year of age.  Primary safety outcome – number and type of 
adverse events in the treated populations of enrolled villages. 
 
3.2.9. Follow-up Procedures: Trained nurses will visit each study village 3 times every 2 weeks over 
the course of the study to investigate and record any adverse events or severe adverse events 
communicated by the study population.  They will also perform active case surveillance 3 times 
every 2 weeks on enrolled village children for clinical malaria episodes, defined as ≥38.0°C fever 
or history of fever in the last 24 hours + positive rapid diagnostic test for Plasmodium falciparum.  
Secondary measures will be collected by the nurses.  
 
3.2.10. Sample Size: Assuming an 80% cumulative incidence of malaria episodes in the control arm 
and an intracluster correlation coefficient of 0.02, 4 clusters are needed per arm and 69 children 
enrolled per cluster to detect a conservative 40% reduction in incidence in the treatment arm with 
80% power and a statistical confidence of 95%. 
 
3.2.11. Data Analysis: Primary efficacy analysis will be the cumulative incidence of uncomplicated 
clinical malaria episodes and will be analyzed using generalized estimating equations (GEE) 
models using poisson distribution to evaluate differences between 2 arms.  The time to malaria 
espisode will be analyzed using a Cox’s proportional hazards model taking into account the 
censored observations throughout the period of study.  The secondary outcome (number of new 
P. falciparum infections acquired over the treatment period) will also be analyzed using a GEE 
model with Poisson distribution. Odds ratios depicting likelihood of malaria with 95% confidence 
limits adjusted for repeated measures over time and adjusted for the cluster will be reported to 
compare the 2 arms. Other potential confounding factors will be considered in a multivariable 
model based on generalized linear regression models.  
 
3.2.12. Partner Institutions: CSU, IRSS, Centre Muraz, Burkina Faso MoH.   
 
 
3.2.13. Funding: The Bill and Melinda Gates Foundation 

12 
 
Table 1.  Summary Table of Study Design, Treatment and Assessment Schedule 
Month (approx) 
1 
2 
3 
4  
5 
6 
Week (approx) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
Phase 
Recruitment 
Phase 
Enrollment Phase 
Treatment Phase; 2 arms; 1) Single MDA, 2) Repeated MDAs 
Post-treatment 
Follow-up Phase 
Pretreatment 
Community 
engagement, 
village 
Enrollment, individual 
consent and baseline 
measures 
 
 
Blood sample 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Stool 
examination 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment by 
Arm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 – Single MDA 
(4 villages) 
 
 
 
 
 
 
MDA: 
IVM+ALB 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2- Repeated 
MDAs 
(4 villages) 
 
 
 
 
 
 
MDA: 
IVM+ALB 
 
 
MDA: 
IVM 
 
 
MDA: 
IVM 
 
 
MDA: 
IVM 
 
 
MDA: 
IVM 
 
 
MDA: 
IVM 
 
 
 
 
 
Active malaria 
case 
surveillance in 
children by 
clinician/nurses 
 
 
 
 
 
 
 
3X 
3X 
3X 
3X 
3X 
3X 
3X 
3X 
3X 
 
 
 
 
 
 
 
 
 
Blood sample and treatment with antimalarials (AL) as needed 
 
 
 
Recording of 
AE’s/SAE’s by 
clinician/nurses 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Questionnaires 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Sampling by 
entomology 
team 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

13 
 
 
 
4. Introduction:  
4.1. Malaria Transmission and Disease in Southwestern Burkina Faso.  Malaria is a major cause of 
morbidity and mortality in Burkina Faso; it has some of the highest transmission intensities in the 
world, as assessed by the entomological inoculation rate (http://www.map.ox.ac.uk/), and there has 
been limited decrease in endemicity of the disease that has been observed in other SSA countries (1).  
The most prevalent species of parasite is Plasmodium falciparum, with less than 20% being 
Plasmodium malariae or P. ovale (7).  A high proportion of persons living in rural, underdeveloped 
villages in endemic areas are infected with the malaria parasites throughout the year, but transmission 
is highly seasonal, beginning with the onset of the rainy season and a subsequent dramatic increase of 
the malaria vector population (8).  As such, the burden of overt clinical disease is on children ≤ 5 years 
of age who have not developed adequate immunity. In the southwest, clinical incidence is between 2-4 
episodes per child per year (9). Clinical incidence in this age stratum spikes at the onset of the rainy 
season, likely due to a sharp increase in transmission events of new parasite clones accompanying 
the rise in mosquito populations at the start of rains (10). 
 
4.2. Malaria Control and Treatment in Burkina Faso.  Treatment options are limited to frontline ACTs 
because of a high prevalence of resistance to older antimalarial drug combinations such as 
sulfadoxine-pyrimethamine and quinine (8).  Due to prevalent infections, especially in rural, 
underdeveloped areas, the National Malaria Control policy is to only treat symptomatic cases of 
malaria in an effort to limit drug resistance to the frontline ACTs.  Outside of anti-malarial treatment, 
most malaria control is achieved through vector control.  LLINs are the primary tools employed for 
limiting vector contact with humans and reducing the vector population through the impregnated 
insecticides in the nets (pyrethroid insecticides).  To a lesser extent, IRS operations using pyrethroid 
and carbamate insecticide classes are performed in some areas.  Unfortunately, mosquito resistance 
to both of these insecticides is widespread, partially due to their widespread application in agricultural 
operations that are prevalent in the same afflicted villages, especially cotton and rice production (11).  
New tools will be critical to achieving malaria control in the country.     
 
4.3. Lymphatic Filariasis and its Control in Burkina Faso.  Lymphatic filariasis is endemic in much of 
SSA, and especially prevalent in parts of West Africa, including southern Burkina Faso.  In Africa, the 
disease is caused by infection with the filarioid nematode Wuchereria bancrofti.  The mosquito vectors 
that transmit LF in Burkina Faso are the same as those that transmit malaria parasites, primarily 
Anopheles gambiae, Anopheles arabiensis, and Anopheles funestus.  Although a general negative 
spatial association between malaria and lymphatic filariasis has been reported in West Africa (12), 
many areas and individual villages are afflicted with both diseases.  LF has been targeted by the WHO 
for elimination by 2020, and GPELF coordinates these elimination efforts with the MoH of endemic 
countries.  The primary method of LF control in Burkina Faso is to perform annual MDAs with IVM (150 
µg/kg) + ALB (400 mg) to the population living in endemic villages (5).  These MDAs clear the 
transmissible microfilaria from infected people to limit parasite spread via the mosquitoes vectors, and 
if performed for at least 5 years, are expected to surpass the estimated fecund life span of the W. 
bancrofti adults worms in infected people.  LLINs are also used in LF control to limit contact of the 
mosquito vectors with people.  MDAs have been performed in Burkina Faso since 2001, almost 3 
times the recommended number of rounds, yet LF prevalence is still stubbornly high in parts of the 
south (5).  The reasons for this continued prevalence is unclear, but it may partly be due to relatively 
low LLIN coverage or use in these regions. Furthermore, there is concern that the widespread 
insecticide resistance observed among the Anopheles vectors in Burkina Faso, especially in cotton 
growing areas, could hamper LF control efforts.  A twice-yearly MDA schedule has recently been 
adopted in 4 health districts of the Sud-Ouest administrative region, which is the study area associated 
with this proposal (5).  However, these MDAs are not specified for a particular time of year, such as the 
rainy season.      
 
4.4. Ivermectin and its Efficacy against Blood Feeding Anopheles Vectors. Ivermectin is a semi-
synthetic avermectin derivative that was first licensed in 1981 as a veterinary drug.  It has a broad 
spectrum of activity against parasitic nematodes and ectoparasites, high potency, and a relatively long 

14 
 
pharmacokinetic persistence in blood and lymph.  The drug is a macrocyclic lactone that targets 
invertebrate-specific ligand gated ion channels, hyperpolarizing their neurons, and causing them 
flaccid paralysis and death (13).  In 1987, IVM was first approved for human-use to control 
onchoceriasis.  Studies on its activity against mosquitoes began in the early 1980’s, where it was soon 
discovered that Anopheles species were particularly sensitive to the drug relative to various Culex and 
Aedes species.  Since then, many reports by us and others have shown its ability to kill and impair 
Anopheles vectors when they ingest blood either directly or indirectly from treated humans and 
animals (Table 2).  Of particular note, the concentrations of ivermectin that occur in human blood after 
ingestion of a standard dose (150 µg/kg) are approximately 2 times the lethal concentration needed to 
kill 50% of Anopheles gambiae, the primary malaria vector in SSA. 
 
Table 2. Efficacy of ivermectin against Anopheles vectors (adapted from Chaccour et al, 2013 Malaria J.)   
Publication 
Method and Dose 
Anopheles species 
Results 
Iakubovich, 1989 (14) 
Membrane and feeding on treated 
rabbits. 
Dose: 340 μg/kg (once, 
subcutaneous) 
An. stephensi 
Death rates among An. stephensi 
fed on rabbits 4, 5 and 
6 days after administration of the 
drug were 93, 70 and 79%, 
respectively. 
Gardner, 1993 (15) 
Feeding on treated dogs 
Dose: 6–24 μg/kg (once, orally) 
An. quadrimaculatus 
Significant increase in mortality. 
LD50= 9.9 μg/kg [6.0, 13.8] 
 
Significant decrease in oviposition 
and egg-hatching from survivors 
Bockarie, 1999 (16) 
Field collections of engorged wild 
mosquitoes before and after MDA 
for LF 
Dose: 400 μg/kg ivermectin +/- 6 
mg/kg DEC (once, orally) 
An. punctulatus 
An. koliensis 
Significant decrease in 9-day 
cumulative survival rate of 
Anopheles spp. collected 1–3 days 
post-treatment (0%) vs those 
collected pre-treatment (67%) 
 
The 48-hr survival rate of An. 
puctulatus collected from two 
houses in the a treated village the 
morning following MDA 
was 31% vs 94% from two houses 
of an untreated village 
Foley, 2000 (17) 
Feeding on one treated human 
volunteer 
Dose: 250 μg/kg (once, orally) 
An. farauti 
12-day cumulative mortality rate of 
mosquitoes was 100%, 
95%, 93%, and 40% for those fed 
0, 7, 10 and 14 days post-treatment 
vs 10% for those fed pre-treatment 
Fritz, 2009 (18) 
Membrane and feeding on treated 
cattle 
Dose: 600 μg/kg (once, 
subcutaneously) 
An. gambiae 
An. arabiensis 
Membrane feeding: LC50 for An. 
gambiae s.l. was 19.8 ± 2.8 ppb; no 
oviposition from mosquitoes fed on 
>10 ppb 
 
Cattle feeding: Total cumulative 
survival of An. gambiae s.s. 
significantly different from controls 
when fed up to 20 days 
post-treatment; no or significantly 
reduced oviposition when fed up to 
17 days post-treatment 
Chaccour, 2010 (19) 
 
Feeding on randomized, treated 
volunteers 
and controls 
Dose: 200 μg/kg (once, orally) 
An. gambiae 
Mean 12-day survival time of 2.38 
days [1.52, 3.24] for mosquitoes 
fed on treated subjects at 1 day 
post-treatment vs 5.52 days [4.65, 
6.4] for mosquitoes fed on 
untreated control Subjects 
No effect on mosquitoes fed on 
treated subjects at 14 days post-
treatment 
*Kobylinski, 2010 (20) 
membrane feedings 
Dose: NA 
An. gambiae 
LC50 = 22.4 ng/ml [18.0, 26.9]. At 
sub-lethal concentrations, 
significantly reduced mosquito re-
blood feeding rates and 
a second ivermectin blood meal, 
even at a decreased concentration, 
further increased mortality 
 
*Sylla, 2010 (21) 
Field collections of engorged wild 
An. gambiae 
 
5-day cumulative survival of An. 

15 
 
mosquitoes before and after MDA 
for onchocerciasis 
Dose: 150 μg/kg ivermectin (once, 
orally) 
An. arabiensis 
gambiae s.s. was significantly 
reduced from 3 treated villages vs 
pair-matched control villages 
*Butters, 2012 (22) 
Membrane feeding 
Dose: NA 
An. gambiae 
Sub-lethal concentrations (LC25 & 
LC5) caused significant knockdown 
and reduced recovery rates 
Fritz, 2012 (23) 
Membrane feeding 
Dose: NA 
An. arabiensis 
LC50 = 7.9 ppb [6.2, 9.9]; 
oviposition among survivors was 
significantly reduced at ≥7 ppb 
Bastiaens, 2012  
Feeding on treated Swiss mice, 
Wistar rats and Cynomolgus 
monkeys 
 
Dose: 200–400 μg/kg (different 
intervals, orally) 
An. stephensi 
3-day cumulative mortality of 
mosquitoes fed on treated 
mice, rats and monkeys 
significantly differed from controls 
when fed up to 2, 4 and 3 days 
post-treatment, respectively 
*Kobylinski, 2012 (24) 
Membrane feeding 
Dose: NA 
An. gambiae 
Sub-lethal concentrations 
significantly inhibited P. falciparum 
sporogony when fed prior to, 
concurrent with, and 6 and 9 days 
after infection with gametocytes 
*Alout, 2014 (6) 
Field collections of engorged wild 
mosquitoes before and after MDA 
for LF or onchocerciasis 
Dose: 150 μg/kg ivermectin, +/- 400 
mg albendazole (once, orally) 
An. gambiae 
An. gambiae s.l. captured in treated 
villages 1–6 days post-treatment 
had significantly reduced survival 
vs. those caught pre-MDA and 
those caught >7 days post-
treatment 
* denotes publications from members of the study team 
LC5, LC25, LC50; the lethal concentrations calculated to kill 5%, 25% and 50% of treated mosquitoes.   
 
 
4.5. Efficacy of Ivermectin MDA to Interrupt Malaria Transmission. In the two decades following the 
initial studies demonstrating the efficacy of ivermectin for killing mosquitoes, the concept was mostly 
limited to ideas centered on total control of a vector population from treating individual hosts and 
testing direct mortality effects against vectors that ingested the drugs in host blood meals.  Over the 
last 5 years, these ideas around malaria vector control were refined, and experiments were undertaken 
to test whether MDA of ivermectin in West African villages for onchocerciasis and/or lymphatic filariasis 
(LF) control, when applied during malaria transmission seasons, could significantly reduce the vectorial 
capacity of vectors biting the community (6). The effects have been strong and consistent.  Single 
MDAs achieving ≥ 75% drug coverage reduced the daily probability of A. gambiae s.l. (indoor-resting, 
blood fed mosquitoes) survival by ~11% for approximately one week.  This mortality effect results in 
~25% reduction in parity rate of mosquitoes collected host-seeking outdoors for approximately 2 
weeks, which demonstrates that the age structure of the vector population significantly shifts to 
younger age classes around the village.  As young mosquitoes have not lived long enough to become 
infectious, this results in at least a ≥78% reduction in vectorial capacity, and significant reductions 
(>77%) in sporozoite rates for two weeks following the MDA (21, 25).  While very transient, these 
reductions are in-line with changes seen in A. gambiae populations around SSA villages when IRS has 
been implemented (26) or LLINs distributed (27) and it is estimated that LLINs reduce, on average, 
incidence of clinical malaria by ~50% (28).  It has been argued that repeated IVM MDAs might achieve 
sustained malaria control if performed repeatedly and during the rainy season where seasonal 
transmission is prevalent (29).   
 
4.6. Modeling of Repeated Ivermectin MDAs for Sustained Effects against Malaria Vectors, 
Sporozoite Transmission, Malaria Prevalence and Disease.  The first modeling performed on the 
expected effects of ivermectin on malaria transmission was by Foley et al (17).  These data were 
based on experiments showing significantly decreased mosquito survivorship after feeding on a single 
IVM-treated volunteer, and the modeling focused on changes in the human inoculation rate relative to 
the proportion of human or animals dosed in the presence of zoophilic or anthropophilic vectors.  Ten 
years later, Sylla et al (21) used mortality data from wild mosquitoes observed in the field following a 
MDA for onchocerciasis control to model the predicted changes in the basic reproductive rate of 
malaria based on differential MDA coverages and treatment intervals.  Both papers predicted 
significant effects on malaria transmission with only modest drug coverage.   Shifts in Anopheles 

16 
 
 
 
Figure 1.  Modelled effect of 6 rounds of IVM MDAs 
on malaria in Burkina Faso.  The left column assumes 
treatment at 3 week intervals, and the right column 
assumes treatment at 2 week intervals.  Colored arrows 
and lines in the top 4 graphs and matching colored bars 
in the bottom two graphs represent the date of the first 
MDA with respect to the start of the rainy season (Time 
0).  Model from Dr. Hannah Slater – Imperial College. 
vector population age structure were subsequently modeled in Foy et al (29), and field data mirroring 
this model were then observed and reported in Alout et al  (6).  Most recently, Slater et al (30) modeled 
how IVM MDAs could enhance and shorten malaria elimination efforts when combined with ACT 
administrations.  A primary advance of this modelling effort was that some of the outcomes were 
clinical measures, namely RDT positivity in ≤5 year 
olds.  Following from this model, Dr. Slater recently 
used data from Alout et al in her model, and with the 
data on the patterns of seasonal malaria in Burkina 
Faso, used it to model the anti-malarial effects of 
repeated IVM MDAs if performed at 2 or 3 week 
intervals and at different starting dates with respect to 
the beginning of the rainy season. The output of the 
model is shown in Figure 1, where it predicts changes 
in mosquito density, clinical incidence in ≤5 year olds, 
and cases averted in ≤5 year olds.  If IVM MDAs are 
limited to 6 rounds (as in this pilot study), the most 
significant effects on predicted clinical incidence is 
IVM MDAs performed at 3 week intervals and initiated 
50-150 days into the rainy season. 
 
4.7. Safety of Ivermectin in Humans.  Ivermectin binds to 
the glutamate-gated chloride channel that is present in 
invertebrates (eg. nematodes and insects), but not 
present in vertebrates.  It can only weakly bind to the 
distantly-related glycine-gated chloride channel in 
vertebrates, but these are sequestered in the central 
nervous system behind the blood-brain barrier, which 
prevents access to the large macrocyclic lactone drug.  
These characteristics are likely reasons for 
ivermectin’s exceptional safety profile.  Since its 
approval for human applications in 1987, more than 
1.8 billion doses of ivermectin have been administered 
across the world.  The standard indicated dose of 
ivermectin to control onchocerciasis and lymphatic 
filariasis is 150-200 µg/kg.  Because it is mass 
administered to impoverished communities in remote locations who often have no scales, dosing in 
these areas is based on height alone.  It is one of a handful of drugs that can be administered to 
communities via MDA and by community health workers (CHW).  Most AEs associated with IVM 
treatment drug are mild, Mazzotti-type reactions linked to parasite lysis and clearance in heavily-
parasitized patients that occurs after their first MDA (31).  The drug is contraindicated in persons from 
areas endemic for Loa loa who also take DEC, because some neurological SAE in heavily Loa-
parasitized persons have been reported exceptionally.  Caution and a physician’s consult are indicated 
before IVM is used by pregnant and breast-feeding women.  However, in a retrospective MDA study in 
Liberia, 200 women treated with the drug were determined later to be pregnant; in comparison with 
untreated mothers in the same population, no significant differences in birth defect rates, development 
status or disease patterns could be found (32).  These findings were later confirmed in hundreds of 
other women from Cameroon (33), Mali (34), Ghana (35) and Uganda (36), and now pregnant women 
in highly onchocerciasis-endemic areas who are at risk of loss of sight are no longer excluded from 
ivermectin treatment (31).  Similarly, the concentrations of IVM in milk from breast-feeding mothers is 
very low, and it now recommended that lactating women from highly onchocerciasis-endemic areas 
who are at risk of loss of sight take IVM if they are breast-feeding children >1 week of age.  Current 
recommended standard dosing regimens for MDA campaigns is 1 or 2 times/year depending on the 
severity of the disease in the area, and for individual patients, retreatment may be considered after a 
3-month interval (see Appendix V, pg. 50).  Studies reporting repeated treatment of communities and 
individuals are numerous, and all have reported no or limited AEs (Table 3).   There are currently two 

17 
 
registered trials in ClinicalTrials.gov who are planning repeated treatment regimens that are more 
frequent than currently indicated (Table 3). 
 
Table 3. Studies reporting frequent, repeated ivermectin administrations and their safety.  
Publication or Trial 
Patient Populations 
Dose 
Frequency 
Safety Outcome 
Duke, 1990 (37) 
36 O. volvulis-infected 
Guatamalan patients 
150 µg/kg 
every month for 
either 4, 8 or 12 
months 
No AEs/SAEs reported 
Duke, 1991 (38) 
30 O. volvulis-infected 
Liberian patients 
~100 µg/kg 
every 2 weeks for 
10 weeks 
No AEs/SAEs reported 
Duke, 1992 (39) 
36 O. volvulis-infected 
Guatamalan patients 
150 µg/kg 
every 3 months for 
either 9, 12 or 31 
months 
No AEs/SAEs reported 
Ismail, 1996  
14 W. bancrofti-infected Sri 
Lankan patients 
400 µg/kg 
11 doses every 2 
weeks  
Mild AEs in 13 subjects but only after the 
first dose - suggestive of a link to 
microfilaria death and clearance; localized 
inguinal/scrotal reactions linked to a 
macrofilaricidal effect. 
Awadzi, 1999 (40) 
85 O. volvulis-infected 
Ghanian patients 
150-800 µg/kg, then 
400-800 µg/kg 
2 doses, 
administered on 
days 1 and 4 
No AEs/SAEs reported 
Kamgno, 2004 (41) 
&  
Gardon, 2002 (42) 
155 O. volvulis-infected 
Cameroonian patients 
150 µg/kg 
every 3 months for 
3 years (12 doses) 
Significantly fewer AEs relative to groups 
receiving one dose annually, including 
fewer sundry pains, back/wrist pain, 
headache, fever, pruritis, & oedematous 
swellings.  No SAEs reported. 
Guzzo, 2002 (43) 
15 healthy American 
patients 
347-594 µg/kg 
3 times over 1 
week 
AEs similar between IVM and placebo and 
did not increase with dose.  No SAEs 
reported; CNS toxicity not detected. 
Multiple versus single 
dose of ivermectin for 
the treatment of 
strongyloidiasis 
(STRONGTREAT) 
NCT01570504 
strongyloidiasis patients 
200 µg/kg 
Days 1, 2, 15, 16 
Not yet reported 
Efficacy and safety of 
ivermectin against 
dengue infection 
NCT02045069 
dengue patients 
200-400 µg/kg 
2-3 times in a 3-day 
period 
Not yet reported 
 
4.8. Integration of malaria and NTD control efforts globally and in Burkina Faso.  The calls for and 
efforts to integrate NTD and malaria control programs have been numerous (44, 45) 
(http://www.malariaconsortium.org/).  Integration of these programs is expected to particularly affect 
anemia in endemic communities, as parasitic worm and malaria parasite infections can cause anemia 
alone, and co-infections can exacerbate this health problem (46). The most common NTD control 
platform is MDAs.  Ivermectin effectively clears treated persons of Wuchereria and Onchocerca 
microfilaria, intestinal roundworms (Ascaris lumbricoides), whipworms (Trichuris trichiura) and 
threadworms (Strongyloides stercoralis), while albendazole has strong effects against roundworms 
and hookworms (47). Integration is not only expected to benefit the health of individuals, but there are 
expected cost savings and logistical benefits.  Integrated control of NTDs in rural Burkina Faso, 
particularly control of LF and STHs, has been successful in gaining increased financial support and 
increasing overall NTD MDA coverage (44).  However, communities of the south and southwest 
continue to have high LF prevalence even after 13 rounds of MDA (4), and high rates of infection with 
STHs (5) (GAHI; www.thiswormyworld.org).  A more intense and focused MDA effort for these regions 
is required.  Importantly, these same communities suffer from intense rainy-season malaria 
transmission from June-October.  Further, many STHs critically expand their transmission and 
prevalence at the beginning of the wet season: STH eggs and preparasitic larvae only survive in moist 
soils and malaria vectors need the rains to proliferate.  Ivermectin and albendazole MDA have a clear 
potential to integrate control of LF, STH and malaria with a single tool, but a) repeated ivermectin 

18 
 
MDAs will be necessary for maximum effectiveness and b) the repeat MDA timing with respect to 
frequency and season needs to be optimal.  Repeated ivermectin MDA starting at the beginning of the 
rainy seasonal is expected to a) achieve sustained transmission-blocking when mosquito numbers are 
low and most vulnerable, b) prevent rapid re-infection of de-wormed people with STH that survive in 
the soil, and c) achieve maximal MDA coverage, as it is commonly observed that drug administrations 
are missed to people who are absent on the day of a yearly MDA.   
 
5. Justification for the study 
5.1. Why is this study needed now?  While global malaria control efforts have succeeded in significantly 
reducing the burden of malaria since the turn of the millennium, these gains have stagnated and are in 
real danger of reversing.  In the Greater Mekong subregion, artemesinin resistance in Plasmodium 
falciparum is rising, and threatens to spread to other regions of the world.  As SSA harbors the majority 
of the global burden of malaria, entry of ACT-resistant parasites into the region would be disastrous; 
there are currently few registered alternatives to treatment with artemesinin-based therapies 
(www.mmv.org).  Furthermore, SSA, and Burkina Faso in particular, is now dealing with widespread 
resistance of mosquito vectors to the insecticides used in LLINs and IRS (11).  The data are very 
alarming. A recent study using standard WHO susceptibility assays showed that Anopheles gambiae 
from southwest Burkina Faso are >1000-fold resistant to deltamethrin, permethrin and DDT 
insecticides used on LLIN and in IRS.  Additionally, the latest LLINs, even when new, killed less than 
half of these mosquitoes in exposure studies, while susceptible reference mosquito strains exhibited 
nearly 100% mortality (2).  New ways to control malaria, especially those that can re-purpose current 
drugs such as ivermectin, are needed soon.  Finally, integration of malaria and NTD control efforts are 
needed to preserve gains against these diseases and to save in costs and logistical complications of 
treating these diseases in remote communities.         
 
5.2. Other relevant ongoing research.  The WHO international Clinical Trials Registry Platform and 
ClinicalTrials.gov were queried for trials that have or plan to study the effects of ivermectin treatment 
on malaria transmission or disease.  One trial in Burkina Faso has been completed and the results 
have been published (48).  This double-blind placebo-controlled study enrolled individual Burkinabé 
patients who had uncomplicated Plasmodium falciparum infections and treated them with either 
artemether-lumefantrine alone or in combination with ivermectin (200 µg/kg), given in either one or two 
doses.  The study showed that the combination of these drugs is safe, that the ivermectin combination 
did not change the efficacy of the AL to clear the patients’ infections, and that mosquitoes fed on the 
treated patients’ blood suffered significant mortality compared to controls.  These data further support 
investigating ivermectin for malaria transmission control and elimination.  Another study is planned, but 
not yet registered, in Kenya. Similar to the previous study, the investigators will enroll individual 
patients who have uncomplicated Plasmodium falciparum, but will treat them with higher doses of 
ivermectin (300 & 600 µg/kg/day for 3 days) plus a different ACT (dihydroartemesinin-piperaquine; 
DP), and assess safety, treatment efficacy, pharmacokinetics, and mosquito survival when fed on the 
blood of treated patients.  Both of these studies, while important, do not examine the efficacy of 
ivermectin by itself and do not examine ivermectin’s effects when administered to whole village 
populations in an MDA strategy for malaria transmission and disease control in a natural setting.  The 
current study will research this important advancement.         
 
6. Hypothesis.  IVM MDAs to the populations of Burkinabé villages (standard clinical dose (150 µg/kg) with 
standard exclusion criteria), when repeated every 3 weeks and starting at the beginning of the rainy 
season, will be well tolerated, and result in significant reductions in Plasmodium spp. transmission by the 
local mosquito vectors over the course of the treatment, which will significantly reduce the cumulative 
incidence of uncomplicated malaria episodes in children ≤5 years of age who live in the treated villages.   
  
 
7. Aim & Objectives.  The overall aim of the study is to compare the effect of standard IVM + ALB MDAs 
given once to Burkinabé village populations at the start of the rainy season, with those same MDAs plus 
additional MDAs of IVM alone, given every 3 weeks thereafter 5 more times, on reducing clinical 
uncomplicated malaria episodes in children ≤5 years of age who live in the villages. 
 

19 
 
 
Figure 2.  From Tiono et al., 2014. PLoS1.  The monthly 
incidence rate of malaria in children ages 0-5 years old 
from Sept. 2009 to Sept. in 2010 in the Cascades region of 
Southwestern Burkina Faso. 
0.00
2.00
4.00
6.00
8.00
10.00
Sep Nov Jan Mar May Jul Sep
Incidence rate per person 
year (95% CI)
7.1. Primary objective. To determine the safety and efficacy of one standard IVM + ALB MDA plus 5 
additional MDAs of IVM alone, given every 3 weeks, for reducing uncomplicated malaria episodes in 
children ≤5 years of age who live in the treated villages. 
 
8.  Design and Methodology. 
 
8.1. Overview of Design. Single-blinded (Outcomes Assessor), cluster-randomized control trial, parallel 
assignment with 2-arms, to examine the primary objective of repeated IVM MDAs for reducing 
uncomplicated malaria episodes in children from treated villages.  The village will be the cluster unit, 
and 4 villages with populations between 250-800 persons will be enrolled in each arm.  Arm 1 will 
receive a single MDA; arm 2 will receive repeated MDAs. Secondary objectives will be measured from 
parasitological data acquired from a subset of treated patients and entomological data acquire from 
mosquitoes caught in the study villages (secondary objectives 8.2.3 – 8.2.7). 
  
8.2. Secondary Objectives. 
 
8.2.1. To determine the effect of repeated IVM MDAs on the number of new Plasmodium clones 
acquired over time in a subset of treated patients 
8.2.2. To determine the effect of repeated IVM MDAs on the prevalence and intensity (eggs/larvae per 
gram of feces) of soil transmitted helminth infections in a subset of treated patients between 6-10 
years of age 
8.2.3. To determine the effect of repeated IVM MDAs on the indoor-resting Anopheles mosquito 
capture rate 
8.2.4. To determine the effect of repeated IVM MDAs on the outdoor-host seeking Anopheles 
mosquito capture rate 
8.2.5. To determine the effect of repeated IVM MDAs on the adult mosquito age structure of captured 
mosquitoes 
8.2.6. To determine the effect of repeated IVM MDAs on the Plasmodium sporozoite 
rate/entomological inoculation rate in captured mosquitoes 
8.2.7. To determine the effect of repeated IVM MDAs on the rate of Wuchereria bancrofti in captured 
mosquitoes 
 
8.3. Design Considerations.    
 
8.3.1. Malaria epidemiology in Burkina Faso.  Understanding the epidemiology of malaria 
transmission and disease in Burkinabé villages is key to understanding the study design.  In rural 
southwestern Burkina Faso villages, malaria is hyper-endemic, meaning that most people are 
infected with malaria parasites during the rainy 
season.  A cross-sectional survey of one of the 
villages in our study area in September, 2014 
showed that 52% of people tested were positive 
for Plasmodium trophozoites by slide 
microscopy, and 78% of children ≤5 years of 
age tested were positive.  These data generally 
translates to 80-90% infection rates if molecular 
analyses were used.  The Burkina Faso National 
Malaria Control policy is to only treat 
symptomatic cases with antimalarial drugs (8) in 
order to preserve the efficacy of the frontline 
drugs, although intermittent preventive drug 
treatment of pregnant women and children is 
beginning to be implemented in certain regions.  
Because of the high prevalence of infections, 
the burden of disease is on children ≤5 years of 
age who have not yet developed strong immunity from years of exposure to Plasmodium 
infections.  This age group experiences a spike in malaria episodes at the start of the rainy season 

20 
 
when mosquito numbers rise, and the higher rate of malaria episodes is sustained until the rains 
diminish (9) (Figure 2).   
 
Rural villages tend to be populated by farmers and pastoralists, and they are made up of clusters 
of households surrounded by their fields.  Thus, most villages are separated from neighboring 
villages by ≥1 km, with fields and bush interspaced between them.  Anopheles vectors breed in 
and around villages in standing water pools, and they get most of their blood meals from the 
human population of the village, so they tend not to fly more than 1 km from their breeding sites.  
In this way, the majority of Plasmodium transmission occurs within the village, between neighbors, 
relatives and family members via the biting mosquitoes, and a minority of transmission is thought 
to occur from human or mosquito immigration and emigration between villages.  It is presumed 
that the spike in malaria episodes at the start of the rains within the ≤5 year old age group (Fig. 2) 
coincides with new infections from new Plasmodium clones transmitted by biting mosquitoes and 
acquired from other gametocytemic individuals in the same village.   
 
8.3.2. The focus on the village as the cluster unit.  The study will enroll entire villages as the cluster 
unit.  This is necessary because patients in each village will have strong intra-cluster associations 
as most Plasmodium transmission occurs between the village residents. Furthermore, IVM MDA is 
given to all persons of a village who meet the inclusion/exclusion criteria, which generally is ≥70% 
of the population (6).  As we have demonstrated, IVM administered to such a high proportion of 
people kills many of the mosquitoes who randomly ingest blood from people in the village 
approximately every 1 or 2 days (6); any one mosquito will have a high probability of ingesting 
blood from a treated person in the week following the MDA when mosquito-lethal concentrations 
of IVM are circulating in the blood of the village population.  This effect reduces the number of 
mosquitoes surrounding the village and limits the remainder from transmitting Plasmodium 
between humans within the village because most are too young to have developed infectious 
parasites in their salivary glands. 
 
8.3.3. The focus on children ≤5 years of age as the patient population for measuring the 
primary outcome.  Most village children between ≤5 years of age are not ≥90 cm in height, and 
so most will not be treated with IVM or ALB.  As explained previously, these drugs do not affect 
Plasmodium infections in a patient, rather they are anti-helmintics administered to clear 
Wuchereria bancrofti microfilaremias in patients to help eliminate LF, and also to clear STH 
infections in patients, however ivermectin also has anti-mosquito effects.  The mode of action of 
ivermectin on malaria is against the mosquito that transmits parasites among the village 
population. Children ≤5 years of age are the subset of the village population who suffers the most 
from malaria episodes due to inadequate anti-Plasmodium immunity being infected with new 
Plasmodium clones when the rains come and the mosquito population rises and begins to bite 
them.  Thus, this population stratum is expected to benefit the most from the anti-mosquito effects 
of ivermectin. 
 
8.3.4. The intervention model - parallel assignment with 2 arms.  This is a pilot study aimed 
primarily at determining whether repeated ivermectin MDA, occurring at the beginning of the rainy 
season, can limit Plasmodium transmission by mosquitoes and subsequently reduce malaria 
disease.  The broader implementation goal is to achieve integrated control of NTDs and malaria 
that commonly afflict the same population of patients in Burkina Faso and similar populations 
across SSA.  The current, once-yearly IVM MDAs are being used for LF control, but they have 
been sub-optimal for eliminating LF in Burkina Faso.  It is expected that new and integrated 
control measures will be needed to achieve both LF elimination and better malaria control in the 
same villages.  Repeated IVM MDAs will inherently be a novel measure that is expected to 
integrate the control of these two different diseases. The eligible populations of four villages, 
randomized to the control arm, will receive the active comparator MDA only once, consisting of 
150 µg/kg of ivermectin + 400 mg albendazole.  At the same time, the eligible populations of four 
other villages, randomized to the treatment arm, will receive the same MDA.  However they will 
subsequently receive 5 more MDAs in three week intervals after the first, consisting of 150 µg/kg 
of ivermectin only.   

21 
 
 
8.4. Study setting 
8.4.1. Study areas.  The study will be conducted in villages along the main east-to-west and north-to-
south travel corridors in the northern Sud-Ouest (South-West) administrative region in Burkina 
Faso that borders Ghana to the east and Cote d’Ivoire to the south.  The villages will be located 
near the town of Diebougou.  This region is mostly populated by villages that have mud-brick 
houses and thatch or corrugated metal roofs, and the population is mostly agricultural workers 
who grow millet, corn and cotton.  The region is endemic for NTDs, including lymphatic filariasis, 
onchocerciasis, and STHs. The area spans a north-south cline where malaria transitions from 
being seasonal to perennial, and where malaria is hyper-endemic during the rainy season.  
Community malaria prevalence is generally >50%, and >70% in children ≤5 years of age during 
the rainy season.   
 
8.5. Eligibility criteria. 
8.5.1. Population of the study villages for receiving MDAs.  Both Arms; one mass drug 
administration with IVM (150 µg/kg) + ALB (400 mg); Experimental Arm only: IVM (150 µg/kg) 
MDA 5 more times every 3 weeks thereafter. 
8.5.1.1. 
Inclusion criteria 
• 
Residence in selected study village  
• 
Able to understand the information and willing to give consent and assent (parent or 
guardian consent if study participant age is < 18 years) 
 
8.5.1.2. 
Exclusion criteria 
• 
Residence outside of the study site  
• 
Height ≤ 90 cm 
• 
Permanent disability or serious medical illness that prevents or impedes study 
participation and/or comprehension 
• 
Pregnancy 
• 
Breast feeding if infant is within 1 week of birth 
• 
Known allergy to the study drugs 
• 
Loa loa as assessed by travel history to Angola, Cameroon, Chad, Central African 
Republic, Congo, Democratic Republic of Congo, Equatorial Guinea, Ethiopia, Gabon, 
Nigeria, and Sudan. 
• 
Enrolled in any other active clinical trials 
 
 
 
8.5.2. Active case surveillance cohort 
8.5.2.1. 
Inclusion criteria 
 
Residence in selected study village 
 
≤5 years of age  
 
Parent or guardian consent  
 
8.5.2.2. 
Exclusion criteria 
 
Residence outside of the study site  
 
Permanent disability, serious medical illness that prevents or impedes study participation  
 
8.6. Interventions 
8.6.1. Mass drug administrations.  In the first phase of the study, 8 villages will be randomized to 
one of two arms: 
1) Active Comparator Arm: A single MDA with IVM (150 µg/kg) + ALB (400 mg), given at the 
beginning of the rainy season (approximately the middle of May) 
2) Experimental Arm: A single MDA with IVM (150 µg/kg) + ALB (400 mg), given at the 
beginning of the rainy season (approximately the middle of May).  In addition, 5 more MDAs 
with IVM (150 µg/kg) only, given every 3 weeks after the first MDA. 
 

22 
 
8.6.1.1. 
Ivermectin (IVM).  3 mg tablets (Merck Sharpe and Dohme) will be administered by 
CHWs associated with the CSPS within the Sud-Ouest district who are responsible for 
distributing MDA for NTD control in this region under the MoH and the DRS.  The CHWs will 
go door-to-door in each village, evaluate which household members are eligible to receive 
treatment, and administer the dose based on the patient’s height as a proxy for their weight, 
as indicated in the drug package insert: 90-119 cm = 1 tablet, 120-140 cm = 2 tablets, 141-
158 cm = 3 tablets, >158 cm = 4 tablets. (see Appendix V, Product characteristics, pg. 50)    
 
8.6.1.2. 
Albendazole (ALB).  One 400 mg tablet (GlaxoSmithKline) will be administered to each 
patient by the CHWs at the same time as the IVM tablets.  The CHWs will go door-to-door in 
each village, evaluate which household members are eligible to receive treatment, and 
administer the dose.      
       
8.6.2. Procedures for Drug Import, Handling and Accountability.  The drugs used in this study are 
procured by the NTD program within the Burkina Faso MoH, who place orders with the Donors 
(World Health Organization, Mectizan Donation Program, Global Program for the Elimination of 
Lymphatic Filariasis).  The Burkina Faso MoH covers the administrative, customs and transit 
costs, receives the drugs at the ports of entry, and stores them in the warehouse of the MoH 
Disease Control Directorate.  The Sud-Ouest DRS, located in the town of Gaoua, receives the 
drugs from supply trucks sent by the MoH NTD Program office, and stores them in their pharmacy.  
Each DRS keeps an inventory of the drug supply they have on hand.  The drugs for this study will 
be provided from the stocks maintained by the pharmacy at the Sud-Ouest DRS and supplied to 
the MCD/CSPS in which the study villages are located.  CHWs associated with the MCD/CSPS 
and affiliated with the study will distribute the first round of drugs, and maintain and share records 
of the patients who received the drugs with the study investigators.  Subsequent IVM MDA in the 
experimental arm villages will be conducted by the study investigators and nurses with 
DRS/MCD/CSPS assistance. 
   
8.6.3. Product Labelling and Storage.  Study drugs are pre-labelled by the manufacturers (IVM – 
Merck Sharp & Dohme BV, Netherlands, ALB – GlaxoSmithKline) in both French and English.  
They will be stored in a secure area, with access limited to the MCD staff and study investigators.  
Products are stored under appropriate product-specific storage conditions as indicted on the drug 
package label (see Appendix V, Product characteristics, pg. 50).    
 
 
8.6.4. Product Accountability.  The site-study investigators will liaise with the MCD & CSPS to 
ensure correct handling of study drug so that:  
8.6.4.1. 
Deliveries of study drug from the DRS are correctly received by a responsible person 
(e.g. pharmacist assistant).  
8.6.4.2. 
Accurate records are maintained for the receipt of study drug, for the dispensing of study 
drug to subjects and for any returned drug.  
8.6.4.3. 
Certificates of delivery and return must be signed preferably by the investigator or 
authorized personnel and copies retained in the investigator file.  
8.6.4.4. 
Study drug is to be handled and stored safely and properly and in agreement with the 
given storage instructions.  
8.6.4.5. 
The study drug is to be prescribed only by the authorized DRS medical director, MCD 
medical director or the study co-investigators that are medical doctors.  
8.6.4.6. 
Study drug is dispensed only to study subjects in accordance with the protocol.  
8.6.4.7. 
At the end of the study, delivery records must be reconciled with records of usage and 
returned stock. Any discrepancies must be accounted for in writing.  
 
8.6.5. Removal of Patients from Treatment or Assessment. Patients can discontinue from the 
study for any of the following reasons. 
1. Screening error resulting in incorrect enrollment (discovery that the subject did not meet the 
required inclusion/exclusion criteria) 

23 
 
2. Withdrawal of assent/consent at any stage or the subject not willing to continue in the study 
(or withdrawal of consent by the parent/guardian to keep his or her child enrolled. 
3. Suspected or confirmed allergic reaction to the study drugs. 
4. Safety reasons as judged by the investigators or the ISM. 
5. Other 
  
 
Patients who discontinue in the study or withdrawal their assent/consent will always be asked 
about their reason(s) for discontinuing and about any adverse events they may have 
experienced.  If a person discontinues, it should be determined whether: 
1. They discontinue treatment, but continue their consent for the data capture and continue 
follow-up.  These subjects will be considered ‘off drug study/on study” and follow the same 
schedule of events except for participation in the interventions 
2. They discontinue all future activities in the study, but continue their consent for the data 
captured up to that point to be used in the research. 
3. They discontinue all future activities in the study and withdrawal their consent for any past 
data captured to be used in the research. 
These scenarios will be recorded in Case Record Forms (CRFs).  Subjects that have 
discontinued the study prematurely will not be replaced. 
8.6.6. Discontinue from storage of blood for future studies.  If a subject discontinues, it will also 
be established whether the subject: 
1. Continues their consent for the long-term storage of any blood or fecal samples collected. 
2. Withdrawals consent for long-term storage of the blood or fecal sample for any future 
studies prior to de-identification of the dataset. 
When a subject’s consent for long-term storage is withdrawn, the stored sample will be 
destroyed and the withdrawal noted in the CRF.  If the request is received after the dataset has 
been anonymized, the stored sample can no longer be withdrawn. 
8.6.7. Adherence to study intervention protocol and strategies for retention. 
 
8.6.7.1. 
Adherence to study protocol and MDA.  Study participants will be reminded of 
upcoming MDA distributions by the study investigators during active case surveillance visits 
the week prior to the intervention, and asked to be present on the morning of that day in 
order to receive the study drugs from the CHWs.  The week prior to the MDAs is also when 
nurses will check the pregnancy status of enrolled women of child-bearing age. Similarly, 
parents whose children are enrolled in the active case surveillance will be reminded of 
upcoming visits by the study nurse and be given mobile phone contact information should 
they suspect a malaria episode in their child on days when the nurse is not scheduled to visit.  
All relevant information will be recorded on the appropriate sections of the CRF. 
 
8.6.7.2. 
Strategies for retention. During screening, potential participants will be asked whether 
they will be willing and able to comply with the frequent intervention and follow-up schedule, 
and whether they need to travel out of the study area for an extended period during the 
follow-up period. Patients referred to the CSPS/hospital for any AE or SAE suspected to be 
related to the study interventions will be reimbursed for the transportation costs they may 
incur going to and from the clinic (see Table 4, Expenses reimbursement and incentives, 
page 38). 
 
8.6.7.3. 
Prior and concomitant therapy.  All concomitant medications taken during the study 
will be recorded in the appropriate sections of the CRF with indication, dose information, and 
dates of administration. 
 
8.6.7.4. 
Permitted medications during active case surveillance.  During active case 
surveillance in the cohort of enrolled children ≤5 years old, if a subject is diagnosed with 
malaria, the investigators will prescribe Artemether-Lumefantrine (AL) antimalarial treatment 

24 
 
for uncomplicated cases per the National Malaria Control Program guidelines, or refer 
complicated cases to the CSPS/MCD.  
 
8.6.7.5. 
Self-medications.  Patients will be counseled to avoid self-medicating for malaria, 
specifically antimalarials that are not prescribed within the trial protocol: chloroquine, 
halofantrine or mefloquine.    
 
8.7. Endpoints/Outcome Measures. 
 
8.7.1. Primary efficacy outcomes. 
8.7.1.1. 
Cumulative incidence of uncomplicated malaria episodes in enrolled study village 
children ≤5 years of age. Uncomplicated malaria episodes in this cohort will be assessed by 
active case surveillance performed by household visits from study nurses, conducted 3 times 
over each 2 week period during the entire study period.  An uncomplicated malaria episode 
will be defined as axillary temperature ≥38.0°C and/or history of fever in the last 24 hours 
and a positive rapid diagnostic test (RDT) for Plasmodium falciparum. 
 
8.7.2. Secondary outcomes. 
8.7.2.1. 
Incidence of new Plasmodium falciparum clones acquired in a subset of patients over 
the study period. 
8.7.2.2. 
Prevalence and intensity (eggs/larvae per gram of feces) of soil transmitted helminth 
infections in a subset of treated patients between 6-10 years of age. 
8.7.2.3. 
Indoor-resting Anopheles mosquito capture rate 
8.7.2.4. 
Outdoor-host seeking Anopheles mosquito capture rate 
8.7.2.5. 
Adult mosquito age structure in captured mosquitoes as assessed by parity rate 
examination of mosquitoes and near-infrared spectroscopy scanning of mosquitoes 
8.7.2.6. 
Plasmodium sporozoite rate/entomological inoculation rate in captured mosquitoes 
8.7.2.7. 
Rate of Wuchereria bancrofti in captured mosquitoes 
 
8.7.3. Tolerability and safety endpoints. 
8.7.3.1. 
Tolerability. 
• 
Any adverse events or reactions assessed in general toxicity questionnaires. 
 
8.7.3.2. 
Safety. 
• 
General toxicity 
• 
CNS effects 
• 
Serious Adverse Events 
• 
Hemoglobin concentrations 
• 
Further criteria for monitoring adverse events may be determined by the ISM. 
 
8.8. Participants Timeline. 
8.8.1. Overview of Study Phases.  The study plan and schedule of assessment is provided in Table 
1, page 12. The study timeline consists of 4 Phases: Recruitment, Enrollment, Treatment, and 
Post-treatment follow-up.  
 
8.8.2. Recruitment Phase.  As this study is a cluster-randomized control trial with Burkinabé villages 
being the cluster unit, community engagement and community-wide consent are critical and are 
the initial method of recruitment.  This is especially important as the primary layer of consent 
because the village population is often tightly interconnected as they are made of extended and 
intermarried families of the same ethnic group, and many of the older population are illiterate.  
Potential villages will be pre-analyzed by the study investigators for similar and appropriate 
characteristics that would make them eligible for the study, such history of malaria and LF (as 
determined by MCD/CSPS records), location, size, and similarities with regard to the primary 
occupation of the populations.  In general, attempts will be made to enroll small to medium-sized 
rural villages that are along the primary road corridors and who are mostly inhabited by stationary 

25 
 
agricultural workers.  Larger towns and settlements with transient populations, such as gold-
mining camps, will be excluded from consideration.  The process will involve the study 
investigators, including the PIs and co-PIs, and may include representative delegates from the 
MoH NTD control program and the MoH malaria control program, the DRS, the MCD, and CSPS 
to meet with interested local village chiefs and elders from selected villages in a public meeting in 
their village.  At the meeting, the investigators will explain to the village elders and chiefs the 
goals, objectives, and interventions of the trial in the local language and in French, and answer 
any questions they have.  It will be made clear that villages will be randomly assigned to one of 
the 2 arms.  The chiefs and elders will be instructed to gather the heads-of-households to discuss 
their collective interest or opposition to being part of the study.  Village leaders who subsequently 
inform us of their village’s initial assent to being part of the study will be brought together for a 
public randomization of study villages.  The names of each of the 8 study villages will be publicly 
written on a card along with one identification number between 1 and 8.  These will then be put in 
matching envelopes, placed in a transparent container for the drawing, and mixed.  Each chief will 
then be asked to draw one envelope and place it, sequentially, in one of 2 containers labeled for 
each arm (1 = single MDA; 2 = repeated MDA).  At the end of the drawing, 4 envelopes will be in 
each container.  Subsequently, each chief will open a single envelope in each container and 
publicly reveal the randomization of clusters.  
          
8.8.3. Enrollment.  Once community consent/assent is affirmed and randomization occurs, consent 
and enrollment will proceed in each study village.  The study investigators will travel to each 
village and meet publicly with the heads-of-households to inform them of the study goals, 
objectives, the results of the public randomization meeting, and the interventions specific to their 
village’s randomization and that will occur with family members in their own households.  These 
interventions include the data and sample collection procedures. The heads-of-households will be 
reminded of the need for them and the family members to be present for any subsequent 
interventions in their village, and of the active case surveillance in any children of theirs which may 
be enrolled in the ACD cohort. If they sign a head-of-household consent document (appendix VII), 
the investigators will walk to each household, take a census of the inhabitants, conduct a 
questionnaire of inhabitants, survey the houses, enroll adults >18 years of age with their verbal 
assent, and enroll children <18 years of age with parental/guardian verbal assent.  Members of 
the study team will subsequently map the household and house locations in the village.    
 
8.8.3.1. 
Assignment of IDs.  Screened subjects who meet all eligibility criteria will be issued a 
study subject code, and their picture may be taken and linked to their study subject number 
during this visit on tablets.  Once issued the study subject code, they will be considered as 
‘enrolled.’ This code is the subject's unique identifier and used to identify the subject on the 
CRFs. Once a code has been assigned no attempt will be made to use that code again, for 
example if a subject withdrawals their consent. 
 
8.8.3.2. 
Clinical assessment of the MDA-eligible population.  After consent is obtained and 
the subject’s eligibility is confirmed, the subject’s demographic data, and all relevant clinical 
information, including previous and current medical history will be recorded in the CRF. 
Blood samples from finger prick will be obtained from a subset of subjects and spotted onto 
an FTA card (for subsequent molecular analysis), onto a slide (for subsequent parasitological 
staining), and put into a Hemocue reader for hemoglobin values. Additionally, a subset of 
MDA-eligible children between 6-10 years of age, with their parents/guardians assent and 
assistance, will be asked to provide a stool sample to the study investigators prior to the first 
MDA.    
 
8.8.3.3. 
Pregnant subjects.  All women who are of child-bearing age will be noted and flagged 
on the CRF at the time of the first MDA by the CSPS CHWs.  The CHWs assess exclusion 
due to pregnancy by questioning the patient on the day of the MDA per their training. 
Assessment of pregnancy in women of child bearing age (ages 15-49) during subsequent 
repeated IVM MDAs in the experimental arm villages will be performed within the week prior 
to the MDAs by the study nurses.  Study nurses will directly but privately asked two 

26 
 
questions. 1) “Are you the pregnant.”; 2) “When was your last menstruation?”  Subjects 
responding in the affirmative to question #1 or responding that their last menstruation was 
more than 28 day prior will be excluded from being administered IVM in the upcoming MDA.  
Subjects who respond that they are not pregnant or that their last menstruation was within 
the previous 28 days will be asked to take a pregnancy test (dipstick urine test for HCG).  If 
they refuse the test, fail to provide urine, or if the test returns a positive result, they will be 
excluded from being administered the study drugs.     
 
8.8.3.4. 
Breastfeeding subjects.  All women who are breastfeeding will be noted and flagged 
on the CRF.  On the day of each MDA in their village, these subjects will be asked if they are 
breastfeeding an infant who is within 1 week of birth.  Those who respond in the affirmative 
will be excluded from receiving the study drug at that time. 
 
8.8.3.5. 
Enrollment and clinical assessment of the ACD cohort.  After head-of-household 
informed consent is gained, parents/guardians of children in enrolled households who are 
between ≤5 years of age will be asked to give their informed consent to enroll their child(ren) 
in the ACD cohort. After assent is obtained and the child subject’s eligibility is confirmed, the 
subject’s demographic data, and all relevant clinical information, including previous and 
current medical history will be recorded in the CRF. Blood samples from finger prick will be 
obtained and spotted onto a filter paper card (for subsequent molecular analysis), onto a 
slide (for subsequent parasitological staining), and put into a Hemocue reader for recording 
hemoglobin values.  
 
8.8.4. Treatment Phase.  Approximately eighteen weeks starting at the beginning of the first MDA 
(Table 1).   
 
8.8.4.1. 
Mass drug administration visits.  CHWs and study investigators will go to the study 
villages in the days prior to the MDAs to remind the populace of MDA occurring in the coming 
planned day.  On the day established for the first MDA, CHWs and study nurses will arrive in 
the morning and go door-to-door to enrolled households to administer the MDA to all eligible 
patients per DRS training.  MDAs with IVM (150 µg/kg) + ALB (400 mg) will occur on this first 
day of the study period in all enrolled villages (Arms 1 & 2).  MDAs with IVM (150 µg/kg) only 
will occur 5 more times every 3 weeks thereafter, only in villages previously randomized to 
study arm 2 (treatment arm), and performed by the study nurses according to this protocol.           
 
8.8.4.2. 
Active case detection and adverse events monitoring.  Starting with the week of the 
first MDA, study nurses will travel to each village 3 times over each 2 week period throughout 
the study period, keeping a regular schedule, and visit all households with children enrolled 
in the ACD cohort.  When there, they will monitor the children for clinical signs of fever, and if 
needed sample blood from finger prick, and perform RDTs as needed.  Positive, 
uncomplicated cases will be prescribed AL by the study physician and monitored for 
recovery.  During their visit, nurses will also record any AEs passively reported by the village 
populace, treat uncomplicated AEs if they are probably associated with the MDA according 
to published WHO guidelines (see Appendix VIII, pg. 56), refer any SAEs to the CSPS or 
nearest hospital, and report any SAEs that are determined to be possibly-related to the 
intervention to the study physician within 24 hours of the nurse becoming aware of it.  
 
8.8.4.3. 
Entomology sampling.  Entomology teams will visit the study villages at least 1 time 
every 3 weeks during enrollment and through follow-up to sample resting mosquitoes from 
pre-selected sleeping houses of enrolled households.  Additionally, they will regularly set up 
overnight host-seeking mosquito sampling stations in study villages using trained, paid 
collectors.     
 
8.8.5. Post-treatment follow-up phase.  Lasting for up to three weeks, starting 3 weeks after the 6th 
MDA (Table 1). 
 

27 
 
8.8.5.1. 
Post-treatment clinical assessment.  A questionnaire will be administered to all 
enrolled patients to assess any past or current adverse signs and/or symptoms, including 
any AEs.  In a subset of patients, a brief clinical examination will be performed as before 
during the enrollment period, whereby blood samples from finger prick will be obtained and 
spotted onto an FTA card (for subsequent molecular analysis), onto a slide (for subsequent 
parasitological staining), and put into a Hemocue reader for hemoglobin values. Additionally, 
the subset of patients who were between 6-10 years of age at the start of the study and who 
previously provided a stool sample will be asked to provide a follow-up stool sample.   
 
8.8.6. Unscheduled visits.  At any time, participants displaying signs or symptoms of severe malaria 
who contact the nurses while they are working in the study sites will be referred to the CSPS or 
MCD for further evaluation and treatment.  If transportation is available, these patients will be 
transported to the clinic by the study team.  Blood samples for malaria smears, parasite genetics 
(filter paper dried blood spots) and hemoglobin will be taken if clinically indicated. 
 
8.9. Sample size. 
 
8.9.1. Primary endpoint sample size and recruitment strategy. The study is powered on the 
primary endpoint measure, cumulative incidence of uncomplicated malaria episodes in enrolled 
study village children ages 0-5 years.  Assuming a cumulative incidence of malaria episodes in the 
control arm of 80% and an intracluster correlation coefficient of 0.02, 4 clusters are needed per 
arm and 69 children enrolled per cluster to detect a conservative 40% reduction in incidence in the 
treatment arm with 80% power and a confidence of 95%.  Importantly, modeling predicts 
approximately a 80% reduction in incidence (Figure 1).  We will attempt to enroll small to medium 
sized villages that have between 250-800 people.  In this region of Burkina Faso, children of this 
age group usually comprise 25-35% of the village population, which should give us enough 
children in each village, assuming most parents/guardians enroll their children in the ACD.  This is 
a fair assumption, because the parents in this region observe the impact that malaria has on their 
children, especially in the rainy season, and usually see the value of having their child monitored 
regularly for malaria episodes.  Tiono et al. (9) had approximately 6% of subjects lost to follow-up 
in their similarly aged ACD cohort over the course of the rainy season, which would still give us 
enough subjects in the two initial arms to detect a significant difference in cumulative incidence of 
malaria episodes.    
  
8.9.2. Secondary endpoints with parasite measures. 
 
8.9.2.1. 
Molecular force-of-infection (number of new Plasmodium clones acquired over 
time).  A subset enrolled patients who live in households at the geographic center of the 
study villages will have a blood sample taken on spot of filter paper upon enrollment and 
again at follow-up, including the children enrolled in the ACD.  Furthermore, we will obtain 
regular finger stick blood samples during the treatment phase from children in the ACD 
cohort when/if they present with a malaria episode.  This will give us at least 1400 pre- and 
post-treatment blood samples from which to score for the number and identify of parasite 
clones in each person and calculate the molecular force-of-infection over the interval of the 
study.   
   
8.9.2.2. 
Soil transmitted helminths (Prevalence and intensity of STHs in a subset of 
treated patients between 6-10 years of age).  A subset enrolled patients who live in 
households at the geographic center of the study villages and who are between 6-10 years of 
age in the study villages will be asked to provide a stool sample via assent from their 
parent/guardian, which will be analyzed for larvae/eggs per gram of feces.  This age stratum 
of patients is assumed to have the highest prevalence of infection with Ascaris lumbricoides 
and Trichuris trichiuria, both of which are partially sensitive to ivermectin treatment, and have 
the highest re-infection rates following single MDAs.  If the infection rates are low, we will try 
to increase our sample size by asking patients who are between 11-15 years of age, with 
assent from their parent/guardian, to provide a stool sample. All of these patients will be 

28 
 
asked to provide a second stool sample in the post-treatment follow-up phase.  We estimate 
his will give us approximately 400 pre- and post-treatment stool samples from which to 
calculate the change in the prevalence and intensity of STH infections over the interval of the 
study period. 
 
8.9.3. Secondary endpoints with entomological measures.  Sleeping houses within enrolled 
households at the geographic center of the study villages will be sampled one or more times at 
every 3 weeks over the study period for resting blood fed Anopheles mosquitoes.  These 
samplings will be performed by the entomology team in the early mornings using hand-held, 
battery-powered aspirators.  Depending on the month, weather conditions and house, >50 blood 
fed Anopheles mosquitoes can be captured in a single house on a single morning. In general, 
between 0-20 mosquitoes are caught per house per morning.  The mosquitoes will be brought 
back to the field lab, identified and enumerated, the blood meal contents smashed on an FTA 
card, and the head+thorax stored in desiccant for subsequent molecular analysis.  The blood 
meals will be subsequently analyzed for the presence of W. bancrofti microfilaria, Plasmodium, 
and other potential pathogens, and the head+thorax will be tested for the presence of Plasmodium 
sporozoites.   
 
8.10. 
Assignment of Interventions 
 
8.10.1. Allocation. The allocation process will be public, and involve the study investigators, including 
the PIs and co-PIs, and some representative delegates from the MoH NTD control program and 
the MoH malaria control program, the DRS, the MCD, and CSPS to meet with interested local 
village chiefs and elders from selected villages in public within the village.  At the meeting, the 
investigators will explain with the village elders and chiefs the goals, objectives, and interventions 
of the trial in the local language and in French, and answer any questions they have.  It will be 
made clear that villages will be randomly assigned to one of the 2 arms.  The chiefs and elders will 
be instructed to discuss with the heads-of-households their collective interest or opposition to 
being part of the study.  Subsequently we will conduct a public meeting with all village leaders who 
subsequently inform us of their village’s initial assent to being part of the study to hold a public 
randomization of study villages.  The names of each of the 8 study villages will be publicly written 
on a card along with one identification number between 1 and 8.  These will then be put in 
matching envelopes, placed in a transparent container for the drawing, and mixed.  Each chief will 
then be asked to draw one envelope and place it, sequentially, in one of 2 containers labeled for 
each arm (1 = single MDA; 2 = repeated MDA).  At the end of the drawing, 4 envelopes will be in 
each container.  Subsequently, each chief will open a single envelope in each container and 
publicly reveal the randomization of clusters. 
 
8.10.2. Blinding.  As this is a pilot safety and efficacy study, and the repeated MDA treatments will be 
distributed by the CHWs and study nurses and investigators, we will neither blind the patients nor 
the study investigators at the study sites.  Rather, the study outcomes assessor/biostatistician (Dr. 
Rao), who will not be present at the study site during treatment and data collection, will be blinded 
when analyzing the data sent to her by the onsite investigators.  
 
9. Data Collection, Management and Analysis. 
9.1. Clinical procedures. 
9.1.1. Malaria episode diagnosis in the ACD cohort. During each village visit, ACD patients will 
have their axillary temperature taken with a thermometer.  Also, parents/guardians will be 
questioned about whether their child had an apparent fever or showed any signs of illness in the 
past 24 hours.   A temperature of ≥38.0°C and/or history of fever in the last 24 hours will warrant 
the nurse to perform a finger prick blood collection with a sterile single-use lancet to a) make a 
thick and thin film blood slide, b) take at least 2 blood spots within 24 hours of each other on filter 
paper for later molecular analysis, and c) perform a rapid diagnostic test (RDT) for Plasmodium 
falciparum. A positive RDT will warrant antimalarial treatment (AL) as to be dispensed by the 
nurse under the direction of the study physician. 
 

29 
 
9.2. Laboratory procedures. 
9.2.1. Thick and thin blood smears for malaria.  Thick and thin blood films for parasite counts will 
be obtained and examined under a microscope.  Malaria parasites will be counted against 300 
white blood cells or 100 high power fields before a slide is declared negative. 
 
9.2.2. Molecular force-of-infection.  Blood samples on filter paper spots will be used for molecular 
analyses of parasite clonality and population dynamics.  Parasite DNA will be extracted using 
standard molecular kits and polymorphic marker genes will be amplified by PCR with tagged 
primers and capillary electrophoresed for fragment sizing. 
 
9.2.3. Hemoglobin testing. Hemoglobin will be tested using HemoCue® (Angelholm, Sweden) 
photometers. 
 
9.2.4. Stool microscopy.  Stool samples will be prepared using the mini-FLOTAC method and 
examined for presence of STH larvae/eggs and eggs will be counted in positive samples. 
 
9.2.5. Plasmodium sporozoites in the head+thorax of captured mosquitoes.  A subset of 
desiccant-dried mosquito thoracies will be extracted for their DNA and analyzed with ELISA or by 
Taqman PCR to detect Plasmodium sporozoite DNA.    
 
9.2.6. Squashed mosquito blood meal spots for detecting Wuchereria bancrofti.  A subset of 
mosquito blood meal spots will be extracted for DNA, and analyzed for the presence of W. 
bancrofti microfilaria DNA using PCR. 
 
9.2.7. Aging of captured in Anopheles vectors. Recently-captured live Anopheles mosquitoes will 
be anesthetized with chloroform, scanned on a near-infrared spectrometer, and their ovaries 
dissected, which will be scored for parity under a microscope via their tracheole skein coiling. 
 
9.3. Data collection methods and storage.  Patient data will be collected using standardized case 
reporting forms on tablet computers or paper forms as a backup. Laboratory results will be maintained 
in paper laboratory books and then entered into an Excel spreadsheet (Microsoft®. Redmond, 
Washington, USA). All data storage will be encrypted and password protected. 
 
9.4. Statistical methods.  A detailed study statistical plan for the final analyses, that will supersede that in 
the study protocol, will be drawn up during the course of the study before the unblinding of data sent to 
the biostatistician (Dr. Rao). 
 
9.4.1. Trial profile and flowchart.  A trial profile will be developed and presented as a flow chart 
following CONSORT guidelines, consisting of the number of villages and their randomization, 
participants screened, eligible, enrolled, followed through the treatment phases, and number 
contributing to primary efficacy outcomes. It will also include the number of participants who 
withdrew or were lost to follow-up. 
 
9.4.2. Baseline characteristics. Descriptive statistics of baseline characteristics, overall and by 
treatment group will be provided in a table consisting of parameters collected at recruitment and 
enrollment. No statistical comparisons will be made between the groups, but any differences 
between groups at baseline which are also associated with the outcome variable will be taken into 
account in subsequent analysis.   
 
9.4.3. Analysis populations. 
 
9.4.3.1. 
Screening failures. 
9.4.3.1.1. 
Enrolled population in the clusters who receive the treatments. It is 
expected that some heads-of-household or individual subjects in a household will be 
lost to follow up or may die during the study.  This population will be included in both 
intention-to-treat (ITT) and according-to-protocol (ATP) analyses.  

30 
 
 
9.4.3.1.2. 
ACD cohort.  If the parent/guardian of a subject in the ACD cohort gives 
informed consent and the subject is provided with a study ID, but then the subject is lost 
to follow up or dies prior to the first MDA at the start of the Treatment Phase, they will 
be classified as a screening failure and excluded from the analysis. 
 
9.4.3.2. 
Primary endpoint analysis population – ACD cohort. The population limited to the 
primary endpoint analysis is defined as all enrolled patients ≤5 years of age who lived in the 
randomized study villages through the Treatment Phase. These patients will be included in 
the primary endpoint analysis using the last-observation-carried-forward-method (LOCF), 
whereby the last available measurement, be that the final measurement of study or at the 
time point prior to withdrawal or being lost-to-follow, is included in the analysis.  Intention-to-
treat analysis (ITT) is not appropriate for this population because the majority will not be 
treated because of their weight/height (MDA is only provided to patients >15 kg/>90 cm).  
Rather the effects in this population are expected to be derived from the treatment of the 
older population in the study villages and its effect on malaria transmission.   
 
9.4.3.3. 
Safety population.  This population is defined as the population of the study villages 
who received at least one treatment during the course of the study and were followed-up (ie. 
provided information on adverse events).  
 
9.4.3.4. 
Treated population.  The treated population is defined as all those enrolled patients 
from the study villages who were treated at least once and lived in the randomized study 
villages during the Treatment Phase.  A subset of this population will be subject to the 
secondary endpoint analyses, a) incidence of infection with new Plasmodium clones and b) 
prevalence and intensity of infection with STH, both of which require providing at least one 
sample during the Enrollment Phase and one during the Post Treatment Follow-Up Phase.  
These secondary analyses will be both ITT and ATP, in order to estimate the effect 
differences between the per-protocol population and the population with protocol violations 
(treatment irregularities, non-compliance, early withdrawal, etc.)      
 
9.4.4. Missing data.  Every effort will be made to minimize the amount of missing data in the trial. 
Whenever possible, information on the reason for missing data will be obtained. No adjustments 
will be made for missing outcome data, but missing data may be imputed for co-variates during 
the analyses. 
 
9.4.5. Assessment of efficacy. Primary efficacy analysis will be based on the count variable 
‘cumulative incidence of malaria episodes’. Generalized Estimating Equations (GEE) based 
regression models will be constructed to estimate risk ratios and corresponding 95% confidence 
intervals while taking the cluster design into account.  A poisson regression will be used to 
compare the risk rates between the two treatment groups by considering the cumulative incidence 
of an individual across the study period as the outcome measure.  Proportion of patients 
experiencing a malaria episode will be compared between arms by odds ratio with corresponding 
95% CI; associations between treatment group and continuous variables will be expressed as 
mean differences and 95% CI.  Proportional hazards model will be used to analyze the ‘time to 
first malaria episode’ as a secondary outcome. 
 
9.4.6. Analysis of adverse events.  Adverse reactions will be reported and tabulated for each 
treatment arm, overall and on per-protocol basis. Adverse reactions are defined as AEs that had 
an onset day on or after the day of the first dose of study medication and probably related to the 
treatment. Adverse events that have missing onset dates will be considered to be treatment-
emergent. Logistic regression models with random effects will be used to compare the risk of 
occurrence of each AE in the experimental group with the risk in the control group. Odds ratios 
with their 95% confidence intervals will be calculated for each AE. All laboratory data will be listed. 
 
9.5. Monitoring 

31 
 
 
9.5.1. Data monitoring.  This study is a clinical trial defined at ‘Moderate Risk’ by the UCH Clinical 
Translational Research Center Policy on Study Monitoring 
(http://www.ucdenver.edu/research/CCTSI/programs-
services/regulatory/Documents/Study_Monitoring_Policy_2010-01-15.pdf), and from this 
document, ‘Moderate Risk’ trials minimally requires an Independent Safety Monitor (ISM).  
Following this recommendation, an ISM will be contracted for the trial. The ISM will be critical to 
ensure that the subjects are protected from harm, while also ensuring that the study integrity is not 
compromised. The ISM will be a person knowledgeable in the conduct of clinical trials, and is 
expected to be based Burkina Faso. This person will work with the biostatistician (Dr. Rao) to 
evaluate the nature and occurrence of AEs and SAEs. S/he will make regular assessments (e.g. 
twice yearly or more frequent if so required) during the data collection period to provide a review of 
blinded (and if requested, unblinded) data to ensure the safety, rights and well-being of trial 
participants. The role of the ISM is described in more detail in Appendix II. Terms of Reference 
Oversight, page 45. 
 
9.5.2. Interim analysis and criteria for termination of the trial. Interim analyses of the safety data 
will be conducted soon after the 3rd MDA. The ISM will be blinded when presented with the interim 
analysis, unless the ISM judges that for safety reasons the blind should be broken. A detailed plan 
for interim analysis, any planned statistical adjustments to be employed as a result of interim 
analysis, the provisional stopping rules and how the stopping rules will be applied, will be drawn 
up prior to the start of the interim analysis. In addition, regular review of the quality of the study 
data will be conducted by the ISM.  
 
Following recommendation from the ISM, the sponsor reserves the right to temporarily suspend or 
prematurely discontinue this study at any time for reasons including, but not limited to, safety or 
ethical issues or severe non-compliance. If the sponsor determines such action is needed, it will 
discuss this with the investigators. When feasible, the sponsor will provide advance notification to 
the investigator of the impending action prior to it taking effect. The sponsor will promptly inform 
the CSU IRB and Comité d’Ethique of the IRSS, and provide the reason for the suspension or 
termination. 
9.6. Safety Monitoring and Reporting.  
 
The principles of Good Clinical Practice require that both investigators and sponsors follow specific 
procedures when notifying and reporting adverse events or reactions in clinical trials. 
 
9.6.1. Definitions. 
 
9.6.1.1. 
Adverse Event (AE).  Any untoward medical occurrence in a patient or clinical trial 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. 
 
9.6.1.2. 
Adverse Reaction (AR).  Any untoward and unintended response to an investigational 
medicinal product related to any dose administered.   
 
Note: All adverse events judged by either the reporting investigator or the sponsor as having 
a reasonable causal relationship to a medicinal product would qualify as adverse reactions. 
The expression ‘reasonable causal relationship’ means to convey, in general, that there is 
evidence or argument to suggest a causal relationship. 
 
9.6.1.3. 
Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR).  Any adverse 
event or adverse reaction that results in death, is life-threatening*, requires hospitalization or 
prolongation of existing hospitalization, results in persistent or significant disability or 
incapacity, or is a congenital anomaly or birth defect.  
 

32 
 
Note: Medical judgment should be exercised in deciding whether an adverse event/reaction 
should be classified as serious in other situations. Important adverse events/reactions that 
are not immediately life-threatening or do not result in death or hospitalization, but may 
jeopardize the subject or may require intervention to prevent one of the other outcomes listed 
in the definition above, should also be considered serious. 
 
*Life-threatening in the definition of a serious adverse event or serious adverse reaction 
refers to an event in which the subject was at risk of death at the time of the event. It does 
not refer to an event which hypothetically might have caused death if it were more severe. 
 
9.6.1.4. 
Suspected Unexpected Severe Adverse Reaction (SUSAR).  An adverse reaction 
that is both unexpected (not consistent with the applicable product information) and also 
meets the definition of a Serious Adverse Event/Reaction. 
 
9.6.1.5. 
Intensity.  The intensity of each AE recorded in the case report form should be assigned 
to a grade (1-5), which will be determined following the definitions set forth in the Common 
Terminology Criteria for Adverse Events v3.0 (CTCAE) (Cancer Therapy Evaluation 
Program, 2006). Use of these standardized guidelines will allow for uniform reporting. The 
grades are defined as follows:  
• 
Grade 1: Mild AE  
• 
Grade 2: Moderate AE  
• 
Grade 3: Severe AE  
• 
Grade 4: Life-threatening or disabling AE  
• 
Grade 5: Death related to AE  
 
9.6.2. Identifying, managing adverse events. Participants who develop common adverse events 
that possibly were a consequence of ivermectin treatment will be identified at follow-up visits and 
treated by the study nurses according to WHO guidelines for treating common AEs that occur from 
MDAs (see appendix VIII).  All adverse events will be noted in the participant’s case report form; in 
the case of mild AE, no further action will be taken by study staff except in the case of vomiting, in 
which case the study medication may need to be re-administered. In the case of any severe 
adverse event (difficulty breathing, convulsions, change in mental status), subjects will be referred 
to the CSPS/MCD for management. Transportation to the hospital will be provided if available. All 
hospitalized participants will undergo record review to identify potential adverse consequences of 
study participation. 
 
9.6.3. Assessment of causality. The investigator physician (Dr. Rouamba), in consult with the field 
physician and the other investigators, is obligated to assess the relationship between the 
investigational product(s) and the occurrence of each AE/SAE. The physician-investigators will 
use clinical judgment to determine the relationship. Alternative causes, such as natural history of 
the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of 
the event to the investigational product will be considered and investigated. The physician-
investigators will also consult the drug information and the ISM as needed in the determination of 
their assessment. 
 
There may be situations when an SAE has occurred and the investigator has minimal information 
to include in the initial report (see 9.6.4.). However, it is very important that the investigator always 
make an assessment of causality for every event prior to transmission of the SAE report to CSU 
and IRSS.  The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE case report form accordingly. 
 
9.6.4. Reporting adverse event procedures. All SAEs deemed as ‘possibly related’ to the 
intervention will be reported to the in-country principal investigator or an assigned representative 
within 24 hours of the nursing staff becoming aware of it via mobile phone or electronically. The 
SAE form asks for nature of event, date of onset, severity, corrective therapies given, outcome 

33 
 
and causality (i.e. unrelated, unlikely, possible, probably, definitely). The responsible study 
clinician should ultimately assign the causality of the event. 
 
9.6.4.1. 
Expedited reporting.  SAEs that are unexpected and are at least ‘possibly related’ to 
the intervention require expedited reporting within 24 hours of nurse becoming aware of it, 
and reporting within 24 hours to the ISM and sponsor by the country principal investigator or 
assigned representative becoming aware of it (e-mail notification); i.e. this will be a maximum 
of 48 hours after the field nurse becomes aware of it (including the 24 hours required for the 
field staff to report to the principal investigator / representative). Additional information will be 
sent within 14 additional days (full SAE report) if the reaction had not resolved at the time of 
e-mail notification. 
 
9.6.4.2. 
Regular Reporting. Other SAEs and AEs will be reported annually in an aggregated 
report. AEs that will not be reported include common illnesses that do not result in 
hospitalization, including but not limited to clinical malaria, respiratory, gastrointestinal, and 
skin diseases, unless they are considered at least possibly related to the intervention. 
 
9.6.4.3. 
Recipients of reports. The study will comply with local regulations pertaining to 
reporting of SAEs to their local Research Ethics Committee and/or Research & regulatory 
offices. In addition to the primary ethics committees, we will report safety data to the ISM and 
to the sponsor. A copy of the final study report will be provided to the ISM, MoH. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3.  Safety Reporting assessment flowchart 
 
IMP: Investigational Medicinal Product 
*See definition of SAE in section 9.6.1.3. 
**Assessed in line with the current approved Investigator’s Brochure (IB) 
Adverse Event
Serious
Serious Adverse Event
(SAE)
Adverse Event
(AE)
Seriousness*
Not 
Related to 
IMP
Serious Adverse Reaction
(SAR)
Suspected Unexpected Serious 
Adverse Reaction (SUSAR)
Causality
Expectedness**
Not Serious
Related to 
IMP
Not 
Related to 
IMP
Related to 
IMP
Adverse 
Event (AE)
Adverse 
Reaction 
(AR)
Serious 
Adverse 
Event 
(SAE)
Serious 
Adverse 
Reaction 
(SAR)
Expected
Unexpected
sSerious?
- Yes
Related?
- Yes
sUnexpected?
- Yes

34 
 
 
 
9.7. Quality Assurance 
 
9.7.1. Clinical monitoring.  Monitoring of this trial will be conducted to ensure compliance with ICH-
Good Clinical Practice and scientific integrity will be managed and oversight retained, by the 
sponsor. Clinical monitoring will also be performed by the ISM, who will be in-country and familiar 
with ICH-GCP. At least 3 monitoring visits will be carried out; one at trial initiation, one at close-out 
and one half-way through the study.  
 
Prior to subject enrollment, the Clinical Trial Monitor (ISM/CTM) will visit the study site to 
determine the adequacy of facilities, review the protocol and data collection procedures and 
discuss the responsibilities of the investigator and other study site personnel.  
 
During the study, the CTM will have regular site contacts, including conducting on-site visits to: 
1. Confirm that the study is being performed according to the protocol, ICH-GCP and applicable 
regulations, data are being accurately recorded in the CRFs and that investigational product 
accountability is being performed. 
2. Conduct source data verification  
3. Confirm facilities remain acceptable  
4. Provide information and support to the investigators  
5. Evaluate study progress  
 
Upon completion of the study the CTM will visit the study site to verify that all CRFs are completed 
and collected, all data queries have been resolved and filed, conduct final accountability, and 
verify all study site records are complete.  
 
The PIs and relevant staff will be available at monitoring visits and agree to allocate sufficient time 
to the monitor to discuss any issues and address their resolution.  
 
9.7.2. Auditing. The independent clinical monitoring process will be audited remotely by a study staff 
member from the sponsor’s IRB office at CSU in Fort Collins, CO.  The auditor will be supplied 
information from the CTM and study investigators via email. After the audit it will be determined by 
the sponsor if more auditing visits are required.  
 
9.7.3. Training. The principal Investigators are responsible for the conduct of the study at the study 
sites, including delegation of specified study responsibilities, and training of study staff. The PIs 
will maintain a record of all individuals involved in the study (medical, nursing and other staff) and 
will ensure that all persons assisting with the trial receive the appropriate training about the 
protocol, the investigational product(s) and their trial-related duties and functions.  This may 
include ICH-GCP training when deemed necessary. During the study, regular spot checks will be 
conducted to assess the performance of study site staff members and re-training provided where 
necessary. 
 
9.7.4. Quality assurance/control of laboratory tests.  Regular audits of laboratory procedures will 
be completed by experienced supervisors according to standard operating procedures. All malaria 
blood smears and homogenized/fixed stool samples will be read by two different microscopists; 
any significantly discordant results based on positive/negative results or difference in parasites 
above a defined threshold will be verified by a third expert microscopist.  Similarly, mosquito 
identifications and age-grading assessments will be regularly cross-checked by at least two 
technicians during mosquito sample processing.   
 
 
9.8. Mitigation and Risk Reduction Plan.  This study is designed to mitigate and reduce the risk to 
patients.  Individual aspects of this plan are:  

35 
 
• 
Prospective screening of patients (eg. pregnancy) prior to repeat MDAs in experimental 
arm villages. 
• 
Weekly visits to all villages by trained nurses to enrolled households, which will document 
any ACD cohort AEs and passively reported AEs on patient CRFs. 
• 
Ongoing physician access to the study site. 
• 
Prompt AE reporting to the study clinician (Dr. Rouamba), and all investigators will 
determine relationship to the investigational drug. 
• 
Reporting of SAEs possibly related to the study interventions to the sponsor within 48 
hours of the investigators becoming aware of it (within 24 hours of the field nurse 
becoming aware of it) 
• 
Review of the study design, AEs and SAEs by the Burkinabé ISM (also the CTM) 
• 
Clinical monitoring by the Burkinabé ISM/CTM; s/he is familiar with ICH-GCP 
• 
Remote auditing by the CSU IRB (sponsor) 
• 
Quality control of laboratory tests 
 
 
10. Timeframe of the study.  The anticipated start time for enrollment is in April 2015.  
 
 
Month 
Activity 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Protocol 
development 
 
 
 
 
 
 
 
 
 
 
 
 
IRB review 
 
 
 
 
 
 
 
 
 
 
 
 
Training 
staff 
 
 
 
 
 
 
 
 
 
 
 
 
Recruitment 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Phase 
 
 
 
 
 
 
 
 
 
 
 
 
Post 
treatment 
follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
Data 
Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
Manuscript 
Preparation 
 
 
 
 
 
 
 
 
 
 
 
 
 
11. Ethical Considerations and Regulatory Approvals. 
 
11.1. 
Declaration of Helsinki.  The trial will be conducted in compliance with the principles of the 
Declaration of Helsinki (1996) (http://www.wma.net/en/30publications/10policies/b3/), the principles of 
ICH-GCP, and in accordance with all applicable regulatory requirements in Burkina Faso. 
 
11.2. 
Regulatory Approval and Trial Authorization.  Since the trial is conducted outside the USA, 
no authorization from an American regulator is required. The trial will be registered with La Direction 
générale de la pharmacie, du médicament et des laboratoires (DGPML) within the Burkina Faso MoH. 

36 
 
 
11.3. 
Research Ethics Approval.   
 
11.3.1. Review Process.  This protocol, the informed consent documents, and patient information 
sheets will be reviewed and approved by the IRB at CSU, the Comité d’Ethique d’IRSS. 
 
11.3.2. Protocol Amendments.  No change will be made to the approved protocol without the 
agreement of the sponsor.  
 
If it is necessary for the protocol to be amended, the protocol amendment will be submitted to the 
primary ethics committee for approval before implementation. Any protocol amendments will be 
submitted to the primary ethics committees (CSU, IRSS) before implementation. Any change to 
the informed consent form must also be approved by the sponsor and the primary ethics 
committee in each country before the revised form is used.  
 
The sponsor will distribute amendments to each principal investigator, who in turn is responsible 
for the distribution of these documents to the staff at his/her study site. 
 
11.4. 
Informed Consent Procedures. 
 
11.4.1. Consent Procedures. Community consent/assent (oral) will first be obtained by public 
meetings with local village chiefs and elders during the recruitment phase where the study will be 
explained to them.  Following this, in the enrollment period, individual consent/assent (oral) 
through a public meeting with village heads-of-households will be obtained and at the end of the 
meeting written informed consent will be obtained from each head-of-household who chooses to 
have their family participate.  Lastly, verbal, witnessed assent from each person in consented 
households will be obtained by going door-to-door to households (directly from adults, and 
informed assent will be obtained from children via their parents/guardians).  Written, informed 
consent from each head-of-household will be in French, but also explained in the local language 
when necessary. The consent process shall be initiated at the time of enrollment into the study 
and shall continue throughout the patient’s participation.  
 
For illiterate participants, an independent witness will be present during the informed consent 
process and will sign the consent form as a witness, while the participant will be asked to indicate 
consent or assent by use of thumbprint. Any participant may withdraw their consent at any time 
throughout the course of the study, and this will be made clear in the informed consent process. 
All individuals will be informed that there is no requirement to join the study and that the standard 
medical care they might have through the CHWs and the CSPS will remain the same regardless 
of study enrollment.  
 
11.4.2. Consent forms.  There will be one information form, consisting of a printed information sheet to 
explain the purpose of the trial, what will happen, and the risks and benefits, all in simplified language.  
This will be given to the enrolled head-of-households.  The consent forms for the head-of-household 
will explain the text of the information form in brief with a place for their signature/fingerprint if they 
provide consent for themselves and their family to participate, and below that will have a place for the 
signature of a witness, and the signature of the trial member who is consenting. The form will give the 
study investigators permission for performing study-related procedures in their household, including 
consenting to visits by CHWs and trial nurses to distribute MDAs, consenting to regular household visits 
by the nurses and entomological team, collecting all relevant clinical information from patients in their 
household and the collection of mosquitoes and biological samples.  
The other consent forms (one for all other household adults, and one for all participants <18 years of 
age), plus the assent form for all participants between 12-18 years of age,  
 

37 
 
will gain patient consent (and assent for those between 12-18 years of age)  to participate in the MDAs, 
to collect all relevant clinical information, and permission to collect biological samples (including stool 
samples in household children between 6-10 years of age).  It will also gain their consent for regular 
monitoring of the ACD cohort patients in their household (children ≤ 5 year of age) by the study nurses 
for malaria episodes, and to collect biological samples including frequent fingerstick blood samples if 
warranted.  Finally, it will gain consent for long-term storage of the blood for future studies as well as for 
genetic studies on the patient’s blood sample related to malaria, LF, and other infectious pathogens, 
and to drug metabolism. These blood samples shall be stored as dried blood spots in filter papers and 
analyzed both in Burkina Faso at the IRSS and in the USA at CSU. 
All consent forms will be translated into French. 
 
11.5. 
Protection of Privacy and Confidentiality.   
 
11.5.1. Privacy.  Personal and medical information relating to research participants will be treated as 
confidential. The risk of disclosure will be minimized by secure storage of documents on password 
protected tablets and computers, and use of linked data by replacing personal identifiers with a 
unique study code to conceal the identity of the patient.  The linked list will be destroyed 5 years 
following the publishing of the study results. 
 
11.5.2. Privacy of individual.  Tests for malaria and hemoglobin will be reported to the parent/guardian 
of the participant at point of care, to relevant study staff and where appropriate will be recorded in 
the patients’ medical record book in addition to study CRFs. 
 
11.5.3. Confidentiality of data.  All information regarding the participants will remain confidential to the 
extent allowed by law. Unique numerical identifiers will be used for data entry. All screening forms 
and case report forms will be kept in a secured location with access limited to authorized study 
staff. Unique numerical identifiers will be used for the computer-based data entry and blood 
samples. Publications will contain only aggregate data. No identifying information will be included. 
 
11.6. 
Declaration of Interest.  None of the principal investigators have paid consultancies with the 
pharmaceutical companies who manufacture the study drugs, or other competing interests for the 
overall trial or in each study site. 
 
11.7. 
Access to source data/documents.  In addition to the ISM/CTM, authorized representatives of 
the sponsor, and the CSU IRB and Comite d’Ethique d’IRSS or regulatory authority may visit the study 
site to perform audits or inspections, including source data verification. The investigators agree to 
allow the sponsor, including the ISM/CTM, the CSU IRB and Comite d’Ethique d’IRSS direct access to 
source data and other relevant documents. 
 
11.8. 
Risk and Benefits.   
 
11.8.1. Risks to Study participants.  
 
11.8.1.1. Ivermectin.  Ivermectin (Merck Sharp & Dohme) has been shown to be well-tolerated 
and safe with the standard doses used in this study, including during pregnancy and during 
breast-feeding when the child is older than 1 week (see Section 4.7 “Safety of ivermectin in 
humans”, page 16). The only confirmed related severe adverse events have been in 
individuals with Loa loa due to lysis of parasites, however Loa loa is not present in Burkina 
Faso, and the patients in the study villages will be questioned about whether they have 
traveled to countries where Loa loa is endemic.  Repeated administrations of ivermectin 
using standard doses in intervals from days to months have been performed numerous times 
to both individuals and communities, with few reports of AEs or SAEs (Table 3).   
 
11.8.1.2. Albendazole.  Albendazole (GlaxoSmithKline) has been shown to be well-tolerated and 
safe within MDA campaigns when administered with ivermectin in the standard doses used 

38 
 
in this study.  ALB will only be mass administered in the first MDA of this study along with 
IVM. While this administration will occur within the timeframe and context of this study, this 
MDA is scheduled regardless of the presence of this study, in all villages within the Sud-
Ouest Administrative Region for LF and STH control and elimination efforts.  SAEs are very 
rare and linked to the presence of Loa loa which is not present in Burkina Faso, and the 
patients in the study villages will be questioned about whether they have traveled to 
countries where Loa loa is endemic.  AEs associated with this MDA combination regimen are 
usually mild and most often include headaches and abdominal cramps and/or diarrhea 
associated with the expulsion of killed helminths.  Other than patient enrollment, sample 
collection and patient monitoring, MDA with ALB will be conducted by the CHWs associated 
the Burkina Faso MoH in a manner no different than that would be normally carried out in the 
study villages in 2015 if they were not enrolled in the study.    
 
11.8.1.3. Blood sampling by finger prick. Blood sampling may be inconvenient to the 
participants, and may cause minor discomfort, fainting (vasovagal syncope), bruising and 
local infection if not conducted appropriately. The volume of blood collected from each 
participant will be not more than 1 mL each time. Well-trained clinicians and nurses or 
laboratory staff employed on the trial will perform blood-sampling. New and sterile disposable 
single-use lancets, alcohol wipes and cotton gauze will used for blood sample collection. 
Universal precaution measures for blood handling and disposal will be observed when 
performing the procedures and used lancets and other waste will be safely discarded 
immediately after use.   
 
11.8.2. Benefits to study participants. 
 
11.8.2.1. Anticipated Benefits to study participants.  Ivermectin is an antihelminth drug and 
may be beneficial to patients who participate in the MDAs with helminth infections and other 
endoparasites and ectoparasites.  Enrolled ACD cohort children will benefit from active 
surveillance for malaria episodes, and will receive antimalarial treatment free of charge upon 
having an episode. Patients will also be provided with a superior level of supervision and 
monitoring than they otherwise would have been. 
 
11.8.2.2. Benefit to the community. This project is designed to generate the information required 
to determine whether repeated ivermectin MDAs during the rainy season can better control 
malaria transmission and disease than the current standard methods. As such the study 
helps support science and potential progress towards enhanced options in the arsenal of 
tools for malaria control and elimination. Subject to the finding, in the longer term, the 
ultimate beneficiaries of this research could be the populations living in malaria endemic 
parts of the world, whose quality of life, health, welfare and creative output will be enhanced 
by reduced malaria transmission.  
 
11.9. 
Ancillary and Post-trial Care. 
 
11.9.1. Health care during the trial.  All care directly related to the proper and safe conduct of the trial, 
and the treatment of immediate adverse events suspected to be related to trial procedures will be 
provided free of charge by the study in the study health clinics/hospitals. The provision of ancillary 
care beyond that immediately required for conduct of the trial will not be covered by the trial. 
 
11.9.2. Trial Insurance.  The sponsor will take out trial insurance such that participants enrolled into 
the study are covered by indemnity for negligent harm and non-negligent harm associated with the 
protocol. This will include coverage for additional health care, compensation or damages whether 
awarded voluntarily by the Sponsor, or by claims pursued through the courts. The liability of the 
manufacturer of the trial drug ivermectin is limited to those claims arising from faulty 
manufacturing of the commercial product and not to any aspects of the conduct of the study. 
 

39 
 
11.9.3. Post-trial care. This is only a pilot study and the budget provided by the funder is not designed 
to fund post-study care or implementation of ivermectin as policy. However, the investigators work 
in close collaboration with local and international policy makers (e.g. WHO) and funders (e.g. 
BMGF) to ensure that policy makers and funders are informed early of germane research findings. 
 
11.10. 
Expenses Reimbursement and Incentives. The study will provide payment for all prescribed 
antimalarials, study procedures, study-related visits and reasonable medical expenses that are 
incurred in study clinics or hospitals as a result of the study, including expenses for transport for any 
study related visits including unscheduled visits in between scheduled visits to study clinics. The study 
will not cover the costs of any non-malaria or non-study related events, including scheduled or 
unscheduled surgery or trauma-related events (e.g. accidents, burns etc.) if this is not deemed to be 
related to the study by the principal investigators or their representative.  
 
Table 4.  Reimbursement of expenses and incentives provided by the study 
To Who 
What 
Approximate Amount 
Regional Hospital/Medical Clinic 
Study procedure costs and antimalarials 
and admission fees for any potential 
inpatients 
~$20 (10,000 XOF) per patient per visit 
Patient 
Personal travel expenses for any study-
related visits to the hospital/medical clinic 
~$3 (1500 XOF) per round trip 
Patient 
Meal or reimbursement for breakfast, 
lunch or dinner for the participant and any 
accompanying if required to stay for more 
than half a day (lunch) or overnight 
(breakfast and dinner), 
~$1 (500 XOF) per person per meal 
Patient 
New LLIN for each enrolled household 
Free of charge from the CSPS/DRS 
 
12. Dissemination and Application of the Results. 
 
12.1. 
Results dissemination and publication policy. At the end of the trial, the results will first be 
disseminated to national policy makers, government departments, academics from local research 
institutions and universities, and professional bodies in Burkina Faso.  Subject to the findings of the 
study and based on consensus emerging at these meetings, project partners in Burkina Faso and the 
USA will support national and international policy makers in deciding whether there is a role for 
ivermectin in malaria control.  
 
Research results will also be disseminated to the global malaria research community, technical 
agencies, and international government bodies via peer reviewed journals and at international 
scientific fora, including the annual American Society of Tropical Medicine and Hygiene (ASTMH) 
meeting, and via meetings at WHO in Geneva comprised of leading scientists in the field of malaria.  
 
We will also inform other international organizations and funders of large scale malaria control 
initiatives such as the USAID and the US President's Malaria Initiative (PMI) which aim to improve 
malaria at regional and local levels and are instrumental in supporting countries to implement malaria 
control policies in Africa. 
 
12.2. 
Impact. New strategies for malaria control and elimination are critically needed. This protocol 
explores a research question that is currently highly discussed. In addition to the other known and 
planned studies occurring in other malaria-endemic countries, this protocol will seek to answer the 
question as to whether it will be feasible to introduce repeated ivermectin MDAs, timed during the rainy 
season, for added control of malaria in Burkina Faso. We expect the results of this protocol to 
stimulate interest and funding for larger, non-pilot trials, as well as to inform national malaria control 
programs in malaria-endemic countries, to inform WHO guidelines, to be published in high-profile peer-
reviewed journals, to be presented at domestic and international conferences, and the data to be 
shared with other groups for meta-analysis.  
 

40 
 
12.3. 
Training and capacity building.  Research capacity in research partner institutes in Burkina 
Faso, and reciprocally at CSU in the USA, will be enhanced by provision of training and mentorship for 
clinic and research staff.  By running this trial, capacity in trial management will be enhanced at CSU 
and the IRSS. The research study will strengthen the clinical and technical skills of IRSS and Centre 
Muraz health workers in managing patients.  
 
In addition, Burkinabé health workers from the Sud-Ouest Health Administrative region and the 
IRSS/Centre MURAZ will have the opportunity to learn new assays and techniques in mosquito 
sampling and age grading. 
 
12.4. 
Authorship and publications. The study will have a publications committee consisting of the 
PIs (BF and RD).  Potential authors include all professionals that have participated in the trial for a 
minimum of 3 months. Authorship of any presentations or publications arising from this study will also 
be governed by the principles for authorship criteria of the International Committee of Medical Journal 
Editors.  Disputes regarding authorship will be settled by the publications committee, with further 
involvement of an independent chair designated by the sponsor if necessary. The manufacturer of the 
study medication will be provided with a draft of the manuscript but will have no role in review, data 
interpretation, or writing of the article. 
 
12.5. 
Data sharing statement.  The full protocol will be available on request to any interested 
professional and may be published in a peer reviewed journals or deposited in an online repository. 
Individual, de-identified participant data will be made available for meta-analyses after the data 
analysis is completed, with the understanding that results of the meta-analysis will not be published 
prior to the results of the individual trial without prior agreement of the investigators. No later than 5 
years after the publication of the trial a fully de-identified data set will be available for sharing 
purposes. All requests for data for secondary analysis will be considered by the publication committee. 
 
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van den Berg H, Kelly-Hope LA, Lindsay SW. Malaria and lymphatic filariasis: the case for integrated 
vector management. Lancet Infect Dis. 2013;13(1):89-94. Epub 2012/10/23. doi: 10.1016/S1473-
3099(12)70148-2. PubMed PMID: 23084831. 

43 
 
46. 
Kobylinski KC, Alout H, Foy BD, Clements A, Adisakwattana P, Swierczewski BE, et al. Rationale for 
the coadministration of albendazole and ivermectin to humans for malaria parasite transmission control. Am J 
Trop Med Hyg. 2014;91(4):655-62. Epub 2014/07/30. doi: 10.4269/ajtmh.14-0187. PubMed PMID: 25070998; 
PubMed Central PMCID: PMC4183382. 
47. 
World Health Organization. Preventative chemotherapy in human helminthiasis.  Coordinated use of 
anthelminthic drugs in control interventions: a manual for health professionals and programme managers. In: 
(NTD) DoCoNTD, editor. Geneva: WHO press; 2006. 
48. 
Ouedraogo AL, Bastiaens GJ, Tiono AB, Guelbeogo WM, Kobylinski KC, Ouedraogo A, et al. Efficacy 
and safety of the mosquitocidal drug ivermectin to prevent malaria transmission after treatment: a double-blind, 
randomized, clinical trial. Clin Infect Dis. 2015;60(3):357-65. Epub 2014/11/22. doi: 10.1093/cid/ciu797. 
PubMed PMID: 25414262. 
 
 
14. Financial Aspects and Conflicts of Interest.  
 
14.1. 
Funding the trial. Funding to conduct the trial is provided by a Grand Challenges Explorations 
grant from the Bill and Melinda Gates Foundation. CSU: the BMGF grant and a grant on ivermectin 
research from the U.S. National Institutes of Health is providing salary support for BF and HA, while 
SR is getting salary support only from the BMGF grant.   The IRSS is providing salary support of RD, 
NR and the BMGF grant is supporting IRSS staff salaries, infrastructural support for the field station, 
transportation, centralized data management and laboratory materials.  The Burkina Faso Ministry of 
Health is providing infrastructural support for the trial conduct in the Burkina Faso Sud-Ouest Health 
Administrative region.  
 
The funder had no role in the design of this trial and will not have any during the execution, analysis, 
interpretation of the data, or decision to submit the results 
 
14.2. 
Provision of the study drugs.  Ivermectin and albendazole will provided free of charge from 
the Burkina Faso Ministry of Health from their stocks for NTD control to be used in their country.  The 
study will provide copies of safety reports of SAEs and AEs to the drug manufacturers (expedited 
where required). The manufacturers will not be involved in the design of the trial.  
 
15. Budget and Budget Justification.   
See 16.3 “Appendix III for budget and budget justification”, pg. 46.   
 
 
16. Appendices. 
 
 

44 
 
 
 
16.1. 
Appendix I.  Role of Investigators. 
 
16.1.1. Protocol development: authors’ contributions.  Brian Foy (BF) conceived the study. BF and 
Haoues Alout (HA) wrote the grant proposal that was funded by the BMGF.  BF and HA drafted 
the initial clinical protocol, and Roch Dabire (RD), Noël Rouamba (JR) added revisions and input 
to construct the final draft.  Sangeeta Rao (SR) edited the protocol and provided statistical 
expertise and verified the sample size calculations. Hannah Slater (HS) provided modeling data in 
support of the studies hypotheses.  All investigators contributed to the refinement of the study 
protocol and approved the final version. 
 
16.1.2. Role of Investigators. 
 
Noël Rouamba (MD), is a physician working on malaria and NTDs at the IRSS and Centre MURAZ, 
based in Bobo Dioulasso, Burkina Faso.  He will act as a co-Principle Investigator and trial coordinator.  
He will serve as the senior medical doctor on the study, overseeing clinical aspects. 
 
Brian Foy (PhD), is an associate professor in the Arthropod-borne and Infectious Diseases Laboratory 
within the Department of Microbiology, Immunology and Pathology at CSU in the USA.  He is a 
Principle Investigator and the grant holder and will carry overall responsibility for the coordination of the 
trial and for the linkages with the sponsor, funders and with international partners involved with similar 
transmission reduction research. 
 
Roch Dabiré (PhD), is head of Infectious Disease research at the IRSS, based in Bobo Dioulasso, 
Burkina Faso.  He is a Principle Investigator and will carry responsibility for the coordination of the field 
and laboratory teams based out of the IRSS and Centre MURAZ.  He will also coordinate the linkages 
with the Burkina Faso MoH, the local village leaders and the regional medical authorities. 
 
Haoues Alout (PhD), is a research scientist in the Arthropod-borne and Infectious Diseases Laboratory 
within the Department of Microbiology, Immunology and Pathology at CSU in the USA.  He is a co-
Principle Investigator, and together with the principal investigators, will share overall responsibility for 
the study, coordination of technicians and staff, and serve as the lead entomologist on the study. 
 
 
16.1.3. Role of non-engaged collaborators. 
 
Sangeeta Rao (PhD), is an assistant professor in the Department of Clinical Sciences at CSU in the 
USA.  She is biostatistician and epidemiologist and will be the trial statistician/outcomes assessor who 
will be blinded to the treatment arms. 
 
Roland Bougma (MD), is the coordinator of the LF control program (Le Programme Nationale 
d’Elimination Filariose Lymphatique) in the Burkina Faso MoH, based in Ouagadougou, Burkina Faso.  
He will act as the primary contact with the Burkina Faso Ministry of Health, coordinate procurement of 
the study drugs from the MoH NTD control program, and facilitate our collaboration with the DRS in the 
Sud-Ouest Region. 
 
 
 
 
 
 
 
 
 
 
 

45 
 
16.2. 
Appendix II: Terms of Reference Oversight Committees 
 
16.2.1. Trial Management Group (TMG) 
 
16.2.1.1. Purpose.  The TMG is responsible for the administrative management and day to day 
running of the trial. 
 
16.2.1.2. Membership.  The TMC will be chaired by one of the Principal Investigators or Co-
Investigators.   
 
1. Principal Investigators 
2. Co-Principal Investigators  
3. Site clinicians  
4. Trial Coordinator  
5. Administrators  
6. Others who are involved in the day to day running of the trial  
16.2.1.3. Responsibilities. 
• 
Study planning  
• 
Organization of site visits by the ISM/CTM and supplying them data  
• 
Provide risk report to regulators, manufacturer and ethics committees  
• 
SAE/SAR/SUSAR  reporting  
• 
Responsible for trial master file  
• 
Budget administration and contractual issues  
• 
Advice for lead investigators  
• 
Organization of central data management and sample collection  
 
16.2.2. Independent Safety Monitor/Clinical Trial Monitor (ISM/CTM) 
 
16.2.2.1. Role. The ISM/CTM is a person with experience in clinical trials and ICH-GCP 
regulations.   
 
S/he shall review the data and the interim analysis, and monitor the trial documents and 
safety reports. They are independent and look at the trial from an ethical point of view of the 
participant safety, future patients and society in general. It is their responsibility to prevent 
patients being exposed to any excess risks by recommending for the trial suspension or 
termination early if the safety or efficacy results are sufficiently convincing. The trial 
statistician will be invited to liase with the ISM/CTM to help analyze the most current data 
from the trial. This will be blinded, unless the ISM/CTM specifically requests for an unblinded 
analysis. 
  
16.2.2.2. Responsibilities. The ISM/CTM has the following defined responsibilities: 
• 
They will consider the blinded or unblinded interim data from the trial and 
relevant data from other sources. 
• 
They will consider any requests for unblinding and release of interim data and to 
recommend to the TMG on the importance of this. 
• 
They will report to the TMG and recommend whether the trial should continue, 
the protocol be modified, or the trial be stopped.  
• 
The will confirm that the study is being performed according to the protocol, ICH-
GCP and applicable regulations, data are being accurately recorded in the CRFs 
and that investigational product accountability is being performed and confirm 
facilities remain acceptable  
 
 
 

46 
 
 
16.3. 
Appendix III.  Budget and Budget Justification 
16.3.1. Budget 
Description 
Cost (USD) 
Personnel 
$50,000 
Laboratory supplies 
$15,000 
Entomology supplies 
$5,000 
Logistical supplies and support 
$10,000 
Transport 
$10,000 
Travel 
$10,000 
Total 
$100,000 
 
16.3.2. Budget Justification 
Personnel $ 50,000 
Key staff will be needed to collect vital study information. These include nurses, microscopists, 
laboratory technicians and entomology assistants.  A portion of the PIs and co-PIs salaries are also 
contained in this part of the budget.  
 
Laboratory supplies $ 15,000 
Important laboratory procedures will be critical to realization of study objectives. These include 
microscopy, RDT tests, AL treatments, hemoglobin testing, stool analysis, and molecular analyses of 
blood samples. Laboratory consumables are also required for the day to day running of the 
laboratories.  
 
Entomology supplies $ 5000 
Mosquito capturing and processing is essential for the secondary objectives.  Supplies include 
aspirators, batteries, CDC-light traps, tents, mosquito cages, microscopes, dissecting forceps, tubes, 
desiccant and disposables.  
 
Logistical supplies and support $10,000  
Data documentation and storage, and communication in the field will be essential.  Supplies include cell 
phone, internet dongles and minute cards, tablets and printing services for CFRs and other documents, 
GPS devices and services, and programs for CRF and lab report generation.  
 
Transport $ 10,000 
Travel to the study villages by the study staff will be regular throughout the study period for all the 
activities, including participating the in the MDAs, sampling and clinical monitoring. Additionally, 
transport reimbursement will be given to study participants that need to attend clinic visits.  
 
Travel $ 10,000 
International travel for study investigators based abroad.  
 
 
 

47 
 
 
16.4. 
Appendix IV. SPIRIT (Standard Protocol Items. Recommendations for International Trials) 2013 
Checklist. 
 
SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related 
documents*  
 
Section/item 
Item 
No. 
Description 
Addressed 
on page 
number 
Administrative Information 
Title 
1 
Descriptive title identifying the study design, population, interventions, and, if 
applicable, trial acronym 
1,8,9 
Trial registration 
2a 
Trial identifier and registry name. If not yet registered, name of intended registry 
1,8,9 
 
2b 
All items from the World Health Organization Trial Registration Data Set 
9 
Protocol version 
3 
Date and version identifier 
1 
Funding 
4 
Sources and types of financial, material, and other support 
19, 42, 46 
Roles & Responsibilities 
5a 
Names, affiliations, and roles of protocol contributors 
1, 8, 44 
 
5b 
Name and contact information for the trial sponsor 
1 
 
5c 
Role of study sponsor and funders, if any, in study design; collection, management, 
analysis, and interpretation of data; writing of the report; and the decision to submit 
the report for publication, including whether they will have ultimate authority over any 
of these activities 
43 
 
5d 
Composition, roles, and responsibilities of the coordinating center, steering 
committee, endpoint adjudication committee, data management team, and other 
individuals or groups overseeing the trial, if applicable (see Item 21a for data 
monitoring committee) 
45 
Introduction 
Background and 
rationale 
6a 
Description of research question and justification for undertaking the trial, including 
summary of relevant studies (published and unpublished) examining benefits and 
harms for each intervention 
13-18, 19-
20 
 
6b 
Explanation for choice of comparators 
20 
Objectives 
7 
Specific objectives or hypotheses 
18-19 
Trial Design 
8 
Description of trial design including type of trial (eg, parallel group, crossover, 
factorial, single group), allocation ratio, and framework (eg, superiority, equivalence, 
non-inferiority, exploratory) 
19-20 
Methods: Participants, interventions and outcomes 
Study setting 
9 
Description of study settings (eg, community clinic, academic hospital) and list of 
countries where data will be collected. Reference to where list of study sites can be 
obtained 
21 
Eligibility criteria 
 
10 
Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for 
study centres and individuals who will perform the interventions (eg, surgeons, 
psychotherapists) 
21 
Interventions 
 
11a 
Interventions for each group with sufficient detail to allow replication, including how 
and when they will be administered 
21-23 
 
11b 
Criteria for discontinuing or modifying allocated interventions for a given trial 
participant (eg, drug dose change in response to harms, participant request, or 
improving/worsening disease) 
22-23 
 
11c 
Strategies to improve adherence to intervention protocols, and any procedures for 
monitoring adherence (eg, drug tablet return, laboratory tests) 
23 
 
11d 
Relevant concomitant care and interventions that are permitted or prohibited during 
the trial 
23 
Outcomes 
12 
Primary, secondary, and other outcomes, including the specific measurement 
variable (eg, systolic blood pressure), analysis metric (eg, change from baseline, 
24 

48 
 
final value, time to event), method of aggregation (eg, median, proportion), and time 
point for each outcome. Explanation of the clinical relevance of chosen efficacy and 
harm outcomes is strongly recommended 
Participant timeline 
13 
Time schedule of enrolment, interventions (including any run-ins and washouts), 
assessments, and visits for participants. A schematic diagram is highly 
recommended (see Figure) 
12, 24-26 
Sample size 
14 
Estimated number of participants needed to achieve study objectives and how it was 
determined, including clinical and statistical assumptions supporting any sample size 
calculations 
27 
Recruitment 
15 
Strategies for achieving adequate participant enrolment to reach target sample size 
27 
Methods: Assignment of interventions (for controlled trials) 
Allocation: 
 
 
 
Sequence 
generation 
16a 
Method of generating the allocation sequence (eg, computer-generated random 
numbers), and list of any factors for stratification. To reduce predictability of a 
random sequence, details of any planned restriction (eg, blocking) should be 
provided in a separate document that is unavailable to those who enroll participants 
or assign interventions 
28 
Allocation 
concealment 
mechanism 
16b 
Mechanism of implementing the allocation sequence (eg, central telephone; 
sequentially numbered, opaque, sealed envelopes), describing any steps to conceal 
the sequence until interventions are assigned 
28, 36 
Implementation 
16c 
Who will generate the allocation sequence, who will enroll participants, and who will 
assign participants to interventions 
28, 36 
Blinding (masking) 
17a 
Who will be blinded after assignment to interventions (eg, trial participants, care 
providers, outcome assessors, data analysts), and how 
28, 36, 44 
 
17b 
If blinded, circumstances under which unblinding is permissible, and procedure for 
revealing a participant’s allocated intervention during the trial 
28,45 
Sequence 
generation 
16a 
Method of generating the allocation sequence (eg, computer-generated random 
numbers), and list of any factors for stratification. To reduce predictability of a 
random sequence, details of any planned restriction (eg, blocking) should be 
provided in a separate document that is unavailable to those who enrol participants 
or assign interventions 
28, 36 
Methods: Data collection, management, and analysis 
Data collection methods 
18a 
Plans for assessment and collection of outcome, baseline, and other trial data, 
including any related processes to promote data quality (eg, duplicate 
measurements, training of assessors) and a description of study instruments (eg, 
questionnaires, laboratory tests) along with their reliability and validity, if known. 
Reference to where data collection forms can be found, if not in the protocol 
28-29 
 
18b 
Plans to promote participant retention and complete follow-up, including list of any 
outcome data to be collected for participants who discontinue or deviate from 
intervention protocols 
23, 29-30 
Data management 
19 
Plans for data entry, coding, security, and storage, including any related processes 
to promote data quality (eg, double data entry; range checks for data values). 
Reference to where details of data management procedures can be found, if not in 
the protocol 
29, 33 
Statistical methods 
20a 
Statistical methods for analyzing primary and secondary outcomes. Reference to 
where other details of the statistical analysis plan can be found, if not in the protocol 
29-30 
 
20b 
Methods for any additional analyses (eg, subgroup and adjusted analyses) 
29-30 
 
20c 
Definition of analysis population relating to protocol non-adherence (eg, as 
randomized analysis), and any statistical methods to handle missing data (eg, 
multiple imputation) 
29-30 
Methods: Monitoring 
Data monitoring 
21a 
Composition of data monitoring committee (DMC); summary of its role and reporting 
structure; statement of whether it is independent from the sponsor and competing 
interests; and reference to where further details about its charter can be found, if not 
in the protocol. Alternatively, an explanation of why a DMC is not needed. 
30 
 
21b 
Description of any interim analyses and stopping guidelines, including who will have 
access to these interim results and make the final decision to terminate the trial 
30 
Harms 
22 
Plans for collecting, assessing, reporting, and managing solicited and spontaneously 
reported adverse events and other unintended effects of trial interventions or trial 
conduct 
31-32 
Auditing 
23 
Frequency and procedures for auditing trial conduct, if any, and whether the process 
will be independent from investigators and the sponsor 
33-34 
Ethics and dissemination 
 

49 
 
Research ethics 
approval 
24 
Plans for seeking research ethics committee/institutional review board (REC/IRB) 
approval 
35 
Protocol amendments 
25 
Plans for communicating important protocol modifications (eg, changes to eligibility 
criteria, outcomes, analyses) to relevant parties (eg, investigators, REC/IRBs, trial 
participants, trial registries, journals, regulators) 
35 
Consent or assent 
26a 
Who will obtain informed consent or assent from potential trial participants or 
authorized surrogates, and how (see Item 32) 
36 
 
26b 
Additional consent provisions for collection and use of participant data and biological 
specimens in ancillary studies, if applicable 
36 
Confidentiality 
27 
How personal information about potential and enrolled participants will be collected, 
shared, and maintained in order to protect confidentiality before, during, and after the 
trial 
36-37, 51-
53 
Declaration of interests 
28 
Financial and other competing interests for principal investigators for the overall trial 
and each study site 
37, 42-43 
Access to data 
29 
Statement of who will have access to the final trial dataset, and disclosure of 
contractual agreements that limit such access for investigators 
37 
Ancillary and post-trial 
care 
30 
Provisions, if any, for ancillary and post-trial care, and for compensation to those 
who suffer harm from trial participation 
38 
Dissemination policy 
31a 
Plans for investigators and sponsor to communicate trial results to participants, 
healthcare professionals, the public, and other relevant groups (eg, via publication, 
reporting in results databases, or other data sharing arrangements), including any 
publication restrictions 
39 
 
31b 
Authorship eligibility guidelines and any intended use of professional writers 
39 
 
31c 
Plans, if any, for granting public access to the full protocol, participant-level dataset, 
and statistical code 
39 
Appendices 
Informed consent 
materials 
32 
Model consent form and other related documentation given to participants and 
authorized surrogates 
51-53 
Biological specimens 
33 
Plans for collection, laboratory evaluation, and storage of biological specimens for 
genetic or molecular analysis in the current trial and for future use in ancillary 
studies, if applicable 
51-53 
The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 
Unported” license. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

50 
 
 
17. Appendix V. Product Characteristics. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

51 
 
18. Appendix VII.  Participant Information Sheets and Informed Consent Forms. 
18.1. 
Informed consent head-of-household information sheet: English 
 
Repeat ivermectin mass drug administrations for control of malaria: a pilot safety and efficacy 
study (RIMDAMAL) 
 
Information Sheet 
 
Purpose of research study  
People in Burkina Faso get lymphatic filariasis (LF), which causes swollen legs and other sickness.  A worm 
parasite causes the swollen leg sickness, and it is transmitted by mosquitoes. In Burkina Faso, health districts 
distribute to the population the drugs ivermectin and albendazole to kill this worm parasite.  People in Burkina 
Faso also get malaria, which is caused by a different parasite but which is transmitted by the same 
mosquitoes.  We have found that ivermectin also kills the mosquitoes that spread both of these parasites.  We 
want to test if giving ivermectin more often during the rainy season may stop malaria and lymphatic filariasis 
from spreading by mosquitoes to other people in the village, especially to the children who can get the most 
sick from malaria. This is why the Institute de Recherche en Sciences de la Santé (IRSS), the Centre MURAZ 
(CM), the Burkina Faso Ministry of Health (MoH) and Colorado State University (CSU) are performing this 
research study.  
 
What we will do 
Eight villages of the District Sanitaire of Diébougou have been selected to be part of this study, they 
are Limania, Kpokologo, Moulé, Tiedia, Djinkargou, Djan-gougourgou, Tempé-gougougré and 
Kolépar. They have been split in two groups: one experimental and one control with four villages in 
each. The chiefs and the elders of your village and the others gave their agreement to participate in 
this study. They were involved in a public draw to determine in which group their village will be. 
The study will occur during the rainy season and will have several phases: 
1. The first phase consists of enrolling persons that consented to participate. We will ask questions about 
person information and medical history. Also we will take a sample of blood on the finger (1ml) on 
selected people and fecal samples on selected children between 6 to 10. These samples will be taken 
on people living in houses the center of the village.  
2. The second phase will start with the mass drug administration of ivermectin and albendazole in the 
eight villages by the health district of Diebougou. After treatement, active case detection of malaria 
cases on the children under 5 years old will start. A nurse will visit each child under 5 twice a week. The 
nurse will check for fever. If one child has fever, the nurse will take a small blood sample to perform a 
rapid diagnostic test. If the test is positive and there is no other problem (uncomplicated malaria), the 
nurse will give an anti-malaria treatment according to national guidelines (CoartemR). If the child 
presents other symptoms he will be referred to the CSPS. During this phase, a team of IRSS/Centre 
Muraz will come to collect mosquitoes in the houses located in the center of the village. In the villages 
of the experimental group, the mass drug administration of ivermectin only will repeated five times at 
three weeks interval. Ivermectin is safe and well tolerated but if you experience adverse events, you 
need inform the nurse as well as the ASC and you will be referred to the CSPS.  
3. The last phase will happen during the three weeks after the last treatment is given to the population. 
Active case detection and passive monitoring of adverse events will continue. Also we will take a 
sample of blood on the finger (1ml) on selected people and fecal samples on selected children between 
6 to 10. These samples will be taken on people living in houses the center of the village.  
 
Potential risks  
 

52 
 
The drug ivermectin is well tolerated and safe in single doses.  Few side effects have been already described 
such as: 
• 
fatigue  
• 
Abdominal pain  
• 
loss of appetite 
• 
constipation 
• 
diarrhea 
• 
nausea 
• 
vomiting 
• 
dizziness 
• Urticaria, rashes, pruritis 
 
We are not sure what risks may be present in having multiple doses, but we will be monitoring your household 
closely.  Nurses will check on you twice a week.  In addition, we will give you a telephone number to call if you 
are concerned at any time.  Ivermectin can give problems to people with Loa loa. However, Loa loa is not 
found in Burkina Faso. If you or anyone of your household have travelled to a country with Loa loa, you may 
not participate in the study.  
 
Privacy and confidentiality  
Information about yourself and your household will be kept confidential to the maximum extent allowable by 
law. The data we collect will be stored securely in locked cabinets and on password-protected computers. Only 
members of the study staff will review the records with the name of you or your family member. We will use the 
information you give to us only for research. The information collected will be shared with other people, but 
your name or members of your household will not appear on any reports. At the end of the study, we will 
remove all names from the data so that no one can identify your or your family’s information or your blood 
sample.  
 
Your rights to participate, say no, or withdraw 
We are asking if you and your family are willing to participate in this study. You are free to choose to have your 
household be part of this study. If you agree, we will ask each member of your family individually to participate. 
You have the right to refuse. If you do not want your household to go on with this study, you can stop at any 
time without any prejudice.  
 
Consent for long-term storage of blood samples for future studies  
We are asking people who join this study if they will let the researchers’ use their blood sample for future 
studies. These future studies may help find new ways to prevent malaria. If you say yes, we will store the blood 
we take from you and members of your household with a unique code and not any names in laboratories in 
Burkina Faso and the US.  We may share the test results with researchers at other organizations but we will 
not give them any names, addresses, or any information that could identify you or your household.  After the 
study period has ended, we will remove any means to link the sample to you and your household, and we will 
not be able to find the samples connected to your household.  If you do not wish to have your blood stored, you 
and your household may still participate in our study.  You and your family will still be provided ivermectin and 
your children regularly examined for malaria.  If they have malaria, we will still treat them.  
 
Costs and compensation for being in the study  
The participation is based on volunteering, no one will be paid for his/her participation. Transport 
reimbursement for sick visits to the health center will be provided to you as per IRSS guidelines.  
 
 
Contact information for questions or concerns  

53 
 
If you have any questions about this study, you can contact the clinical team in the field, through Dr 
Gafar Abdoul Victor COULIDIATY at 70566623.  
You can also contact Dr. Roch Dabire at the IRSS, 399 Ave de la Liberté, Bobo Dioulasso, Houet, 
Burkina Faso, 10400-000, at 70 73 90 69.  
You can also contact the Comité d’éthique of IRSS (CEIRES), or if you want to talk about the study 
with someone who is not directly involved with this study, please contact Dr PARE/TOE Léa Mélanie 
au 70759361. 
If you do not have access to a telephone, or you do not know how to read and write, this will not stop 
you from participating in this study. You may ask for contact information from the nearest health 
facility if you wish to talk with one of the listed individuals to raise any concerns.  
If you are sick, do not call these numbers. Please go to the nearest health facility.  
Thank you very much for your time. If you agree to take part in this study, we will ask you to sign this form. 
 
 
18.2. 
Consent documents: English 
 
Repeat ivermectin mass drug administrations for control of malaria: a pilot safety and efficacy 
study (RIMDAMAL) 
 
Head-of-Household Consent Statement 
 
I have been invited to give approval for my family to participate in the study named “Repeat ivermectin mass 
drug administrations for control of malaria: a pilot safety and efficacy study (RIMDAMAL)”. The 
objectives and the protocol were provided through the information sheet and have been explained to me. 
I agree to have my household take part in the study. I understand that my family and I are free to choose to 
participate in this study and that refusing will have no effect on my household or me. Every member of my 
family can ask question whenever they want. 
 
I agree to provide blood and fecal samples that will be sent to IRSS/Centre Muraz in Burkina Faso or to CSU in 
the USA for detecting malaria and other parasites. I agree to have these blood samples stored for later 
analysis. 
 
I give my approval to IRSS/Centre MURAZ, Ministry of Health of  Burkina Faso and CSU to access and consult 
the medical history of my family and me. I agree to let those information to be shared with researchers at other 
organizations if no one could identifiy my family and me. I have been informed that all Information about myself 
and my household will be kept confidential and that any names, addresses, or any information that could 
identify my family and me will not be released.   
 
If you have any questions about this study, you can contact the clinical team in the field, through Dr 
Gafar Abdoul Victor COULIDIATY at 70566623. You can also contact Dr. Roch Dabire at the IRSS, 
399 Ave de la Liberté, Bobo Dioulasso, Houet, Burkina Faso, 10400-000, at 70 73 90 69. You can 
also contact the Comité d’éthique of IRSS (CEIRES), or if you want to talk about the study with 
someone who is not directly involved with this study, please contact Dr PARE/TOE Léa Mélanie au 
70759361. 
 
Concession number 
 

54 
 
 
Name 
Signature or fingerprint  
Date 
Head of Household 
 
 
 
Witness 
 
 
 
Study staff  
 
 
 
 
Repeat ivermectin mass drug administrations for control of malaria: a pilot safety and efficacy 
study (RIMDAMAL) 
 
Adult consent form  
 
This form is for all family member above the age of 18 years old for which the approval from 
head of household has been obtained.  
 
I have been invited to participate in the study named “Repeat ivermectin mass drug administrations for 
control of malaria: a pilot safety and efficacy study (RIMDAMAL)”. The objectives and the protocol were 
provided through the information sheet and have been explained to me. 
 
I agree as an adult family member and after approval of the head of household to participate voluntarily in this 
study and to follow the protocol. I particularly agree to : 
 
1. Provide a blood sample to detect malaria parasites and other parasites at IRSS in Burkina Faso or 
at CSU in the USA. 
 
2. Disclose my relevant medical history to IRSS/Centre MURAZ, Ministry of Health of  Burkina Faso 
and CSU I agree to let those information to be shared with researchers at other organizations if no 
one could identifiy me. 
 
I have been informed that I can stop at any time without any prejudice and without losing the benefit 
related to this study.  
 
Concession number 
 
 
Name 
Signature or fingerprint  
Date 
Head of Household 
 
 
 
Witness 
 
 
 
Study staff  
 
 
 
 

55 
 
 
Repeat ivermectin mass drug administrations for control of malaria: a pilot safety and efficacy 
study (RIMDAMAL) 
 
Child consent form 
 
This form concerns all family member under the age of 18 years old for which the approval 
from head of household has been obtained. It has to be signed by the head of household. 
 
My child/nephew/grand-child/………………………………… (Name) has been requested to participate in the 
study named : named “Repeat ivermectin mass drug administrations for control of malaria: a pilot safety 
and efficacy study (RIMDAMAL)”. The objectives and the protocol were provided through the information 
sheet and have been explained to me. 
 
I agree as the head of household that my child/nephew/grand-child will participate voluntarily in this study and 
will follow the protocol. I particularly agree to  : 
 
1. Provide a blood sample to detect malaria parasites and other parasites at IRSS in Burkina Faso or 
at CSU in the USA. 
 
2. Disclose my relevant medical history to IRSS/Centre MURAZ, Ministry of Health of  Burkina Faso 
and CSU I agree to let those information to be shared with researchers at other organizations if no 
one could identifiy me. 
 
I have been informed that child/nephew/grand-child can stop at any time without any prejudice and 
without losing the benefit related to this study.  
 
Concession number 
 
 
Name 
Signature or fingerprint  
Date 
Participant 
 
 
 
Person giving the 
consent for the child 
 
 
 
Witness 
 
 
 
Study staff  
 
 
 
 
 
Repeat ivermectin mass drug administrations for control of malaria: a pilot safety and efficacy 
study (RIMDAMAL) 
 
Assent form  

56 
 
 
 
This form is for all family members between the age of 12 to 18 years old for which the 
approval from the head of household has been obtained.  
 
I have been invited to participate in the study named “Repeat ivermectin mass drug administrations for 
control of malaria: a pilot safety and efficacy study (RIMDAMAL)”. The objectives and the protocol were 
provided through the information sheet and have been explained to me. 
 
I agree as an adult family member and after approval of the head of household to participate voluntarily in this 
study and to follow the protocol. I particularly agree to : 
 
1. Provide a blood sample to detect malaria parasites and other parasites at IRSS in Burkina Faso or 
at CSU in the USA. 
 
2. Disclose my relevant medical history to IRSS/Centre MURAZ, Ministry of Health of  Burkina Faso 
and CSU I agree to let those information to be shared with researchers at other organizations if no 
one could identify me. 
 
I have been informed that I can stop at any time without any prejudice and without losing the benefit 
related to this study.  
Concession number 
 
 
Name 
Signature or fingerprint  
Date 
Participant 
 
 
 
Person giving the 
consent for the child 
 
 
 
Witness 
 
 
 
Study staff  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

57 
 
19. Appendix VIII.  Guidelines for study nurses managing AEs and SAEs following MDA that are 
possibly related to the study treatment. 
 
19.1. 
These guidelines come from the WHO 2011 publication, ‘Assuring Safety of Preventative 
Chemotherapy Interventions for the Control of Neglected Tropical Diseases: Practical Advice for 
National Programme Managers on the Prevention, Detection and Management of Serious Adverse 
Events.’ and ‘A Handbook for Managing Adverse Events Following Mass Drug Administration (AEs-f-
MDA) and Serious Adverse Events (SAEs)’, published in August of 2014 by USAID, Envision, RTI 
International, and the Task Force for Global Health.   
 
19.1.1.  Treating patients at home or in the CSPS 
• 
Obtain clinical history including past history and medications used. 
• 
Make rapid clinical assessment.  Record and monitor temperature, pulse rate, blood 
pressure and respiratory rate.  Consult with the attending or study physician if possible. 
• 
Explain to the patient that the adverse event is likely not a reaction to the medicine itself, 
but due to the killing of the parasite by the medicine.  Emphasize that it is a sign that the 
medicine is working and is needed 
 
19.1.1.1. Abdominal pain, vomiting diarrhea 
• 
Put patient at rest, protected from excessive temperature, noise and light.  
• 
Use traditional remedies (e.g. sour fruit juices), if available, to manage nausea and 
vomiting. Make sure patient can drink water or fruit juices.  
• 
Watch for possible signs of dehydration such as thirst, dry skin, dark colored urine, 
dry mouth, fatigue, and weakness.  
• 
Administer oral/intravenous fluid if necessary.  
• 
Give antispasmodics and antiemetic, if necessary. 
 
19.1.1.2. Fever, headache, aches in other parts of the body, pain in the joints or inflammation 
(usually in the inguinal area or scrotum) 
• 
Advise the patient to rest 
• 
Apply cold compress in the affected area when there is localized inflammation. 
• 
Give paracetamol tablets. The recommended doses are: 
o Children 1-5 years: 125-250mg;  
o Children 6-12 years: 250-500mg;  
o from 12 years old: 500mg-1g  
o (these doses can be repeated after 4-6 hours if necessary)  
 
19.1.1.3. Dizziness 
• 
 Advise the patient to rest.  
• 
Check the blood pressure to rule out postural hypotension.  
• 
Prop the head up with pillows when in bed to reduce the likelihood of orthostatic 
hypotension when getting up. Advise the patient to get up slowly from a sitting or lying 
position. 
 
19.1.1.4. Malaise (feeling unwell), feeling sleepy, tired, weak 
• 
Advise the patient to rest.  
• 
Put patient at rest, protected from excessive temperature, noise and light.  
 
19.1.1.5. Photophobia 
• 
Protect the patient’s eyes from light. 
 
19.1.1.6. Urticaria, rashes, pruritis 
• 
Assess the skin signs and symptoms. Be aware that they could be the earliest signs 
of conditions (e.g. Stevens Johnson Syndrome or Toxic Epidermal Necrolysis) which 
could be very serious and require rapid response. If Stevens Johnson Syndrome or 

58 
 
Toxic Epidermal Necrolysis are suspected, refer patient to the nearest hospital 
immediately. 
• 
Give antihistamines. The recommended doses are:  
o Chlorphenamine tablets:  
 
children 2-5 years: 1mg;  
 
children 6-12 years: 2mg;  
 
from 12 years old: 4mg  
 
(can be repeated after 4-6 hours if necessary)  
o Promethazine tablets:  
 
children 2-5 years: 5-15mg/day in 2 doses;  
 
children 6-12 years: 10-25mg/day in 2 doses;  
 
from 12 years old: 10-20mg up to 3 times a day  
 
19.1.1.7. Wheezing (occurring in a person that has no history of asthma or other respiratory 
disease) 
• 
Make sure the administered tablet is not choking the patient.  
• 
Give antihistamines (see dosage schedule above).  
• 
If symptoms are not controlled or worsen, refer patient to appropriate health facility.