Clinical trial NCT03967054
Conditions: Malaria
Keywords: mosquito ivermectin Anopheles Plasmodium
Sponsor: Brian Foy
Start date: 2019-07-13; Completion date: 2024-08-01
Enrollment: 4124 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
RIMDAMAL II is a double-blind, cluster randomized trial in Burkina Faso designed to test whether repeated ivermectin mass drug administrations, integrated into a monthly delivery platform with standard malaria control measures of seasonal malaria chemoprevention and insecticide-treated bed net distribution in the Sahel, will reduce childhood malaria incidence.

Detailed description:
The RIMDAMAL II trial is designed to determine the efficacy of adding seasonal ivermectin mass drug administrations to the standard-policy malaria control measures in the Sahel (seasonal malaria chemoprevention in children, maximum long-lasting insecticidal net coverage, intermittent preventive treatment in pregnancy), for reducing the incidence of uncomplicated malaria episodes in enrolled village children (≤ 10 years of age) assessed by active case surveillance. The investigators will also examine the safety of the intervention, as well as entomological and parasitological endpoints. This is a double-blind, cluster randomized trial in that will occur in villages in southwestern Burkina Faso over two consecutive rainy seasons. For the intervention, mass administration of ivermectin or placebo will be given monthly over 4 months of each rainy season to the eligible village population, each as 3-day course of 300 µg/kg/day. These mass drug administrations will occur simultaneously with the distribution of seasonal malaria chemoprevention drugs on the same monthly schedule to eligible children aged 3-59 months.

Arms: arm 1: Ivermectin given monthly from July-October (4 times) as a 3-day course of 300 µg/kg/day to all eligible persons per exclusion/inclusion criteria. Per package insert, dosing of IVM will be according to height to approximate weight: 90-119 cm = 1 tablet/day for 3 days; 120-140 cm = 2 tablets/day for 3 days; 141-158 cm = 3 tablets/day for 3 days; \>158 cm = 4 tablet/day for 3 days. arm 2: Placebo given monthly from July-October (4 times) as a 3-day course to all eligible persons per exclusion/inclusion criteria. Dosing of placebo will be according to height to approximate weight: 90-119 cm = 1 tablet/day for 3 days; 120-140 cm = 2 tablets/day for 3 days; 141-158 cm = 3 tablets/day for 3 days; \>158 cm = 4 tablet/day for 3 days.
Interventions: intervention 1: Ivermectin intervention 2: Placebo oral tablet
Intervention descriptions: intervention 1: Ivermectin (6 mg tablet) given monthly from July-October each rainy season as a 3-day course of approximately 300 mcg/kg/day as estimated by height bands. intervention 2: placebo in the same size, color and shape at the ivermectin tablet

Protocol documents:
Prot_000.pdf: 
DMID  Protocol 18-0007 
Version 1.3 
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29 February 2020 
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DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 2.0, Dated August 10, 2017 
Repeat Ivermectin Mass Drug Administrations for MALaria Control II 
(RIMDAMAL II): a double-blind, cluster-randomized control trial for 
integrated control of malaria. 
DMID Protocol Number: 18-0007 
DMID Funding Mechanism: U01 AI138910-01 
Pharmaceutical Support Provided by: Laboratorio Elea (or other)  
Lead Principal Investigator: Brian D. Foy, PhD 
DMID Clinical Project Manager: Walt Jones, RN, MPH 
DMID Medical Officer: Greg Deye, MD 
DMID Medical Monitor: Venus Shahamatdar, M.D. 
Draft or Version Number: v. 1.3 
Day Month Year 
 29 February 2020 
 
 
 
 


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LIST OF ABBREVIATIONS 
ACD 
Active Case Detection 
AE 
Adverse Event/Adverse Experience 
AL 
Artemether-lumefantrine 
ALT 
Alanine Aminotransferase 
AQ 
Amodiaquine 
ASAQ 
Artesunate-Amodiaquine 
AST 
Aspartate Aminotransferase 
BLA 
Biologics License Applications 
CAR 
Clinical Agents Repository 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
Cr 
Creatinine 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR  
Clinical Study Report 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH, DHHS 
DOT 
Directly Observed Therapy 


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DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
HIC 
Human Investigations Committee 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IRSS 
Institute de Recherche en Sciences de la Santé 
IVM 
Ivermectin 
IPTp 
Intermittent Preventative Treatment in Pregnancy 
JAMA 
Journal of the American Medical Association 
LLIN 
Long-lasting Insecticide-Treated Bed Net 
MDA 
Mass Drug Administration 
MedDRA 
Medical Dictionary for Regulatory Activities 


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mFOI 
Molecular Force of Infection 
MoH 
Ministry of Health 
MOI 
Multiplicity of Infection 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NDOT 
Non-directly Observed Therapy 
NEJM 
New England Journal of Medicine 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
NIH 
National Institutes of Health 
NMCP 
National Malaria Control Program 
OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PD 
Pharmacodynamics 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SMC 
Seasonal Malaria Chemoprevention 
SOC 
Safety Oversight Committee 
SOP 
Standard Operating Procedure 
SPAQ 
Sulfadoxine-Pyrimethamine-Amodiaquine 


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US 
United States 
WHO 
World Health Organization 
 
 
 
 


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PROTOCOL SUMMARY 
Title: 
Repeat Ivermectin Mass Drug Administrations for MALaria Control II 
(RIMDAMAL II): a double-blind, cluster-randomized control trial for 
integrated control of malaria. 
Phase: 
3 
Population: 
14 villages, 2 arms (7 clusters/arm); all heathy and eligible 
participants (both genders and all ages), approximately 4,700 people 
who live in southwestern Burkina Faso 
Number of Sites: 
1 site in southwestern Burkina Faso 
Study Duration: 
3 years (between 2018-2021) 
Subject Participation Duration: 
2.5 years (2019-2021) 
Description of Agent or 
Intervention: 
generic ivermectin, 6 mg tablet; dose: 3-day oral regimen of 300 
µg/kg/day estimated by height bands, administered monthly for 4 
months/rainy season over 2 consecutive rainy seasons. 
Objectives: 
 
Primary: 
• 
To assess the impact of a combined approach of repeated 
IVM MDA and SMC on malaria incidence in children, with the 
purpose of testing the superiority of IVM compared to 
placebo for reducing malaria incidence. Our hypothesis that 
IVM MDAs (the intervention), coinciding with standard of care 
antimalarial procedures in Burkina Faso (four SMC rounds 
during the rainy season, maximum LLIN coverage and IPTp for 
pregnant women), will significantly reduce the incidence of 
childhood malaria in the intervention arm compared to the 
control arm. The IVM MDAs will consist of generic IVM or IVM 
placebo (e.g. Iver P®, Elea Labs; 6 mg tablet) given monthly 


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from July-October (4X) as a 3-day course to all eligible persons 
who meet inclusion criteria (≥90 cm and not treated with SMC 
(≥ 5 years), not pregnant or breast feeding an infant less than 
1 week old). Dosing of IVM or placebo will be according to 
height as indicated on the package: 90-119 cm = 1 tablet/day 
for 3 days; 120-140 cm = 2 tablets/day for 3 days; 141-158 cm 
= 3 tablets/day for 3 days; >158 cm = 4 tablet/day for 3 days. 
Secondary: 
• 
To measure whether the IVM MDAs will increase harms in the 
participants 
• 
To measure the entomological indices (mosquito survival rate 
after blood feeding, mosquito population age structure, 
sporozoite rate if they are infected with Plasmodium 
parasites, human exposure to Anopheles mosquito bites) 
between the intervention and control arm and over the time 
of the intervention phase.  
• 
To measure the parasitological indices obtained from blood 
samples collected during the active case surveillance of 
cohort children, between the intervention and control arms 
and over the time of the intervention phase. These indices are 
asexual parasite prevalence, species, density, the multiplicity 
of infection, and the molecular force of infection (mFOI).  
• 
To link the pharmacokinetics-dynamics of ivermectin in a sub-
cohort of the treated study population to mosquito blood 
feeding and survival. 
Exploratory: 
• 
NA     
 
 
 


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Outcome Measures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary: 
• 
The incidence of malaria episodes in cohort children ≤10 
years of age as assessed by active case surveillance. Malaria 
incidence in children is the most clinically-relevant outcome 
measure in this field setting from an anti-vector intervention 
that targets blood feeding mosquitoes, and its reduction 
following repeated IVM has been validated from our prior 
RIMDAMAL I study. Study nurses will visit each child weekly to 
monitor for malaria episodes. At each visit, a temperature 
reading will be recorded. If the axillary temperature is ≥37·5°C 
(or analogous temperature from another site) and/or history 
of fever in the last 24 hours, a blood sample will be taken and 
assessed by rapid diagnostic test (RDT) for Plasmodium spp. If 
this is also positive, this will be considered a positive malaria 
episode. 
Secondary: 
• 
AE monitoring will occur both actively and passively. All AE 
will be graded and analyzed by seriousness, intensity and 
causality. AE monitoring in this study is crucial to properly 
weigh the potential benefits vs. potential risks of the study. 
In the entire enrolled populace, passive monitoring of AEs will 
occur through spontaneous reporting of adverse events to 
the study clinical team and recorded on CRFs. Active 
monitoring of AEs will occur among participants in two ways, 
a) on the days of distribution of ivermectin/placebo through 
direct questioning of participants for AEs and recording on 
CRFs by study nurses and, b) in a weekly visit and assessment 
of participants living in selected households located on our 
entomological sampling transects. AEs will be recorded from 
the entire enrolled populace, regardless if they were treated 
with ivermectin/placebo or not eligible to take the 
intervention. AE will be recorded over the intervention period 
occurring during the 1st and 2nd rainy seasons. More 


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specifically, AEs will be recorded from the start of the first 
MDA of each rainy season to 1 month after the last MDA of 
that season.  
For those children enrolled in the active case detection 
cohort, where children are visited weekly to assess for 
malaria incidence, active monitoring of AEs will occur through 
direct questioning of AEs by the study team. Additionally, 
passive monitoring of AEs will occur by participants 
spontaneously reporting directly to the nurses when the 
nurses are in the villages performing active case detection of 
malaria in the child cohort, or spontaneously reporting 
indirectly to the nurses via communication through the village 
community health worker (who will then communicate the AE 
directly to the nurse or field physician).  
For women that become pregnant during the intervention 
period, monitoring for birth outcomes will be conducted.   
• 
Entomological indices will provide a first-order mechanistic 
explanation of the intervention’s effect on malaria incidence 
(the primary outcome): Wild, blood-fed, indoor-aspirated, 
Anopheles will be held in cages and scored for survival rates 
over time, which will be analyzed across arms. The age 
structure of captured Anopheles will be analyzed over time 
and analyzed across arms. Captured wild mosquitoes will be 
dissected and analyzed for sporozoite infection rates over 
time and analyzed across arms. A cohort of participants’ sera 
immuno-reactivity to an Anopheles saliva antigen will be 
analyzed over the intervention period of each season. 
• 
Parasitological indices will provide a second-order 
mechanistic explanation of the intervention’s effect on 
malaria incidence (the primary outcome): Prevalence, species 
and densities of asexual parasitemias will be scored from 
stain blood smears and analyzed over time and across arms, 
in both blood samples taken during the active case 
surveillance of cohort children, and in cross-sectional 


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Description of Study Design: 
sampling of the whole study population. The genetic markers 
of parasites in participant dried blood spots will be analyzed 
for the multiplicity of infection, and the molecular force of 
infection over time. 
• 
Pharmacokinetics-dynamics will be studied in a sub-cohort of 
participants to link the presence of drug with mosquito biting 
and survival: Ivermectin in blood samples from different 
treated subjects (different age strata and genders) will be 
quantified and used to construct models to estimate and 
compare the pharmacokinetic parameters (e.g. Cmax, T1/2) 
across strata in blood. Entomology sampling in the houses of 
these participants following treatment will collect blood fed 
mosquitoes that will be 1) analyzed for survival, 2) tested for 
ivermectin in their blood meals, and 3) for the genetic 
signatures of the studied participants in the blood meal. 
 
 
A cluster-randomized control trial will be conducted in a single region 
of southwestern Burkina Faso over two consecutive rainy seasons and 
designed to integrate repeated high-dose IVM MDA (the intervention) 
into the regular, monthly SMC delivery platform and with other existing 
malaria control methods conducted in the villages. Fourteen villages 
(clusters) in the region will be recruited to participate in this double-
blind, parallel-assignment trial with two arms randomized in a 1:1 ratio 
(Table 1; Figure 1). The intervention (IVM MDA) is predicted to 
primarily reduce the survival of biting Anopheles mosquito vectors, 
which will reduce Plasmodium transmission. Since children suffer a 
high burden of malaria due to the inadequate immunity they have 
developed against repeated Plasmodium infections, reduced 
Plasmodium transmission is expected to reduce malaria incidence in 
the child cohort. The hypothesis is that IVM MDAs coinciding with SMC 
rounds will significantly reduce the incidence of malaria in children 
compared to the standard malaria control interventions currently 


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conducted (four SMC rounds to 3-59 month old children, high LLIN 
coverage, and IPTp). The two arms will specifically receive: 
• 
Standard of care:  
o Active LLIN distribution in the villages will be 
maintained by the MoH. 
o SMC given monthly from July-October (4X) with SP+AQ 
(e.g. SPAQ-CO™, Guilin Pharmaceutical; 500/25 mg S/P 
and 153 mg AQ for children 12-59 months; 250/12.5 
mg S/P and 76.5 mg AQ for children 3-11 months. SMC 
will be provided by the Burkina Faso MoH  
o IPTp provided to all pregnant women with SP by the 
Burkina Faso MoH. WHO and Burkina Faso MoH policy 
recommends at least 3 treatments, 1 month apart, 
starting in second trimester. Provided by the Burkina 
Faso MoH (e.g. Fansidar®, Roche; 500/25 mg S/P per 
tablet, 3 tablet dosage (1500/75 mg S/P)). 
• 
Study intervention: 
o Generic IVM or placebo (6 mg tablet) given monthly 
from July-October (4X) as a 3-day course to all eligible 
persons per exclusion/inclusion criteria. Per package 
insert, dosing of IVM or placebo will be according to 
height to approximate weight: 90-119 cm (15-25 kg) = 
1 tablet/day for 3 days; 120-140 cm (26-44 kg) = 2 
tablets/day for 3 days; 141-158 cm (45-64 kg) = 3 
tablets/day for 3 days; >158 cm (65-84 kg) = 4 
tablet/day for 3 days. 
 
Village population size is expected average approximately 360 people, 
and all eligible persons in each village will be asked to enroll, thus giving 
us an enrolled population of approximately 5000 participants. These 
will be otherwise healthy individuals who live in a hyperendemic 
malaria region. Our primary outcome is the incidence of malaria 


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episodes in children ≤ 10 years of age over two rainy seasons. The 
sample size is based on a mathematical modeling of this outcome and 
suggests we should observe an effect size in the intervention arm over 
the control arm of 43.1%, assuming a rate incidence in our ≤10 yr. old 
cohort of 1.088 malaria episodes/child/year and 0.619 malaria 
episodes/child/year in the control and intervention arms, respectively, 
in the presence of standard LLINs. The primary outcome will be 
analyzed as intention-to-treat. Safety of IVM will be assessed as a 
secondary outcome to ensure the intervention does not increase 
harms to the populace, and entomological, parasitological, and 
pharmacokinetic-dynamic parameters also assessed as secondary 
outcomes to provide an understanding of the basis of IVM’s impact in 
the context of this trial.  
Estimated Time to Complete 
Enrollment: 
 
1 year. 
 
 
 


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Table : 
Treatment Arms 
Arms 
Participant population 
Intervention 
Arm 1 
7 villages; ~2500 participants 
• 
~75% will receive the 
placebo MDA 
intervention (all eligible 
persons ≥90 cm not 
taking SMC (≥ 5 years) 
or pregnant or breast 
feeding an infant < 1 
week old). 
• 
>700 cohort children 
≤10 yrs. of age (~10- 
children/cluster) 
followed by active case 
detection for malaria 
standard of care plus placebo 
MDA 
Arm 2 
7 villages; ~2500 participants 
• 
~75% will receive the 
ivermectin MDA 
intervention (all eligible 
persons ≥90 cm not 
taking SMC (≥ 5 years) 
or pregnant or breast 
feeding an infant < 1 
week old). 
• 
>700 cohort children 
≤10 yrs. of age (~100 
children/cluster) 
followed by active case 
detection for malaria 
standard of care plus ivermectin 
MDA 
 


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Figure 1: 
 Schematic of Study Design 
 
 
Figure 2: 
Study Graphic  
 
 
SMC
IVM MDA
LLIN
active case surveillance
passive AE monitoring
IPTp-SP
Clinical monitoring
Control Measures


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1. 
KEY ROLES 
For questions regarding this protocol, contact Greg Deye, MD in the Parasitology and Medical Programs 
Branch of the DMID/NIAID/NIH at 1-240-292-4199 or gregory.deye@nih.gov 
 
Individuals: 
Site Principal Investigators: 
 
                                    
 
 
 
 
 
 
 
 
 
 
 
 
 
PI: Brian D. Foy, PhD  
Professor, Department of Microbiology, Immunology & Pathology 
Arthropod-borne & Infectious Diseases Laboratory 
Colorado State University 
1692 Campus Delivery, Fort Collins, CO, USA, 80523-1692 
Office Tel: 1-970-491-3470 
Mobile: 1-970-443-5251 
FAX: 1-970-491-1815 
Email: Brian.Foy@colostate.edu 
 
PI: Sunil Parikh, MD, MPH 
Associate Professor of Epidemiology (Microbial Diseases) and 
Medicine (Infectious Diseases) 
Yale University School of Public Health 
60 College Street, P.O. Box 208322, New Haven, CT, USA, 06520 


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DMID Medical Officer 
Office Tel: 1-203-737-7906 
Mobile: 1-650-862-1266 
FAX: 1-203-737-1662 
Email: sunil.parikh@yale.edu 
 
Greg Deye, MD 
Medical Officer/Program Officer Parasitology and International 
Programs Branch  
DMID/NIH/NIAID 
BG 560 1FL RM 8A39, 5601 Fishers Lane, Rockville, MD, USA, 20852  
Office Tel: 1-240-292-4199 
Email: Gregory.Deye@nih.gov 
DMID Clinical Project Manager  
 
Walt Jones, RN, MPH 
Clinical Project Manager 
NIH/NIAID/DMID/PIPB 
5601 Fishers Lane, Room 8A37, Rockville, MD, USA, 20892  
Office Tel: 1-240-627-3283 
Email: joneswalter@niaid.nih.gov 
 


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DMID Medical Monitor: 
 
Venus Shahamatdar, M.D.  
Medical Monitor 
OCRA/DMID/NIAID 
5601 Fishers Lane, 7E54 
Bethesda, Maryland 20892-9826 
Phone:  240-627-3369 
Email: shahamav@mail.nih.gov 
 
Institutions: 
 
Institute de Recherche en Sciences de la Santé (IRSS), Direction 
Régionale de l’Ouest  
399 Ave de la Liberte, Bobo Dioulasso, Houet, Burkina Faso, 10400-
0000 
Investigator: Roch K. Dabiré, PhD – Regional Director  
Tel: +226 70 73 90 69  
Email: dabireroch@gmail.com 
Administrative Contract: Marie Thérèse Compoaré 
Email: kangambega50@yahoo.fr 
 
Radboud University Medical Centre  
Postbus 9101, 6500 HB Nijmegan, the Netherlands 


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Investigator: Teun Bousema, PhD - Professor 
Tel: +31 (0)24 361 75 74  
Email: Teun.Bousema@radboudumc.nl 
 
Imperial College London 
MRC Centre for Outbreak Analysis & Modelling, Department of 
Infectious Disease Epidemiology, G26, Norfolk Place, St. Mary’s 
Campus, London, United Kingdom 
Investigator: Hannah Slater, PhD – Research Associate 
Tel: +44 (0) 207 594 3217  
Email: hannah.slater08@imperial.ac.uk 
 
Colorado State University and the Colorado Clinical and 
Translational Sciences Institute – Biostatics, Epidemiology, & 
Research Design (BERD) 
Colorado State University Diagnostic Medicine Center, Rm 210, 
1644 Campus Delivery, Fort Collins, CO, 80523-1644 
Investigator: Sangeeta Rao, PhD - Faculty 
Tel: 970-297-5117  
Email: Sangeeta.Rao@colostate.edu 
 
Colorado State University Research Integrity and Compliance 
Review Office (RICRO) - Institutional Review Board (IRB)  
2011 Campus Delivery, Fort Collins, CO, USA.  80523-2011 


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Staff: Tammy Felton-Noyle – Biomedical IRB Coordinator; Cat Bens – 
Quality Assurance Manager 
Tel: 1-970-491-1553 
 
FAX: 1-970-491-2293 
Emails: Tammy.Felton-Noyle@colostate.edu; 
Cat.Bens@colostate.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
 
Background Information 
 
Ivermectin (IVM) is the drug to be used in the intervention.  It 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 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 (1).  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 highly sensitive to 
serum drug levels achieved from standard doses to persons as an anthelmintic.  Since then, many 
reports 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).   
Table 1:  
Efficacy of ivermectin against Anopheles vectors 
 
Publication 
Method and Dose 
Anopheles species 
Results 
Iakubovich, 1989 (2) 
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 (3) 
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] 
 


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Significant decrease in 
oviposition and egg-
hatching from survivors 
Bockarie, 1999 (4) 
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 (5) 
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 (6) 
Membrane and feeding 
on treated cattle 
An. gambiae 
Membrane feeding: 
LC50 for An. gambiae 


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Dose: 600 μg/kg (once, 
subcutaneously) 
An. arabiensis 
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 (7) 
 
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 


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*Kobylinski, 2010 (8) 
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 (9) 
Field collections of 
engorged wild 
mosquitoes before and 
after MDA for 
onchocerciasis 
Dose: 150 μg/kg 
ivermectin (once, 
orally) 
An. gambiae 
An. arabiensis 
 
5-day cumulative 
survival of An. gambiae 
s.s. was significantly 
reduced from 3 treated 
villages vs pair-
matched control 
villages 
*Butters, 2012 (10) 
Membrane feeding 
Dose: NA 
An. gambiae 
Sub-lethal 
concentrations (LC25 & 
LC5) caused significant 
knockdown and 
reduced recovery rates 
Fritz, 2012 (11) 
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 
An. stephensi 
3-day cumulative 
mortality of 


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and Cynomolgus 
monkeys 
 
Dose: 200–400 μg/kg 
(different intervals, 
orally) 
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 (12) 
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 (13) 
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. 
(adapted from Chaccour et al, 2013 Malaria J.)     
 


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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 8 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 (13). The 
effects have been strong and consistent.  Single MDAs of 150 µg/kg and achieving ≥ 75% drug coverage 
of the village population 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 (9, 14).  While very transient, these reductions are in-line with 
changes seen in A. gambiae populations around SSA villages when IRS has been implemented (15) or 
LLINs distributed (16).   
There are several ways to achieve a longer lasting mosquitocidal effect so that malaria transmission 
control might be sustained over limited malaria transmission seasons, like occur in the countries of the 
African Sahel. Using currently-approved IVM drug formulations and doses, the dose could be increased 
up to 400 µg/kg, such as is approved for lymphatic filariasis and scabies control in some regions, and/or 
given repeatedly. New IVM formulations might also be eventually developed that produced longer 
pharmacokinetic-dynamic profile in the blood of treated individuals, however this will require a long 
period of time for development and safety testing.  
Frequent, repeat IVM treatment is necessary and has been used for cases of persistent helminthiasis, 
and for hyper-encrusted scabies patients (17, 18). A number of older trials have reported on the efficacy 
and safety of frequently repeated IVM treatment in small groups of healthy or helminth-infected 
individuals.  These are summarized in Table 3. 


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Table 2: 
Studies reporting frequent, repeated ivermectin administrations and their 
safety. 
Publication or 
Trial 
Patient 
Populations 
Dose 
Frequency 
Safety Outcome 
Duke, 1990 (19) 
36 O. volvulis-
infected 
Guatamalan 
patients 
150 µg/kg 
every month 
for either 4, 8 
or 12 months 
No AEs/SAEs reported 
Duke, 1991 (20) 
30 O. volvulis-
infected Liberian 
patients 
~100 µg/kg 
every 2 
weeks for 10 
weeks 
No AEs/SAEs reported 
Duke, 1992 (21) 
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 (22) 
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 (23) 
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 
(24) 
155 O. volvulis-
infected 
150 µg/kg 
every 3 
months for 3 
Significantly fewer AEs 
relative to groups 


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&  
Gardon, 2002 (25) 
Cameroonian 
patients 
years (12 
doses) 
receiving one dose 
annually, including fewer 
sundry pains, back/wrist 
pain, headache, fever, 
pruritis, & oedematous 
swellings.  No SAEs 
reported. 
Guzzo, 2002 (26) 
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. 
 
Overall, these studies demonstrated that frequent and repeated IVM treatment were well-tolerated and 
induce few or no AE/SAEs in the patients. More recently-completed clinical trials have validated 
repeated and higher dose IVM’s effect against malaria vectors (two of these paired the IVM treated with 
antimalarials), the safety of these treatments, and their efficacy in reducing disease.  
The individually-randomized, double-blind, placebo-controlled ACTIVE trial (NCT0160325) was 
conducted in Burkina Faso in 2013, and examined the safety and mosquitocidal efficacy of a treatment 
regimen for asymptomatic P. falciparum-infected individuals aged 15-25 years, consisting of a regular 
artemether-lumefantrine (AL) course plus 200 µg/kg IVM given with the first AL dose (AL-IVM1) or first 
and fifth AL dose (AL-IVM2) compared to AL plus placebo (27). The trial showed that both AL-IVM 
treatments were well-tolerated and cleared asexual parasites equal to the control. Furthermore, 
Anopheles gambiae survivorship over 10 days after membrane-feeding on participants’ blood 3 days 
post-treatment was ~75% in the control arm, ~65% in the AL-IVM1 arm, and ~30% in the AL-IVM2 arm, 
suggesting a 27% and 35% reduction, respectively, in the estimated malaria transmission during the first 
week after treatment.  
IVERMAL (NCT02511353) was a similarly-conducted, individually-randomized, double-blind, placebo-
controlled trial conducted in Kenya in 2015, which examined the safety and mosquitocidal efficacy of a 
treatment regimen for symptomatic P. falciparum-infected individuals aged 15-50 years (28). The 
treatment arms consisted of a regular dihydroartemisinin-piperaquine (DP) course (320/40 mg once a 
day for 3 days) plus placebo or IVM at 300 µg/kg/day or 600 µg/kg/day on the same 3 days. The 
investigators showed that the DP plus IVM 300 µg/kg/day regimen did not increase harms to the 


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participants, and the mosquitocidal effect from participants’ blood lasted nearly 1 month post treatment 
compared to placebo controls.  
Our own team conducted a pilot, phase 2/3 cluster-randomized clinical trial on the safety and efficacy of 
repeated IVM MDA in Burkina Faso (RIMDAMAL trial; NCT02509481) in 2015. We enrolled 8 villages 
(2712 participants) and administered 6 rounds IVM MDA to 4 randomized intervention arm villages, 
every 3 weeks, from late July through late November (control arm villages received only the first IVM 
MDA, as per standard policy for LF elimination ongoing at the study site). IVM, as per label guidelines, 
was only administered to individuals whose height was ≥90cm. Our primary outcome was cumulative 
incidence of clinical malaria episodes in children ≤5 years of age. Active surveillance by trained nurses 
was performed 3 times every 2 weeks, and rapid diagnostic test (RDT)-positive malaria episodes were 
immediately treated with AL. The results showed that approximately 500 cases of malaria were averted 
per 1000 intervention arm children over the 18 week study (malaria incidence intervention arm=2.00, 
control arm=2.49, risk ratio=0.80 [0.70-0.91], P=0.0009). The safety outcome from this trial was the 
number and type of adverse events (AE) recorded in the enrolled populace (2712 participants). The risk 
of AE was not noticeably different among participants of the intervention arm (3.1% of participants 
[45/1447]) vs. the control arm (1.9% of participants [24/1265]); risk ratio = 1.63 [1.01-2.67], P = 0.06. 
Most AE (85%; 55/65) were classified as “not related” to the intervention, while 5 were classified as 
“unlikely related”, 1 as “possibly related”, 7 as “probably related”, and 1 was unclassified. Of the 
“possibly” and “probably” intervention-related AE, all were sub-classified as adverse reactions of mild or 
moderate intensity that consisted of vomiting, pruritus, edema in the limbs, or tremors, and all were 
monitored until resolved or given standard treatment as outlined by WHO guidelines(29). 20 deaths 
were recorded over the study period, all classified as either “unlikely” or “not related” to the 
intervention. The risk of AE between arms among all participants was similar, as was the risk of AE 
among the child cohort. The proportions of each sub-class of AE, the graded intensity category, or the 
outcomes did not differ between the arms. In total, these data suggest that administering repeated IVM 
to entire villages does not increase harms in the populace. 
 
Rationale 
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 (30).  The most prevalent species of parasite is Plasmodium 
falciparum, with less than 20% being Plasmodium malariae or P. ovale (31).  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 


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and a subsequent dramatic increase of the malaria vector population (32).  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 (33). 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 (34). 
Treatment options are limited to frontline ACTs because of a high prevalence of resistance to older 
antimalarials such as sulfadoxine-pyrimethamine (SP), chloroquine (CQ), and amodiaquine (AQ) (32).  
Current National Malaria Control Program (NMCP) recommends either AL or artesunate plus AQ (ASAQ) 
as first-line for the treatment of malaria in Burkina Faso. Due to prevalent infections, especially in rural, 
underdeveloped areas, the NMCP policy is to only treat symptomatic cases of malaria to limit drug 
resistance to the first-line 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 (35).  New tools will be critical to 
achieving malaria control in the country. 
Anti-vector strategies are critical to the efficacy and sustainability of any malaria control measure, 
because the efficiency of vector transmission is so strong. Further, they are key for sustaining the 
efficacy of antimalarials.  However, LLINs seems to have reached their maximum efficacy for reducing 
malaria further, and new chemistries for LLINs are slow to be implemented.  Further, insecticide 
resistance among vectors is now widespread (36). Thus, new anti-vector tools are necessary to add 
combinatorial chemistries and new target sites to combat vector transmission. 
Our study is designed to study a new vector control tool, repeated high-dose IVM MDA (the 
intervention), through its integration into the regular, 4-monthly/season SMC delivery platform and 
with other existing malaria control methods conducted in the study villages. The intervention, generic 
IVM or IVM placebo (e.g. Iver P®, Elea Labs; 6 mg tablet) in 300 µg/kg dose estimated by height bands, 
will be administered orally for 3 days to eligible individuals NOT receiving SMC. Per the package insert, 
dosing of IVM or placebo will be according to height to estimate weight: 90-119 cm (15-25 kg) = 1 
tablet/day for 3 days; 120-140 cm (26-44 kg) = 2 tablets/day for 3 days; 141-158 cm (45-64 kg) = 3 
tablets/day for 3 days; >158 cm (65-84 kg) = 4 tablet/day for 3 days. Rounds will be administered in a 
monthly schedule from July-October (4X) as a 3-day course to all eligible persons per exclusion/inclusion 
criteria. The intervention period will last two rainy seasons (2019-2020). The interventional drugs will be 


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administered by the study personnel working with CHWs via the door-to-door delivery (DDD) method and 
using directly and then non-directly observed therapy (DOT/NDOT), whereby the first day of treatment of 
each month will be given by the study team and treatments for the second and third days will be given by 
the caregiver at home for each monthly round. These delivery methods were chosen based on clinical trial 
data suggesting they are the optimal balance of being logistically simple while achieving optimal coverage 
(37).  
The hypothesis is that MDA with ivermectin coinciding with SMC rounds and on top of other standard 
malaria control interventions currently conducted (four SMC rounds to 3-59 month old children, high LLIN 
coverage, and IPTp) will significantly reduce the incidence of malaria in children compared to MDA with 
placebo. 
 
Potential Risks and Benefits 
 
 
Potential Risks 
The primary potential risks from participating in the intervention include adverse reactions to the study 
drug, ivermectin. IVM is well-tolerated, but can induce Mazzotti-type reactions in helminth-infected 
patients that are linked to parasite lysis and clearance in heavily-parasitized patients after their first 
treatment in MDA (38). The most common of these adverse reactions are abdominal pain, 
urticaria/rashes/pruritis, fever and chills, gland or eye reactions, loss of appetite, constipation, diarrhea, 
nausea, fatigue, vomiting, dizziness, (Appendix A & B) (29, 39). However, many of the villages in the 
southwest region of Burkina Faso participate in yearly anthelmintic MDAs with IVM and albendozole 
that have occurred for more than a decade, and so worm burden is absent or low in many villagers. In 
RIMDAMAL I, evidence of Wuchereria bancrofti infections in our study villages by xenomonitoring was 
absent, and a cross-sectional examinations of children 5-10 years for STHs revealed only 2 cases of 
ascariasis. Out of 2712 participants, we recorded only 8 adverse events of mild or moderate intensity 
that were determined to be possibly or probably related to taking IVM in a MDA. Per the Mectizan label 
(Appendix A), severe skin reactions have been very rarely reported following IVM MDA, but the only 
confirmed IVM-related serious adverse events (SAE) have been in individuals heavily-infected with Loa 
loa due to lysis of parasites. However Loa loa is not present in Burkina Faso, and the participants in the 
study villages will be excluded from participating in IVM MDAs if they have traveled to countries where 
Loa loa is endemic.  
A recent review of neurological SAE from ivermectin treatment outside an onchocerciasis indication was 
published by Chandler from an analysis of data in VigiBase (40). Most of these SAE (20/28) were cases 
where concomitant medications were given with ivermectin. No participant in RIMDAMAL I had a SAE 


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that was determined to be related to IVM treatment, and none had the SAE reported in Chandler’s 
review.  
Caution and a physician’s consult are indicated before IVM is used by pregnant and breast-feeding 
women. Importantly, as in RIMDAMAL I, this study will avoid treating pregnant women by screening 
those of reproductive age with a urine pregnancy rapid test before each MDA, and we will only treat 
those women breast-feeding infants >1 week old, as per the label.   
Another recent review analyzed the safety of ivermectin treatment in children <5 yrs. of age and 
weighing less than 15 kg, most for a scabies indication (41). The authors stated that while more studies 
are required to establish the safety profile of ivermectin in this age group, they note that the drug was 
well-tolerated and without any evidence of serious or long-term adverse events in the available 
literature.  
Our currently proposed 3x300 µg/kg dosing regimen (estimated by height bands) has been studied in 
the IVERMAL trial, whereby it was administered once alongside DP in a small cohort of Kenyan adults 
(age 18-50 years) with uncomplicated malaria (28). The regimen was tested as way to maximize the time 
of mosquitocidal activity in treated persons’ blood, and because high doses have been remarkably well-
tolerated in the literature (23-26, 42, 43). Overall, the regimen was well-tolerated in their patients, with 
8 AE in 48 ivermectin-treated patients and 9 AE in 46 placebo-treated patients, with no statistically-
significant risk differences of AE between the groups. Treatment-related AE were confined to minor 
visual disturbances and occurred in 4% (2/48) of treated participants, while no SAE were observed.  
Our study will administer the 3x300 µg/kg (estimated by height bands) regimen in 4-monthly rounds 
over 2 seasons and to approximately 1800 persons who are ≥90 cm height (and ≥ 5 years of age) in each 
study village. Thus, the greatest potential risk of this trial is in giving this dosing regimen more frequently 
(monthly x 4 months each season), to more participants, and to a broader range of age groups than in 
the IVERMAL trial. Because the length of mosquitocidal activity from this dosing regimen is a key 
determinant in the large expected effect size on malaria incidence (44), and also this 4-monthly schedule 
achieves logistic synergy with standard-of-care SMC treatment of children < 59 months old in the same 
households, an alternative to the 4-monthly treatment schedule may not be feasible relative to the 
project’s goals. It may be possible to give a 1x400 µg/kg dose (estimated by height) schedule each 
month instead of the 3x300 µg/kg dose (estimated by height) schedule, if the latter is deemed as not 
well-tolerated after the first MDA. However, this change could affect our blinding, and preliminary 
modeling data we have obtained suggests a nearly a week less mosquitocidal activity would be achieved 
in the treated population, which would lessen the expected effect size considerably and so this may also 
not be feasible.    


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Other risks are minimal, and include psychological harm to study participants if their private information 
are disclosed, but we will make every effort to prevent this. Small bruising at the site of the finger stick 
and/or at the site of venipuncture are also possible, as is syncope from blood draws, but these 
procedures will all be conducted by the study clinical team who will be trained to treat these possible 
problems.   
In summary, the risks to the subjects are moderate with respect to receiving the intervention (IVM MDA 
at the aforementioned dose and frequency) and minimal with respect to the clinical team taking blood 
samples or the investigators making public their personal information accidentally. These risks are 
reasonable in relation to the anticipated benefit of significantly less malaria among the populace, which 
causes yearly debilitating disease and death in the communities in which we will work.   
 
Known Potential Benefits 
Ivermectin is a potent endectocide that is approved around the world for the treatment of patients 
infected with many different parasitic worms (Onchocera volvulis, Wuchereria bancrofti, Strongyloides 
stercoralis, as well as patients infected with scabies mites (Sarcoptes scabei). It also has documented 
activity against many other internal and external parasites, including some STHs such as roundworms 
(Ascaris lumbricoides) and whipworms (Trichuris trichuria), and head lice (Pediculus humanus capitis) 
(45). Thus, control of NTDs caused by these parasites in treated participants is a known potential 
benefit. Also, the known potential benefits of the research to the participants is the expected reduction 
in malaria incidence among participants who live in the intervention villages, especially among those 
vulnerable groups most at risk of uncomplicated and complicated malaria episodes, children and 
pregnant women. In RIMDAMAL I, the children of the control arm experienced a mean incidence of 2.49 
malaria episodes as compared to 1.99 malaria cases in the intervention arm over the 18 week trial 
during the rainy season. This was an approximate 20% reduction in malaria incidence among the treated 
cohort (or a risk difference of approximately 0.5 episodes/child). In this study, we have modeled a 
reduction of malaria incidence in the child cohort of approximately 43%.  
Furthermore, despite not receiving the intervention, those living in the control arm villages will also 
receive potential benefits of increased and frequent health care afforded by the regular active case 
detection visits from the study nurses and other members of study clinical team, which includes 
screening for malaria-related febrile illness and other general health problems, and subsequent free 
consultation and treatment with antimalarials and other medicines. The value of these benefits were 
reported to us by the populace in the control villages of the RIMDAMAL I trial. These potential health 
benefits might be expected to translate to psychological benefits from feeling supported in their 


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physical care, and economic benefits from a healthier workforce being better able to complete their jobs 
and sell their goods. 


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3. 
OBJECTIVES AND OUTCOME MEASURES 
 
Study Objectives  
 
Primary 
• 
The primary study objective is to assess the impact of a combined approach of repeated IVM 
MDA and SMC on malaria incidence in children, with the purpose of testing the superiority of 
IVM compared to placebo for reducing malaria incidence. Our hypothesis that IVM MDAs (the 
intervention), coinciding with standard of care antimalarial procedures in Burkina Faso (four 
SMC rounds during the rainy season, maximum LLIN coverage and IPTp for pregnant women), 
will significantly reduce the incidence of childhood malaria in the intervention arm compared to 
the control arm. The IVM MDAs will consist of generic IVM or IVM placebo (e.g. Iver P®, Elea 
Labs; 6 mg tablet) given monthly from July-October (4X) as a 3-day course to all eligible persons 
who meet inclusion criteria (≥90 cm and not treated with SMC (≥ 5 years), not pregnant or 
breast feeding an infant less than 1 week old). Dosing of IVM or placebo will be according to 
height as indicated on the package: 90-119 cm = 1 tablet/day for 3 days; 120-140 cm = 2 
tablets/day for 3 days; 141-158 cm = 3 tablets/day for 3 days; >158 cm = 4 tablet/day for 3 days. 
 
Secondary 
The study’s secondary objectives are several-fold. This first secondary objective is safety: 
• 
To measure whether the IVM MDAs will increase harms in the participants.    
We also aim to characterize entomological, parasitological and pharmacological indices associated with 
the primary outcome. Because IVM MDA primarily effects the survivorship of malaria vectors that blood 
feed on treated people, there are several related effects we expect will be able to mechanistically 
explain the reduction in clinical incidence among children that we should observe in the intervention 
arm.  
• 
To measure the entomological indices (mosquito survival rate after blood feeding, mosquito 
population age structure, sporozoite rate if they are infected with Plasmodium parasites, human 
exposure to Anopheles mosquito bites) between the intervention and control arm and over the 
time of the intervention phase.  
• 
To measure the parasitological indices obtained from blood samples collected during the active 
case surveillance of cohort children, between the intervention and control arms and over the 


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time of the intervention phase. These indices are asexual parasite prevalence, species, density, 
the multiplicity of infection, and the molecular force of infection (mFOI).  
• 
To link the pharmacokinetics-dynamics of ivermectin in a sub-cohort of the treated study 
population to mosquito blood feeding and survival. 
 
 
Study Outcome Measures 
 
Primary  
• 
The incidence of malaria episodes in cohort children ≤10 years of age as assessed by active case 
surveillance. Malaria incidence in children is the most clinically-relevant outcome measure in 
this field setting from an anti-vector intervention that targets blood feeding mosquitoes, and its 
reduction following repeated IVM has been validated from our prior RIMDAMAL I study. Study 
nurses will visit each child weekly to monitor for malaria episodes. At each visit, a temperature 
reading will be recorded. If the temperature is ≥37·5°C and/or history of fever in the last 24 
hours, a blood sample will be taken and assessed by rapid diagnostic test (RDT) for Plasmodium 
spp. If this is also positive, this will be considered a positive malaria episode. 
 
Secondary  
• 
AE monitoring will occur both actively and passively. All AE will be graded and analyzed by 
seriousness, intensity and causality. AE monitoring in this study is crucial to properly weigh the 
potential benefits vs. potential risks of the study. 
• 
In the entire enrolled populace, passive monitoring of AEs will occur through spontaneous 
reporting of events to the study clinical team, and recorded on CRFs. AEs will be recorded 
from the entire enrolled populace, regardless if they were treated with ivermectin/placebo 
or not eligible to take the intervention. AEs will also be actively monitored on the days of 
distribution of ivermectin/placebo through direct questioning of AEs and recording on CRFs 
by study nurses for all participants. AE will be recorded over the intervention period 
occurring during the 1st and 2nd rainy seasons. More specifically, AEs will be recorded from 
the start of the first MDA of each rainy season to 1 month after the last MDA of that season.  
• 
For those children enrolled in the active case detection cohort, where children are visited 
weekly to assess for malaria incidence, active monitoring of AEs will occur through direct 
questioning of AEs by the study team. Additionally, passive monitoring of AEs will occur by 


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participants spontaneously reporting directly to the nurses when the nurses are in the 
villages performing active case detection of malaria in the child cohort, or spontaneously 
reporting indirectly to the nurses via communication through the village community health 
worker (who will then communicate the AE directly to the nurse or field physician).  
• 
For women that become pregnant during the intervention period, monitoring for birth 
outcomes will be conducted.  Pregnancies will be followed in both arms of the study. 
• 
Entomological indices will provide a first-order mechanistic explanation of the intervention’s 
effect on malaria incidence (the primary outcome): Wild, blood-fed, indoor-aspirated, Anopheles 
will be held in cages and scored for survival rates over time, which will be analyzed across arms. 
The age structure of captured Anopheles will be analyzed over time and analyzed across arms. 
Captured wild mosquitoes will be dissected and analyzed for sporozoite infection rates over 
time and analyzed across arms. A cohort of participants’ sera immuno-reactivity to an Anopheles 
saliva antigen will be analyzed over the intervention period of each season. 
• 
Parasitological indices will provide a second-order mechanistic explanation of the intervention’s 
effect on malaria incidence (the primary outcome): Prevalence, species and densities of asexual 
parasitemias will be scored from stain blood smears and analyzed over time and across arms, in 
both blood samples taken during the active case surveillance of cohort children, and in cross-
sectional sampling of the whole study population. The genetic markers of parasites in 
participant dried blood spots will be analyzed for the multiplicity of infection, and the molecular 
force of infection over time. Samples will also be obtained at additional timepoints in a subset of 
participants, in order to obtain a baseline estimate for prevalence estimates.  These finger prick 
blood samples will be collected during the dry seasons in 2020 and 2021, during the wet season 
in 2021 and at up to 4 other timepoints throughout the year. Baseline samples will allow for 
better assessment of changes occurring with IVM and SMC drug pressure. (This additional 
sampling will utilize a separate information sheet and consent document. Only participants who 
consent to participate in the additional sampling will do so.) 
• 
Pharmacokinetics-dynamics will be studied in a sub-cohort of participants to link the presence of 
drug with mosquito biting and survival: Ivermectin in blood samples from different treated 
subjects (different age strata and genders) will be quantified and used to construct models to 
estimate and compare the pharmacokinetic parameters (e.g. Cmax, T1/2) across strata in blood. 
Entomology sampling in the houses of these participants following treatment will collect blood 
fed mosquitoes that will be 1) analyzed for survival, 2) tested for ivermectin in their blood 
meals, and 3) for the genetic signatures of the studied participants in the blood meal.  


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4. 
STUDY DESIGN 
A cluster randomized trial will be conducted in a single region of southwestern Burkina Faso over two 
consecutive rainy seasons and designed integrate repeated high-dose IVM MDA into the existing 
monthly SMC delivery platform and distribution of LLINs performed by CHWs. The hypothesis is that 
IVM MDAs coinciding with SMC rounds will significantly reduce the incidence of childhood malaria 
compared to the standard of care anti-malaria interventions (SMC, LLIN distribution, IPTp) alone. Twelve 
villages (clusters) in the region will be recruited to participate in this phase 3, double-blind, parallel-
assignment trial with two arms randomized in a 1:1 ratio. A cluster-randomized trial is necessary 
because the intervention is IVM MDA which primarily targets the mosquito population that randomly 
feed on the people in the village, thus the effect is village-wide. Village population size is expected 
average approximately 360 people, and all eligible persons in each village will be asked to enroll, thus 
giving us an enrolled population of approximately 5000 participants. These will be otherwise healthy 
individuals who live in a hyper-endemic malaria region. Thus, most are infected with malaria parasites 
during the rainy season when vector numbers and parasite transmission peaks, and children suffer a 
high burden of malaria due to the inadequate immunity they have developed against Plasmodium 
infections. Our primary outcome is the incidence of malaria episodes in children ≤ 10 years of age over 
two rainy seasons. Safety of IVM will be assessed as a secondary outcome to ensure the intervention 
does not increase harm to the populace, and entomological, parasitological, and pharmacokinetic 
parameters also assessed as secondary outcomes to provide a clear understanding of the basis of IVMs 
impact in the context of this trial.  
The sample size is based on a mathematical modeling of the intervention on the primary outcome 
and suggests we should observe an effect size in the intervention arm over the control arm of 43.1%, 
assuming a rate incidence in our 0-10 yr. old cohort of 1.088 malaria episodes/child/year and 0.619 
malaria episodes/child/year in the control and intervention arms, respectively. Using an intra-cluster 
coefficient of 0.258 and setting the α=0.05, 6 clusters/arm with a minimum of 48 children/cluster in our 
child cohort is necessary to detect a significant difference in the rates between the arms with 80% 
power. In January 2019, the sample size modeling exercise was re-performed because it was learned 
that that villages in the Diebougou health district (the study site) were expected to receive new 
Interceptor G2 LLINs prior to the 2019 rainy season. These new LLINs are made with two different 
insecticides (chlorphenapyr and alpha-cypermethrin) to circumvent the prevalent pyrethroid-resistance 
seen in Burkina Faso the much of SSA. Thus, we assumed a 12%-50% reduction in malaria incidence in 
both arms due to distribution of these nets.  Keeping with an effect size of 43.1% in the intervention am 
over the control arm, using an intra-cluster coefficient of 0.2, and increasing the sample size to 100 
children/cluster in our child cohort, we need between 4.9 and 5.5 clusters/arm to detect a significant 


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difference in the rates between the arms with 80% power. The primary outcome will be analyzed as 
intention-to-treat, meaning it will include all enrolled cohort children (≤10 years old) in the groups to 
which they were randomly assigned, regardless of their compliance with the entry criteria, regardless of 
the treatment they actually received, and regardless of subsequent withdrawal from treatment or 
deviation from the protocol. Importantly, all eligible cohort children ages 3-59 months are expected to 
receive SMC, and all eligible cohort children ≥90 but not taking SMC are expected to receive either 
ivermectin or placebo as the intervention. However all these children, no matter their treatment, will be 
included in the primary outcome analysis. The incidence of episodes from the children cohort will be 
used as the primary measurable outcome to evaluate the impact of the intervention when compared to 
the control arm. The primary analysis will use either cluster-level analyses, or multilevel/hierarchical 
regression modeling techniques to account for clustering at the level of the randomization unit (village), 
as well as analyze individuals with multiple time points where both unadjusted and adjusted analyses 
will be performed. The unadjusted as well as adjusted estimates depicting the impact of the intervention 
versus control will be reported along with 95% confidence intervals. The time-to-first infection will also 
be analyzed using a survival analysis within each arm and calculation of a hazard ratio with 95% 
confidence interval. Secondary data generated from Aim 1 will include adverse events (AE) and serious 
adverse events (SAE). The risk of SAE and AE will be compared between intervention and control arms 
by calculating risks ratios and attributable risks with 95% confidence intervals. Standard statistical 
hypothesis testing, as well as estimating the effect sizes and confidence intervals, will be used to 
measure the differences in entomological, parasitological, and pharmacokinetic secondary outcomes 
between arms and the exploratory outcome measures. 
The pre-intervention phase will take up to 1 year and consist of writing and finalizing all protocols 
and SOPs, securing all regulatory documents, permissions and approvals, hiring and training study staff, 
setting up and the field station, securing study equipment, supplies and drugs, engagement, 
randomization and allotment of study villages, and enrolling and consenting all study participants.  
At the start of the intervention phase, expected to be July of the 1st rainy season, the first of four SMC 
rounds will occur, and continue at the beginning of each month from July-October. On the same dates, 
and leveraging the SMC infrastructure, our IVM MDA rounds (or placebo) will occur in each village. 
Pregnant women will be encouraged to receive their publicly-provided antenatal care treatment, 
including at least three SP treatments once/month after the start of their second trimester (per WHO and 
Burkina Faso Ministry of Health (MoH) policy). The trial staff will work with regional and local health 
authorities, including community health workers assigned to each village, to administer the intervention. 
The two arms will specifically receive: 
1) Standard of care:  


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a. Active LLIN distribution in the villages will be maintained by the MoH. Time of distribution 
of new G2 bednets will be recorded. 
b. SMC given monthly from July-October (4X) with SP+AQ  (500/25 mg S/P and 153 mg AQ 
for children 12-59 months; 250/12.5 mg S/P and 76.5 mg AQ for children 3-11 months. 
SMC will be provided by the Burkina Faso MoH. 
c. IPTp provided to all pregnant women with SP. WHO and Burkina Faso MoH policy 
recommends at least 3 treatments, 1 month apart, starting in second trimester. Provided 
by the Burkina Faso MoH ((500/25 mg S/P per tablet, 3 tablet dosage (1500/75 mg S/P)). 
2) Study intervention: 
a. IVM or placebo (6 mg tablet) given monthly from July-October (4X) as a 3-day course to 
all eligible persons per exclusion/inclusion criteria (≥90 cm and not treated with SMC (≥ 5 
years), not pregnant or breast feeding an infant less than 1 week old). Per package insert, 
dosing of IVM or placebo will be according to height: 90-119 cm = 1 tablet/day for 3 days; 
120-140 cm = 2 tablets/day for 3 days; 141-158 cm = 3 tablets/day for 3 days; >158 cm = 
4 tablet/day for 3 days. 
 
A study nurse will be assigned to each village to work with the village CHWs to distribute the study drugs 
and LLINs. LLINs and SMC/IPTp drugs will be health services provided by the Burkina Faso MoH NMCP. 
Generic IVM and placebo will be purchased through the study from Laboratorio Elea or another provider. 
Malaria episodes in enrolled study village children ≤10 years of old will be determined by active case 
surveillance via study nurses visiting each child weekly with the CHW during the intervention to monitor 
for malaria episodes. An uncomplicated malaria episode will be defined as axillary temperature ≥37.5 °C 
(with adjustment for temperature taken at other locations) and/or history of fever in the last 24 hours, 
and a positive RDT for Plasmodium spp. Complicated malaria is defined in Appendix D. As per MoH 
guidelines, a standard course of AL will be administered to all children with uncomplicated malaria cases, 
while complicated malaria cases will be referred to the nearest district hospital to for treatment with 
either intravenous quinine or artesunate. Blood will also be preserved on slides and filter papers for later 
analysis. The nurse will record positive malaria episodes in children, as well as any spontaneously-reported 
AEs communicated by the study populace, into CRFs and treat them as able or refer them to the district 
hospital.  Throughout the intervention phase, entomology teams will capture mosquitoes from 
intervention and control clusters, and parasitology teams will sample blood from selected study villagers 
along transects and at cross-section. 


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The intervention phase will be completed one month following the 8th SMC/IVM MDA round at 
the end of the 2nd rainy season, and the clinical component of the trial will be closed. Limited cross-
sectional mosquito and blood sampling will occur in study villages in the 3rd rainy season, after the 
intervention is complete, to analyze any potential changes in mosquito or parasite populations in the 
villages. The blood sampling schedule is in table 4.    
Samples will also be obtained at additional timepoints from all cross-sectional households and 
select others. A separate information sheet and consent document will be used for this purpose and 
participants will be approached separately about participating in this additional sampling.  These 
finger prick blood samples will be collected during the dry seasons in 2020 and 2021, estimated to 
be between March and June following MDA , during the wet season in 2021 and at up to 4 other 
timepoints throughout the year. Blood samples will be drawn via finger prick and will be preserved 
on slides and filter papers for later analysis.  
 
Table 3: 
Summary of the study groups and schedule for blood sampling. 
Group 
Numbe
r to 
sample 
Ages 
What and when samples collected 
BS=blood smear 
FP=filter paper 
Child cohort 
(followed with 
active case 
surveillance) 
~1800  
 
≤10 yr. olds 
BS&FP 
-when malaria 
diagnosed 
BS&FP 
-before 
season 
BS&FP 
-between 
the second 
and third 
MDA each 
season 
BS&FP 
-post season 
BS&FP 
-dry season/ 
post 
intervention 
(only from 
select 
participants) 
Households# on 
village transects (3 
villages/arm; ~8 
households/village) 
~380  
all 
note: ≤10 yr. olds will 
be sampled in the ACD 
cohort 
 
BS&FP 
-before 
season 
BS&FP 
-between 
the second 
and third 
MDA each 
season 
BS&FP 
-post season 
BS&FP 
-dry season/ 
post 
intervention 
PK-PD modeling 
cohort  
180 
5-10yo (n=30 per arm) 
11-18yo (n=30 per arm) 
≥19yo (n=30 per arm) 
Each participant sampled for capillary blood up to 5 of the following time 
points after their last dose of IVM: 0h (pre-last dose), 1h, 4h*, 8h, 12h*, 24h, 
48h, 52h, 60h, 72h, 7d*, 14d, 21d and 28d. *venous blood will be collected 
simultaneously at these time points 
# Hemoglobin analyses will also be performed on the capillary blood from a sub-sample of adults and children over the study using a 
Hemocue (or other) device.  
 
 


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Trial monitoring will be according to the Data Safety and Monitoring Plan and an independent 
Data Safety and Monitoring Board (DSMB) will established by the DMID to provide safety review and trial 
guidance, including advice on continuing, modifying or terminating the study. The study monitor will be 
an in-country contract research organization (CliMAfrica-CRO or other) who will provide external 
monitoring for the study. During the intervention phase, trained clinical trial monitoring experts from the 
CRO will conduct at least six monitoring visits (before, during and immediately after the intervention 
phase of the study, in rainy seasons 1 and 2). These will include assessment of site compliance and 
standard operating procedures, review of consents, assents, training documents, research/study 
approvals and data collection forms, review of site facilities, and laboratory sample storage, shipment, 
and labeling. An interim analysis of the safety data will be conducted after the 2rd MDA occurs in the first 
rainy season, and also in-between the first and second rainy seasons.  
 


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5. 
STUDY ENROLLMENT AND WITHDRAWAL 
Malaria-endemic villages in southwestern Burkina Faso that will participate in SMC in season 1 of the 
study will be recruited to participate.  The subject population in this region consists of West Africans 
mainly from the Mossi, Bobo, Dagara, Lobi and Fulani ethnic groups and who are mostly subsistence 
farmers and traders. All eligible village residents will be asked to enroll, which encompasses people of all 
ages and genders and reproductive capability, and small to medium size villages ranging between 200-
500 people will be recruited; per our power analysis, we require 7 villages per arm and ~100 children 
who are ≤10 years of age per cluster. If possible, we will also attempt to choose villages that have 
distinct boundaries and non-populated buffer zones of agricultural fields or bush land surrounding them 
in order to minimize mosquito movement between control and intervention clusters and between study 
and non-study villages. 
 
 
Subject Inclusion Criteria 
Subjects must meet all the inclusion criteria in order to be eligible to participate in the study. Subject 
Inclusion and Exclusion Criteria will be confirmed by a study clinician licensed to make medical 
diagnoses. No exemptions will be granted on Subject Inclusion/Exclusion Criteria in this DMID-sponsored 
study.  
 
We will attempt to enroll all inhabitants of selected villages who the leaders and majority of village 
heads-of-household first give their verbal consent to participate in the study. 
 Inclusion criteria are: 
• 
Residence in selected study village 
• 
Able to understand the information and willing to give consent or assent (age 
12-18) and parent/guardian consent if study participant age is < 18 years of age.  
We will attempt to enroll all children who live in the selected and verbally-consented villages in our 
active case surveillance cohort. 
Active case surveillance cohort inclusion criteria: 
 
Residence in selected study village 


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 
≤10 years of age  
 
Parent/guardian consent  
 
 
Subject Exclusion Criteria 
Exclusion criteria for participating in the intervention (IVM/placebo MDA): 
• 
Residence outside of the study village  
• 
Height < 90 cm (*note: if subject becomes ≥90cm over course the trial, this 
exclusion criteria will no longer be valid in subsequent MDA)  
• 
Current treatment with SP+AQ as part of SMC (restricted to children 3-59 
months old) (*note: if subject discontinuous SP+AQ treatment because they 
become older than 59 months over course the trial, this exclusion criteria will no 
longer be valid in subsequent MDA) 
• 
Permanent disability or serious medical illness that prevents or impedes study 
participation and/or comprehension 
• 
Pregnancy (screened for in women of child-bearing age [ages 12-45] using a 
pregnancy urine rapid test [e.g. SD Bioline hCG] the week prior to each MDA), as 
well as older females who have not yet had menopause 
• 
Breast feeding if infant is within 1 week of birth 
• 
Known allergy to ivermectin 
• 
Possibility of Loa loa infection 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 
Active case surveillance cohort exclusion criteria: 
 
Residence outside of the study site  
 
Permanent disability, serious medical illness that prevents or impedes study 
participation  


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Additional PK/PD cohort exclusion criteria: 
 
Concurrent use of drugs known to interfere with CYP3A4 metabolism within the 
past 14 days. (Section 6.6) 
 
Hemoglobin < 7g/dL 
 
Treatment Assignment Procedures 
 
Randomization Procedures 
This will be a cluster (village)-randomized trial.  Once the chiefs/leaders and heads-of-households of all 
fourteen selected villages give their verbal consent to participate following informational and question 
and answer meetings with the study team, a village representative and the CHWs representing each 
village will be asked to participate in a public randomization event at the facilities of the district health 
authority, attended by the district medical director and members of the study team. In front of the 
attendees, the numbers “1” and “2” will be written on 7 cards each, which will be sealed in identical 
opaque envelopes, mixed in a container, and then randomly pulled from the container by each village 
representative. Villages will be assigned to the arm written on the card selected by this representative, 
and the procedures will be video recorded. These arm designations will be linked to the masked active 
ingredient tablet or placebo (below).     
 
 
Masking Procedures 
The study pharmacist in charge of the drug stock rooms will originate the masking, written on three 
paper copies and put in identical and sealed opaque envelopes, which will be kept: 1- In the inventory 
paperwork binder at the drug stock room, and with each PI (2-with Dr. Foy in the Investigator’s 
Brochure, 3- with Dr. Parikh). The study pharmacist will allocate the IVM and placebo tablets for each 
IVM MDA round according to the original randomization throughout the trial, and distribute the drug in 
sealed containers labeled by a code (e.g. “Village X(1-7) – Arm 1” and “Village Y(1-7) – Arm 2”) to the clinical 
team prior to each round.  
 
 
Reasons for Withdrawal and Discontinuation of Study Product Administration 
Participants (or parent/guardians) may voluntarily withdraw their consent/assent at any stage for study 
participation without penalty or loss of benefits to which they are otherwise entitled.   


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An investigator may withdraw a subject from receiving the study product for any reason. Follow-up 
safety evaluations will be conducted, if the subject agrees.  If a subject withdraws or is withdrawn prior 
to completion of the study, the reason for this decision must be recorded in the case report forms 
(CRFs).  
The reasons, might include, but are not limited to the following: 
• 
Screening error resulting in incorrect enrollment (discovery that the subject did not meet the 
required inclusion/exclusion criteria) 
• 
Withdrawal of assent/consent at any stage or the subject is not willing to continue in the study 
(or withdrawal of consent by the parent/guardian to keep his or her child enrolled). 
• 
Suspected or confirmed allergic reaction to the study drugs. 
• 
Safety reasons as judged by the investigators or the DSMB after a meeting to review safety. 
• 
Subject no longer meets eligibility criteria (e.g. becomes pregnant) 
• 
Subject becomes noncompliant 
• 
Medical disease or condition, or new clinical finding(s) for which continued participation, in the 
opinion of the investigator might compromise the safety of the subject, interfere with the 
subject's successful completion of this study, or interfere with the evaluation of responses 
• 
Subject lost to follow-up 
• 
Determined by a physician’s discretion to require additional therapy not indicated in the 
protocol to ensure subject’s health and well-being (or treatment failure, if applicable) 
The investigator should be explicit regarding study follow-up (e.g. safety follow-up) that might be carried 
out despite the fact the subject will not receive further study product.  If the subject consents, every 
attempt will be made to follow all AEs through resolution.  The procedures that collect safety data for 
the purposes of research must be inclusive in the original informed consent or the investigator may seek 
subsequent informed consent using an IRB/IEC-approved consent form with the revised procedures. 
The investigator will inform the subject that already collected data will be retained and analyzed even if 
the subject withdraws from this study.  


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Handling of Withdrawals and Discontinuation of Administration 
Participants 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).   
 
 
Subject Replacement 
Subjects that have discontinued the study prematurely will not be replaced. New inhabitants that move 
into the study area will be approached for consent during the study. 
 
Termination of Study  
 
The study’s safety data will be analyzed by the DSMB after the interim analyses conducted soon after 
the 2rd MDA, and another conducted after the first full season of treatment. 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.  
Following the recommendation from the DSMB, 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 
DMID/NIH, the CSU and Yale IRBs and the Comité d’Ethique of the IRSS, and provide the reason for the 


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suspension or termination. The study may also be suspended or terminated at the discretion of the 
DMID/NIH based on funding decisions.  
If the study is prematurely terminated by the sponsor, any regulatory authority, or the investigator for 
any reason, the investigator will promptly inform the study subjects and assure appropriate therapy or 
follow-up for the subjects, as necessary. The investigator will provide a detailed written explanation of 
the termination to the IRBs and IEC. 


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6. 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
 
Study Product Description 
 
Acquisition 
Product 1 – generic IVM  
IVM (generic IVM, 6 mg tablets) will be purchased either from Laboratorio Elea, Argentina, who also 
produced these for the IVERMAL trial (48), or from another supplier. These will be shipped from the 
production facility to Burkina Faso with a tracking number on a commercial transport service, and 
transported to the study site with all the required regulatory documents. Electronic temperature 
monitors will be included during shipping and transport to ensure the quality of the product is not 
compromised during shipment.  
Product 2 - placebo 
Placebo (e.g. sucrose) will be purchased from either from Laboratorio Elea, Argentina, who also 
produced these for the IVERMAL trial (48), or from another supplier. These will be shipped from the 
production facility to Burkina Faso with a tracking number on a commercial transport service, and 
transported to the study site with all the required regulatory documents. Electronic temperature 
monitors will be included during shipping and transport to ensure the quality of the product is not 
compromised during shipment. 
 
 
Formulation, Packaging, and Labeling 
Product 1 –generic IVM 
See the package insert.   
 
Product 2 - placebo 
To be determined by the manufacturer. 
 


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Product Storage and Stability 
Product 1 – generic IVM  
Per the package insert, the product will be maintained in a climate-controlled study drug storage room 
that is <30°C and free from high humidity. When traveling to the villages, the product will be kept in cool 
boxes during transport. 
 
Product 2 - placebo 
Similar to the package insert, the product will be maintained in a climate-controlled study drug storage 
room that is <30°C and free from high humidity. When traveling to the villages, the product will be kept 
in cool boxes during transport. 
 
 
Dosage, Preparation and Administration of Study 
Intervention/Investigational Product 
IVM or IVM placebo will be given monthly from July-October (4X) over 2 consecutive seasons as a 3-day 
course to all eligible persons per exclusion/inclusion criteria. Similar to the Mectizan and Iver P package 
inserts, dosing of IVM or placebo will be according to height as an estimate for weight (Table 5) 
 
Table 4: 
 Dosing of ivermectin or placebo 
Height (cm) 
 
Estimated 
weight (kg) 
# of Tablets 
Total mg per 
dose 
Total mg per 3-day 
course 
90-119 
15-25 
1 tablet 
6mg 
18mg 
120-140 
26-44 
2 tablets 
12mg 
36mg 
141-158 
45-64 
3 tablets 
18mg 
54mg 
>158 
65-84 
4 tablets 
24mg 
72mg 
 
The study pharmacist (who will be unblinded) will allocate the IVM and placebo tablets for each IVM 
MDA round according to the original randomization throughout the trial, and distribute the drug in 
sealed containers labeled by the codes “Village X(1-7) – Arm 1” and “Village Y(1-7) – Arm 2” to the clinical 
team no more than 2 days prior to each round. 
 


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Modification of Study Intervention/Investigational Product for a 
Subject 
If the 3x300 µg/kg dose (estimated by height) schedule is observed to incur drug-related AE (see section 
2.3.1 and Appendix B for known drug-related AE) in more than 10% of the treated population after the 
first MDA by the study physician, the dosing schedule may be modified to a 1x400 µg/kg dose 
(estimated by height) schedule each month for the remainder of the trial. This would only change the 
number of consecutive days a dose of ivermectin (or placebo) would be given per MDA, from 3 
consecutive days per MDA to only once per MDA (see Table 5); it would not change the number of 
tablets or the total mg per dose corresponding to each height band. This change in dosing will be done 
in an online or phone ad hoc consult with the DSMB in the month after the 2nd MDA, and may depend 
on the follow-up clinical evaluations of participants. The clinical reasons for this change will be written 
into a report authored by study physician prior to the next MDA and will be sent to the IRBs/EC, CRO 
and to the DMID prior to the next MDA. 
If an individual participant is determined unable to take a dose of IVM/placebo due to a known allergy 
to the drug or other reason, the product or dosage will not be modified in any way. Instead, this and/or 
all future doses will not be administered to the participant and this will be noted accordingly on the 
participant’s case report form. 
 
 
Accountability Procedures for the Study 
Intervention/Investigational Product(s) 
The study drugs will be shipped from the supplier directly to the IRSS in Burkina with all appropriate 
permits and documentations.  They will be transported to the drug stock room at the field site, 
accounted for by the unblinded study pharmacist, dispensed as describe in 6.2 above in containers 
labeled per village and in accordance with the blind, and distributed to the clinical team no more than 2 
days prior to their administration by the clinical team.  
The Investigator is responsible for ensuring that a current record of product disposition is maintained 
and product is dispensed only at the study site by authorized personnel. Records of product disposition, 
will consist of the date received, date administered, quantity administered, and the subject number to 
whom the drug was administered.  
The unblinded study pharmacist will be responsible for maintaining accurate records of the shipment 
and dispensing of the investigational product. The pharmacy records must be available for inspection by 
the CRO at any time. 


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Unused investigational product will be stored in the designated climate-controlled study drug storage 
room <30°C and free from high humidity in the Investigational Pharmacy until clinical trial accountability 
is completed. At study termination, all unused investigational product will be disposed of in accordance 
with the manufacturer’s operation protocol following complete drug accountability and monitoring. 
 
 
Assessment of Subject Compliance with Study 
Intervention/Investigational Product/Investigational Device  
The clinical team will distribute the drugs door-to-door at the same time as the CHWs distribute the SMC 
door-to-door to the village children, at the beginning of each treatment round month (July, August, 
September, October) in two consecutive seasons. Treatment with the study drugs will be via DOT/NDOT, 
and unused drug will be returned to the pharmacist after each MDA. Administration will be documented 
on the CRFs in the nurse tablets. 
 
 
Concomitant Medications/Treatments 
No medications are restricted on the Iver P and Mectizan package inserts, so none will restrict treatment 
eligibility. All concomitant medications known to be taken during the study by study participants will be 
recorded in the appropriate sections of the CRF with indication, dose information, and dates of 
administration. 
However, due to potential CYP3A4-mediated drug-drug interactions, participants in the PK/PD sub-study 
will not be eligible if they have received any of the following medications within 14 days of IVM 
administration:  
 
Carbamazepine 
 
Clarithromycin 
 
Erythromycin (oral) 
 
Ketoconazole 
 
Phenobarbital 
 
Phenytoin 
 
Rifabutin 
 
Rifampin 
 
Halofantrine 
 
Any other medication known to significantly affect CYP450 metabolism. 


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7. 
STUDY SCHEDULE 
 
Recruitment 
Malaria-endemic villages in southwestern Burkina Faso that will participate in SMC in season 1 of the 
study will be recruited to participate. Small to medium size villages ranging between 200-500 people will 
be recruited; per our power analysis, we require 7 villages per arm and ~100 children who are ≤10 years 
of age per cluster.  
Recruitment will follow the procedures performed during RIMDAMAL I, whereby prospective areas in 
Southwest Burkina Faso from which villages could be recruited will be identified by consultations 
between the IRSS regional director (Dr. Dabire) and scientists, and the national and regional health 
authorities at the Burkina Faso MoH. Primary considerations will be whether or not SMC is ongoing in 
the prospective areas, whether other scientific or clinical studies in the prospective areas are planned or 
ongoing, and whether other malaria control and/or NTD control interventions (e.g. IRS, MDA with 
albendazole or azithromycin) are planned or ongoing in the prospective areas. 
Once an ideal study area is targeted for recruitment, we will obtain spatial maps and visit the area to 
understand the layout of villages, and make lists of ideal villages to recruit. We will attempt to choose 
villages that have distinct boundaries and non-populated buffer zones of agricultural fields or bush land 
surrounding them in order to minimize mosquito movement between control and intervention clusters 
and between study and non-study villages. 
Subsequently, Dr. Dabire, other scientists of the IRSS, and regional health authority officers will 
approach the village chiefs, elders and CHWs, and describe the study to them and answer any questions 
they may have in an open meeting in the village. If these village leaders give their consent to proceed 
recruiting the village populace, a subsequent public meeting of all the heads-of-households in the village 
may be planned to again describe the study, and further answer any questions they may have. Upon 
gaining these community consents, randomization/allotment will occur at the public event described in 
section 5.3.1, and following that, screening and enrollment will begin.  
  
 


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Screening  
Once community consent is affirmed and randomization/allotment occurs, screening, consent and 
enrollment will proceed with individual participants in each study village.  The study investigators will 
travel to each village and meet publicly with the heads-of-households to re-inform them of the study 
goals and objectives, of the process of the public randomization event, and the intervention procedures 
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 their 
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 active case detection (ACD; referring 
to children who will be regularly checked for malaria cases/episodes by the clinical team) cohort.  
The administration of the interventions will proceed at the beginning of the months designated by the 
regional health authorities for SMC round administrations (July-October in each intervention phase 
season). As the intervention proceeds, if the status of any individual changes regarding their eligibility to 
is more standard participant in the intervention (e.g., an allergic response to the study drug is 
determined), this information will be recorded on the case report form and flagged for the subsequent 
IVM MDAs. In the case of pregnancy, since this is contra-indicated for IVM treatment, all women of 
possible child-bearing age (ages 12-45 or still not had menopause) will screened using a pregnancy urine 
rapid test (e.g. SD Bioline hCG) in the week prior to each IVM MDA, and if positive, they will be excluded 
from the MDA. 
 
 
Enrollment/Baseline 
All persons who live in each study village and who do not have a permanent disability or serious medical 
illness that prevents or impedes study participation and/or comprehension will be asked to enroll. Once 
a head-of-household signs his/her household consent document (appendix VII), the investigators will 
engage all the members of each household, take a census of the inhabitants, conduct a questionnaire of 
inhabitants, survey the houses, and enroll adults ≥18 years of age with their written consent. Enrollment 
of children between 12-17 years of age will also be gained by obtaining their written assent, and 
children <12 years of age by obtaining the written consent of their parent/guardian.  All consents and 
assents will be obtained in the presence of a community witness, who will sign his or her name to these 
documents. Members of the study team will subsequently map the household and house locations in 
the village. Screening and participant information will be recorded on eCFRs on tablets, and individual 
participant exclusions/inclusions for participating in the intervention will be recorded (see 5.1).  
 


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PK/PD cohort 
PK/PD cohort children will be chosen from one control and one intervention village, using the arm code 
so as not to break the blind. They will be subject to follow-up at an increased frequency. Enrollment 
criteria are otherwise as for the ACD cohort, with additional exclusion criteria of a 1) hemoglobin <7 
g/dL (done by Hemocue or other instrument), and 2) use of concomitant medications (Section 6.6). The 
total number of participants in the PK/PD cohort is n=180 and participants will be age-stratified. Up to 
one individual may be enrolled from each age strata within the same household: 
• 
5-10yo (n=60, 30 from each village-arm) 
• 
11-18yo (n=60, 30 from each village-arm) 
• 
≥19yo (n=60, 30 from each village-arm) 
 
 
Follow-up  
Active case surveillance will be conducted by study nurses visiting each enrolled ACD cohort child weekly 
following the start of the first MDA and ending 30 days following the last MDA of the season. At each 
visit, the nurse will record patient information in the CRF, measure axillary temperature, take a blood 
sample (for the RDT, slide and filter paper) if indicated, and treat with AL if an uncomplicated malaria 
episode is confirmed by the RDT. Any other treatment (e.g., paracetamol) will be in consultation with 
the study physicians.  
All episodes of malaria will be classified as uncomplicated or complicated based on the following 
criteria:   
Uncomplicated malaria (all the following must be present) 
1) Fever (> 37.5°C) or history of fever in the previous 24 hours 
2) Positive RDT 
3) Absence of complicated malaria 
 
Complicated malaria (any of the following) 
1) Evidence of severe malaria (see Appendix D) and parasitemia  
2) Parasite density > 500,000/µL* 


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* Note that clinical decisions are made by RDT. However, if a nurse/doctor requests a blood 
smear to be read urgently, this will be performed. If the parasite density is above this threshold 
in this instance, the participant will be treated as having severe malaria. 
During these visits, the nurse will inquire about, and record in the CRF, any AEs spontaneously 
communicated by the rest of the enrolled village populace (passive surveillance), and treat them as able 
in consultation with the study physicians or refer them to the district health clinic or hospital. 
Complicated malaria or other SAE will be referred to the district hospital immediately. Interim safety 
and efficacy analyses will be performed in the middle of season 1 (between the 2nd MDA and the 3rd 
MDA) and in between the two intervention phase seasons, and presented to the DSMB as described in 
9.5.  
In addition to the active case surveillance by the study nurses, entomology teams will periodically 
sample mosquitoes from households in the village during each season, and members of the parasitology 
team or the nurses will take a finger blood sample from all cohort children and a subset of enrolled adult 
participants at cross-sectional time points each season. 
 
 
PK/PD cohort 
Participants in the PK/PD cohort will be subject to PK sampling during a single month either season over 
the course of the study. During that month, for enrolled participants, each of the three IVM doses will 
be directly observed. Small volume capillary blood samples (≤0.5mL) will be taken to determine IVM 
plasma concentration at up to 5 time points following the last dose of IVM. Participants will be visited on 
days 0 (day of 1st dose of IVM), day 1, and 2 to observe IVM dosing. PK sampling will occur at selected 
time points on up to 5 additional days (day 2, 3, 4, 7, 14, 21, and 28). 
 
 
Final Study Visit 
The active case surveillance final study visit of the intervention phase will occur 30 days following the 
final IVM MDA in season 2, approximately in November. On this visit, members of the parasitology team 
or the nurses will take a finger blood sample from all cohort children and a cross-sectional blood sample 
from subset of enrolled adult participants. Additional follow-up will occur for pregnancy follow-up 
 


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Early Termination Visit (if needed) 
No early termination visits will occur if early termination is required or requested by a participant. 
 
Unscheduled Visit (if needed) 
All participants will be encouraged to directly contact their assigned nurse or the field physician 
regarding any health emergencies or consultations at any time during the intervention phase each rainy 
season by mobile phone supplied to the CHW stationed in each village. During unscheduled visits, the 
nurse will record patient information in the CRF and diagnose and treat any simple AEs as able under the 
consultation of the study physicians and/or refer the participant to the district health clinic or hospital. If 
a participant is found to meet the case definition of malaria during this visit, a blood smear and filter 
paper will be collected. 
 
Additional Sampling 


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SAMPLES WILL ALSO BE OBTAINED AT ADDITIONAL TIMEPOINTS 
IN A SUBSET OF PARTICIPANTS--ALL CROSS-SECTIONAL 
HOUSEHOLDS AND SELECT OTHERS--IN ORDER TO OBTAIN A 
BASELINE ESTIMATE FOR PREVALENCE ESTIMATES.  THESE 
FINGER PRICK BLOOD SAMPLES WILL BE COLLECTED DURING 
THE DRY SEASONS IN 2020 AND 2021, DURING THE WET SEASON IN 
2021 AND AT UP TO 4 OTHER TIMEPOINTS THROUGHOUT THE 
YEAR. BLOOD SAMPLES WILL BE DRAWN VIA FINGER PRICK AND 
WILL BE PRESERVED ON SLIDES AND FILTER PAPERS FOR LATER 
ANALYSIS. BASELINE SAMPLES WILL ALLOW FOR BETTER 
ASSESSMENT OF CHANGES OCCURRING WITH IVM AND SMC 
DRUG PRESSURE. THIS ADDITIONAL SAMPLING WILL UTILIZE A 
SEPARATE INFORMATION SHEET AND CONSENT DOCUMENT. 
ONLY PARTICIPANTS WHO CONSENT TO PARTICIPATE IN THE 
ADDITIONAL SAMPLING WILL DO SO. STUDY 
PROCEDURES/EVALUATIONS 
 
Clinical Evaluations 
Clinical evaluations during active case surveillance will be specific to looking for signs and symptoms of 
uncomplicated malaria; specifically: 1) fever or history of fever in the previous 24 hours and 2) a positive 
malaria rapid diagnostic test. Signs and symptoms of complicated (serious) malaria (as listed in Appendix 
D) will also be assessed. AEs reported to the clinical team will be assessed for their seriousness, 
intensity, and causality related to the intervention by the field physician.  Known common side effects 
from IVM MDA such as pruritis, dizziness, diarrhea or vomiting will be evaluated and treated according 
WHO guidelines (Appendix B), and the nurse will consult with the field physician if a full clinical 
evaluation or referral should be performed. 
 


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Laboratory Evaluations 
 
Clinical Laboratory Evaluations 
No pre-specified formal clinical laboratory evaluations will occur during the intervention phase of the 
trial, other than in the PK/PD cohort. Rather, only field tests with RDTs will be performed, and blood 
samples taken for later analyses that will occur between the 2 rainy seasons or after the intervention 
phase. RDTs for parasite infection to diagnose malaria episodes will be used by nurses in the field, as will 
urine RDTs to determine pregnancy status in women 12-45 years of age (and those not yet reaching 
menopause) in the week prior to each IVM MDA. Blood smears taken by nurses and the parasitology 
team will be stored for later staining and counting of asexual parasites and species by trained 
parasitologists. Blood smears will only be read urgently when advised by the clinical team to rule out 
severe malaria. 
 
7.10.1.1. PK/PD cohort 
Participants in the PK/PD will be subject to capillary PK sampling up to 5 time points from the following 
sampling times 0 (pre-last dose), 1, 4, 8, 12, 24, 48, 52, 60, 72 hours, and on day 7, 14, 21, and 28. At up 
to 3 time points, simultaneous capillary and venous samples will be taken to assess the correlation 
between concentrations in these matrices, enabling us to compare our data with previous studies, and 
inform our mosquito-based studies. Clinical laboratory safety monitoring (5 mL venous draw) will also be 
conducted on days 0 (pre-IVM), day 14, and day 28 in all PK/PD participants, which will entail a complete 
blood count (CBC) with differential, liver enzymes (alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST)), and creatinine (Cr). 
 
7.10.1.2. Instructions for Specimen Preparation, Handling, and Storage 
Capillary blood from participants will be obtained by study nurses wearing disposable gloves, and by first 
wiping down the participant’s finger using an alcohol wipe, and using a sterile, single-use lancet. Nurses 
handling patient blood will follow safety guideline SOPs and training for handling potentially-infectious 
human blood and body fluids. Dried blood spots and blood slide smears will be taken during ACD by 
study nurses will be labeled with the appropriate date and participant ID, and will be stored in their 
backpacks and slide cases until they return from the field. Upon return, the nurses will store the blood 
spots in designated containers at the field station, and fix and stain the blood slides following a SOP to 
be written by the parasitology team. The stained slides will then be transferred to the parasitology 


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laboratory monthly by car at the IRSS for subsequent examination and dried blood spots will be stored 
at -20°C for later molecular analyses. 
These participant samples will be retained at the IRSS and/or at laboratories in the U.S or the 
Netherlands for further tests. Consent for the future use of these coded specimens is written into the 
ICFs. 
 
Capillary and venous samples taken from the PK-PD cohort will be used to assess the correlation 
between concentrations in the time and compartment matrices. Samples will be placed on ice and 
centrifuged, plasma stored at-80°C, and shipped to Yale on dry ice. IVM will be quantified using an 
Agilent 6550 Quadrupole LC/MS/MS that is coupled in line to an Agilent 1290 Infinity LC system. Blood 
fed mosquito samples collected from the same participant’s house will be similarly frozen individually at 
-80°C and ship them to CSU for subsequent analysis. The presence of IVM in blood meals will be 
determined using a derivatization + HPLC-fluorescence method. Additionally, a subset capillary blood 
spots representing those sleeping in each sampling house, and mosquito blood meals from that house 
will be profiled using DNA fingerprinting analysis. Data will be analyzed to determine if certain 
individuals/demographic strata (e.g. age groups and sex) receive more bites than expected over time, 
and how this relates to their IVM plasma concentration.  
 
Clinical labs (CBC, AST, ALT, and Cr) will be collected in appropriate vacutainers and analyzed at the 
central IRSS laboratory. 
7.10.1.3. Specimen Shipment 
These samples will be coded according to the participants study ID and time-stamped and signed. They 
will be maintained and tracked by the study pharmacologist in a specimen-tracking log, including details 
on tracking shipments from Burkina Faso to the laboratories in the U.S and the Netherlands. 
 


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8. 
ASSESSMENT OF SAFETY 
 
Definitions 
Adverse Event (AE): (ICH) E6 defines an AE as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product regardless of its causal relationship to the 
study treatment. FDA defines an AE as any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product. The 
occurrence of an AE may come to the attention of study personnel during study visits and interviews of 
a study recipient presenting for medical care, or upon review by a study monitor. 
All AEs, will be captured on the appropriate data collection form. Information to be collected for AEs 
includes event description, date of onset, an assessment of severity, relationship to study product and 
alternate etiology (assessed only by those with the training and authority to make a diagnosis), date of 
resolution, seriousness, and outcome. AEs occurring during the trial collection and reporting period will 
be documented appropriately regardless of relationship. AEs will be followed through resolution. 
Any medical condition that is present at the time that the subject is screened will be considered as 
baseline and not reported as an unsolicited AE. However, if the severity or frequency of any pre-existing 
medical condition increases, it will be recorded as an unsolicited AE. 
If an event meets both the criteria of a study endpoint and an adverse event, the event will be reported 
either as a study endpoint or as an adverse event (not both). 
Serious Adverse Event (SAE): An AE is considered “serious” if, in the view of either the site principal 
investigator or sponsor, it results in any of the following outcomes: 
• 
Death, 
• 
A life-threatening AE: An AE is considered “life-threatening” if, in the view of either the site 
principal investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an AE that, had it occurred in a more severe form, might have 
caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization, 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or 


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• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical judgment 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
 
Note: Medical judgment should be exercised in deciding whether an adverse event should be classified 
as serious in other situations. Important adverse events 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. 
 
Adverse Events Grading 
All AEs (laboratory and clinical symptoms) will be graded for severity and assessed for relationship to 
study product (see definitions). AEs will be graded initially by the study team on-site, typically the nurse 
and/or study physician, and final grading of AEs will occur in consultation with Dr. Parikh. AEs 
characterized as intermittent require documentation of onset and duration of each episode.  The start 
and stop date of each reported AE will be recorded on the appropriate data collection form. Changes in 
the severity of an AE will be documented to allow an assessment of the duration of the event at each 
level of intensity. 
 
Severity of Event: 
Severity will be determined following the definitions set forth in the standardized grading of adverse 
events (NIH Division of AIDS Adult and Pediatric Toxicity Tables, November 2014, version 2.0; see:  
https://rsc.tech-res.com/docs/default-source/safety/daids_ae_grading_table_v2_nov2014.pdf). 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: Potentially Life-threatening AE  
• 
Grade 5: Death  


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Changes in the severity of an AE should be documented to allow for assessment of the duration of the 
event at each level of intensity to be performed.  Adverse events characterized as intermittent require 
documentation of onset and duration of each episode. 
 
Relationship to Study Product:  
The assessment of the relationship of an AE to the administration of study product is made only by 
those with the training and authority to make a diagnosis based on all available information at the time 
of the completion of the case record form.  Whether the AE is related or not, is not a factor in 
determining what is or is not reported in this trial. If there is any doubt as to whether a clinical 
observation is an AE, the event should be reported. In a clinical trial, the study product must always be 
suspect. To help assess, the following general guidelines are used: 
• 
Related – There is a reasonable possibility that the study product caused the AE. Reasonable 
possibility means that there is evidence to suggest a causal relationship between the study 
product and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study product 
caused the event. 
The physician-investigators will use clinical judgment to determine the relationship with more specific 
objective criteria. 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 DSMB 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. 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, Yale, IRSS and 
DMID.  The investigator may change his/her opinion of causality in light of follow-up information, 
amending the SAE case report form accordingly. 
 
Management and Reporting of AEs 
AE monitoring will occur both actively and passively. All AE will be graded and analyzed by seriousness, 
intensity and causality. AE monitoring in this study is crucial to properly weigh the potential benefits vs. 
potential risks of the study. 
• 
In the entire enrolled populace, passive monitoring of AEs will occur through spontaneous reporting 
of events to the study clinical team, and recorded on CRFs. AEs will be recorded from the entire 


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enrolled populace, regardless if they were treated with ivermectin/placebo or not eligible to take 
the intervention. AEs will also be actively monitored on the days of distribution of 
ivermectin/placebo through direct questioning of AEs and recording on CRFs by study nurses. AE will 
be recorded over the intervention period occurring during 1st and 2nd rainy seasons. More 
specifically, AEs will be recorded from the start of the first MDA of each rainy season to 1 month 
after the last MDA of that season.  
• 
For those children enrolled in the active case detection cohort, where children are visited weekly to 
assess for malaria incidence, active monitoring of AEs will occur through direct questioning of AEs by 
the study team. Additionally, passive monitoring of AEs will occur by participants spontaneously 
reporting directly to the nurses when the nurses are in the villages performing active case detection 
of malaria in the child cohort, or spontaneously reporting indirectly to the nurses via communication 
through the village community health worker (who will then communicate the AE directly to the 
nurse or field physician).  
• 
For women that become pregnant during the intervention period, from the time of 1st intervention 
to 1 month after the last intervention for each rainy season, monitoring for birth outcomes will be 
conducted.   
Participants who develop common AEs 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 B) as well as standard approaches in Burkina 
Faso.  All adverse events will be noted in the participant’s CRF.  
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. AEs will be followed until resolution 
even if this extends beyond the study-reporting period.  Resolution of an AE is defined as the return to 
pretreatment status or stabilization of the condition with the expectation that it will remain chronic. 
These will be collated from CRFs by the field physician and study data managers in the 4th week 
following each IVM MDA and reported to the PIs prior to the administration of the next IVM MDA. 
 
Serious Adverse Events 
 
SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology. 
• 
Recorded on the appropriate SAE data collection form. 


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• 
Followed through resolution. 
• 
Reviewed and evaluated by the DSMB (periodic review unless related), DMID, and the IRB. 
In the case of any SAE, subjects will be referred to the district hospital for management. Transportation 
to the hospital will be provided. All hospitalized participants will undergo record review to identify 
potential adverse consequences of study participation. 
At any time after protocol follow up period or completion of this study, if the site principal investigator 
or appropriate sub-investigator becomes aware of an SAE that is suspected to be related to study 
product, the site principal investigator or appropriate sub-investigator will report the event to the DMID 
Pharmacovigilance Group.  
All SAEs will be reported to the DMID (see below), to the Physician-PI (Dr. Parikh) and to the in-country 
investigator (Dr. Dabiré), or their assigned representatives, within 24 hours of the nursing staff 
becoming aware of it via mobile phone or electronically. The SAE form in the CRF will ask for nature of 
event, date of onset, severity, corrective therapies given, outcome and causality (i.e. unrelated, unlikely, 
possible, probably, definitely). The responsible study clinician should ultimately assign the causality of 
the event. 
AEs that are serious or 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 
sponsor by the country 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 country investigator / representative). The DMID 
will report all SAEs to the DSMB. 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. 
Table 5:  
Reporting of Adverse Events 
Institution 
Type of Adverse Events 
When to Report 
• 
Yale-HIC 
• 
CSU IRB 
• 
IRSS/Centre 
Muraz 
• 
Related and Not Related to 
participation in the research 
AND Serious OR Unexpected 
(in terms of nature, 
specificity, severity, or 
frequency) 
• 
Within 5 days of awareness 
• 
Related Events not meeting 
prompt reporting 
requirements are 
reportable in summary form 
at time of continuing review 


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DMID 
Pharmacovigilance 
Group¥ 
• 
All Serious Adverse Events (as 
defined in 9.1) 
• 
Within 24 hours 
¥All SAEs must be submitted within 24 hours of site awareness on an SAE form to the DMID 
pharmacovigilance contractor, at the following address: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Phone Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
The DMID Medical Monitor and DMID Clinical Project Manager will be notified of the SAE by the DMID 
Pharmacovigilance Group. The DMID Medical Monitor will review and assess the SAE for potential 
impact on study subject safety and protocol conduct. 
At any time after completion of the study, if the Principal Investigator or appropriate co-investigator 
becomes aware of an SAE that is suspected to be related to study product, the Principal Investigator or 
appropriate co-investigator will report the event to the Sponsor and the DMID Pharmacovigilance 
Group. 
 
Reporting of Pregnancy 
Pregnancies communicated by any participants to the clinical team, or discovered by the clinical team 
with the use of screening by urine RDT pregnancy tests prior to each IVM MDA, will be noted on the 
participant’s CRF. The CRF indicator will then be used to identify these participants as not being eligible 
for receiving the intervention (IVM or placebo). The pregnancy status of these individuals will not be 
reported to the IRBs, sponsor, or regulatory agencies.  
Enrolled women that become pregnant during the intervention period, from the time of 1st intervention 
to 1 month after the last intervention for each rainy season, monitoring for birth outcomes will be 
conducted. 


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Halting Rules 
Interpretation of results and decisions about discontinuation of any treatment arms will be made by the 
DSMB, using the suggested guidelines given here. We do not propose that the DSMB be strictly bound 
by pre-specified criteria, because of the complexity of the trade-offs between safety, efficacy, and costs 
of the intervention, and the possibility that new information from contemporaneous ivermectin trials 
will change considerations. Rather, consideration of stopping guidelines requires a reasoned judgment 
based on all information that is available at the time of data review. As this is a double-blind, placebo-
controlled study that uses malaria incidence as the primary outcome, it will not be possible to 
accurately-measure the expected, modeled effect size (Figure 4, ~43%) until the end of the second 
treatment season (after MDA 8). Therefore, interim analysis of superiority of effect size in one blinded 
arm over the other will not be available in an appropriate timeframe to stop the study over the course 
of the two-year intervention. Furthermore, important secondary outcomes that ideally need 2 season of 
intervention are designed to determine if repeated ivermectin MDA treatment affects ACT resistance in 
malaria parasites and the possible development of ivermectin resistance in mosquitoes.  
Instead, the interim analyses of safety (AEs) , relative to the expected benefits in possible reduced 
malaria incidence in the cohort and reduced NTD among the treated populace, will provide the main 
data points for consideration of early halting of the trial. The expected AE incidence of the present study 
can be estimated from the RIMDAMAL I and IVERMAL trials, and used to decide if drug-related AE 
incidence is abnormally high relative to the expected benefit. The RIMDAMAL I trial had a dosing 
regimen of 150-200 µg/kg every 3 weeks for 18 weeks (6 treatments) to eligible participants in villages 
of the same region as this study. This resulted in AE being observed in 3% of the entire population of the 
study arm (45 AE in 1447 participants). However only ~75% of these participants were repeatedly 
treated with drug in the arm, and only 5 of these AE were considered possibly or probably related to the 
intervention (5/787 treated participants; 0.6%).  All were classified as standard AE (see Appendix B) of 
mild or moderate intensity that consisted of vomiting, pruritus, edema in the limbs, or tremors.  In the 
IVERMAL trial, 48 adult participants with confirmed symptomatic uncomplicated Plasmodium falciparum 
malaria were treated with one dose of an ivermectin regimen consisting of 3 days of 300 µg/kg/day that 
was co-administered with a 3-day course of dihydroartemisinin-piperaquine. This resulted in 8% (4/48) 
participants having an AE, but only 4% (2/48) of which were considered treatment-related. These AE 
were minor visual disturbances. Neither trial observed any treatment-related SAE.  
Each round of MDA is given to the entire study population over the course of 3 days. Data on AEs/SAEs 
will accumulate over the course of the month following each MDA, and data will be entered into the 
eCRFs. Thus, the data at the end of each round of MDA should capture all enrolled individuals by either 
active or passive follow-up.  The study team will review these data on an ongoing basis for any 
concerning safety signals. It is anticipated that the first full safety review of the initial round of MDA will 


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occur around between the 2nd and 3rd MDA round due to the time it will take to input and collate data. 
At the time of this review, and all others, it is recommended that if treatment-related AEs (Grade 2 or 
above) occur in 10% of the treated participants in the intervention arm, or if treatment-related SAE 
occur in 2% of the treated participants in the intervention arm, the following will take place: 
• 
The dose of IVM will be reduced to a 1x400 µg/kg dose (see section 6.3).  
• 
The DSMB should immediately convene an ad-hoc meeting that considers both unblinded 
safety data, as well as efficacy data (modeled and actual effect size of the primary outcome), to 
consider whether the study should be halted early or continue with a 1x400 µg/kg dose. 
The DSMB will have a scheduled meeting between the 2nd and 3rd MDA round, and after the completion 
of 1st rainy season. At this point, the DSMB will review all safety data to determine if dose modification is 
potentially warranted. 
Following recommendation from the DSMB, 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 DMID/NIH, the 
CSU and Yale IRBs and the Comité d’Ethique of the IRSS, and provide the reason for the suspension or 
termination. The study may also be suspended or terminated at the discretion of the DMID/NIH based 
on funding decisions. 
 
Data and Safety Monitoring Board 
Safety oversight will be conducted by a DSMB that is an independent group of experts that monitors 
subject safety and advises DMID.  The DSMB members will be separate and independent of study 
personnel participating in this trial and should not have scientific, financial or other conflict of interest 
related to this trial.  The DSMB will consist of members with appropriate expertise to contribute to the 
interpretation of the data from this trial, and include a biostatistician, clinicians and scientists who are 
knowledgeable about malaria and field-based research in sub-Saharan Africa, and persons 
knowledgeable in the conduct of clinical trials. 
The DSMB will operate under the rules of a DMID-approved charter that will be written at the 
organizational meeting of the DSMB. Procedures for DSMB reviews/meetings will be defined in the 
charter. DSMB reports may include enrollment and demographic information, medical history, 
concomitant medications, physical assessments, clinical laboratory values, dosing compliance, and 
solicited and unsolicited AE/SAEs.  The DSMB will review SAEs on a regular basis and ad hoc during this 
trial. The DMID Medical Monitor will be responsible for reviewing SAEs in real time.  


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The DSMB will conduct the following reviews:  
• 
The study’s safety data will be analyzed by the DSMB after the interim analyses conducted after 
the 2nd MDA, and another conducted after the first full season of treatment. 
• 
Ad hoc when a halting rule is met or DMID/DSMB chair may convene an ad hoc meeting if there 
are immediate concerns regarding observations during the course of this trial. 
• 
Final review meeting: 6 to 8 months after clinical database lock to review the cumulative 
unblinded safety data for this trial. The data will be provided in a standard summary format. The 
DSMB may be asked to provide recommendations in response to questions posed by DMID. 
Additional data may be requested by the DSMB, and interim statistical reports may be generated as 
deemed necessary and appropriate by DMID. The DSMB may receive data in aggregate and presented 
by treatment arm. The DSMB may also be provided with expected and observed rates of the expected 
AEs in an unblinded fashion, and may request the treatment assignment be unblinded for an individual 
subject if required for safety assessment. The DSMB will review grouped and unblinded data in the 
closed session only. As an outcome of each review/meeting, the DSMB will make a recommendation as 
to the advisability of proceeding with the study intervention, and to continue, modify, or terminate this 
trial. 


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9. 
CLINICAL MONITORING 
 
Site Monitoring Plan by CRO 
During the intervention phase, trained clinical trial monitoring experts (e.g. ClimAfrica-CRO or another 
contract research organization [CRO]) will conduct at least six monitoring visits (before, during and 
immediately after the intervention phase of the study, each in rainy seasons 1 and 2). These will include 
assessment of site compliance and standard operating procedures, review of consents, assents, training 
documents, research/study approvals and data collection forms, review of site facilities, and laboratory 
sample storage, shipment, and labeling. The study monitor will collate and promptly share their reports 
with the study investigators and study sponsor. The investigators will provide these reports to the DMID 
for their assessments of the study’s adherence to GCP practices and recommendations and/or 
considerations of early trial termination due to possible data quality or safety concerns. 


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10. 
STATISTICAL CONSIDERATIONS 
 
 
Study Hypotheses 
The primary objective hypothesis is that repeated IVM MDAs (the intervention) coinciding with SMC 
rounds and other standard-of-care malaria control measures (LLIN distribution, IPTp) will significantly 
reduce the incidence of childhood malaria compared to the placebo intervention. This hypothesis will be 
tested in a 2-arm superiority trial with a cluster randomized design. The primary outcome measures of 
incidence of malaria episodes among village children ≤ 10 years of age in each arm will be used to test 
the hypothesis.  The primary objective null hypothesis is that that repeated IVM MDAs coinciding with 
SMC rounds and other standard-of-care malaria control measures will have no effect on the incidence of 
childhood malaria compared to placebo MDAs coinciding with SMC rounds and other standard-of-care 
malaria control measures. 
Secondary objective hypotheses: 
• 
The risk of adverse events (AEs) per participant in the intervention arm occurring over the 
intervention phase of the trial will not differ relative to the risk of adverse events in the control arm. 
Null: The risk of adverse events (AEs) per participant in the intervention arm occurring over the 
intervention phase of the trial will not differ relative to the risk of adverse events in the control arm.     
• 
The survival rates of wild blood fed Anopheles gambiae s.l. will be significantly reduced, and age-
structure and entomological inoculation rate in wild Anopheles gambiae s.l. significantly 
younger/lower, in those captured from intervention arm villages as compared to those captured 
control arm villages at equivalent time intervals during the intervention phase. Also, the immuno-
reactivity of intervention-arm participants’ IgG over time to an Anopheles salivary gland peptide will 
be significantly lower than than that from control arm participants.  Null: The survival rates of wild 
blood fed Anopheles gambiae s.l., and parity and sporozoite rates in wild Anopheles gambiae s.l., will 
not differ in those captured from intervention arm villages as compared to those captured control 
arm villages at equivalent time intervals during the intervention phase. Similarly, the immuno-
reactivity of intervention-arm participants’ IgG over time to an Anopheles salivary gland peptide will 
be no different than that from control arm participants. 
• 
The Plasmodium falciparum multiplicity of infection per episode or blood sample, and number of 
new Plasmodium falciparum clones per unit time per child, will be significantly reduced in 
intervention arm children compared to control arm children. Null: The Plasmodium falciparum 
multiplicity of infection per episode or blood sample, and number of new Plasmodium falciparum 


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clones per unit time per child, will not differ in intervention arm children compared to control arm 
children.  
• 
The concentration of ivermectin in participant’s plasma will change over time post-drug 
administration and vary between age and gender strata. Mosquitoes that feed on recent ivermectin-
treated participants will have detectable ivermectin in their blood meals. Null: The concentration of 
ivermectin in participant’s plasma will not change over time post-drug administration and will not 
vary between age and gender strata. Mosquitoes that feed on recent ivermectin-treated participants 
will not have detectable ivermectin in their blood meals. 
 
 
Sample Size Considerations 
The trial design and power calculation is guided by the Malaria Transmission model developed at 
Imperial College, London (http://www.imperial.ac.uk/malaria-modelling/tools-and-data/) and informed 
by data from our RIMDAMAL I trial as well as the longer mosquitocidal effect (up to 30 days) from the 
intervention dose and regimen predicted from IVERMAL data. The model suggests we should observe an 
effect size in the intervention arm over the control arm of 43.1% (Figure 4). This assumes a rate 
incidence in our 0-10 yr. old cohort of 1.088 malaria episodes/child/year and 0.619 malaria 
episodes/child/year in the control and intervention arms, respectively. To determine the cluster sample 
size and cluster population (children cohort size) we used the sample size formula for obtaining the 
number of clusters in an unmatched CRT design with a ‘rate’ endpoint (49). The formula uses the 
coefficient of variation (κ; SD/mean) of the true rates between clusters within each group, which we 
estimated in southwestern Burkina Faso to be 0.258 (50). From these variables, and setting the α=0.05 
(Type I error rate or probability of detecting a false negative result = 1.96), 6 clusters/arm with a 
minimum of 48 children/cluster in our child cohort is necessary to detect a significant difference in the 
rates between the arms with 80% power (Type II error rate or probability of rejecting a false positive 
result = 0.84). Relatedly, if we instead calculate the cluster population sample size using the intracluster 
correlation coefficient retrospectively calculated from RIMDAMAL I data (ICC=0.059), and setting the 
α=0.05, with 6 clusters/arm the necessary number of children to follow per cluster is 9.  
In January 2019, the sample size modeling exercise was re-performed because it was learned 
that that villages in the Diebougou health district (the study site) were expected to receive new 
Interceptor G2 LLINs prior to the 2019 rainy season. These new LLINs are made with two different 
insecticides (chlorphenapyr and alpha-cypermethrin) to circumvent the prevalent pyrethroid-resistance 
seen in Burkina Faso the much of SSA. Thus, we assumed a 12%-50% reduction in malaria incidence in 


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both arms due to distribution of these nets.  Keeping with an effect size of 43.1% in the intervention am 
over the control arm, using an intra-cluster coefficient of 0.2, and increasing the sample size to 100 
children/cluster in our child cohort, we need between 4.9 and 5.5 clusters/arm to detect a significant 
difference in the rates between the arms with 80% power. Given that we will select 7 villages per arm, 
which are expected to have population sizes of 0-10 year old children of approximately 100, we feel we 
will have >80% power to reject the null hypothesis if it is false, even if some children drop out of the 
study or are lost to follow-up.  
 
The primary outcome will be analyzed as intention-to-treat. The incidence of episodes from the 
children cohort will be used as the primary measurable outcome to evaluate the impact of the 
intervention when compared to the control arm. The primary analysis will use either cluster-level 
analyses, or multilevel/hierarchical regression modeling techniques to account for clustering at the level 
of the randomization unit (village), as well as analyze individuals with multiple time points. and 
comparisons using a critical value of α at 0.05. The analysis may need to be corrected to account for the 
relatively few number of clusters in the study design.  The unadjusted as well as adjusted estimates 
depicting the impact of the intervention versus control will be reported along with 95% confidence 
intervals. The statistical programs R (r-project.org), SAS v9.4 (SAS Institute Inc., Cary, NC), or others will 
be used for the primary statistical analyses. 
 


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Figure 3: 
Modeling of the primary outcome when adding IVM MDA to SMC 
 
 
Planned Interim Analyses  
 
Interim Safety Review  
AE risk data for each arm following the first MDA round will be accumulated and provided to the DSMB 
between the 2nd and 3rdMDAs, as well as following the entire first season of MDAs for safety analyses. 
The DSMB will review the AE compared between intervention and control arms by examining calculated 
risks ratios and attributable risks with 95% confidence intervals. Serious adverse events (SAE) will be 
similarly analyzed. The statistical program (e.g. R or SAS or others will be used for the AE statistical 
analyses. The DSMB will operate under the rules of a DMID-approved charter that will be written at the 
organizational meeting of the DSMB. The frequency of DSMB meetings, the statistical techniques, rules 
 
Modeling of the primary outcome when adding IVM MDA 
to SMC. Clinical incidence in 0-10 year olds is predicted to 
drop by 54% in SMC+IVM MDA villages (red line) compared 
to no intervention (gray dotted line) and by 43% over those 
receiving the currently approved regimen of SMC alone 
(yellow line). Cases per 1000 0-10 yr. olds/yr are assumed to 
be 1351 with no intervention based on past data, and 
predicted to be 1088 with SMC alone but 619 with SMC+IVM 
MDA. Arrows on the X-axis denote each monthly treatment 
round.      


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and recommendations for stopping guidelines based on AE rates and types, and the types of analyses 
expected for DSMB reviews/meetings will be defined in the charter.  
 
 
Final Analysis Plan 
The final statistical plan will be written in detail in the finalized standard operating procedure, f before 
the start of the intervention phase, to ensure that the sampling plan (e.g. number of nurse visits, 
number of mosquitoes and blood samples) collected are appropriate for the intended analyses. In 
general, standard, two-tailed statistical hypothesis testing α=0.05, as well as estimating and comparing 
the effect sizes and confidence intervals, will be used to measure the differences in entomological and 
parasitological secondary outcomes between arms. The tests used will depend on the type of data 
collected (e.g., survivorship of blood fed mosquitoes in each arm per collection interval, proportion of 
mosquitoes parous/arm per collection interval, average counts of trophozoites/slide or counts of the 
parasite molecular force of infection, sporozoite rates in mosquitoes), and their distributions. These data 
will also be used to make generalized linear and non-linear mixed effects models in R, SAS or other 
programs to understand the functional relationships of measured entomological and parasitological 
variables and the relative contributions of various independent variables on variation in the dependent 
variable. 
 


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11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
All CRFs containing participant demographic and clinical data (active case surveillance data on the 
children cohort and AE data for all participants) will be entered on password-protected tablets that will 
be maintained and updated daily by the clinical team working at the field site. This data will gathered in 
an electronic data capture system (e.g. REDCap) and be collated and sent encrypted over the internet to 
be entered into the study database managed by the study data manager(s). Data from participant blood 
smears will be kept on laboratory notebooks kept by the parasitological team at the IRSS in Burkina 
Faso, and entered in the same CRFs and study data base by the study data managers. Only the study 
team will have access to the source data. Long-term maintenance of the participant codes will be held 
only by the study PIs on password-protected computers and files.  
We will permit authorized representatives of the sponsor(s), DMID, and regulatory agencies to examine 
(and when required by applicable law, to copy) clinical records for the purposes of quality assurance 
reviews, audits, and evaluation of the study safety and progress. 


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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
A detailed quality management plan will be written before the start of the intervention phase of the trial 
that is in accordance with DMIP guidelines for assuring the quality of the research being conducted. This 
plan will have standard operating procedures (SOPs) for quality management which describe how the 
data will be evaluated for compliance with the protocol and for accuracy in relation to source 
documents. How the documents will be reviewed (e.g., CRFs, notes, product accountability), who is 
responsible for the reviews, and the frequency for reviews. Methods of training for staff will also be 
outlined in SOPs and the staff will need to sign off on each training they receive. 
The study monitor (CliMAfrica-CRO or other) will verify that the clinical trial is conducted and data are 
generated, documented (recorded), and reported in compliance with the protocol, ICH/GCP guidelines, 
and the applicable regulatory requirements. Clinical monitoring reports will be submitted to the 
investigators, the sponsor, and the DMID. 


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13. 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
Ethical Standard 
 
The investigator will ensure that this study is conducted in full conformity with the principles set forth in 
The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research 
of the US National Commission for the Protection of Human Subjects of Biomedical and Behavioral 
Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the ICH E6; 62 Federal Regulations 25691 
(1997). 
The trial will also 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 by Agence Nationale de Régulation Pharmaceutique (ANRP) 
within the Burkina Faso Ministry of Health. 
The principal investigators and other key personnel have no competing interests or conflicts of interest 
for the overall trial. 
 
 
Institutional Review Board 
This protocol, the informed consent documents, and participant case report forms will be reviewed and 
approved by the IRBs at Colorado State University, Yale University, and the Comité d’Ethique d’IRSS. Any 
amendments to the protocol or consent materials must also be approved before they are placed into 
use. 
Each site principal investigator will obtain IRB approval for this protocol to be conducted at his/her 
research site(s), and send supporting documentation to the DMID before initiating recruitment of 
subjects.  The investigator will submit applicable information to the IRB/IEC on which it relies for the 
review, to conduct the review in accordance with 45 CFR 46, ICH E6 GCP, and as applicable, 21 CFR 56 
(Institutional Review Boards) and 21 CFR 50 (Protection of Human Subjects), other federal, state, and 
local regulations. DMID must receive the documentation that verifies IRB/IEC-approval for this protocol, 
associated informed consent documents, and upon request any recruitment material and handouts or 
surveys intended for the subjects, prior to the recruitment and enrollment of subjects.     
Any amendments to the protocol or consent materials will be approved by the IRB/IEC before they are 
implemented.  IRB/IEC review and approval will occur at least annually throughout the enrollment and 


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follow-up of subjects, and may cease if annual review is no longer required by applicable regulations.  
The investigator will notify the IRB/IEC of deviations from the protocol and reportable SAEs, as 
applicable to the IRB/IEC policy. 
Each institution engaged in this research will hold a current Federalwide Assurance (FWA) issued by the 
Office of Human Research Protection (OHRP) for federally funded research. 
A single IRB of record, Colorado State University IRB, will be accountable for compliance with regulatory 
requirements for this multi-centered study. The SMART IRB reliance agreement in accordance with NIH 
policies will government the agreement between the CSU and Yale IRBs.  Participating sites will then rely 
on the IRB of record to satisfy the regulatory requirements relevant to the IRB review. The participating 
sites will maintain essential required documentation of IRB reviews, approvals, and correspondence, and 
must provide copies of any agreements and essential documentation to the DMID or regulatory 
authorities upon request. 
The IRB/IEC will determine that adequate provisions are made for soliciting the permission of each 
child's parent(s) or legal guardian, including whether permission of one parent is sufficient for research 
or whether permission is to be obtained from both parents. The IRB/IEC will determine how consent 
from subjects will be obtained when participation in the study is ongoing, and the subject has reached 
the age of majority.  
 
Informed Consent Process 
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, witnessed informed 
consent will be obtain from each person in orally-consented households by going door-to-door to 
households. The informed consent discussion will be in the appropriate language for the adult or the 
parents/guardians; translators will be used if necessary. The study information sheet given to each 
head-of-household will be written in French, as well as local languages predominately spoken in the 
region. Written, informed consent from each head-of-household will be in French and verbally 
translated into the appropriate language for the adult or the parents/guardians by translators. If the 
parent/guardian/participant is unable to read or write, their fingerprint will substitute for a signature, 
and a signature from a witness to the informed consent procedures will be obtained. The witness may 
be a family member, clinic staff not conducting the informed consent discussions, or a translator. The 


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consent process shall be initiated at the time of enrollment into the study and shall continue throughout 
the patient’s participation.  
Participants will receive an explanation that the trial involves research, and a detailed summary of the 
proposed study procedures and study interventions/products.  This will include aspects of the trial that 
are experimental, the probability for random assignment to treatment groups, any expected benefits, all 
possible risks (including a statement that the particular treatment or procedure may involve risks to the 
subject or to the embryo or fetus, if the subject is or may become pregnant, that are currently 
unforeseeable), the expected duration of the subject’s participation in the trial. 
Subjects will be informed that they will be notified in a timely manner if information becomes available 
that may be relevant to their willingness to continue participation in the trial. Subjects will receive an 
explanation as to whether any compensation and any medical treatments are available if injury occurs, 
and, if so, what they consist of, or where further information may be obtained. They will be informed of 
whom to contact (e.g., the investigator) for answers to any questions relating to the research project.  
Information will also include the foreseeable circumstances and/or reasons under which the subject’s 
participation in the trial may be terminated. The subjects will be informed that participation is voluntary 
and that they are free to withdraw from the study for any reason at any time without penalty or loss of 
benefits to which the subject is otherwise entitled.   
The extent of the confidentiality of the subjects’ records will be defined, and subjects will be informed 
that applicable data protection legislation will be followed. Subjects will be informed that the 
monitor(s), auditors(s), IRB, NIAID, and regulatory authority(ies) will be granted direct access to the 
subject’s original medical records for verification of clinical trial procedures and/or data without 
violating the confidentiality of the subject, to the extent permitted by the applicable laws and 
regulations, and that, by signing a written informed consent form, the subject is authorizing such access.  
Subjects will be informed that records identifying the subject will be kept confidential, and, to the extent 
permitted by the applicable laws and/or regulations, will not be made publicly available and, if the 
results of the trial are published, the subject’s identity will remain confidential. Subjects will be informed 
whether private information collected from this research and/or specimens will be used for additional 
research, even if identifiers are removed.   
Subjects will be allowed sufficient time to consider participation in this research trial, and have the 
opportunity to discuss this trial with their family, friends or legally authorized representative, or think 
about it prior to agreeing to participate. 


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Considering the villages are populated by many 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 local health district 
will remain the same regardless of study enrollment.  
In accordance with the IRSS Comité d’Ethique, the head-of-household will be given a study information 
sheet explaining the study, as well as a head-of-household consent statement to read and sign.  All 
adults will be asked to read the consent for (or if illiterate, be read the consent form) and sign an adult 
consent form.  
 
Informed Consent/Assent Process (in Case of a Minor) 
Investigators will follow IRB/IEC requirements for enrollment of minors in this study.  Minors will be 
informed about the study to the extent understandable to the minor.  Investigators or designee will 
conduct the consent process with the parent(s)/legal guardian, who will be given an IRB/IEC-approved 
permission form, which may be referred to as a consent form, to read, review, and sign prior to any 
study procedures. The parent(s)/legal guardian will be provided meaningful study information including 
a statement that this study involves research, the child may not benefit from the trial, and the study 
involves risk. The required elements will be clearly presented, including the purpose of the study, the 
experimental procedures, the potential risks and discomforts, known adverse effects, possible benefits 
of the study for the subject, alternative therapies that may be beneficial, use and disclosure of private 
information, and other elements that are part of obtaining proper consent. The subject’s parent(s)/legal 
guardian will be allowed sufficient time to discuss questions with the investigator.   
The investigator or designee will describe in simplified terms the details of the study 
intervention/product, study procedures, risks and discomforts, benefits, and other consent elements, as 
appropriate. A separate IRB/IEC-approved assent form will be used for the minor, who may read and 
sign the form, or have it read to him/her prior to participation in study procedures.  Assent may be 
obtained verbally or waived when approved by the IRB/IEC as appropriate to age.  If a child declines to 
participate in the trial when assent is required by the IRB/IEC, the subject will not be enrolled even 
though the parents have provided permission.  
To ensure that consent is an ongoing process throughout the subject’s participation in the study, the 
investigator and staff will review information as needed with the subject and the parent(s)/legal 
guardian and confirm that assent and permission are continuing.  The permission and assent documents 


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will be updated when new information is acquired that may impact the decision to continue in the 
study, and the subject’s assent and the parent(s)/legal guardian’s permission will be obtained, as 
applicable.   
The subject who reaches the age of majority will be consented at the next visit prior to study 
procedures.  When no further visits are planned but the subject’s participation is ongoing, the consent 
will be obtained via IRB/IEC-approved processes. 
 
Exclusion of Women, Minorities, and Children (Special 
Populations) 
To complete the aims and purpose of this study, we will attempt to enroll the entire populace of each 
village invited to participate. Thus, this study will not exclude any women, minorities or children, nor 
special populations, including illiterate or non-writing individuals. 
 
Subject Confidentiality 
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. 
Tests for malaria 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. All participant information 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. 
 
 
Study Discontinuation 
If the study is prematurely terminated by the sponsor, any regulatory authority, or the investigator for 
any reason, the investigator will promptly inform the study subjects and assure appropriate therapy or 
follow-up for the subjects, as necessary. The investigator will provide a detailed written explanation of 
the termination to the IRB/IEC. If any subject’s private information will continue to be collected for this 
study, the IRB/IEC must approve a consent form with the study procedures, any risks and discomforts, 


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and applicable elements, and the investigator or designee will re-consent the subjects as approved by 
the IRB/IEC. 
 
Costs, Subject Compensation, and Research Related Injuries 
There is no cost to subjects for the research tests, procedures, and study product while taking part in 
this trial. If it is determined by the site principal investigator that an injury occurred to a subject as a 
direct result of the tests or treatments that are done for this trial, then referrals to appropriate health 
care facilities will be provided to the subject.  Study personnel will try to reduce, control, and treat any 
complications from this trial.   
 
Future Use of Stored Specimens and Data 
The consent documents will contain language asking for participant’s consent to use their blood samples 
for future studies that may help in the prevention of malaria. The consent states that we will store blood 
with a code that does not contain any unique identifiers in laboratories in the U.S. and Burkina Faso, and 
that we may share the test results on their samples with researchers at other organizations but we will 
not give them any names, addresses, or any information that could identify them or their household.  
Also, after the study period has ended, we will remove any means to link the sample them and their 
household, and we will not be able to find the samples connected to them.   


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14. 
DATA HANDLING AND RECORD KEEPING 
The investigators are responsible to ensure the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  Black ink is required to ensure clarity of reproduced copies.  When making 
changes or corrections, cross out the original entry with a single line, and initial and date the change.  
DO NOT ERASE, OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained for 
recording data for each subject enrolled in the study.  Data reported in the eCRF derived from source 
documents should be consistent with the source documents or the discrepancies should be explained. 
DMID and/or it designee will provide guidance to investigators on making corrections to the source 
documents and eCRF. 
 
 
Data Management Responsibilities 
All source documents and laboratory reports must be reviewed by the clinical team and data entry staff, 
who will ensure that they are accurate and complete.  Adverse events must be graded, assessed for 
severity and causality, and reviewed by the physician-PI (Dr. Parikh) or designee. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of Dr. 
Dabiré.  During the study, the investigator must maintain complete and accurate documentation for the 
study. 
The study site data manager and team, in conjunction with the study biostatistician (Dr. Rao) and the 
Colorado Clinical and Translational Sciences Institute (CCTSI), will serve to coordinate data entry, 
management and statistical analysis for this study and will be responsible for data management, quality 
review, analysis, and reporting of the study data. 
All investigators on this study will have access to the final dataset. 
 
Data Capture Methods 
Participant demographic data and clinical data (including malaria episodes and AEs) and clinical 
laboratory data will be entered into eCRFs and downloaded into a 21 CFR Part 11-compliant Internet 
Data Entry System (IDES) approved by the IRBs.  The data system will includes password protection and 
internal quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate.  Clinical data will be entered directly from the source documents.  


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Types of Data 
Data for this study will include participant demographics, malaria episodes and their treatment, safety 
data (AEs and their characteristics and treatment), and laboratory (blood parasite prevalence and 
parasitemias)  
 
 
Timing/Reports 
Study monitor reports will be required at the beginning, middle and end of the intervention phase. 
Interim safety reports will be conducted and submitted after the 2nd MDA and between the 1st and 2nd 
seasons, and reviewed by the investigators and IRBs, the DMID and the DSMB. Data analyses and 
reports to the DSMB, sponsor and the DMID/NIH will begin following season 1 and continue until the 
end of the project period in Year 5. Care will be taking not to break the blind when performing analyses 
before the end of the intervention phase is complete. 
 
 
Study Records Retention 
Study documents will be retained for a minimum of 5 years after the close out of the study at the study 
site.  These documents should be retained for a longer period, however, if required by local regulations.  
No records will be destroyed without the written consent of the sponsor, if applicable.  It is the 
responsibility of the sponsor to inform the investigator when these documents no longer need to be 
retained. 
 
 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, or Good Clinical Practice (GCP) 
requirements.  The noncompliance may be either on the part of the subject, the investigator, or the 
study site staff.  As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly.  
These practices are consistent with ICH E6: 
4.5 
Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
5.1 
Quality Assurance and Quality Control, section 5.1.1 


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5.20 
Noncompliance, sections 5.20.1, and 5.20.2. 
It is the responsibility of the site principal investigator and personnel to use continuous vigilance to 
identify and report deviations within five working days of identification of the protocol deviation, or 
within five working days of the scheduled protocol-required activity.  All deviations must be promptly 
reported to the IRBs. 
All protocol deviations, as defined above, must be addressed in study subject data collection forms.  A 
completed copy of the Protocol Deviation Form must be maintained in the Regulatory File, as well as in 
the subject's chart.  Protocol deviations must be sent to the local IRB/IEC per their guidelines.  The site 
principal investigator and personnel are responsible for knowing and adhering to their IRB 
requirements. 
 


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15. 
PUBLICATION POLICY 
Following completion of the study, we will to publish the results of this research in peer-reviewed 
scientific journals.  Following the International Committee of Medical Journal Editors (ICMJE) member 
journals publication policy, this trial will be registered at ClinicalTrials.gov, which is sponsored by the 
National Library of Medicine.  The trial will be registered on or before participant enrollment.   
 
The PI and MPI must submit or have submitted for them to the National Library of Medicine’s PubMed 
Central (http://www.ncbi.nlm.nih.gov/pmc/) an electronic version of their final, peer-reviewed 
manuscript describing the primary outcome upon acceptance for publication, to be made publicly 
available no later than 12 months after the official date of publication.  The NIH Public Access Policy 
ensures the public has access to the published results of NIH funded research.  It requires investigators 
to submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive 
PubMed Central upon acceptance for publication.  Further, the policy stipulates that these papers must 
be accessible to the public on PubMed Central no later than 12 months after publication. 
Refer to: 
• 
NIH Public Access Policy, http://publicaccess.nih.gov/ 
• 
NIH Office of Extramural Research (OER) Grants and Funding, 
http://grants.nih.gov/grants/oer.htm 
As of January 2018, all clinical trials supported by the NIH must be registered on ClinicalTrials.gov, no 
later than 21 days after the enrollment of the first subject. Results of all clinical trials supported by the 
NIH, generally, need to be submitted no later than 12 months following the primary completion date. A 
delay of up to 2 years is available for trials that meet certain criteria and have applied for certification of 
delayed posting. 
As part of the result posting a copy of this protocol (and its amendments) and a copy of the Statistical 
Analysis Plan will be posted on ClincialTrials.gov. 
For this trial the responsible party is Dr. Foy, who will register the trial and post results.   
The responsible party does not plan to request certification of delayed posting. 
Refer to: 
• 
Public Law 110-85, Section 801, Clinical Trial Databases 
• 
42CFR11 


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NIH NOT-OD-16-149 
The funder and sponsor of the study will have no role in, or authority over, the study design, data 
collection, data analysis, data interpretation, writing, or the decision to submit publications and reports 
from this study.  
The PI (Dr. Foy) and MPI (Dr. Parikh) will consult together, and have final decisions over who is eligible 
for authorship on any publications stemming from this study. They will also decide together on how the 
full protocol is disseminated or published, and if and how participant-level data or statistical code will be 
shared with investigators or entities outside of the study team.  


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16. 
LITERATURE REFERENCES 
 
1. 
Campbell WC. Ivermectin and Abamectin. New York: Springer Verlag; 1989. 363 p. 
2. 
Iakubovich VI, Zakharova NF, Alekseev AN, Alekseev EA. Evaluation of ivermectin on blood-
sucking mosquitoes. Medicinskaya Parazitologia Moskva. 1989;3:60-4. 
3. 
Gardner K, Meisch MV, Meek CL, Biven WS. Effects of ivermectin in canine blood on Anopheles 
quadrimaculatus, Aedes albopictus and Culex salinarius. J Am Mosq Control Assoc. 1993;9(4):400-2. 
PubMed PMID: 8126472. 
4. 
Bockarie MJ, Hii JL, Alexander ND, Bockarie F, Dagoro H, Kazura JW, Alpers MP. Mass treatment 
with ivermectin for filariasis control in Papua New Guinea: impact on mosquito survival. Med Vet 
Entomol. 1999;13(2):120-3. PubMed PMID: 10484157. 
5. 
Foley DH, Bryan JH, Lawrence GW. The potential of ivermectin to control the malaria vector 
Anopheles farauti. Trans R Soc Trop Med Hyg. 2000;94(6):625-8. PubMed PMID: 11198644. 
6. 
Fritz ML, Siegert PY, Walker ED, Bayoh MN, Vulule JR, Miller JR. Toxicity of bloodmeals from 
ivermectin-treated cattle to Anopheles gambiae s.l. Ann Trop Med Parasitol. 2009;103(6):539-47. 
PubMed PMID: 19695159. 
7. 
Chaccour C, Lines J, Whitty CJ. Effect of ivermectin on Anopheles gambiae mosquitoes fed on 
humans: the potential of oral insecticides in malaria control. J Infect Dis. 2010;202(1):113-6. PubMed 
PMID: 20482251. 
8. 
Kobylinski KC, Deus KM, Butters MP, Hongyu T, Gray M, da Silva IM, Sylla M, Foy BD. The effect 
of oral anthelmintics on the survivorship and re-feeding frequency of anthropophilic mosquito disease 
vectors. Acta Trop. 2010;116(2):119-26. Epub 2010/06/15. doi: 10.1016/j.actatropica.2010.06.001. 
PubMed PMID: 20540931; PMCID: 2939250. 
9. 
Sylla M, Kobylinski KC, Gray M, Chapman PL, Sarr MD, Rasgon JL, Foy BD. Mass drug 
administration of ivermectin in south-eastern Senegal reduces the survivorship of wild-caught, blood fed 
malaria vectors. Malar J. 2010;9:365. PubMed PMID: 21171970. 
10. 
Butters MP, Kobylinski KC, Deus KM, da Silva IM, Gray M, Sylla M, Foy BD. Comparative 
evaluation of systemic drugs for their effects against Anopheles gambiae. Acta Trop. 2012;121(1):34-43. 
Epub 2011/10/25. doi: 10.1016/j.actatropica.2011.10.007. PubMed PMID: 22019935; PMCID: 3236608. 
11. 
Fritz ML, Walker ED, Miller JR. Lethal and sublethal effects of avermectin/milbemycin 
parasiticides on the African malaria vector, Anopheles arabiensis. J Med Entomol. 2012;49(2):326-31. 
Epub 2012/04/13. PubMed PMID: 22493850. 
12. 
Kobylinski KC, Foy BD, Richardson JH. Ivermectin inhibits the sporogony of Plasmodium 
falciparum in Anopheles gambiae. Malar J. 2012;11:381. Epub 2012/11/23. doi: 10.1186/1475-2875-11-
381. PubMed PMID: 23171202; PMCID: 3519548. 
13. 
Alout H, Krajacich BJ, Meyers JI, Grubaugh ND, Brackney DE, Kobylinski KC, Diclaro JW, 2nd, 
Bolay FK, Fakoli LS, Diabate A, Dabire RK, Bougma RW, Foy BD. Evaluation of ivermectin mass drug 


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DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 2.0, Dated August 10, 2017 
administration for malaria transmission control across different West African environments. Malar J. 
2014;13:417. Epub 2014/11/05. doi: 10.1186/1475-2875-13-417. PubMed PMID: 25363349; PMCID: 
4226880. 
14. 
Kobylinski KC, Sylla M, Chapman PL, Sarr MD, Foy BD. Ivermectin mass drug administration to 
humans disrupts malaria parasite transmission in Senegalese villages. Am J Trop Med Hyg. 2011;85(1):3-
5. Epub 2011/07/08. doi: 10.4269/ajtmh.2011.11-0160. PubMed PMID: 21734116; PMCID: 3122335. 
15. 
Garrett-Jones C, Grab B. The Assessment of Insecticidal Impact on the Malaria Mosquito's 
Vectorial Capacity, from Data on the Proportion of Parous Females. Bull World Health Organ. 
1964;31:71-86. Epub 1964/01/01. PubMed PMID: 14230896; PMCID: 2555159. 
16. 
Trape JF, Tall A, Diagne N, Ndiath O, Ly AB, Faye J, Dieye-Ba F, Roucher C, Bouganali C, Badiane 
A, Sarr FD, Mazenot C, Toure-Balde A, Raoult D, Druilhe P, Mercereau-Puijalon O, Rogier C, Sokhna C. 
Malaria morbidity and pyrethroid resistance after the introduction of insecticide-treated bednets and 
artemisinin-based combination therapies: a longitudinal study. Lancet Infect Dis. 2011. PubMed PMID: 
21856232. 
17. 
Chaccour C, Hammann F, Rabinovich NR. Ivermectin to reduce malaria transmission I. 
Pharmacokinetic and pharmacodynamic considerations regarding efficacy and safety. Malar J. 
2017;16(1):161. doi: 10.1186/s12936-017-1801-4. PubMed PMID: 28434401; PMCID: PMC5402169. 
18. 
Centers for Disease C. Prescription medication 
for the treatment of scabies. 2017 [cited 2017 September]. 
19. 
Duke BO, Zea-Flores G, Castro J, Cupp EW, Munoz B. Effects of multiple monthly doses of 
ivermectin on adult Onchocerca volvulus. Am J Trop Med Hyg. 1990;43(6):657-64. PubMed PMID: 
2267970. 
20. 
Duke BO, Pacque MC, Munoz B, Greene BM, Taylor HR. Viability of adult Onchocerca volvulus 
after six 2-weekly doses of ivermectin. Bull World Health Organ. 1991;69(2):163-8. Epub 1991/01/01. 
PubMed PMID: 1860146; PMCID: 2393085. 
21. 
Duke BO, Zea-Flores G, Castro J, Cupp EW, Munoz B. Effects of three-month doses of ivermectin 
on adult Onchocerca volvulus. Am J Trop Med Hyg. 1992;46(2):189-94. Epub 1992/02/01. PubMed 
PMID: 1539754. 
22. 
Ismail MM, Weil GJ, Jayasinghe KS, Premaratne UN, Abeyewickreme W, Rajaratnam HN, Sheriff 
MH, Perera CS, Dissanaike AS. Prolonged clearance of microfilaraemia in patients with bancroftian 
filariasis after multiple high doses of ivermectin or diethylcarbamazine. Trans R Soc Trop Med Hyg. 
1996;90(6):684-8. PubMed PMID: 9015519. 
23. 
Awadzi K, Attah SK, Addy ET, Opoku NO, Quartey BT. The effects of high-dose ivermectin 
regimens on Onchocerca volvulus in onchocerciasis patients. Trans R Soc Trop Med Hyg. 1999;93(2):189-
94. Epub 1999/08/18. PubMed PMID: 10450448. 
24. 
Kamgno J, Gardon J, Gardon-Wendel N, Demanga N, Duke BO, Boussinesq M. Adverse systemic 
reactions to treatment of onchocerciasis with ivermectin at normal and high doses given annually or 
three-monthly. Trans R Soc Trop Med Hyg. 2004;98(8):496-504. PubMed PMID: 15186939. 


DMID  Protocol 18-0007 
Version 1.3 
RIMDAMAL II 
29 February 2020 
 ________________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH  
 
 
 
 
 
 
 
 
101 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 2.0, Dated August 10, 2017 
25. 
Gardon J, Boussinesq M, Kamgno J, Gardon-Wendel N, Demanga N, Duke BO. Effects of standard 
and high doses of ivermectin on adult worms of Onchocerca volvulus: a randomised controlled trial. 
Lancet. 2002;360(9328):203-10. PubMed PMID: 12133654. 
26. 
Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, Sciberras DG, Hsieh JY, 
Lasseter KC. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy 
adult subjects. J Clin Pharmacol. 2002;42(10):1122-33. PubMed PMID: 12362927. 
27. 
Ouedraogo AL, Bastiaens GJ, Tiono AB, Guelbeogo WM, Kobylinski KC, Ouedraogo A, Barry A, 
Bougouma EC, Nebie I, Ouattara MS, Lanke KH, Fleckenstein L, Sauerwein RW, Slater HC, Churcher TS, 
Sirima SB, Drakeley C, Bousema T. 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. 
28. 
Smit MR, Ochomo EO, Aljayyoussi G, Kwambai TK, Abong'o BO, Chen T, Bousema T, Slater HC, 
Waterhouse D, Bayoh NM, Gimnig JE, Samuels AM, Desai MR, Phillips-Howard PA, Kariuki SK, Wang D, 
Ward SA, Ter Kuile FO. Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered 
with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a 
randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2018. doi: 10.1016/S1473-
3099(18)30163-4. PubMed PMID: 29602751. 
29. 
WHO. Assuring Safety of Preventative Chemotherapy Interventions for the Control of Neglected 
Tropical Diseases. Geneva: World Health Organization, 2011. 
30. 
Organization WH. World Malaria Report 2013. In: Programme WGM, editor. Geneva: WHO 
Press; 2013. 
31. 
Gneme A, Guelbeogo WM, Riehle MM, Tiono AB, Diarra A, Kabre GB, Sagnon N, Vernick KD. 
Plasmodium species occurrence, temporal distribution and interaction in a child-aged population in rural 
Burkina Faso. Malar J. 2013;12:67. Epub 2013/02/21. doi: 10.1186/1475-2875-12-67. PubMed PMID: 
23421809; PMCID: 3583752. 
32. 
Brieger B, Badolo O, Yansaneh A, Waxman R, Roman E. A Documentation of Malaria Program 
Implementation in Burkina Faso: Prepared by the MCHIP/USAID in Collaboration with the National 
Malaria Control Program. Baltimore, Maryland: Jhpiego Corporation; 2013. 
33. 
Tiono AB, Kangoye DT, Rehman AM, Kargougou DG, Kabore Y, Diarra A, Ouedraogo E, Nebie I, 
Ouedraogo A, Okech B, Milligan P, Sirima SB. Malaria incidence in children in South-West Burkina Faso: 
comparison of active and passive case detection methods. PLoS One. 2014;9(1):e86936. Epub 
2014/01/30. doi: 10.1371/journal.pone.0086936. PubMed PMID: 24475198; PMCID: 3901722. 
34. 
Mueller I, Schoepflin S, Smith TA, Benton KL, Bretscher MT, Lin E, Kiniboro B, Zimmerman PA, 
Speed TP, Siba P, Felger I. Force of infection is key to understanding the epidemiology of Plasmodium 
falciparum malaria in Papua New Guinean children. Proc Natl Acad Sci U S A. 2012;109(25):10030-5. 
Epub 2012/06/06. doi: 10.1073/pnas.1200841109. PubMed PMID: 22665809; PMCID: 3382533. 
35. 
Dabire RK, Namountougou M, Diabate A, Soma DD, Bado J, Toe HK, Bass C, Combary P. 
Distribution and frequency of kdr mutations within Anopheles gambiae s.l. populations and first report 
of the ace.1 G119S mutation in Anopheles arabiensis from Burkina Faso (West Africa). PLoS One. 


DMID  Protocol 18-0007 
Version 1.3 
RIMDAMAL II 
29 February 2020 
 ________________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH  
 
 
 
 
 
 
 
 
102 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 2.0, Dated August 10, 2017 
2014;9(7):e101484. Epub 2014/08/01. doi: 10.1371/journal.pone.0101484. PubMed PMID: 25077792; 
PMCID: 4117487. 
36. 
Mapper I. 2017. Available from: www.irmapper.com. 
37. 
Barry A, Issiaka D, Traore T, Mahamar A, Diarra B, Sagara I, Kone D, Doumbo OK, Duffy P, Fried 
M, Dicko A. Optimal mode for delivery of seasonal malaria chemoprevention in Ouelessebougou, Mali: A 
cluster randomized trial. PLoS One. 2018;13(3):e0193296. doi: 10.1371/journal.pone.0193296. PubMed 
PMID: 29505578; PMCID: PMC5837084. 
38. 
Brown KR. Changes in the use profile of Mectizan: 1987-1997. Ann Trop Med Parasitol. 1998;92 
Suppl 1:S61-4. Epub 1998/12/23. PubMed PMID: 9861268. 
39. 
De Sole G, Remme J, Awadzi K, Accorsi S, Alley ES, Ba O, Dadzie KY, Giese J, Karam M, Keita FM. 
Adverse reactions after large-scale treatment of onchocerciasis with ivermectin: combined results from 
eight community trials. Bull World Health Organ. 1989;67(6):707-19. PubMed PMID: 2633886; PMCID: 
PMC2491300. 
40. 
Chandler RE. Serious Neurological Adverse Events after Ivermectin-Do They Occur beyond the 
Indication of Onchocerciasis? Am J Trop Med Hyg. 2018;98(2):382-8. doi: 10.4269/ajtmh.17-0042. 
PubMed PMID: 29210346; PMCID: PMC5929173. 
41. 
Wilkins AL, Steer AC, Cranswick N, Gwee A. Question 1: Is it safe to use ivermectin in children 
less than five years of age and weighing less than 15 kg? Arch Dis Child. 2018;103(5):514-9. doi: 
10.1136/archdischild-2017-314505. PubMed PMID: 29463522. 
42. 
Awadzi K, Opoku NO, Addy ET, Quartey BT. The chemotherapy of onchocerciasis. XIX: The 
clinical and laboratory tolerance of high dose ivermectin. Trop Med Parasitol. 1995;46(2):131-7. PubMed 
PMID: 8525285. 
43. 
Fobi G, Gardon J, Kamgno J, Aimard-Favennec L, Lafleur C, Gardon-Wendel N, Duke BO, 
Boussinesq M. A randomized, double-blind, controlled trial of the effects of ivermectin at normal and 
high doses, given annually or three-monthly, against Onchocerca volvulus: ophthalmological results. 
Trans R Soc Trop Med Hyg. 2005;99(4):279-89. PubMed PMID: 15708387. 
44. 
Slater HC, Walker PG, Bousema T, Okell LC, Ghani AC. The Potential Impact of Adding Ivermectin 
to a Mass Treatment Intervention to Reduce Malaria Transmission: a Modelling Study. J Infect Dis. 2014. 
Epub 2014/06/22. doi: 10.1093/infdis/jiu351. PubMed PMID: 24951826. 
45. 
Foy BD, Kobylinski KC, da Silva IM, Rasgon JL, Sylla M. Endectocides for malaria control. Trends 
Parasitol. 2011;27(10):423-8. Epub 2011/07/06. doi: 10.1016/j.pt.2011.05.007. PubMed PMID: 
21727027; PMCID: 3178713. 
46. 
da Cruz FP, Martin C, Buchholz K, Lafuente-Monasterio MJ, Rodrigues T, Sonnichsen B, Moreira 
R, Gamo FJ, Marti M, Mota MM, Hannus M, Prudencio M. Drug screen targeted at Plasmodium liver 
stages identifies a potent multistage antimalarial drug. J Infect Dis. 2012;205(8):1278-86. doi: 
10.1093/infdis/jis184. PubMed PMID: 22396598; PMCID: PMC3308910. 
47. 
Mendes AM, Albuquerque IS, Machado M, Pissarra J, Meireles P, Prudencio M. Inhibition of 
Plasmodium liver infection by ivermectin. Antimicrob Agents Chemother. 2016. doi: 
10.1128/AAC.02005-16. PubMed PMID: 27895022. 


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Version 1.3 
RIMDAMAL II 
29 February 2020 
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DMID/NIAID/NIH  
 
 
 
 
 
 
 
 
103 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 2.0, Dated August 10, 2017 
48. 
Smit MR, Ochomo E, Aljayyoussi G, Kwambai T, Abong'o B, Bayoh N, Gimnig J, Samuels A, Desai 
M, Phillips-Howard PA, Kariuki S, Wang D, Ward S, Ter Kuile FO. Efficacy and Safety of High-Dose 
Ivermectin for Reducing Malaria Transmission (IVERMAL): Protocol for a Double-Blind, Randomized, 
Placebo-Controlled, Dose-Finding Trial in Western Kenya. JMIR Res Protoc. 2016;5(4):e213. doi: 
10.2196/resprot.6617. PubMed PMID: 27856406; PMCID: PMC5133431. 
49. 
Hayes RJ, Bennett S. Simple sample size calculation for cluster-randomized trials. Int J Epidemiol. 
1999;28(2):319-26. PubMed PMID: 10342698. 
50. 
Tiono AB, Ouedraogo A, Ogutu B, Diarra A, Coulibaly S, Gansane A, Sirima SB, O'Neil G, 
Mukhopadhyay A, Hamed K. A controlled, parallel, cluster-randomized trial of community-wide 
screening and treatment of asymptomatic carriers of Plasmodium falciparum in Burkina Faso. Malar J. 
2013;12:79. doi: 10.1186/1475-2875-12-79. PubMed PMID: 23442748; PMCID: PMC3599538. 
 

SAP_001.pdf: 
 
Statistical Analysis Plan 
Repeat Ivermectin Mass Drug Administrations for MALaria Control II 
(RIMDAMAL II): a double-blind, cluster-randomized control trial for 
integrated control of malaria. 
DMID Protocol Number: 18-0007 
DMID Funding Mechanism: U01 AI138910-01 
Pharmaceutical Support Provided by: Laboratorio Elea (or other) 
Lead Principal Investigator: Brian D. Foy, PhD 
DMID Clinical Project Manager: Walt Jones, RN, MPH 
DMID Medical Officer: Greg Deye, MD 
DMID Medical Monitor: Venus Shahamatdar, M.D. 
Draft or Version Number: v. 1.4 
Day Month Year: October 17, 2022 
 
 
 
 
 


Statistical Analysis Plan 
RIMDAMAL II Trial 
 
1. OVERVIEW OF THE STATISTICAL DESIGN FOR RIMDAMAL II 
 
1.1 Design overview:  RIMDAMAL II is a double-blind cluster randomized controlled trial of 
repeated ivermectin (IVM) mass drug administration (MDA) in addition to standard malaria 
control (SMC) for integrated control of malaria. The primary hypothesis is that repeated IVM 
MDAs coinciding with SMC rounds and distribution of long-lasting insecticidal nets (the 
intervention) will significantly reduce the cumulative incidence of malaria in children ≤ 10 years 
of age compared to SMC and long-lasting insecticidal nets (LLIN) alone. The primary objective 
is to determine the efficacy of adding seasonal ivermectin mass drug administrations (IVM 
MDA) to the standard-policy malaria control measures in the Sahel (SMC in children, LLIN 
coverage, IPTp in pregnant women), for reducing the incidence of uncomplicated malaria 
episodes in enrolled village children (≤ 10 years of age) assessed by active case surveillance. 
IVM or placebo MDA will be given monthly over 4 months of the rainy season to the eligible 
village population, each as 3-day course of 300 µg/kg/day for two consecutive years.  
 
1.2 Study population: The RIMDAMAL II study population is comprised of fourteen spatially-
delineated villages in southwest Burkina Faso, equally divided between placebo and IVM. 
Villagers are indigenous Burkinabé from various ethnic groups, most of whom farm and rear 
livestock. The village population sizes range between approximately 150-450 people with 
approximately 100 children between 0-10 years old in each village. 
 
1.3 Sample size and power: The primary endpoint for the trial is the incidence rate of malaria 
episodes in children ≤10 years of age as assessed by active case surveillance by study nurses 
with weekly visits to each child, starting at the first round of MDA and continuing for 4 months in 
year 1 (1 month after MDA #4), and continuing for another 4 months in year 2 (starting with 
MDA #5 and ceasing 1 month after MDA #8). The sample size and power for RIMDAMAL II is 
based on data from our previous trial (RIMDAMAL) and another published trial, IVERMAL. 
Calculations assume seasonal incidence rates (per year) of approximately 1.088 and 0.619 in 
the control and intervention arms, respectively, thus corresponding to an incidence rate ratio of 
0.619/1.088 = 0.569 (i.e., an incidence rate reduction of 0.431). The initial sample size 
evaluation shows that RIMDAMAL II has 80% power with 6 villages per arm and 48 children per 
cluster assuming that the coefficient of variation between clusters is approximately 0.258. 
During trial initiation, sample size was increased from 12 to 14 villages (7 per arm) with 
approximately 100 children per village/cluster. The larger sample size provides over 90% power 
in the detailed simulation studies of the statistical models that were considered for the primary 
analysis of trial results (Jackson, et al. Trials 2021). 
 
2. ANALYSIS PLAN 
 
2.1 Primary analysis 
The primary outcome will be analyzed as intention-to-treat (ITT). The number of episodes per 
week among the active case detection (ACD) cohort (children age ≤ 10 years) will be used as 
the primary measurable outcome to evaluate the impact of the intervention when compared to 
the control arm. The active case detection cohort includes all enrolled children regardless of 


eligibility or receipt of MDA or SMC. A mixed effects regression analysis with Poisson 
distribution will be used to assess the impact. The primary analysis will include a random effect 
for cluster (village), and 3 fixed effects (treatment effect, year, and sex; all binary covariates, no 
interactions evaluated). Subgroup analyses will include an evaluation of fixed effects such as 
LLIN use, age, and treatment with SMC or IVM. Estimates for the intervention effect from the 
primary analysis as well as subgroup analyses will be reported along with 95% confidence 
intervals. The statistical program SAS v9.4 (SAS Institute Inc., Cary, NC) will be used for 
primary statistical analyses. Secondary data generated from Aim 1 will include adverse events 
(AE), severe adverse events (SAE), and their relationship to the intervention/placebo. The risk 
of SAE and AE will be compared between intervention and control arms by calculating risks 
ratios and attributable risks with 95% confidence intervals. 
 
2.1.1 Definition of analysis populations 
Primary incidence analysis – We will use ITT analysis method for our prospective randomized 
trial and the population for the primary incidence outcome will be all enrolled children aged 10 
years and younger.  
Secondary safety analysis – Safety is being assessed with active and passive surveillance of all 
enrolled study participants, regardless of age. AEs will be further categorized by their 
relationship to the intervention and as SAEs based on their severity. 
2.1.2 Definition of primary efficacy endpoint 
A malaria episode is defined as the presence of a temperature of ≥37·5°C and/or history of 
fever in the last 24 hours, along with a positive rapid diagnostic test (RDT) for Plasmodium 
species (any species). 
 
A participant’s time-at-risk will be considered as censored for 14 days following a diagnosis and 
treatment of malaria due to the impacts of treatment on risk of recurrent malaria. Person time 
will be defined in 7-day consecutive intervals, with one or more visits occurring during this time 
considered as an eligible person-week.  
 
Eligibility for MDA is determined at the beginning of each intervention season and is retained for 
the remainder of that season.  
• 
Newborns are eligible for inclusion and will be considered exposed beginning at the time 
of their 1st ACD visit.   
• 
Children who turn 11 years of age during an intervention season will remain eligible for 
the ACD cohort for the remainder of that season.  
• 
If a participant ages out of ACD cohort in the first season, they will not be eligible for the 
ACD cohort in the second season.  
• 
Eligibility for SMC is determined by the MoH community workers, not by the RIMDAMAL 
II study team. Participants may age out of SMC (>59 months) in the 1st season and 
become eligible for MDA (≥90 cm and >59 months) in the second season. They will not 
become eligible for MDA during the season where this occurred. 
 
2.1.3 Analysis methods for primary endpoint 
Primary efficacy analysis: 
• 
Intention-to-treat analyses will include the assigned treatment arms and results from all 
clusters. Incidence rates will be determined using a Poisson regression that models 


counts of malaria episodes and includes an offset that accounts for log person-weeks. 
This yields a malaria rate per week per child per rainy season for intervention and 
control villages (averaged across year 1 and 2).  
• 
The estimate for the primary analysis is the exponentiated beta coefficient for the 
treatment covariate across both seasons. This rate ratio corresponds to the difference 
in rates between treatment and control villages.  
• 
Statistical Model: 
 
The model below shows the outcome (malaria episodes), a coefficient for 
treatment group (intervention vs control), a coefficient for year (rainy season 1 vs 
rainy season 2), a coefficient for sex, an offset term to account for person-weeks, 
and a random effect to account for clustering at the village level.  
 
• 
Detailed simulation studies were used to determine the appropriate analysis procedure for 
this trial (Jackson, et al. Trials 2021)  
• 
Software: 
 
SAS v9.4 (SAS Institute Inc., Cary, NC) will be used for the primary statistical 
analyses.  
 
A Kenward Roger degrees of freedom correction will be applied to account for the 
limited number of clusters 
 
Code Example: 
proc glimmix data=WORK.DataExample; 
class Village_code Treatment YEAR Sex; 
Model Episodes = Treatment  Year Sex/ s dist=Poisson ddfm=kr offset = 
lnPersonWeeks; 
Random  INT / subject= Village_code; 
Run; 
 
 
2.2 Secondary endpoints 
2.2.1 Adverse events analysis: Safety is a secondary endpoint and will be assessed by 
relative risk (RR).  
a. Groups 
i. 
All participants will be followed actively and passively for adverse 
events and the Risk Ratios (RR) of AEs in those in the intervention 
versus control clusters will be compared. 
ii. 
Active Case Detection Cohort  


1. SMC-treated children only – children age 3-59 months who 
receive SMC. RR of AEs in children who receive SMC and live in 
IVM-treated clusters versus those who receive SMC and live in 
placebo-treated clusters  
2. IVM/placebo-treated only – children ≥90cm and eligible for 
MDA/placebo. RR of AEs in those children receiving MDA versus 
those receiving placebo. 
iii. 
Non-ACD participants that were enrolled in the study were actively 
followed in the study on the days of study intervention through 24-hours 
post study intervention, and then passively for the rest of the MDA round. 
 
b. Type – AEs will be further classified by seriousness, severity, relationship to the 
intervention, outcome, and organ system.  
i. 
Classification (AE, SAE, etc) 
 
Adverse Event: (ICH) E6 defines an AE as any untoward medical 
occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product regardless of its causal relationship to the study 
treatment. FDA defines an AE as any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered 
drug related. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal product. 
 
Serious AE (SAE): An AE is considered “serious” if, in the view of either 
the site principal investigator or sponsor, it results in any of the following 
outcomes: 
1. Death, 
2. A life-threatening AE: An AE is considered “life-threatening” if, in 
the view of either the site principal investigator or sponsor, its 
occurrence places the patient or subject at immediate risk of 
death. It does not include an AE that, had it occurred in a more 
severe form, might have caused death. 
3. Inpatient hospitalization or prolongation of existing hospitalization, 
4. A persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions, or 
5. A congenital anomaly/birth defect. 
6. Important medical events that may not result in death, be life-
threatening, or require hospitalizations may be considered serious 
when, based upon appropriate medical judgment they may 
jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic 
reaction requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency 
or drug abuse. 


 
ii. 
Severity (grade) 
• 
Grade 1 (mild) 
• 
Grade 2 (moderate) 
• 
Grade 3 (severe) 
• 
Grade 4 (potentially life-threatening) 
• 
Grade 5 (death) 
 
iii. 
Outcome 
• 
recovered/resolved without sequelae (grade for the event 
returned to <2) 
• 
recovering/resolving (grade for event is decreasing and not 
greater than 2) 
• 
not recovered/not resolving (adverse event still present but 
stable) 
• 
recovered/resolved with sequelae (grade for the event returned to 
<2, however some pathological condition resulting from a 
disease, injury, or other trauma) 
• 
Death 
• 
unknown (example for using this code is when a participant is lost 
to follow up and outcome cannot be determined) 
 
iv. 
By body system and preferred term - using MedDRA coding (27 
groups) 
 
2.2.2 Parasitological secondary endpoints and analysis. 
 
The following are key secondary parasitological endpoints, and the method of analysis 
will depend on the type of data collected: 
• 
Parasite prevalence. Parasite prevalence of Plasmodium falciparum will be assessed 
either by: 
• 
molecular assay (PCR-based off of filter paper from capillary finger-prick 
samples). Filter paper samples are obtained at the beginning and end of 
each intervention season, and monthly, prior to each MDA in the ACD 
cohort. In addition, filter paper was obtained in the entire cohort at the 
beginning and end of the 2020 intervention season.  
• 
blood smear (only for ACD children at the time of diagnosed malaria 
infection by RDT) 
• 
Multiplicity of infection (MOI, also sometimes referred to as complexity of infection 
(COI). This is defined as the number of unique clones per individual at the time of 
diagnosis of malaria infection (count data). It is based either on microsatellite typing 
or amplicon sequencing 
• 
Molecular force of infection (mFOI; also sometimes further subclassified as molFOB 
(molecular force of blood stage infection). Defined as the number of new 
Plasmodium clones acquired over time (count data). Will be determined using 
monthly filter paper samples in ACD children only.  
 


An approach consistent with the primary analysis will be adopted here with both unadjusted and 
adjusted regression models. For parasite prevalence, a binomial regression model will be used, 
and for MOI and mFOI, Poisson and Negative Binomial regression model will be used, with the 
final model choice being indicated by the distribution of the dependent variable.  
 
 
2.2.3 Entomological secondary endpoints and analysis 
 
The tests used will depend on the type of data collected (e.g., survivorship of blood fed 
mosquitoes in each arm per collection interval, proportion of mosquitoes parous/arm per 
collection interval, etc…) The following are key secondary entomological outcomes. 
 
• 
Human biting rate (HBR). This is defined as the number of mosquitoes captured per 
person per time period. For aspirated, indoor resting, blood fed mosquitoes, the HBR 
is calculated by dividing the house or household catch by the number of humans 
living in that house or household. For host-seeking mosquitoes caught in light traps 
placed next to individual persons sleeping in tents (outdoors) or under bednets 
(indoors), the HBR is simply the catch number per 1 person. 
o This will be compared between intervention and control arms and further 
analyzed by mosquito species (An. gambiae s.l [or An. gambiae s.s., An. coluzzi, 
An. arabiensis]; An. funestus)  
 
Indoor blood fed HBR 
 
Indoor host-seeking HBR 
 
Outdoor host-seeking HBR 
 
Total HBR 
• 
Sporozoite rate. A representative proportion of mosquitoes captured per time period 
and per mosquito species will be tested for prevalence of infection with Plasmodium 
sporozoites by genetic testing of their heads+thoracies. 
o This will be compared between intervention and control arms and analyzed in 
total. 
o This will also be analyzed by identified Plasmodium species: P. falciparum, P. 
ovale, P. malariae, or P. vivax. 
• 
Changes in participants’ antibody responses to Anopheles saliva protein(s). 
Antibodies will be eluted from filter paper samples containing a representative 
proportion of participants’ capillary finger-prick blood that were collected at the 
beginning and end of each intervention season. Paired sets antibodies from 
individual participants (beginning and end of season collections) will then be tested 
for binding to Anopheles saliva protein(s), the binding change per person calculated, 
and then these data compared between participants from the intervention and control 
arms. 
• 
The survival rate of blood fed mosquitoes. These blood fed mosquitoes were 
collected per time period, brought back to the field insectary and held for 3 days to 
measure their survivorship over that time. Survivorship will be compared between 
intervention and control arms and analyzed by time period captured, by mosquito 
species, and by location in clusters where they were captured.  
 
These data (except for survival rate, see below) will also be used to make generalized 
linear and non-linear mixed effects models in R and SAS to understand the functional 
relationships of measured entomological and parasitological variables and the relative 


contributions of various independent variables on variation in the dependent variable. 
Final model choices will be indicated by the distribution of the dependent variable as well 
as assessments for the need to model an additional parameter to account for variability 
in the data (e.g., Poisson vs Negative Binomial). The survival rate of blood fed 
mosquitoes will be analyzed using a log-rank test and visualized using a Kaplan Meier 
curve.  
 
2.2.4 Missing data 
 
Missed weekly ACD visits will be accounted for by using person-weeks at-risk. If an ACD 
child does not have a documented visit during a 7-day period, this will be considered a 
missed person-week at-risk. Missed visits may be due to the child not being present 
(school, travel, etc..), refusal, or incomplete data entry in the REDCap instrument. 
Participants can enter the cohort and exit the cohort as described in 2.1.2, and this will 
be accounted for using person-time at-risk as well. 
 
2.3 Tertiary and exploratory analyses 
 
2.3.1 Tertiary clinical/parasitological endpoints 
2.3.1.1 Drug resistance mutations – The prevalence of parasite mutations associated with 
reduced susceptibility to antimalarials used both for treatment and prevention will be 
compared between intervention and control arms. These include mutations in 
transporters Pfcrt, Pfmdr1, and antifolate pathways (DHFR and DHPS). 
2.3.1.2 Prevalence of anemia- IVM may improve anemia by reducing malaria and/or soil-
transmitted helminths in the intervention populace. Changes in the prevalence of anemia 
will be compared between 1) ACD children in the intervention and control villages; 2) 
individuals in cross-sectional HHs in the intervention and control villages. 
 
 
2.3.2 Tertiary entomological endpoints 
2.3.2.1 Measures of insecticide resistance- Changes in mosquito phenotypic susceptibility to 
standard insecticides will be analyzed between times this was tested at the study site  
and related to the prevalence of mosquito SNPs (or quantity of gene transcripts) that 
correlate with known, genetic insecticide resistance markers.  
2.3.2.2 Age structure of the mosquito population over time- This will be defined as the estimated 
median age of the adult female An. gambiae s.l. population per unit time or the 
proportions estimated in certain age classes per unit time. Estimates will be done with 
traditional and novel age grading techniques.  
 
2.3.3 Subgroup analysis 
2.3.3.1 SMC-treated children only – incidence will be compared between those children who 
received SMC only (age 3-59 months) 
2.3.3.2 IVM/placebo-treated children only – incidence will be compared between those children 
who received MDA/placebo only (≥90 cm and ≤10 y/o) 
 
 
Other notes regarding covariates/effects to consider: 
• 
Analyze the IRs by cluster and arm over short time periods (by week) for each season - 
using regression approaches 


• 
Malaria transmission intensity naturally varies over each season due to changing 
weather and mosquito vector species and densities and changing human 
immunity. 
• 
Each of the 4 ivermectin MDAs per season acts like a “pulse” of insecticidal 
blood that starts high and then the mosquito-killing efficacy wanes over time as 
the ivermectin is eliminated from treated persons’ blood. We estimate the 
mosquito killing activity lasts for 2-3 weeks but is highest in the week after the 
MDA is given. On top of this, there would be a time delay, as the killing would 
reduce biting, and then a week to 2 later, the numbers of parasitemic individuals 
would decrease 
• 
Spatial effects between and within clusters 
• 
The incidence difference based on child/ HH location in cluster – inner vs. outer 
edge of the cluster 
• 
Differences based on the density of non-study populations nearby (within several 
km of the cluster boundaries)  
• 
Random effect within HHs in clusters (due to HH size, proportion of males to females in 
a HH, age proportion in a HH proportion, HH members treated and/or treated over time) 
 
3. PLANNED TABLES, FIGURES, LISTINGS 
Manuscript Tables: 
1. Participant characteristics 
2. Primary efficacy analyses 
3. Adverse events 
4. Subgroup analysis of malaria risk 
 
Manuscript Figures: 
1. CONSORT diagram 
2. Map of study area 
3. Rainfall and weekly malaria incidence 
 
Supplementary appendix tables: 
• 
S2.1: Percentage reduction in clinical incidence during the trial period 
• 
S3.1: Risk in epidemiological strata 
• 
S3.2: Exploratory analysis of the frequency of malaria episodes per child in each group  
 
Figures: Supplementary appendix 
• 
S1.1: Map of study area 
• 
S2.1: Estimated reduction in clinical incidence 
• 
S3.1: Flow diagram for all RIMDAMAL participants with respect to MDA participation 
and AE analysis. 
• 
S3.2: Weekly malaria incidence per person-year in the RIMDAMAL study cohort 
children plotted over the study period. 
 
Supplementary appendix Listing: 


• 
S4.1: Descriptions of reported adverse events (AE) in RIMDAMAL villages (excluding 
uncomplicated malaria recorded from the child cohort.  
• 
S4.2: Summary of deaths during intervention season 
 
Additional figures/tables: 
• 
Seasonality: Risk by month with rainfall  
• 
Interaction of Interceptor G2 bed net distribution by cluster/HH/individual (only in 2020) 
• 
Interaction of proportion of people treated per cluster and over time. 
• 
MOI 
• 
mFOI 
• 
anemia 
• 
entomology outcome figures 
 
 
 


4. LITERATURE INFORMING THIS SAP   
• 
Foy BD, Alout H, Seaman JA, Rao S, Magalhaes T, Wade M, Parikh S, Soma DD, 
Sagna AB, Fournet F, Slater HC, Bougma R, Drabo F, Diabaté A, Coulidiaty AGV, 
Rouamba N, Dabiré RK. Efficacy and risk of harms of repeat ivermectin mass drug 
administrations for control of malaria (RIMDAMAL): a cluster-randomised trial. Lancet. 
2019 Apr 13;393(10180):1517-1526. doi: 10.1016/S0140-6736(18)32321-3. Epub 2019 
Mar 14. PubMed PMID: 30878222; PubMed Central PMCID: PMC6459982. 
• 
Lengeler C. Insecticide-treated bed nets and curtains for preventing malaria. The 
Cochrane database of systematic reviews. 2004(2):CD000363. Epub 2004/04/24. doi: 
10.1002/14651858.CD000363.pub2. PubMed PMID: 15106149. 
• 
Griffin JT, Hollingsworth TD, Okell LC, Churcher TS, White M, Hinsley W, Bousema T, 
Drakeley CJ, Ferguson NM, Basanez MG, Ghani AC. Reducing Plasmodium falciparum 
malaria transmission in Africa: a model-based evaluation of intervention strategies. PLoS 
Med. 2010;7(8). doi: 10.1371/journal.pmed.1000324. PubMed PMID: 20711482; PMCID: 
PMC2919425. 
• 
Griffin JT, Bhatt S, Sinka ME, Gething PW, Lynch M, Patouillard E, Shutes E, Newman 
RD, Alonso P, Cibulskis RE, Ghani AC. Potential for reduction of burden and local 
elimination of malaria by reducing Plasmodium falciparum malaria transmission: a 
mathematical modelling study. Lancet Infect Dis. 2016;16(4):465-72. doi: 
10.1016/S1473-3099(15)00423-5. PubMed PMID: 26809816; PMCID: PMC5206792. 
• 
Slater HC, Walker PG, Bousema T, Okell LC, Ghani AC. The Potential Impact of Adding 
Ivermectin to a Mass Treatment Intervention to Reduce Malaria Transmission: a Modelling 
Study. J Infect Dis. 2014. Epub 2014/06/22. doi: 10.1093/infdis/jiu351. PubMed PMID: 
24951826. 
• 
Hayes RJ, Bennett S. Simple sample size calculation for cluster-randomized trials. Int J 
Epidemiol. 1999;28(2):319-26. PubMed PMID: 10342698. 
• 
Tiono AB, Ouedraogo A, Ogutu B, Diarra A, Coulibaly S, Gansane A, Sirima SB, O'Neil 
G, Mukhopadhyay A, Hamed K. A controlled, parallel, cluster-randomized trial of 
community-wide screening and treatment of asymptomatic carriers of Plasmodium 
falciparum in Burkina Faso. Malar J. 2013;12:79. doi: 10.1186/1475-2875-12-79. PubMed 
PMID: 23442748; PMCID: PMC3599538. 
• 
Jackson CL, Colborn K, Gao D, Rao S, Slater HC, Parikh S, Foy BD, Kittelson J. Design 
and analysis of a 2-year parallel follow-up of repeated ivermectin mass drug 
administrations for control of malaria: Small sample considerations for cluster-randomized 
trials 
with 
count 
data. 
Clin 
Trials. 
2021 
Oct;18(5):582-593. 
doi: 
10.1177/17407745211028581. 
Epub 
2021 
Jul 
3. 
PMID: 
34218684; 
PMCID: 
PMC8478782. 
 
 
 
 
 


5. APPENDIX: FUTURE WORK TO BE CONSIDERED 
1. Pharmacokinetic/dynamic parameters 
a. Impact of age on IVM PK 
b. Evaluation of IVM metabolites 
c. Relationship of IVM PK with blood-feeding results done at CSU 
d. Safety of IVM (clinical, hematology, chemistry) 
e. Comparison on capillary and venous measurements of IVM 
2. Parasite data 
a. Parasitemia [Count data] – done by quantitative PCR – compare (log10) 
distributions in populations between arms 
i. SMC-treated only 
ii. IVM/placebo-treated only 
iii. all cohort 
b. Multiplicity of Infection (MOI) per episode or sampling timepoint and molecular 
Force of Infection (mFOI) per child [Count data] – done by either genotyping 
microsatellites or amplicon deep sequencing 
i. Regression analysis with Poisson distribution, in an unadjusted analysis 
followed by an adjusted analysis taking into account the random effects of 
the cluster (village) and household and fixed effects such as sex, LLIN 
use, age, and treatment with SMC or IVM.  
3. Entomology data  
a. Survivorship bioassays of blood fed mosquitoes [Survival assays] 
i. Consider time variable  
b. Catch density [count data] 
i. Consider time variable  
c. Age structure 
i. Age distribution of mosquitoes in Intervention vs. Control clusters 
ii. Proportion of mosquitoes caught over an age cut-off (>10 days) 
1. Consider time variable   
d. Proportion of mosquito blood meals taken from humans vs other animals  
i. Consider time variable  
e. Proportion of mosquitoes with sporozoites  
i. Consider time variable  
f. Entomological inoculation rates (human biting proportion x sporozoite rate) 
i. Consider time variable 
4. Other studies 
a. Impact of IVM on the prevalence of drug and insecticide resistance 
b. Impact of IVM on all-cause anemia in children 
c. Household survey – association of household factors and vector density