Exposure-Response Evaluation of IV Artesunate in Children With Severe Malaria
Phase: PHASE4
Conditions: Plasmodium Falciparum Infection
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

DMID Protocol 19-0007 
Version 6.0 
IV Artesunate in Children with Severe Malaria 
23 Aug 2023 
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Exposure-Response Evaluation of IV Artesunate in Children with 
Severe Malaria 
DMID Protocol Number: 19-0007  
 
DMID Funding Mechanism: VTEU Contract HHSN2722013000221;  NIH UM1AI148689 
Principal Investigator: Matthew B. Laurens, MD, MPH 
Site Principal Investigator: Pauline Byakika-Kibwika, MSc, MMed, PhD 
DMID Clinical Protocol Manager: Ranjodh S. Gill, RN, MPH 
 
Draft or Version Number: 6.0 
23 Aug 2023 
 
 

DMID Protocol 19-0007 
Version 6.0 
IV Artesunate in Children with Severe Malaria 
23 Aug 2023 
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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following (use applicable regulations depending on study location and sponsor requirements; 
samples follow): 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46; 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) 
• 
International Council for Harmonisation (ICH) E6; 62 Federal Register 25691 (1997)  
• 
National Institutes of Health (NIH) Clinical Terms of Award 
• 
Uganda National Council for Science and Technology (UNCST) Guidelines 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 
 
 
 
 

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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
Site Principal Investigator: 
 
Signed: 
 
Date: 
 
 
Pauline Byakika-Kibwika, MBChB, MSc, MMed, PhD 
Professor of Medicine 
 
 
 
 
Principal 
Investigator: 
 
 
 
 
Signed: 
 
Date: 
 
 
Matthew B. Laurens, MD, MPH 
Professor of Pediatrics and of Medicine 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
Statement of Compliance .................................................................................................................2 
Signature Page .................................................................................................................................3 
Table of Contents .............................................................................................................................4 
List of Tables ...................................................................................................................................7 
List of Figures ..................................................................................................................................8 
List of Abbreviations .......................................................................................................................9 
Protocol Summary .........................................................................................................................11 
1 
Key Roles ..............................................................................................................................15 
2 
Background Information and Scientific Rationale ...............................................................17 
2.1 
Background Information ...........................................................................................17 
2.2 
Rationale ...................................................................................................................19 
2.3 
Potential Risks and Benefits .....................................................................................20 
2.3.1 Potential Risks ..............................................................................................20 
2.3.2 Known Potential Benefits .............................................................................21 
3 
Objectives .............................................................................................................................22 
3.1 
Study Objectives & Outcome Measures ...................................................................22 
3.1.1 Primary Study Objective ...............................................................................22 
3.1.2 Secondary Study Objectives .........................................................................22 
3.1.3 Exploratory Study Objectives .......................................................................22 
4 
Study Design .........................................................................................................................24 
5 
Study Enrollment and Withdrawal........................................................................................27 
5.1 
Site Description .........................................................................................................27 
5.2 
Subject Inclusion Criteria .........................................................................................28 
5.3 
Subject Exclusion Criteria ........................................................................................28 
5.4 
Treatment Procedures ...............................................................................................28 
5.4.1 Reasons for Withdrawal ................................................................................28 
5.4.2 Handling of Withdrawals ..............................................................................28 
5.4.3 Termination of Study ....................................................................................29 
6 
Study Intervention/Investigational Product ..........................................................................30 
6.1 
Study Product Description ........................................................................................30 
6.1.1 Acquisition ....................................................................................................30 
6.1.2 Formulation, Packaging, and Labeling .........................................................30 
6.1.3 Product Storage and Stability........................................................................31 
6.2 
Dosage, Preparation and Administration of Study Intervention/Investigational 
Product ......................................................................................................................31 
6.3 
Modification of Study Intervention/Investigational Product for a Participant .........31 

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6.4 
Accountability Procedures for the Study Supply of IV Artesunate ..........................31 
6.5 
Concomitant Medications/Treatments ......................................................................32 
7 
Study Schedule......................................................................................................................33 
7.1 
Screening...................................................................................................................33 
7.2 
Enrollment/Baseline ..................................................................................................34 
7.3 
Follow-up ..................................................................................................................34 
7.4 
Final Study Visit .......................................................................................................34 
7.5 
Early Termination Visit ............................................................................................35 
7.6 
Unscheduled Visit .....................................................................................................35 
8 
Study Procedures/Evaluations ..............................................................................................36 
8.1 
Daily Study Procedures.............................................................................................36 
8.2 
Clinical Evaluations ..................................................................................................41 
8.2.1 Neurodevelopmental Assessments................................................................41 
8.3 
Laboratory Evaluations .............................................................................................41 
8.3.1 Clinical Laboratory Evaluations ...................................................................41 
8.3.2 Special Assays or Procedures .......................................................................43 
8.3.3 Specimen Preparation, Handling, and Shipping ...........................................43 
9 
Assessment of Safety ............................................................................................................45 
9.1 
Specification of Safety Parameters ...........................................................................45 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters .................................................................................................................45 
9.2.1 Adverse Events .............................................................................................45 
9.2.2 Serious Adverse Events ................................................................................46 
9.3 
Reporting Procedures ................................................................................................47 
9.3.1 Serious Adverse Events ................................................................................47 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events .........................48 
9.5 
Halting Rules ............................................................................................................48 
9.6 
Safety Oversight (ISM) .............................................................................................48 
10 
Clinical Monitoring ...............................................................................................................50 
10.1 
Site Monitoring Plan .................................................................................................50 
11 
Statistical Considerations ......................................................................................................51 
11.1 
Study Hypothesis ......................................................................................................51 
11.2 
Sample Size Considerations ......................................................................................51 
11.3 
Final Analysis Plan ...................................................................................................53 
11.3.1 Analysis of Demographics and Baseline Characteristics ..............................53 
11.3.2 Analysis of Safety .........................................................................................53 
11.3.3 Clinical Laboratory Parameters ....................................................................53 
11.3.4 Analysis of Pharmacokinetics of Dihydroartemisinin ..................................53 

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11.3.5 Analysis of Pharmacodynamics of Dihydroartemisinin ...............................54 
11.3.6 Missing Data .................................................................................................56 
11.4 
Study Cohorts/Datasets to be Evaluated ...................................................................56 
12 
Source Documents and Access to Source Data/Documents .................................................57 
13 
Quality Control and Quality Assurance ................................................................................58 
14 
Ethics/Protection of Human Subjects ...................................................................................59 
14.1 
Ethical Standard ........................................................................................................59 
14.2 
Institutional Review Board .......................................................................................59 
14.3 
Informed Consent/Assent Process ............................................................................59 
14.3.1 Screening and Study Informed Consent/Assent ...........................................60 
14.3.2 Compensation and Reimbursement ..............................................................61 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) ....................61 
14.5 
Subject Confidentiality .............................................................................................61 
14.6 
Study Discontinuation ...............................................................................................62 
14.7 
Future Use .................................................................................................................62 
14.7.1 PAXgene Collection for Transcriptomics Assessments ...............................62 
14.7.2 Use of Stored Specimens ..............................................................................62 
15 
Data Handling and Record Keeping .....................................................................................63 
15.1 
Data Management Responsibilities...........................................................................63 
15.2 
Data Capture Methods ..............................................................................................64 
15.3 
Types of Data ............................................................................................................64 
15.4 
Timing/Reports .........................................................................................................64 
15.5 
Study Records Retention...........................................................................................64 
15.6 
Protocol Deviations ...................................................................................................64 
16 
Publication Policy .................................................................................................................66 
17 
Literature References ............................................................................................................67 
18 
Supplements/Appendices ......................................................................................................68 
19 
Appendix A: Schedule of Events ..........................................................................................69 
 
 
 
 

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LIST OF TABLES 
Table 19.1: Schedule of Events .................................................................................................... 69 
 
 

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LIST OF FIGURES 
Figure 1.1: Study Schematic ......................................................................................................... 14 
Figure 5.1: Map of Uganda showing Tororo district .................................................................... 27 
 
 

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LIST OF ABBREVIATIONS 
ACT 
Artemisinin Combination Therapy 
AE 
Adverse Event/Adverse Experience 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area Under the Curve 
BCS 
Blantyre Coma Score 
BQL 
Below Quantification Limit 
BUN 
Blood urea nitrogen 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
Cmax 
Maximum Concentration 
CMS 
Clinical Materials Services 
COI 
Conflict of Interest 
CRF 
Case Report Form 
CROMS 
Clinical Research Operations and Management Support 
DAIDS 
Division of AIDS 
DHA 
Dihydroartemisinin 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH, 
DHHS 
DNA 
Deoxyribonucleic acid 
eCRF 
Electronic Case Report Form 
Emax 
Maximal Effect at High Drug Concentrations 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HPLC 
High-Performance Liquid Chromatography 
IATA 
International Air Transport Association 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDES 
Internet Data Entry System 
IDI 
Infectious Diseases Institute 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 

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ISM 
Independent Safety Monitor 
IV 
Intravenous 
JHU 
Johns Hopkins University 
LC-MS/MS 
Liquid Chromatography and Tandem Mass Spectrometry 
LLC 
Limited Liability Company 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHG 
Millimeter(s) of Mercury 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, 
DHHS 
NIH 
National Institutes of Health 
NONMEM 
Nonlinear Mixed Effects Modeling 
OCRA 
Office of Clinical Research Affairs, DMID, NIAID, NIH, 
DHHS 
PCE 
Parasite Clearance Estimator 
PCT50 
Parasite Clearance Half-Life 
PCT90 
Parasite Clearance Time to 90% Reduction   
PD 
Pharmacodynamic 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
QA 
Quality Assurance 
QC 
Quality Control 
REC 
Research Ethics Committee  
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAP 
Statistical Analysis Plan 
SDCC 
Statistical and Data Coordinating Center 
SDW 
Source Document Workbooks 
SOCS 
Safety Oversight Committee Support 
SOP 
Standard Operating Procedure 
t1/2 
Half-Life 
Tmax 
Time to Reach Cmax 
UMB 
University of Maryland, Baltimore 
UNCST 
Uganda National Council for Science and Technology 
US 
United States 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WWARN 
WorldWide Antimalarial Resistance Network 

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PROTOCOL SUMMARY 
Title: 
Exposure-Response Evaluation of IV Artesunate in Children 
with Severe Malaria 
Phase: 
4 
Population: 
Children with severe malaria who are 6 months to 14 years of 
age living in or near Tororo District, Uganda 
Number of Sites: 
1 
Study Duration: 
1 year 
Subject Participation 
Duration: 
6 months 
Description of Agent or 
Intervention: 
Intravenous (IV) artesunate 
Objectives: 
 
Primary: 
• 
To determine the relationship between dihydroartemisinin 
(DHA) exposures following IV dosing and markers of 
physiologic dysfunction associated with severe malaria  
Secondary: 
• 
To determine the relationship between DHA exposures and 
time to hospital discharge  
• 
To determine the relationship between DHA exposures and 
parasite clearance associated with treatment of severe 
malaria. 
Exploratory: 
• 
To determine the relationship between DHA exposures and 
neurodevelopmental outcomes associated with treatment of 
severe malaria outcomes and explore predictors that may 
affect this relationship   

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• 
To evaluate the role of parasite clearance as a mediator of the 
relationship between DHA exposures and markers of 
physiologic dysfunction associated with severe malaria 
• 
To develop a score comprised of markers of physiologic 
dysfunction and describe its relationship to clinical outcomes 
• 
To assess Plasmodium falciparum infections for artemisinin 
resistance  
• 
To store blood for future use, such as identification and 
characterization of parasite gene expression.   
Description of Study Design: This clinical study is a phase 4, single-site, open-label 
pharmacokinetic (PK) study of IV artesunate in up to 100 
Ugandan children 6 months-14 years of age who are diagnosed 
with severe malaria according to standardized World Health 
Organization (WHO) criteria (any P. falciparum parasitemia and 
the presence of danger signs). Participants will receive the 
standard of care IV artesunate for initial treatment of severe 
malaria per WHO guidelines: children weighing <20 kg should 
receive 3.0 mg/kg/dose compared to children weighing ≥20 kg 
who should receive 2.4 mg/kg/dose, at times 0, 12, 24, 48 and 72 
hours (WHO 2015). Parenteral treatment will be administered 
for a minimum of 24 hours (irrespective of the patient’s ability to 
tolerate oral medication earlier), after which patients will be 
evaluated clinically and assessed for ability for oral intake of 
antimalarials. Children who are able to transition to oral 
antimalarial therapy will initiate a 3-day course of artemisinin-
combination oral therapy per national guidelines. Biomarkers of 
physiologic dysfunction will be quantified at regular intervals, 
including serum lactate, serum glucose, total and direct bilirubin, 
bicarbonate levels, Blantyre Coma Score (BCS), creatinine and 
hemoglobin. These biomarkers will be considered both 
independently and together as a weighted score to relate to the 
PK of the active metabolite of IV artesunate, DHA and to 
efficacy markers that more accurately reflect clinical outcomes. 
We will also quantify P. falciparum parasitemia using 
standardized thick blood smear and relate this outcome to DHA 
dose and exposure for comparison with historical studies. 

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Children 6 months to 14 years of age living in or near Tororo 
District, Uganda, who are diagnosed with severe malaria and 
who meet inclusion and exclusion criteria will be enrolled.  
Estimated Time to Complete 
Enrollment:  
6 months 

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Schematic of Study Design: 
 
  
Prior to  
Enrollment 
 
 
 
 
 
 
 
 
Study Day 1: 
Enrollment 
 
Study Days 2-7*:  
Follow-up 
 
Study Day 14*: 
Follow-up 
 
Study Day 28*: 
Follow-up 
 
Study Day 183*: 
Final Study Visit 
 
 
 
*Study day windows: 
Day 7 (±2 days) 
Day 14 (±2 days) 
Day 28 (±4 days) 
Day183 (±14 days) 
 
 
Total N: up to 100    
Obtain informed consent. Screen subjects by criteria; obtain history, 
establish severe malaria diagnosis. 
 
Collect blood for assays; administer IV artesunate per Uganda and WHO guidelines; clinical and AE 
assessment 
Up to100 
subjects 
Collect blood for assays; administer IV artesunate and artemether-lumefantrine per Uganda and 
WHO guidelines; clinical and AE assessment 
Clinical and AE assessment 
Assessment of Final Study Outcome 
Measures 
Figure 1.1: Study Schematic 
Clinical and AE assessment 

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1 
KEY ROLES 
Individuals: 
DMID Clinical Project Manager:  
Ranjodh S. Gill, RN, MPH 
Parasitology & International Programs Branch (HNM53) 
Division of Microbiology & Infectious Diseases 
National Institute of Allergy & Infectious Diseases 
National Institutes of Health 
5601 Fishers Lane 
Bethesda, MD 20852 
Phone:  (202) 631-1075 
Email:  Ranjodh.gill@nih.gov  
 
Principal Investigator:   
Matthew B. Laurens, MD, MPH 
Center for Vaccine Development and Global Health 
University of Maryland School of Medicine 
685 W Baltimore St, Room 480 
Baltimore, MD 21201 
Phone: 410-706-5462 
Email: mlaurens@som.umaryland.edu 
 
 
Site Principal Investigator:   
Pauline Byakika-Kibwika, MBChB, MSc, MMed, PhD 
Makerere University College of Health Sciences 
Upper Mulago Hill Rd 
Kampala, Uganda 
Phone: (+256) 772 626885  
Email: pbyakika@gmail.com 
 
 
Institutions: 
Center for Vaccine Development and Global Health 
University of Maryland School of Medicine 
685 W Baltimore St, Room 480 
Baltimore, MD 21201 
Phone: 410-706-5328 
Fax: 410-706-6205 

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https://www.medschool.umaryland.edu/cvd/ 
 
Makerere University College of Health Sciences 
Upper Mulago Hill Rd 
Kampala, Uganda  
https://chs.mak.ac.ug/  
 
  
Statistical and Data 
Coordinating Center: 
The Emmes Company, LLC 
401 N. Washington St, Suite 700 
Rockville, MD 20850 
Phone: 301-251-1161 
Fax: 301-251-1355 
 
DMID Study Materials 
Services Contractor: 
DMID-Clinical Materials Services (CMS)  
Thermo Fisher Scientific 
4650 New Design Road, Suite F 
Frederick, MD 21703 
Phone: 240-405-1060 
Email: DMID.CMS@ThermoFisher.com 
www.fisherbioservices.com  
 

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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
 
Despite recent advances in malaria control, Plasmodium falciparum continues to kill almost half 
a million persons annually, most of whom are children living in sub-Saharan Africa (WHO 
2019).  
 
Plasmodium falciparum is the most prevalent malaria parasite specie and the cause of the most 
severe form of disease and death. It accounted for 99.7% of all malaria cases in the WHO 
African Region in 2018.  
 
Children younger than 5 years of age and pregnant women are most at risk of malaria and death. 
They accounted for 67% of the estimated 405,000 malaria deaths worldwide, with 94% of these 
in the African Region. Although there was an overall reduction in malaria deaths in 2018 
compared with 2010, the malaria mortality reduction rate slowed since 2016 and this has malaria 
researchers questioning if current malaria treatment regimens are optimal and based on sound 
scientific evidence.  
 
Severe malaria is defined as presence or history of fever plus a positive blood film for P. 
falciparum malaria with at least one of the following symptoms and signs: 
• Impaired consciousness: A Glasgow coma score < 11 in adults or a Blantyre coma score 
< 3 in children 
• Prostration: Generalized weakness so that the person is unable to sit, stand or walk 
without assistance  
• Multiple convulsions: More than two episodes within 24 h  
• Acidosis: A base deficit of > 8 mEq/L or, if not available, a plasma bicarbonate level of < 
15 mmol/L or venous plasma lactate ≥ 5 mmol/L. Severe acidosis manifests clinically as 
respiratory distress (rapid, deep, laboured breathing).  
• Hypoglycaemia: Blood or plasma glucose < 2.2 mmol/L (< 40 mg/dL)  
• Severe malarial anaemia: Haemoglobin concentration ≤ 5 g/dL or a haematocrit of ≤ 15% 
in children < 12 years of age (< 7 g/dL and < 20%, respectively, in adults) with a parasite 
count > 10 000/µL  
• Renal impairment: Plasma or serum creatinine > 265 µmol/L (3 mg/dL) or blood urea > 
20 mmol/L  

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• Jaundice: Plasma or serum bilirubin > 50 µmol/L (3 mg/ dL) with a parasite count > 100 
000/ µL 
• Pulmonary oedema: Radiologically confirmed or oxygen saturation < 92% on room air 
with a respiratory rate > 30/ min, often with chest indrawing and crepitations on 
auscultation  
• Significant bleeding: Including recurrent or prolonged bleeding from the nose, gums or 
venepuncture sites; haematemesis or melaena  
• Shock: Compensated shock is defined as capillary refill ≥ 3 s or temperature gradient on 
leg (mid to proximal limb), but no hypotension. Decompensated shock is defined as 
systolic blood pressure < 70 mm Hg in children or < 80 mmHg in adults, with evidence 
of impaired perfusion (cool peripheries or prolonged capillary refill).  
• Hyperparasitaemia: P. falciparum parasitaemia > 10%  
 
Severe malaria is a medical emergency with an immediate threat to life and so requires prompt 
treatment with effective therapy. The priority requirement for successful diagnosis and treatment 
is early recognition of the signs and symptoms of severe malaria that should lead to emergency 
care in an in-patient setting. Artemisinin derivatives are highly effective and rapidly 
schizonticidal drugs, devoid of major side-affects and their use does not warrant intensive 
monitoring. Large randomized clinical trials and systematic reviews demonstrated superiority of 
artesunate to quinine for treatment of severe malaria, with significant reduction in mortality and 
complications associated with malaria as well as less adverse effects. These trials provided 
support for parenteral artesunate to replace parenteral quinine as drug of first choice in treating 
severe malaria. Currently, the WHO recommends use of IV artesunate as first line treatment for 
severe malaria, administered for at least 24 hours, until the patient can tolerate oral medication 
and to complete treatment with a full course of an artemisinin combination therapy (ACT). In 
case of unavailability of artesunate, to use intramuscular artemether in preference to quinine for 
treatment of severe malaria.  
 
Uganda adopted this policy for severe malaria treatment, however; parenteral artesunate is not 
widely available and effort to improve accessibility should be reinforced. 
 
Since 1991 and before April 2019, the only Food and Drug Administration (FDA)-approved 
treatment for severe malaria in the US was IV quinidine gluconate. Availability of quinidine 
gluconate in the US has declined over the past 20 years, such that the last lot manufactured 
reached expiry in March 2019. A replacement essential medicine is needed in the US for 
treatment of severe malaria. IV artesunate is now the only option available for treatment in the 
US and is uniquely available through the Centers for Disease Control and Prevention (CDC) 
under an expanded access investigational new drug (IND) protocol via scattered distribution 

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centers located near transportation hubs. Unfortunately, severe malaria can progress rapidly, and 
delays in delivery of IV artesunate from treatment distribution centers to patients with severe 
malaria may lead to complications, including treatment failure and death. To mitigate risk of 
severe malaria complications, pharmacologic treatment for severe malaria treatment should be 
optimized for patients with severe malaria.  
 
Malaria treatment and Drug Pharmacokinetics 
Severe malaria is a medical emergency which if not immediately treated results in 100% 
mortality. It is fundamental that plasma concentrations of a highly effective antimalarial drug are 
achieved as rapidly as possible. Artesunate is a water soluble hemisuccinate artemisinin 
derivative; available as sodium hemisuccinate salt for injection (Guilin Pharmaceutical Factory, 
Guangxi, People’s Republic of China). Artesunate’s excellent antimalarial property 
demonstrated by rapid parasite clearance, is enhanced by its high initial maximum concentration 
(Cmax) and rapid hydrolysis to its active metabolite DHA. High plasma concentrations of 
artesunate and DHA are achieved within 5 minutes of drug administration and artesunate is 
rapidly cleared from circulation. The Cmax for both artesunate and DHA are observed rapidly post 
dose administration indicating rapid conversion of artesunate to DHA. Artesunate is cleared from 
circulation rapidly while DHA has a longer elimination half-life (t1/2). Accurate measurement of 
plasma concentrations of artesunate and DHA should guide adequate dosing as well as facilitate 
differentiation of treatment failure due to inadequate drug exposure from failure due to drug 
resistance. 
2.2 
Rationale 
Current dosing regimens for IV artesunate are based on time to parasite clearance and not 
clinical endpoints related to physiologic changes that occur with parasitemia. Other measures of 
physiologic dysfunction can be used as study endpoints for a malaria treatment outcome analysis 
of current regimens for IV artesunate for severe malaria treatment. Improved dosing regimens 
will lead to fewer complications and likely fewer deaths. Such a strategy is needed to further 
reduce public health gains against malaria mortality that seem to have recently stalled. 
 
For pediatric patients, IV artesunate dosing is weight-based to adjust for artesunate clearance and 
has been developed based on time to parasitemia clearance times, which may not completely 
reflect clinical cure. The most recent WHO 2015 guidelines state that children weighing <20 kg 
should receive IV artesunate as 3.0 mg/kg/dose compared to children weighing ≥20 kg and 
adults who should receive 2.4 mg/kg/dose at times 0, 12, 24, 48 and 72 hours (WHO 2015), 
Parenteral treatment should be given for a minimum of 24 hours (irrespective of the patient’s 
ability to tolerate oral medication earlier), after which patients should be evaluated clinically and 
assessed ability to take medications orally. Children who are able to transition to oral 

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antimalarial therapy will initiate a 3-day course of oral artemisinin-combination therapy per 
national guidelines. The December 2016 CDC guidelines recommended 2.4 mg/kg/dose for all 
pediatric and adult patients, regardless of weight (CDC 2016), while the recently updated 
October 2019 CDC guideline recommends the same weight-based dosing scheme as the WHO 
(CDC 2019). A recent study of severe malaria in sub-Saharan African children documented 
equivalent time to parasite clearance using 2.4 mg/kg/dose at 0, 12, 24, 48 and 72 hours; and a 
larger 4.0 mg/kg/dose at 0, 24 and 48 hours. 
 
P. falciparum parasites are known for their capacity to infect red blood cells that then display 
variant surface antigens that adhere to endothelial vasculature in target organs. For this reason, 
measurement of parasite clearance in the peripheral blood may not reflect physiologic effects of 
severe malaria that result from end organ damage, whether through direct impairment of blood 
flow and decreased delivery of oxygen, a local inflammatory response directed against infected 
red blood cells attached to vascular endothelium, or rosetting of infected and uninfected red 
blood cells at the vasculature. Other measures of physiologic dysfunction when quantified alone 
or in an algorithmic fashion such as a score, may more accurately reflect successful treatment, 
including serum lactate, serum glucose, bicarbonate levels, BCS, creatinine and hemoglobin. 
These measures, compared to the standard parasite clearance times from peripheral blood, may 
be more important to quantify and relate to pharmacologic dosing of antimalarial therapy.  
2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
No significant additional risks are anticipated as participants will be receiving standard of care 
antimalarial therapy per national guidelines. Frequent blood draws are also common for patients 
with severe malaria. The amount of blood drawn for research purposes will be minimized to 
reduce added risk. 
2.3.1.1 Risks from blood drawing 
Risks associated with blood drawing include small risks of bleeding, hematoma and infection. To 
minimize this risk, the skin is cleaned with alcohol before puncture; sterile, single-use needles 
and lancets will always be used; and pressure will be held at the puncture site after removal of 
the needle or lancet. Trained technicians and medical staff will perform the procedure to reduce 
potential risk. Clinicians will be available for evaluation if there is any untoward effect. 
2.3.1.2 Potential risk of loss of confidentiality 
There is a potential risk of loss of confidentiality to study participants. Private health information 
recorded on participant case report forms (CRFs) could theoretically become available to non-

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study personnel. To protect against this potential risk, the Principal Investigator (PI) will 
carefully monitor study procedures to protect the safety of participants and the quality of the 
data. Participant samples will be labeled with a participant ID number. The key to this number, 
and all private health information will be kept in a locked cabinet in a locked room that is 
accessible only to study personnel. 
2.3.1.3 Risks to study personnel 
The main risks to study personnel are from accidental exposure to blood and body fluid-borne 
infections. Standard Operating Procedures (SOPs) for staff safety are used in clinical and 
laboratory areas, including sharps management, hazardous waste management, etc. Universal 
precautions are used for handling all body fluids. 
2.3.2 Known Potential Benefits 
No direct benefit is anticipated for study participants. If this research is successful and an 
improved IV artesunate dosing regimen for treatment of severe malaria in children is developed, 
the community of Tororo District, Uganda and the rest of the P. falciparum-endemic world will 
benefit. 

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3 
OBJECTIVES 
3.1 
Study Objectives & Outcome Measures 
3.1.1 Primary Study Objective  
• 
To determine the relationship between DHA exposures following IV artesunate dosing and 
markers of physiologic dysfunction associated with severe malaria in Ugandan children  
3.1.1.1 Primary Outcome Measure 
• 
DHA PK following the first dose of IV artesunate after enrollment, including Cmax, area 
under the curve over hours 0-12 (AUC0-12) and t1/2 and time to Cmax (Tmax) 
• 
Physiologic measures such as temperature, blood pressure, venous serum lactate and 
bicarbonate levels, serum glucose, BCS, total and direct bilirubin, hemoglobin and creatinine 
3.1.2 Secondary Study Objectives  
• 
To determine the relationship between DHA exposures and time to hospital discharge  
• 
To determine the relationship between DHA exposures and parasite clearance associated 
with treatment of severe malaria  
3.1.2.1 Secondary Outcome Measures 
• 
Time to hospital discharge 
• 
Measures of parasite clearance calculated from parasite density, as measured by thick blood 
smear such as parasite clearance t1/2, parasite clearance by Day 2, and time to 90% reduction 
in parasitemia 
3.1.3 Exploratory Study Objectives 
• 
To determine the relationship between DHA exposures and neurodevelopmental outcomes 
associated with treatment of severe malaria outcomes and explore predictors that may affect 
this relationship 
• 
To evaluate the role of parasite clearance as a mediator of the relationship between DHA 
exposures and markers of physiologic dysfunction associated with severe malaria 
• 
To develop a score comprised of markers of physiologic dysfunction and describe its 
relationship to clinical outcomes 
• 
To assess P. falciparum infections for markers of artemisinin resistance  

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• 
To store blood for future use, such as identification and characterization of parasite gene 
expression.   
 
3.1.3.1 Exploratory Outcome Measures 
• 
Neurodevelopmental outcomes at 1 and 6 months after severe malaria diagnosis 
• 
The proportion of the effect of DHA exposure on markers of physiologic dysfunction 
attributable to parasite clearance 
• 
The association between the physiologic dysfunction score, resolution of symptoms, time to 
hospital discharge, and return to normal range in markers of physiologic dysfunction 
• 
Presence of known K13 mutations associated with artemisinin resistance  
 

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4 
STUDY DESIGN 
This clinical study is a phase 4, single-site, open-label PK and pharmacodynamic (PD) study of 
IV artesunate in up to 100 Ugandan children 6 months-14 years of age who are diagnosed with 
severe malaria according to standardized WHO criteria (any P. falciparum parasitemia and the 
presence of danger signs).  
 
Treatment 
Participants will receive the standard of care with IV artesunate (Guilin Pharmaceutical Factory, 
Guangxi, People’s Republic of China), for treatment of severe malaria per WHO guidelines.  
Artesunate will be reconstituted as follows:  
 
• 30 mg vial of artesunate powder will be dissolved in 0.5 mL sodium bicarbonate and 
provided in the pack to form sodium artesunate and then mixed with 2.5 mL of sodium 
chloride (9mg/ml for injection).  
 
• 60 mg vial of artesunate powder will be dissolved in 1 mL sodium bicarbonate and 
provided in the pack to form sodium artesunate and then mixed with 5 mL of sodium 
chloride (9mg/ml for injection).  
 
• 120 mg vial of artesunate powder will be dissolved in 2 mL sodium bicarbonate and 
provided in the pack to form sodium artesunate and then mixed with 10 mL of sodium 
chloride (9mg/ml for injection).  
 
This will be injected as a bolus into an indwelling IV cannula. 
 
Dosage of Artesunate 
Children weighing <20 kg will receive IV artesunate at a dose of 3.0 mg/kg/dose compared to 
older children weighing ≥ 20kg, who will receive 2.4 mg/kg/dose, at times 0, 12, 24, After the 
initial 24 hours of IV artesunate, children will be assessed clinically and for ability to take oral 
medications. If unable to take oral medication, IV artesunate will continue at 48 and 72 hours 
(WHO 2015). Children who recover and are able to transition to oral antimalarial therapy after a 
minimum of 24 hours or later, will initiate a 3-day course of oral artemisinin-combination 
therapy per national guidelines. Participants will be given standardized instructions by a nurse on 
how to take the artemether-lumefantrine regimen according to standard practice and told that all 
doses should be taken 30 minutes to 1 hour after food, preferably containing fat or oil. 
 
Variables 

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Biomarkers of physiologic dysfunction will be quantified at regular intervals, including serum 
lactate, bicarbonate, serum glucose, total and direct bilirubin, creatinine, BCS and hemoglobin. 
These biomarkers will be considered both independently and together as a weighted score to 
relate to the PK of the active metabolite of IV artesunate, DHA and to efficacy markers that more 
accurately reflect clinical outcomes. We will also quantify P. falciparum parasite density using 
standardized thick blood smear and determine the presence of known artemisinin resistance K13 
mutations and relate these outcomes to DHA dose and exposure for comparison with historical 
studies. 
 
Study Population 
Children 6 months-14 years of age living in or near Tororo District, Uganda, who are diagnosed 
with severe malaria and who meet inclusion and exclusion criteria will be enrolled. 
 
Additional study design elements: 
• 
Study monitoring delegated to IDI internal monitors and DMID or DMID representative 
• 
Screening will be done within 24 hours before enrollment 
• 
Data collection forms will serve as source documents. Only information that cannot be 
collected initially onto data collection forms (namely, clinical laboratory test results and 
adverse event (AE) medical records) will first be collected onto separate source documents 
before transcription into data collection forms. The information in the data collection form 
will then be entered directly into the Internet data entry system (IDES). 
• 
Clinical laboratory evaluations will occur at the clinical laboratory onsite at the Lancet 
Laboratory  
• 
Blood samples for PK assays will be processed and stored temporarily at the onsite 
laboratory at the Infectious Diseases Research Collaboration Laboratory at Tororo Hospital, 
before shipment to the Translation Laboratory, at the Infectious Diseases Institute, Mulago, 
Kampala (IDI Mulago). Frozen samples will be transported to the IDI Translation lab at the 
IDI in Kampala or the Clinical Pharmacology Analytical Laboratory at JHU, Baltimore, 
Maryland, USA, and stored there in temperature-monitored freezers.  
• 
P. falciparum parasitemia will be quantified at the IDRC laboratory according to SOP. 
• 
A dried blood spot will be obtained at enrollment for assessment of known K13 artemisinin 
resistance mutations. Specimens will be shipped to the University of Maryland, Baltimore 
(UMB) for parasite deoxyribonucleic acid (DNA) extraction and sequencing. 
• 
PK samples for DHA will be quantified by liquid chromatography and tandem mass 
spectrometry (LC-MS/MS) (See Section 8.3.2). 

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• 
Study duration will be 6 months per participant, and the entire clinical trial will last 
approximately 12 months 
• 
7-day surveillance (day of treatment initiation and 6 days thereafter) is planned for initial PK 
and biophysical parameter measurements 
• 
Follow-up of serious adverse events (SAEs) until resolution or stability; follow-up of AEs 
until resolution or stability or until the end of follow-up. 
• 
Once the last participant has completed the final visit, the clinical database will be cleaned 
and locked. The analysis of the primary and secondary outcome measures will be included in 
the Clinical Study Report (CSR) following database lock. Any available data from the 
exploratory endpoints may also be included. Additional exploratory endpoint data not 
available at the time of CSR preparation may be included in one or more addenda to the 
CSR.  

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5 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
Site Description 
Participants for this study will be drawn from the population of children aged 6 months to 14 
years residing in Tororo District, Uganda (Figure 5.1).   
 
  
 
 
Tororo District is a district in Eastern Uganda of 487,900 inhabitants. The town of Tororo serves 
as the district’s headquarters and has a population of about 41,906 inhabitants.  
 
Tororo has two rainy seasons in the year from March to May and from October to December. 
The primary economic activity in the district is agriculture. The predominant ethnic groups are 
the Itesot and Japhadhola. A number of languages are spoken including; Ateso, Japadhola, 
Swahili, Lugisu, and Lugwere . English is the official language of Uganda.  
 
Tororo Hospital is a 200-bed public hospital funded by the Uganda Ministry of health. General 
care in the hospital is free of charge. 
Figure 5.1: Map of Uganda showing Tororo district 

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5.2 
Subject Inclusion Criteria 
1. Children ages 06 months-14 years at the time of severe malaria diagnosis, inclusive 
2. Meet the case definition for severe malaria, per WHO standardized guidelines 
3. Parent/guardian willing to provide informed consent  
4. Assent for children between 8 and 14 years who are conscious and otherwise able to 
provide assent, inclusive 
5.3 
Subject Exclusion Criteria 
1. Receipt of >24 hours of artemisinin therapy 
5.4 
Treatment Procedures 
Participants will receive IV artesunate for severe malaria according to national guidelines. After 
a minimum of 24 hours and when they can tolerate oral therapy, they will transition to oral ACT, 
also per national guidelines. No blinding of study participants, their parent/guardian, or study 
staff will be done as this is an open label PK study of standard of care IV artesunate.  
5.4.1 Reasons for Withdrawal 
The following criteria will be checked before IV artesunate administration. If any become 
applicable before completion of a study product administration regimen, further IV artesunate 
will not be administered but the participant will be followed for the duration of the study. If any 
become applicable during the study but after an IV artesunate administration regimen is 
completed, the participant will not be required to discontinue the study.  
• 
Grade 3 hypersensitivity to IV artesunate 
• 
Severe side effects following IV artesunate administration 
 
A child between 8-14 years may withdraw or a parent/guardian of a study participant may 
withdraw a participant voluntarily from continuing study follow-up upon request for any reason. 
5.4.2 Handling of Withdrawals 
Every effort will be made to collect data on any participant discontinued from receipt of 
additional IV artesunate for any reason. If possible, participants who leave the study area will be 
traced and visited by clinical investigators to collect safety follow-up data. 

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5.4.3 Termination of Study  
The trial may be suspended or terminated by DMID or by the PI due to any major safety concern 
identified by the independent safety monitor (ISM). The trial may also be suspended by the IRBs 
if deemed necessary. 

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6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
6.1 
Study Product Description 
 
Artesunate for Injection 
Artesunate for injection that is WHO-prequalified, procured by the Infectious Diseases Institute 
(IDI), and kept under the proper storage conditions at the clinical sites will be used. This is 
currently the first-line drug used by the Ministry of Health Uganda for treatment of severe 
malaria, and no potential safety concerns exist as we plan to use the WHO-recommended dosing 
regimen. 
6.1.1 Acquisition 
Study drug will be procured by the IDI.  
6.1.2 Formulation, Packaging, and Labeling 
Artesunate for injection appears as a white, crystalline powder.  
Solvent (sodium bicarbonate injection) appears as a clear, colorless liquid.  
 
Each 30 mg box contains: 
• 
1 vial of 30 mg artesunate powder for solution for injection,  
• 
1 ampoule of 0.5 mL sodium bicarbonate 50 mg/mL solution for injection, and  
• 
1 ampoule of 2.5 mL sodium chloride 9 mg/mL for injection; 
 
Each 60 mg box contains: 
• 
1 vial of 60 mg artesunate powder for solution for injection,  
• 
1 ampoule of 1 mL sodium bicarbonate 50 mg/mL solution for injection, and  
• 
1 ampoule of 5 mL sodium chloride 9 mg/mL for injection; 
 
Each 120 mg box contains: 
• 
1 vial of 120 mg artesunate powder for solution for injection,  
• 
1 ampoule of 2 mL sodium bicarbonate 50 mg/mL solution for injection, and  
• 
1 ampoule of 10 mL sodium chloride 9 mg/mL for injection; 

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6.1.3 Product Storage and Stability 
Artesunate for injection should be stored at <30 degrees Celsius and protected from light. The 
reconstituted solution should be stored at <30 degrees Celsius and should be used within 1 hour. 
Artesunate will be procured by IDI, transported under monitored temperature conditions to 
Tororo site and stored in the Infectious Diseases Research Collaboration (IDRC) Pharmacy 
which has adequate 24-hour temperature monitoring. It will be dispensed by the study nurse. 
6.2 
Dosage, Preparation and Administration of Study 
Intervention/Investigational Product 
Artesunate for injection will be administered by study nursing staff per Ministry of Health 
Uganda guidelines. 
6.3 
Modification of Study Intervention/Investigational Product for a 
Participant 
Dosing of IV artesunate will not be adjusted due to toxicity or other reasons. If a participant 
experiences toxicity related to IV artesunate, then the investigators will follow Ministry of 
Health Uganda guidelines for alternative treatment of severe malaria. 
6.4 
Accountability Procedures for the Study Supply of IV Artesunate 
The study team will procure a supply of artesunate for injection and will maintain this study 
stock in a temperature-controlled area with daily temperature monitoring at the IDRC Pharmacy. 
The Site PI is responsible for the distribution and disposition of the study stock of artesunate for 
injection, and has ultimate responsibility for accountability. The Site PI may delegate to the 
study coordinator responsibility for study product accountability. The study coordinator will be 
responsible for maintaining complete records and documentation of study product receipt, 
accountability, dispensation, temperature monitoring, storage conditions, and final disposition of 
artesunate for injection. All artesunate for injection, whether administered or not, must be 
documented on the appropriate study product accountability record or dispensing log. Unused 
study product will be retained as per DMID requirements. 
 
Upon completion of the study and after the final monitoring visit, any remaining unused study 
product will be donated to the hospital, or in accordance with disposition plans. Further details 
regarding final accountability and disposition of used and unused study product are included in 
the protocol-specific Manual of Procedures (MOP).  

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6.5 
Concomitant Medications/Treatments 
At enrollment and at subsequent study visits, investigators will question the participant’s 
parent/guardian about any medication taken, including traditional, herbal, supplements and over-
the-counter medicines. Concomitant medication, including any administered during the period 
starting from 7 days before enrollment and ending at the end of the study follow-up period will 
be recorded with trade name and/or generic name of the medication, medical indication, start and 
end dates of treatment.  
 
The study team will procure a supply of medications for treatment of common concurrent 
ailments that patients with severe malaria may develop such as paracetamol for fever, and 
antibiotics for sepsis but these should not have any antimalarial effects. Antibiotics such as 
cotrimoxazole which are known to have some antimalarial effects will not be administered for 
such ailments; however, participants who are taking concomitant medications that have some 
antimalarial effect for conditions in which the medication is standard of care may be continued, 
including but not limited to Septrin (cotrimoxazole) in HIV coinfected children. This stock of 
concomitant medications will ensure that study participants do not buy or receive additional 
medications outside the study or without the knowledge of the study physicians. The site PI will 
ensure that this additional study stock of concomitant medications is stored in a temperature-
controlled area at the IDRC Pharmacy, with daily temperature monitoring. The Site PI is 
responsible for the distribution and disposition of the study stock of concomitant medications 
and has ultimate responsibility for accountability. The Site PI may delegate to the study 
coordinator responsibility for study concomitant drug accountability. The study coordinator will 
be responsible for maintaining complete records and documentation of study concomitant drug 
receipt, accountability, dispensation, temperature monitoring, storage conditions, and final 
disposition of drugs. All drugs whether administered or not, must be documented on the 
appropriate study concomitant drug accountability record or dispensing log. Unused study drug 
will be retained as per DMID requirements. 
 

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7 
STUDY SCHEDULE 
7.1 
Screening  
Starting at the emergency department of the hospital, participants diagnosed by the attending 
physician and have received a prescription of artesunate for severe malaria will be screened for 
study eligibility and enrolled. 
 
Recruitment will be progressive over a single malaria transmission season so that up to 100 
children of either sex who fulfill the inclusion criteria are enrolled. Participants will be recruited 
by non-coercive methods among children aged 6 months-14 years residing near the study site. A 
parent/guardian of a child diagnosed with severe malaria will be informed of the study to 
determine if they are interested to have their child participate. Children who are of the age of 
assent (age 8 in Uganda) and above and who are conscious will also be informed of the study to 
determine if they are interested. Informed consent of a parent/guardian and assent for children >8 
and <18 years of age who are conscious at enrollment and otherwise able to provide assent is 
required for enrollment. After the study has been explained to a potential participant’s 
parent/guardian, and to a potential participant in the case of a conscious child aged 8-14 years 
old, they will be provided with a copy of the consent form and assent form if applicable. The 
consent/assent process will be conducted in a semi-private area to ensure confidentiality, to 
reduce the likelihood of other participants influencing their decision, and to allow further time to 
make a final decision. A single informed consent document, and a single assent document when 
applicable, will be used for screening and other study procedures. Only participants who receive 
a first dose of IV artesunate are considered enrolled in the study. Administration of artesunate 
therapy will not be delayed for enrollment procedures. Participants may still be enrolled up to 24 
hours after first dose of IV artesunate.  In the case of unconscious children who are the age of 
assent, only informed consent of a parent/guardian is required for enrollment. Once the child 
becomes conscious, assent will be obtained from the child to determine if their participation in 
the study will continue. 
 
All screening tests, medical history and examinations will be performed only after study 
consent/assent where applicable is obtained. If an individual’s medical chart or results diagnostic 
tests performed as part of an individual’s medical care are going to be used for screening, written 
informed consent must be obtained before review of that information.  
 
An eligibility checklist will be prepared for each participant and will later become part of the 
source document for participants enrolled in the trial. A unique identification number will be 
assigned to each study participant. A medical history will be taken. Concomitant medications 
will be documented. Physical examination (including Blantyre coma score (BCS)) and laboratory 

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screening tests will include: hemoglobin, platelets, white blood cell (WBC) count, neutrophil 
count; serum lactate, bicarbonate, blood urea nitrogen (BUN), calcium, creatinine, glucose, 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and direct bilirubin, 
sodium, and potassium; and urinalysis. Laboratory testing will be performed at the Lancet 
laboratory at the study site and at a local reference laboratory if needed. Results obtained within 
24 hours prior to enrollment can be included as baseline labs and would satisfy both screening 
and enrollment/baseline labs. A thick and thin blood smear will be performed for estimation of 
parasite density. A dried blood spot specimen will be collected for artemisinin resistance 
assessment. A blood specimen will be collected in a PAXgene tube for P. falciparum gene 
expression analysis. Recruitment will continue over a single malaria transmission season until up 
to 100 eligible participants have fulfilled all the inclusion criteria and none of the exclusion 
criteria.  
7.2 
Enrollment/Baseline 
On study day 1, study staff will collect baseline blood and urine samples, conduct a physical 
exam and document vital signs (axillary temperature, respiratory rate, blood pressure, pulse), and 
record medication and medical history. Results of baseline blood and urine samples are not 
necessarily resulted and reviewed before IV artesunate. After they receive their first dose of IV 
artesunate, participants are considered enrolled into the study. 
 
A complete physical examination, including neurological assessment and determination of the 
BCS, will be performed and documented at least daily for each patient while hospitalized. Vital 
signs (pulse, respiratory rate, blood pressure, and axillary temperature will be measured 
approximately every 6 h until 6 h post parasite clearance. 
 
Additional details of the schedule of events are included in the Study Schedule (Table 19.1). 
7.3 
Follow-up  
Details of the schedule of events, including laboratory analyses, are included in the summary of 
study procedures (Section 8.1) and Schedule of Events (Table 19.1). If a subject is discharged 
before study day 7, the required follow-up visits are study day 7, 14, 28, and 183.  
7.4 
Final Study Visit 
The final study visit should occur six months after study treatment administration initiation 
(study day 183±14 days). 
  

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Evaluations to be done during the final study visit are listed in the daily study procedures and in 
the summary of study procedures. Procedures include the following:  
• 
Medical history including concomitant medication review 
• 
Physical exam, including vital signs, height, and weight 
• 
Venous blood collection for hemoglobin, platelets, WBC count, and neutrophil count 
• 
Neurodevelopmental assessments 
7.5 
Early Termination Visit 
If a participant wishes to end their participation early and is willing to have evaluations 
performed, a targeted physical examination should be done if needed. If termination occurs 
before or on study day 7, then study day 7 blood collections should be obtained. If termination 
occurs between study days 8-14, 3 mL venous blood may be drawn for serum bicarbonate, 
hemoglobin, platelets, WBC count, and neutrophil count. If termination occurs after study day 
14, 1 mL venous blood may be drawn for hemoglobin, platelets, WBC count, and neutrophil 
count.  
 
Investigators will make every effort to continue follow-up visits for any participant who has 
received one or more doses of IV artesunate for the duration of the study even if it is determined 
that subsequent IV artesunate should not be administered.  
7.6 
Unscheduled Visit  
Unscheduled visits may occur at any time during the trial and may prompt a history and targeted 
physical examination when indicated, clinical laboratory tests if indicated, documentation of any 
AEs, and any other medically indicated diagnostic or therapeutic procedures. These visits will be 
recorded as observations in the participant’s study record. 

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8 
STUDY PROCEDURES/EVALUATIONS 
8.1 
Daily Study Procedures 
 
Screening (may take place over more than one visit) up to 24 hours before enrollment 
• 
Written assent for children ≥ 8 years as applicable 
• 
Informed consent obtained from the parent 
• 
Check of inclusion and exclusion criteria 
• 
Participant identification number assigned 
• 
Demographics and medical history of participant  
• 
Concomitant medication documentation 
• 
Physical examination and vital signs (pulse, respiratory rate, blood pressure, axillary 
temperature) 
• 
Document height and weight 
• 
BCS 
• 
Urinalysis 
• 
Collect 8.25 mL venous blood sample for:  
• 
Hematology: hemoglobin, platelets, WBC count, neutrophil count 
• 
Biochemistry: serum creatinine, AST, ALT, total and direct bilirubin, bicarbonate, 
lactate, sodium, potassium, glucose, BUN, calcium 
• 
P. falciparum parasite quantification 
• 
Artemisinin resistance 
• 
Population PK study per sampling plan specified in Section 8.3.1 
• 
P. falciparum mRNA collection using PAXgene tube 
 
Day 1  
Enrollment  
• 
Physical examination and vital signs (pulse, respiratory rate, blood pressure, axillary 
temperature every 6 hours until 6 hours post-parasite clearance) 
• 
Urinalysis  

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• 
An IV cannula will be inserted for administration of study drugs and for PK blood sampling 
and blood draws.  
• 
Collect venous blood samples for population PK study per sampling plan specified in 
Section 8.3.1 
• 
Administration of IV artesunate dose in accordance with WHO and Uganda guidelines 
• 
Collect 11.5 mL venous blood sample for:  
• 
Hematology: hemoglobin, platelets, WBC count, neutrophil count (at least 12 hours after 
initial screening collection) 
• 
Biochemistry: serum creatinine, AST, ALT, total and direct bilirubin, serum bicarbonate, 
lactate, sodium, potassium, glucose, BUN, calcium (at least 12 hours after initial 
screening collection) 
• 
Population PK study per sampling plan specified in Section 8.3.1 
• 
P. falciparum parasite quantification 
• 
Concomitant medication review 
• 
BCS 
 
Day 2  
Follow-up 
• 
Physical examination and vital signs (pulse, respiratory rate, blood pressure, axillary 
temperature) 
• 
Administration of IV artesunate dose or ACT in accordance with WHO and Uganda 
guidelines 
• 
Urinalysis  
• 
Collect 3.5 mL venous blood sample for:  
• 
Hematology: hemoglobin, platelets, WBC count, neutrophil count 
• 
Biochemistry: serum creatinine, AST, ALT, total and direct bilirubin, serum bicarbonate, 
lactate, sodium, potassium, glucose, BUN, calcium 
• 
P. falciparum parasite quantification 
• 
Concomitant medication review 
• 
BCS 
 
Day 3  
Follow-up 

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• 
Physical examination and vital signs (pulse, respiratory rate, blood pressure, axillary 
temperature) 
• 
Administration of IV artesunate dose or ACT in accordance with WHO and Uganda 
guidelines 
• 
Urinalysis  
• 
Collect 3.25 mL venous blood sample for:  
• 
Hematology: hemoglobin, platelets, WBC count, neutrophil count 
• 
Biochemistry: serum creatinine, AST, ALT, total and direct bilirubin, serum bicarbonate, 
lactate, sodium, potassium, glucose, BUN, calcium 
• 
P. falciparum parasite quantification 
• 
Concomitant medication review 
• 
BCS 
 
Day 4  
Follow-up 
• 
Physical examination and vital signs (pulse, respiratory rate, blood pressure, axillary 
temperature) 
• 
Administration of IV artesunate dose or AL in accordance with WHO and Uganda guidelines 
• 
Urinalysis  
• 
Collect 3.25 mL venous blood sample for:  
• 
Hematology: hemoglobin, platelets, WBC count, neutrophil count 
• 
Biochemistry: serum creatinine, AST, ALT, total and direct bilirubin, serum bicarbonate, 
lactate, sodium, potassium, glucose, BUN, calcium 
• 
P. falciparum parasite quantification 
• 
Concomitant medication review 
• 
BCS 
 
Day 5  
Follow-up 
• 
Physical examination and vital signs (pulse, respiratory rate, blood pressure, axillary 
temperature) 

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• 
Administration of IV artesunate dose or ACT in accordance with WHO and Uganda 
guidelines 
• 
Urinalysis  
• 
Collect 3.25 mL venous blood sample for:  
• 
Hematology: hemoglobin, platelets, WBC count, neutrophil count 
• 
Biochemistry: serum creatinine, AST, ALT, total and direct bilirubin, serum bicarbonate, 
lactate, sodium, potassium, glucose, BUN, calcium  
• 
P. falciparum parasite quantification 
• 
Concomitant medication review 
• 
BCS 
 
Day 6  
Follow-up 
• 
Physical examination and vital signs (pulse, respiratory rate, blood pressure, axillary 
temperature) 
• 
Urinalysis  
• 
Collect 3 mL venous blood sample for:  
• 
Hematology: hemoglobin, platelets, WBC count, neutrophil count 
• 
Biochemistry: serum creatinine, AST, ALT, total and direct bilirubin, serum bicarbonate, 
lactate, sodium, potassium, glucose, BUN, calcium 
• 
Concomitant medication review 
• 
BCS 
 
Day 7 (±2 days) 
 
Follow-up 
• 
Physical examination and vital signs (pulse, respiratory rate, blood pressure, axillary 
temperature) 
• 
Urinalysis  
• 
Collect 3 mL venous blood sample for:  
• 
Hematology: hemoglobin, platelets, WBC count, neutrophil count 
• 
Biochemistry: serum creatinine, AST, ALT, total and direct bilirubin, serum bicarbonate, 
lactate, sodium, potassium, glucose, BUN, calcium 

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• 
Concomitant medication review 
• 
BCS 
• 
Neurodevelopmental assessments 
 
Day 14 (±2 days) 
Follow-up 
• 
Concomitant medication review 
• 
Record blood pressure, pulse, respiratory rate and axillary temperature 
• 
Targeted physical examination if needed 
• 
BCS 
• 
Neurodevelopmental assessments 
• 
Collect 3 mL venous blood sample for hemoglobin and serum bicarbonate 
Day 28 (±4 days) 
Follow-up 
• 
Concomitant medication documentation 
• 
Record blood pressure, pulse, respiratory rate, axillary temperature, height and weight 
• 
Targeted physical examination if needed 
• 
BCS 
• 
Neurodevelopmental assessments 
• 
Collect 1 mL venous blood sample for hemoglobin 
 
Day 183 (±14 days) Final Study Visit 
• 
Concomitant medication review 
• 
Physical exam, including blood pressure, pulse, axillary temperature, height, and weight 
• 
Collect 1 mL venous blood for hemoglobin, platelets, WBC count, and neutrophil count 
• 
BCS 
• 
Neurodevelopmental assessments 

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8.2 
Clinical Evaluations 
8.2.1 Neurodevelopmental Assessments 
8.2.1.1 Children 6 months to 6 years of age at time of assessment will undergo testing using the 
Malawi Developmental Assessment Testing. Details are provided in a separate SOP.  
8.2.1.2 Children >6 years of age will not undergo neurodevelopmental assessment 
8.3 
Laboratory Evaluations 
8.3.1 Clinical Laboratory Evaluations 
Malaria Diagnostics 
Samples for malaria diagnostics will be collected according to the following schedule in hours: 0 
(0-2 hour acceptable window), 6 (4-8 hour acceptable window), 12 (10-14 hour acceptable 
window), 24 (22-26 hour acceptable window), 36 (34-38 hour acceptable window) and 48 (46-50 
hour acceptable window), and then parasitemia should be measured at least every 24 hours until 
clearance. Thick and thin blood smears for malaria diagnosis will be stained with Giemsa stain 
and read at 100X power light microscope. Parasites will be quantitated by counting the number 
of asexual P. falciparum parasites per 200 WBC using the patient’s WBC count per µL of blood. 
Thick blood smears will be used for diagnosis and thin blood smears for typing the species of 
malaria parasites. Thin and thick blood smears will be repeated on all follow up days because the 
different species of malaria parasites have different incubation periods.   
 
Collection of blood for Artesunate Pharmacokinetic assays 
Approximately 10mLs (~2 mL/timepoint) of venous blood will be collected into fluoride-oxalate 
tubes from the arm opposite of that used for drug administration at 0 (pre-dosing), and 4 times 
following the first dose in the hospital during different sampling windows. Sampling windows 
are defined for post-dose collections: 0-1 hour, 1-2.5, 2.5-4, 4-6 and 6-24 hours post-dose. 
Participants will be randomly assigned to either the 4-6 hour or the 6-24 hour collection 
timepoint via the Screening and Enrollment Log. All blood samples will be chilled immediately 
to prevent artesunate degradation by plasma esterases. Samples will be centrifuged within 30 
minutes to minimize hemolysis, and aliquots of plasma will be stored at -80°C (-60°C or colder 
acceptable). Plasma aliquots will be shipped intermittently to the IDI Core Laboratory for storage 
prior to quantification. Plasma samples will be assayed by a validated high-performance liquid 
chromatography (HPLC) method. 
 
Diagnosis of Severe Malaria 

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Severe malaria is defined as presence or history of fever plus a positive blood film for P. 
falciparum malaria with at least one of the following symptoms and signs: 
• Impaired consciousness: A Glasgow coma score < 11 in adults or a Blantyre coma score 
< 3 in children 
• Prostration: Generalized weakness so that the person is unable to sit, stand or walk 
without assistance  
• Multiple convulsions: More than two episodes within 24 h  
• Acidosis: A base deficit of > 8 mEq/L or, if not available, a plasma bicarbonate level of < 
15 mmol/L or venous plasma lactate ≥ 5 mmol/L. Severe acidosis manifests clinically as 
respiratory distress (rapid, deep, laboured breathing).  
• Hypoglycaemia: Blood or plasma glucose < 2.2 mmol/L (< 40 mg/dL)  
• Severe malarial anaemia: Haemoglobin concentration ≤ 5 g/dL or a haematocrit of ≤ 15% 
in children < 12 years of age (< 7 g/dL and < 20%, respectively, in adults) with a parasite 
count > 10 000/µL  
• Renal impairment: Plasma or serum creatinine > 265 µmol/L (3 mg/dL) or blood urea > 
20 mmol/L  
• Jaundice: Plasma or serum bilirubin > 50 µmol/L (3 mg/ dL) with a parasite count > 100 
000/ µL 
• Pulmonary oedema: Radiologically confirmed or oxygen saturation < 92% on room air 
with a respiratory rate > 30/ min, often with chest indrawing and crepitations on 
auscultation  
• Significant bleeding: Including recurrent or prolonged bleeding from the nose, gums or 
venepuncture sites; haematemesis or melaena  
• Shock: Compensated shock is defined as capillary refill ≥ 3 s or temperature gradient on 
leg (mid to proximal limb), but no hypotension. Decompensated shock is defined as 
systolic blood pressure < 70 mm Hg in children or < 80 mmHg in adults, with evidence 
of impaired perfusion (cool peripheries or prolonged capillary refill).  
• Hyperparasitaemia: P. falciparum parasitaemia > 10% 
 
Blood samples for hematologic and biochemical assays  
Serum biochemistries will be examined on site using a COBAS C111 Analyzer. Full blood count 
will be measured with a Haematology - Mindray Shenzhen analyzer.  
 
Urinalysis 
Urine will be collected into a clean container. A dipstick will be used that measures a variety of 
analytes, including pH, urobilinogen, bilirubin, protein, glucose, hemolyzed and nonhemolyzed 
blood, nitrites, ketones, and leukocyte esterase. 

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8.3.2 Special Assays or Procedures 
DHA analyte  
Blood Samples for IV artesunate/DHA will be collected in fluoride-oxalate tubes. Blood samples 
will be delivered within 15 min of collection to the Infectious Diseases Research Collaboration 
laboratory in Tororo Hospital for plasma separation. Aliquots of plasma will be stored at -80°C. 
Plasma aliquots will be shipped intermittently to the IDI Core Laboratory for storage prior to 
quantification. Aliquots will be tested at either at the IDI Core Laboratory or at the Clinical 
Pharmacology Analytical Laboratory at JHU, Baltimore, Maryland, USA.   
 
Dried blood spot for known K13 artemisinin resistance mutations 
A dried blood spot will be obtained at enrollment for assessment of known K13 artemisinin 
resistance mutations. Specimens will be shipped to the University of Maryland, Baltimore 
(UMB) for parasite deoxyribonucleic acid (DNA) extraction and sequencing. The presence of 
K13 mutations known to be associated with artemisinin resistance will be determined for each 
specimen.  
 
RNA preservation for parasite variant surface antigen expression analysis 
Venous blood will be collected in PAXgene tubes at screening for future analysis of preserved 
parasite RNA. RNA will be analyzed to determine the predominant variant surface antigens 
expressed by malaria parasites, allowing for classification of severe malaria cases in this regard. 
 
Other special procedures including neurodevelopmental assessments and BCS will be included 
in the study MOP and/or SOPs.  
8.3.3 Specimen Preparation, Handling, and Shipping 
Samples for DHA will be processed using solid-phase extraction and DHA will be quantified by 
LC MS/MS with an assay validated according to FDA guidelines. 
8.3.3.1 Instructions for Specimen Preparation, Handling, and Storage 
Detailed SOPs are maintained for these activities. Briefly, blood samples are obtained and 
processed in the sample processing laboratory according to SOPs. Plasma is frozen in freezers 
according to SOPs. Dried blood spot specimens will be shipped to the UMB. Frozen samples 
will be transported to the IDI Translation lab at the IDI in Kampala, and stored there in 
temperature-monitored freezers or shipped to the DMID clinical material services (DMID-CMS). 
International Air Transport Association (IATA) guidelines will be followed for specimen 
handling, transport and shipping. 

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8.3.3.2 Specimen Shipment 
The Investigators will maintain detailed SOPs for specimen transport and storage. All staff and 
investigators will be trained in the SOPs relevant to their duties and will sign copies of the SOPs 
to document this training. Copies of SOPs will be available for inspection and review by DMID 
and study monitors. During the study, SOPs may be modified to improve them, and new SOPs 
may be developed as needed to improve operations and ensure adherence with the protocol. 

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9 
ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
No safety outcome measures are planned for this trial. 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
9.2.1 Adverse Events 
An AE includes any noxious, pathological or unintended change in anatomical, physiological or 
metabolic functions as indicated by physical signs, symptoms and/or laboratory-detected changes 
occurring in any phase of the clinical study whether associated with the study product and 
whether or not considered related to the intervention. This definition includes an exacerbation of 
pre-existing conditions or events, intercurrent illnesses, or drug interaction. Anticipated day-to-
day fluctuations of pre-existing conditions that do not represent a clinically significant 
exacerbation need not be considered AEs. Discrete exacerbations of chronic conditions that are 
deemed to be different than regularly sustained day-to-day fluctuations, occurring during a study 
period will be reported as AEs in order to assess changes in frequency or severity. 
 
AEs will be documented in terms of a medical diagnosis. When this is not possible, the AE will 
be documented in terms of signs and/or symptoms observed by the investigator or reported by 
the subject at each study visit. Abnormalities in clinical findings and in clinical laboratory testing 
will only be captured as AEs after the baseline visit. Pre-existing conditions or signs and/or 
symptoms (including any which are not recognized at study entry but are recognized during the 
study period) present in a participant before the start of the study will be recorded on the 
participant’s CRF and will be recorded as an AE if deterioration or exacerbation in the condition 
occurs during the study. Any inpatient overnight hospitalization other than the inpatient stay for 
severe malaria treatment will be considered an SAE.  Information to be collected include event 
description, date of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), relationship to study 
procedures and date of resolution/stabilization of the event. All AEs will be followed to adequate 
resolution or stabilization.  
 
All AEs must be graded for severity. 
 
FDA defines AE as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 

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Severity of Event: All AEs will be assessed by the PI or appropriate sub-investigator using the 
Division of AIDS (DAIDS) Table for Grading of Severity of Adults and Pediatric Adverse 
Events. For unsolicited events not included in the DAIDS Table, the following guidelines will be 
used to quantify intensity:  
• 
Mild (Grade 1)- events require minimal or no treatment and do not interfere with the 
participant’s daily activities. 
• 
Moderate (Grade 2)- events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning and 
daily activities. 
• 
Severe (Grade 3)– events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually incapacitating. 
 
If an AE changes in severity, it is not a new event, and each AE is documented at its highest 
severity grading. AEs characterized as intermittent require documentation of onset and duration 
of each episode. 
9.2.2 Serious Adverse Events 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes:  
• 
Death, 
• 
A life-threatening AE*,  
• 
Inpatient hospitalization or prolongation of existing hospitalization,  
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or  
• 
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. 
 

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* Life-threatening AE. An AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It 
does not include an AE, had it occurred in a more severe form, might have caused death. 
 
All SAEs will be: 
• 
recorded on the appropriate SAE form and electronic case report form (eCRF) 
• 
reviewed and evaluated by an ISM, DMID, and the IRB, if indicated 
9.3 
Reporting Procedures 
AEs and SAEs will be documented from the first study intervention, through the end of the 
follow-up period.  
 
All AEs and SAEs will be captured on the appropriate data collection form. Information to be 
collected includes event description, date of onset, investigator assessment of severity, 
relationship to study product, date of resolution of the event, and outcome.  
9.3.1 Serious Adverse Events 
AEs will be followed to adequate resolution or stabilization for participants enrolled in the study. 
After termination of the study, participants will be referred to appropriate care for follow-up of 
ongoing AEs. Any AE that is associated with the study drug will be followed to resolution or 
stabilization with the expectation that it will remain chronic. Any AE that meets a protocol-
defined serious criterion must be submitted to DMID within 24 hours of site awareness via the 
IDES or a DMID SAE form. SAE information is reported via the Adverse Event eCRF in 
Advantage eClinical. At the time of submission of the AE eCRF in Advantage eClinical, an 
automatic email will be sent to the DMID Medical Monitor, DMID, and the study PI, alerting 
them to the occurrence of an SAE. No further steps are necessary to notify the DMID Medical 
Monitor. Updates to the SAE should be reported via the AE eCRF. 
 
In addition to the reporting to DMID, the investigator must also report to the ethics committee 
and IRB. Any AE that meets a protocol-defined serious criterion and is considered related to the 
investigational product must be submitted, unless otherwise requested by the ISM, sponsor or the 
investigators: 
• 
Within 48 hours to the Uganda IRB 
• 
Within 5 days to the University of Maryland IRB 
 

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For other AEs that meet a protocol-defined serious criterion and are considered not related to the 
investigational product, this information can be submitted, unless otherwise requested by the 
ISM, sponsor or the investigators: 
• 
In the annual summary to the Uganda IRB 
• 
In the annual summary to the University of Maryland IRB 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events 
Investigators will follow up subjects with AEs and SAEs until the event has resolved, or, if a 
chronic condition has developed, until the end of the study follow-up period. Outcome will be 
assessed as Recovered/Resolved, Recovered/Resolved with Sequelae, Recovering/Resolving, 
Not recovered/Not resolved, or Fatal. 
9.5 
Halting Rules 
Decisions to halt or pause the study will be made by the host REC and DMID.  
 
Subsequent review of serious, unexpected, and related AEs by the Medical Monitor, ethics 
review committee, the sponsor, or relevant local regulatory authorities may also result in 
suspension of further trial interventions/administration of study product at a site. The host REC 
and study sponsor retain authority to suspend additional enrollment and study 
interventions/administration of study product for the entire study, as applicable. 
 
9.6 
Safety Oversight (ISM) 
A Safety Monitoring Committee is not required for this protocol. 
 
An ISM is a physician with relevant expertise whose primary responsibility is to provide to 
DMID an independent safety assessment in a timely fashion. Participation is for the duration of 
the DMID study and is a voluntary position that does not receive payment. 
 
The ISM: 
• 
Is near the study site and has the authority and ability to readily access study participant 
records in real time. 
• 
May be a member of the participating institution’s staff but preferably be from a different 
organizational group within the institution. 
• 
Should not be in a direct supervisory relationship with the investigator. 
• 
Should have no direct involvement in the conduct of the study. 

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The ISM will: 
• 
Sign a Conflict of Interest (COI) certification at the time they are asked to participate and 
provide updates to this information as needed. 
• 
Receive reports of SAEs from the site investigator and will be notified by email when the 
REC and DMID are notified of the SAE. 
• 
Evaluate the SAE and report their clinical assessment to the REC and DMID, through 
DMID-Clinical Research Operations and Management Support (CROMS) Safety Oversight 
Committee Support (SOCS) in a timely manner and email the report to REC and DMID-
CROMS SOCS. 
• 
Communicate with the investigator at the participating site as needed. 
• 
Review additional safety related events at the request of the REC and DMID. 
• 
Provide additional information to REC and DMID by teleconference as requested. 

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10 
CLINICAL MONITORING 
10.1 Site Monitoring Plan 
Study site monitoring will be conducted by the internal IDI monitor and DMID clinical 
monitoring contractor to ensure that the conduct of the trial is in compliance with the currently 
approved protocol, amendment(s), ICH, sponsor requirements  GCP standards, and regulatory 
guidelines are being followed. Clinical monitoring will also verify that any critical study 
procedures are completed following specific instructions in the protocol-specified MOP. A pre-
trial monitoring visit will be made to the study site, including the clinical laboratory. All records 
will be made available to monitors, including regulatory files, CRFs and source documents, 
quality assurance (QA)/quality control (QC) documentation, SOPs, etc. Additional study site 
visits may be made during the trial and at the end of the surveillance period. 
 
In addition, monitors from the University of Maryland may make study site visits, in 
coordination with the primary monitoring group designated by DMID. 
 
In conjunction with the clinical monitoring contractor designated by the sponsor, a detailed 
monitoring plan will be developed. This document describes who will conduct the monitoring, at 
what frequency monitoring will be done, and what level of detail monitoring will be conducted. 
The clinical monitoring plan will be written by DMID and the DMID clinical monitoring 
contractor. This separate monitoring plan will be agreed upon with the Office of Clinical 
Research Affairs (OCRA) and will describe protocol-specific items to be monitored. The 
monitoring plan will include the number of participant charts to be reviewed, which/what 
proportion of data fields and what will be monitored, who will be responsible for conducting the 
monitoring visits, and who will be responsible for ensuring that monitoring findings are 
addressed.  Monitoring visits will include, but are not limited to, review of regulatory files, 
accountability records, electronic case report forms (eCRFs), ICFs, medical and laboratory 
reports, site study intervention storage records, training records, and protocol and GCP 
compliance. Site monitors will have access to each participating site, study staff and all study 
documentation according to the DMID-approved CMP. Study monitors will meet with all 
participating site PIs to discuss any problems and outstanding issues and will document site visit 
findings and discussions. 

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11 
STATISTICAL CONSIDERATIONS 
11.1 Study Hypothesis 
The primary objective of this study is to determine the relationship between DHA exposures 
following IV dosing and markers of physiologic dysfunction associated with severe malaria. This 
objective can be framed as a series of statistical hypothesis tests, each evaluating the effect of the 
DHA exposure parameter on the marker of physiologic dysfunction, measured at a specific 
timepoint, while adjusting for covariates. The null hypothesis is that there is no effect of 
exposure on response, and the alternative hypothesis is that there is an effect. The secondary 
objectives can be framed in an analogous manner, with time to hospital discharge and measures 
of parasite clearance as the response variables.  
11.2 Sample Size Considerations 
A maximum of 100 subjects would provide sufficient sample size to achieve precision on PK 
parameters following the FDA pediatric precision criteria for conducting PK studies (achieving a 
95% confidence interval (CI) within 60% and 140% of the geometric mean).   
 
Simulations in R version 3.4.2 were used to explore power to detect simple linear relationships 
between exposure and response in the analysis of the primary objective with the planned sample 
size. The primary objective of this study encompasses multiple exposure and response variables, 
and the response variables are measured at multiple timepoints. Thus, there are multiple 
exposure-response relationships that are of interest (one for each unique combination of exposure 
variable, response variable, and timepoint), and there is a need to control type I error. As this 
study is exploratory (hypothesis-generating) rather than confirmatory, Benjamini-Hochberg 
procedure is used to control the false discovery rate at 0.05 (Benjamini 1995). 
 
For a multiple hypothesis test, average power is defined as the proportion of false null 
hypotheses that were correctly rejected (Benjamini 1999). Table 11.1 provides the average power 
computed from 5000 simulations, varying the following quantities: 
• 
Number of total statistical tests, representing the number of combinations of exposure 
variable, response variable, and timepoint to be tested in support of the primary objective 
• 
Value of R2 for the true, non-null exposure-response relationships 
• 
Proportion of tests with true, non-null exposure-response relationships with the specified R2 
• 
Sample size 

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Table 11.1: Average Power for Identifying Simple Linear Exposure-Response 
Relationships  
Number of 
Tests 
R2 
Proportion of Tests with 
Specified R2 
Power for N=100 
Subjects 
Power for N=80 
Subjects 
24 
0.2 
0.05 
0.95 
0.88 
48 
0.2 
0.05 
0.95 
0.88 
24 
0.2 
0.10 
0.97 
0.92 
48 
0.2 
0.10 
0.98 
0.92 
 
Simulation results indicate that the target sample size of 100 subjects provides >90% power for 
detecting simple linear relationships with an underlying R2 of at least 0.2, if the proportion of 
non-null relationships among those tested is at least 5%. If only 80 subjects complete follow-up 
for the primary endpoint, power for the same scenario is approximately 88%.  
Figure 11.1: Example Data with R2 = 0.2 and N=100 Observations 
 

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11.3 Final Analysis Plan 
Further details on the analyses discussed below will be provided in the Statistical Analysis Plan 
(SAP), which will be finalized prior to data lock. In case the language in this section differs from 
the language in the SAP, the SAP will take precedence. 
11.3.1 Analysis of Demographics and Baseline Characteristics 
Demographic characteristics (age, sex, and town/village of residence) of each participant will be 
tabulated. Weight-for-age and height-for-age z-scores will be determined based on WHO Child 
Growth Standards (WHO, 2006). Summary statistics (e.g. mean, range, and standard deviation) 
of age, weight, height, weight z-score, and height z-score will be tabulated by sex.  
11.3.2 Analysis of Safety 
The number of subjects experiencing unsolicited AEs, classified using the Medical Dictionary 
for Regulatory Activities (MedDRA®) System Organ Classes and Preferred Terms, reported 
throughout the study after study drug administration will be tabulated by severity, and 
relationship to study product. SAEs will be described. A complete listing of AEs for each subject 
will provide details including severity, relationship to study drug, onset, duration, and outcome. 
11.3.3 Clinical Laboratory Parameters 
Hematological and biochemical laboratory parameters will be measured at study days 1, 2, 3, 4, 
5, 6 and 7. Clinically relevant abnormal values based on reference intervals determined in a 
similar population will be tabulated and a trend analysis performed if deemed necessary. 
11.3.4 Analysis of Pharmacokinetics of Dihydroartemisinin 
Population PK models for DHA have been previously published but have not described the 
population PK of DHA in critically ill malaria patients and related it to the PD and clinical 
outcomes in the same analysis. This planned analysis involves use of the data to characterize the 
PK of DHA in these critically ill pediatric patients, and for the assessment of selected covariates 
on intersubject variability in the PK of DHA. Overall, the information gained from the planned 
analyses will support the understanding of exposure-response relationship to support dose 
regimen selection.  
Population PK analyses will be performed using Nonlinear Mixed Effects Modelling 
(NONMEM) v7.3 or higher, Pumas, or similar software. The general procedure that will be 
followed for the development of the population PK model is outlined below: 
1. 
Exploratory data analysis 

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The number of samples per subject and by timing relative to last dose will be summarized. 
Concentration outliers and other implausible values will be identified using scatterplots. 
Frequency of below quantification limit (BQL) concentrations will be determined. Outliers 
detected by exploratory data analysis may be queried prior to data lock and may be flagged for 
exclusion from analysis if problematic for fitting the model. 
2. 
Base structural model development for PK 
One- and two-compartment parent-metabolite models of artesunate and DHA will be considered, 
as well as one- and two-compartment models that do not explicitly model artesunate since 
artesunate concentrations will not be measured. Competing models will be distinguished by their 
objective function value, the plausibility of parameter estimates, and standard diagnostic plots, 
including observed vs. individual-fitted concentrations, observed vs. population-fitted 
concentrations and weighted residuals.  
3. 
Evaluation of covariate effects 
Allometric scaling will be evaluated using both standard values (0.75 for clearance and 1.0 for 
volume) and estimated coefficients. Sex and whether the subject had a dose of artesunate prior to 
enrollment will also be evaluated. Additional covariates for evaluation may be specified in the 
SAP. Inclusion of covariate relationships in the final model will be based on forward selection, 
with criteria mainly based on a statistically significant likelihood ratio test but also considering 
reduction of unexplained between subject variability and improved characteristics seen in 
diagnostic plots. 
4. 
Final model refinement 
Backwards elimination will be used to remove statistically or clinically insignificant covariate 
relationships. Distributions of individual random effect values will be used to assess outliers or 
possible subpopulations unaccounted for in the model. 
5. 
Model evaluation 
Predictive performance of the final model will be assessed using visual predictive checks and 
normal prediction distribution error. 
11.3.5 Analysis of Pharmacodynamics of Dihydroartemisinin 
Analysis Plan for Primary Outcome 
The primary outcome response variables are: temperature, serum lactate, serum glucose, 
acidosis, BCS, total and direct bilirubin, anemia. For each subject, values of the DHA exposure 

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parameters AUC0-12 and Cmax values for each individual subject and treated as fixed in 
downstream PD analyses.  
 
Regression methods will be used to characterize the relationship between exposure and 
responses, while controlling for covariates. For continuous response variables (temperature, 
serum lactate, serum glucose, acidosis, and anemia), linear, polynomial and Emax models with 
random effects will be considered. BCS is an ordinal scale designed to assess malarial coma in 
children, with possible values of 0, 1, 2, 3, 4, 5. Proportional odds mixed effects logistic 
regression will be used to model BCS.  
 
Covariates will include exposure, timepoint, the interaction between exposure and timepoint, and 
potential confounding variables such as receipt of artesunate or artemisinin-based therapy prior 
to enrollment. Specific details of all models will be described in the SAP, and will include: 
• 
The precise definition or derivation of each response variable, including potential 
transformations and the method for accounting for baseline values and/or associations 
between the baseline value and exposure 
• 
The pre-specified covariates to be included in the model 
• 
The procedure for choosing the covariance structure 
• 
The alternative methods which may be considered, if model assumptions do not hold 
For the analysis of the response variables included in the primary outcome, the set of p-values 
corresponding to tests of the effect of exposure on response at each timepoint will be adjusted 
using the Benjamini-Hochberg procedure to preserve the false discovery rate for the primary 
outcome at 0.05. The corresponding point estimates and CIs will be reported. Graphical displays 
of response by exposure at each timepoint will show individual measurements alongside model 
estimates. Individual trend plots of responses over time will also be generated for each response 
variable. 
Analysis Plan for Secondary Outcomes 
The secondary outcome response variables are time to hospital discharge, and measures of 
parasite clearance calculated from parasite density, as measured by thick blood smear such as 
parasite clearance half-life, total parasite clearance by Day 2, and time to 90% reduction in 
parasitemia. Parasite clearance half-life (PCT50) and time to 90% reduction (PCT90) will be 
estimated using the WorldWide Antimalarial Resistance Network (WWARN) parasite clearance 
estimator (PCE) algorithm (Flegg 2011). The relationship between AUC0-12 and Cmax and the 
time-to-event response variables will be analyzed using Cox proportional hazards regression. 

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The relationship between AUC0-12 and Cmax and the binary variable of total parasite clearance by 
Day 2 will be analyzed using logistic regression. Covariates will include exposure and potential 
confounding variables. The full list of covariates to be considered and the variable selection 
strategy will be described in the SAP. Analyses of secondary outcome variables will not be 
adjusted for multiplicity. 
11.3.6 Missing Data 
Every effort will be made to minimize missing data and collect all endpoints specified in this 
protocol. Subjects who discontinue treatment will be followed after treatment discontinuation for 
collection of all scheduled follow-up data with their consent. Sensitivity analyses will be 
conducted to exclude the subset of subjects who received IV artesunate prior to enrollment. No 
adjustments for missing safety data will be performed for the secondary analyses. Handling of 
missing dosing, PK, covariate, and outcome data will be described in the SAP.  
11.4 Study Cohorts/Datasets to be Evaluated 
 
Safety Population 
The safety population will include all subjects who received at least 1 dose of IV artesunate 
 
Population PK Analysis Population 
The Population PK Analysis Population will include all evaluable subjects who received at least 
1 dose of IV artesunate and had at least 1 measurable DHA concentration.  
 
Pharmacodynamic Analysis Population 
The PD Analysis Population will include all subjects for which exposure parameters can be 
obtained from the final population PK model and for which post-baseline response data are 
available.  

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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The participating study site will maintain appropriate medical and research records for this trial, 
in compliance with ICH harmonised tripartite guideline E6(R2): GCP, Section 4.9 and regulatory 
and institutional requirements for the protection of confidentiality of subjects.  
 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ memory aid or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and participant files and records 
kept at the pharmacy, at the laboratories, and medico-technical departments involved in the 
clinical trial. 
 
eCRFs will be supplied by The Emmes Company, LLC under contract to the National Institute of 
Allergy and Infectious Diseases (NIAID), and a remote data entry system will be used. Data 
collection forms derived from the eCRFs will be made available on the project website as Source 
Document Workbooks (SDWs). The SDW for each participant will be maintained at the study 
site. All SDWs will be filled out completely and by appropriate study personnel. These data 
collection forms compiled as SDWs will serve as source documents. 
 
The study site will permit authorized representatives of DMID, DMID designees, and 
appropriate regulatory agencies to examine (and when required by applicable law, to copy) 
clinical records for the purposes of QA reviews, audits and evaluation of the study safety and 
progress. These representatives will be permitted access to all source data. 

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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted study site quality management plan, the study site will 
conduct routine QA and QC activities to internally monitor study progress and protocol 
compliance. The quality management plan is located in the University of Maryland Center for 
Vaccine Development Office of Regulatory Affairs and Quality Management. The protocol-
specific quality management plan is in conjunction with the University of Maryland Center for 
Vaccine Development Office of Regulatory Affairs and Quality Management and describes the 
study site’s internal quality management activities including how the data will be evaluated for 
compliance with the protocol, which documents will be reviewed, and methods of training staff. 
 
SOPs will be used at all clinical and laboratory sites. Routine monitoring will be performed 
according to ICH/GCP (E6) (e.g., data monitoring). IDI and DMID-designated clinical monitors 
will verify that the clinical trial is conducted, and data are generated, documented (recorded), and 
reported in compliance with the protocol, GCP, and the applicable regulatory requirements. The 
study site will provide direct access to all trial-related sites, source data/documents, and reports 
for the purpose of monitoring and auditing by DMID, and inspection by local and regulatory 
authorities.  
 
Emmes and the study site data manager will implement QC procedures beginning with the data 
entry system and generate data QC checks that will be run on the database. Any missing data or 
data anomalies will be communicated to the study site for clarification/resolution. 

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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 Ethical Standard 
The IDI Research Ethics Committee (REC), the National Drug Authority and the Uganda 
National Council for Science and Technology (UNCST) will review and approve the protocol 
before study start. In addition, the study will be reviewed by DMID and the University of 
Maryland IRB. Documentation of the approval by these ethical review boards will be kept in the 
study site’s regulatory file. 
14.2 Institutional Review Board 
All amendments will be submitted to the local REC, the University of Maryland, Baltimore 
(UMB) IRB, and to DMID. No amendments will go into effect without written approval from the 
local REC, the UMB IRB, and DMID except when necessary to eliminate immediate hazards to 
the participants. Protocol deviations will also be reported to each REC/IRB according to the 
policy of each IRB.  
 
The investigators will inform all the REC/IRBs and DMID of the following: 
• 
All subsequent protocol amendments, informed consent/assent form (ICF) changes or 
revisions of other documents originally submitted for review 
• 
Serious and/or unexpected AEs occurring during the study, where required 
• 
New information that may affect adversely the safety of the participants or the conduct of the 
study 
• 
An annual update and/or continuing review reports, as required 
• 
A final report including SAE outcomes will be provided when the study has been completed. 
14.3 Informed Consent/Assent Process 
The principles of informed consent/assent in the current edition of the Declaration of Helsinki 
will be implemented before any protocol-specified procedures or interventions are carried out. 
 
Information will be given in both oral and written form whenever possible. The written 
consent/assent documents will embody the elements of informed consent/assent as described in 
the current edition of the Declaration of Helsinki, will adhere to the ICH Harmonised Tripartite 
Guideline for Good Clinical Practice and 45CFR46 and 21CFR50, and will also comply with 
applicable host country regulations. The oral consent/assent process will be consistent with 
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used to attest that illiterate persons have understood the contents of the informed consent/assent 
document before signing the written consent/assent document. 
14.3.1 Screening and Study Informed Consent/Assent 
A period of 24 hours is allotted for screening and recruitment to allow plenty of time for a 
participant or participant’s parent/guardian to consider their decision about participating and to 
discuss their/their child’s participation. At the times of screening and recruitment, the 
consent/assent forms are either provided in written English or local languages (Ateso, Lugwere, 
Kiswahili, Luganda and Japadhola) or read to illiterate participants who speak English or local 
languages (Ateso, Lugwere, Kiswahili, Luganda and Japadhola). For illiterate participants, 
informed consent will be administered by oral translation of the text in presence of a witness. In 
all cases, the investigator will give the participants ample opportunity to inquire about the details 
of the study and to ask any questions before dating and signing the consent/assent forms, 
including the opportunity to take a copy of the consent/assent form home to review with family 
members or others before returning on a later day with their decision. All illiterate individuals 
will have the study and consent/assent forms explained to them point by point by the interviewer 
in the presence of a witness who will sign the consent form. Witnesses will have no association 
with the conduct of the study and will not be related to the study participant. Witnesses receive 
training that emphasizes protection of confidentiality and assist with ensuring full and accurate 
oral translation of the information on the consent/assent forms. Individual consent/assent to 
participate in research studies is given freely and is not subject to approval by village elders or 
others. Investigators will carefully explain to potential participants that they may withdraw their 
participation from the study at any point in the future. 
 
Informed consent/assent will be documented using a written consent/assent form approved by the 
IRBs and signed or thumb printed and dated by the participant, and by the person who conducted 
the informed consent/assent discussion. Thumb printing will be used for illiterate persons, who 
are expected to constitute the majority of participants. The English consent/assent form will be 
translated into local languages spoken at the study site. For illiterate participants who do not 
speak English, consent will be administered by a study clinician who is fluent in local language, 
or the study clinician use a translator. A witness will assist during the procedure. After the 
participant clearly states that she/he has understood what was explained and agrees to participate 
in the study, the consent/assent forms will be completed. The participant will be asked if she/he 
prefers to thumbprint or to sign. In the case of the thumbprint option, the distal end of her/his left 
thumb will be applied to a stamp inker and then firmly applied to the space on the consent/assent 
forms reserved for thumbprints.  
 

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The signature/thumbprint confirms that the consent/assent is based on information that has been 
understood. Each participant’s signed ICF/assent is kept on file by the investigator for possible 
inspection by regulatory authorities. The participant will receive a copy of the signed and dated 
written ICF/assents and any other written information provided by the investigator, and will 
receive copies of any signed and dated consent/assent form updates and any amendments to the 
written information. 
 
Since most study participants do not use telephones, fax or mail, contact information is provided 
in terms of local study site staff who can be visited directly and who can themselves reach the 
investigators directly or by telephone. 
14.3.2 Compensation and Reimbursement 
To compensate the participant for time lost to income generating activities as a result of 
participating in the study, each participant will receive 50,000 Ugandan shillings per inpatient 
day and 20,000 Ugandan shillings per outpatient follow-up visit, according to local ethics 
standards. Additionally, participants will be provided transport reimbursement of 20,000 
Ugandan shillings for transport costs on scheduled study visits. 
14.4 Exclusion of Women, Minorities, and Children (Special Populations) 
As most severe malaria illnesses occur in children, it is deemed ethical to perform this study first 
in children whose parent/guardian can give full, informed independent consent and assent where 
applicable. Persons will be screened, recruited, and enrolled into this study without regard for 
ethnicity or gender.  
14.5 Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and 
the sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participating subjects. 
 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study, or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
 
The study monitors or other authorized representatives of the sponsor may inspect all documents 
and records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the subjects in this study. The study 
site will permit access to such records. 

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Participants will be assigned a unique participant ID number. All results will be keyed to this 
number. Study records will only be available to staff members and will be kept locked at the 
study site conforming to the investigators’ SOPs. Following the conclusion of the study, all 
records will be maintained on site for a minimum of two years, after which they will be stored 
long-term in the data storage facilities at the IDI. Representatives of DMID may review these 
records. 
14.6 Study Discontinuation 
The study may be discontinued at any time by DMID, the IRB, or the investigators. If the study 
is discontinued before completion, all participants who received study product will be asked to 
follow up with the study team for debriefing. Study team personnel will be available for 
questions or follow-up should evaluation be needed.  
 
When the study ends, participants will be instructed to seek routine medical care offered at the 
local health clinic. AEs that are ongoing at the time of study discontinuation will be followed by 
study staff to resolution, or, if a chronic condition has developed, until the end of the study 
follow-up period.  
14.7 Future Use 
14.7.1 PAXgene Collection for Transcriptomics Assessments 
Whole blood in PAXgene tubes will be collected for future research for RNA-Seq. The goal of 
these analyses could include identification and characterization of parasite gene expression.   
14.7.2 Use of Stored Specimens 
Future use of specimens is planned for this protocol. Assent and Parent/guardian consent for 
future use of leftover specimen will be required for storage of specimens for future use. If 
assent/parent/guardian consent for future use of leftover specimen is not obtained, any leftover 
specimen will be destroyed according to institutional SOPs after assays are completed and results 
are verified.  

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15 
DATA HANDLING AND RECORD KEEPING 
The PI is 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 or blue 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. 
 
CRFs will serve as source documents. Only information that cannot be collected initially onto 
CRFs (namely, clinical laboratory test results and AE medical records) will first be collected 
onto separate source documents before transcription into CRFs. The information in the CRF will 
then be entered directly into the Internet data system. 
 
CRFs derived from the eCRF will be provided and maintained for recording data for each 
participant 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 its designee will provide guidance to investigators on making corrections to the 
source documents and eCRF. 
 
A copy of the cleaned and locked database will be provided to DMID and the PI at the end of the 
study. 
15.1 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. AEs must be graded, assessed 
for severity and causality, and reviewed by the study site PI or designee. 
 
Data collection is the responsibility of the clinical trial staff at the study site under the 
supervision of the PI. During the study, the investigator must maintain complete and accurate 
documentation for the study. 
 
The Emmes Company, LLC will serve as the Statistical and Data Coordinating Center (SDCC) 
for this study and, in collaboration with the study data manager, will be responsible for data 
management, quality review, analysis, and reporting of the study data. 

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15.2 Data Capture Methods 
Clinical data (including AEs and concomitant medications) and clinical laboratory data will be 
entered into a 21 CFR Part 11-compliant IDES provided by Emmes. The data system 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. 
15.3 Types of Data 
Safety assessments will be based on reports collected from review of AE and SAE reports. All 
AEs will be MedDRA® coded for Preferred Term and System Organ Class. The rate of AEs in 
aggregate, and by MedDRA® codes, will be computed. 
 
The number of SAEs is likely to be small in this study and will be reported by a detailed listing 
showing the type, MedDRA® coding, relevant dates (study drug administration and AE), 
severity, and outcome for each event.  
 
An individual forms grid, which indicates the current status of forms submission for each 
participant is provided as part of Emmes’ Advantage eClinicalSM IDES. 
15.4 Timing/Reports 
Primary data analysis will occur after the primary study endpoint is reached at study day 183. 
Results of this primary data analysis will be available for public release.  
 
Coding of AEs will be according to the MedDRA classification and will be managed by the 
statistical data and coordinating center as AE data is entered into the online database. 
15.5 Study Records Retention 
Study documents should be retained for a minimum of 2 years. 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 DMID. It is the responsibility of DMID to inform the 
investigator when these documents no longer need to be retained. 
15.6 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or MOP 
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 study site 
and implemented promptly.  

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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 
 
5.20 
Noncompliance, sections 5.20.1, and 5.20.2. 
 
It is the responsibility of the study site to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation, or within 5 working 
days of the scheduled protocol-required activity. All deviations must be promptly reported to 
DMID, via Emmes’ IDES . 
 
All deviations from the protocol must be addressed in study subject source documents. A 
completed copy of the DMID Protocol Deviation Form (IDES form) must be maintained in the 
regulatory file, as well as in the subject’s source document. Protocol deviations must be sent to 
the local IRB/IEC per their guidelines. The study site PI/study staff is responsible for knowing 
and adhering to their IRB/IEC requirements. 

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16 
PUBLICATION POLICY 
Following completion of the study, the investigator is expected to publish the results of this 
research in a scientific journal. The International Committee of Medical Journal Editors (ICMJE) 
member journals have adopted a trials-registration policy as a condition for publication. This 
policy requires that all clinical trials be registered in a public trials registry such as 
ClinicalTrials.gov, which is sponsored by the National Library of Medicine. Other biomedical 
journals are considering adopting similar policies. It is the responsibility of DMID to register this 
trial in an acceptable registry. Any clinical trial starting enrollment after 01 July 2005 must be 
registered on or before patient enrollment.  
 
The ICMJE defines a clinical trial as any research project that prospectively assigns human 
subjects to intervention or comparison groups to study the cause-and-effect relationship between 
a medical intervention and a health outcome. Studies designed for other purposes, such as to 
study PK or major toxicity (e.g., Phase I trials), would be exempt from this policy. 

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17 
LITERATURE REFERENCES 
1. World Health Organization. Guidelines for the treatment of malaria [Internet]. World 
Health Organization; 2015 Aug 13. 317 p. Available from: 
https://apps.who.int/iris/bitstream/handle/10665/162441/9789241549127_eng.pdf. 
2. World Health Organization. World malaria report 2019 [Internet]. 2019. 232 p. Available 
from: https://www.who.int/publications/i/item/9789241565721. 
3. World Health Organization. Guidelines for the treatment of malaria [Internet]. World 
Health Organization; 2015 Aug 13. 317 p. Available from: 
https://apps.who.int/iris/bitstream/handle/10665/162441/9789241549127_eng.pdf. 
4. Centers for Disease Control and Prevention. Intravenous artesunate for treatment of 
severe malaria in the United States. IND Protocol [Internet]. 2007 [Updated 2016 Dec 
19]. 50p. Available from: 
https://www.cdc.gov/malaria/resources/pdf/artesunate/Artesunate_protocol_12_19_2016.
pdf. 
5. Centers for Disease Control and Prevention. Guidelines for treatment of malaria in the 
United States [Internet]. Atlanta: Centers for Disease Control and Prevention. 2013. 4 p. 
Available from: 
https://www.cdc.gov/malaria/resources/pdf/Malaria_Treatment_Table_120419.pdf. 
6. World Health Organization. Guidelines for the treatment of malaria [Internet]. World 
Health Organization; 2015 Aug 13. 317 p. Available from: 
https://apps.who.int/iris/bitstream/handle/10665/162441/9789241549127_eng.pdf. 
7. Benjamini Y, & Hochberg, Y. Controlling the false discovery rate: a practical and 
powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol. 1995 
Jan;57(1):289-300. doi: https://doi.org/10.1111/j.2517-6161.1995.tb02031.x. 
8. Benjamini Y, Liu W. A step-down multiple hypotheses testing procedure that controls the 
false discovery rate under independence. J Stat Plan Inference. 1999;82(1):163-70. doi: 
https://doi.org/10.1016/S0378-3758(99)00040-3. 
9. World Health Organization. WHO child growth standards: length/height-for-age, weight-
for-age, weight-for-length, weight-for-height and body mass index-for-age: methods and 
development. World Health Organization; 2006 Nov 11. 312 p. Available from: 
https://www.who.int/publications/i/item/924154693X. 
10. Flegg JA, Guerin PJ, White NJ, Stepniewska K. Standardizing the measurement of 
parasite clearance in falciparum malaria: the parasite clearance estimator. Malar J. 
2011;10:339. Epub 2011/11/15. doi: 10.1186/1475-2875-10-339. PubMed PMID: 
22074219; PMCID: PMC3305913. 
 
 

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18 
SUPPLEMENTS/APPENDICES 

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19 
APPENDIX A: SCHEDULE OF EVENTS 
Table 19.1: Schedule of Events 
Procedures 
Screening 
Day -1 to 1 
Enrollment 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 (±2 days) 
Day 14 (±2 days) 
Day 28 (±4 days) 
Final Study Visit,  
Day 183 (±14 
d
)
Early termination 
(ET) Visit 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
Administer IV artesunate 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Administer oral ACT 
 
 
 
 
X 
X 
X 
 
 
 
 
 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam  
X 
X 
X 
X 
X 
X 
X 
X 
X* 
X* 
X 
X* 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Vital signs*** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Weight 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Thick blood smear for Pf 
parasitemia (per parasitemia 
sampling plan) 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Dried blood spot for artemisinin 
resistance 
X 
 
 
 
 
 
 
 
 
 
 
 
PAXgene tube for mRNA 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology  
X 
X 
X 
X 
X 
X 
X 
X 
X** 
X** 
X 
X^ 
Serum bicarbonate 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X^ 
Serum lactate  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X^ 
Serum sodium 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X^ 
Serum potassium 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X^ 
Serum creatinine 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X^ 
Serum glucose 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X^ 
Serum bilirubin, ALT and AST 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X^ 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Blantyre coma score 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacokinetic assessments 
(per PK sampling plan) 
X 
X 
 
 
 
 
 
 
 
 
 
 
Neurodevelopmental 
assessments (parent or caregiver 
interview, standardized 
developmental, cognitive & 
behavioral measures)  
 
 
 
 
 
 
 
X 
X 
X 
X 
 
* Targeted physical exam, if needed 
**Only hemoglobin 
*** approximately every 6 h until 6 h post parasite clearance 
^ If ET is before D7, collect D7 blood samples; if D8 to D14 may collect serum bicarbonate, hemoglobin, platelets, WBC count, and 
neutrophil count. If >D14 blood for hemoglobin, platelets, WBC count, and neutrophil count.