Extended Duration Artemether-lumefantrine Treatment for Malaria in Children
Phase: PHASE4
Conditions: Uncomplicated Plasmodium Falciparum Malaria
Sponsor: University of California, San Francisco

EXALT TRIAL: EXTENDED DURATION ARTEMETHER-LUMEFANTRINE 
TREATMENT FOR MALARIA IN CHILDREN 
A UCSF/ YALE/
INFECTIOUS DISEASES RESEARCH COLLABORATION (IDRC)
 Sponsored by: 
The National Institute of Child Health and Human Development 
Principal UCSF Investigator: 
Francesca Aweeka, Pharm.D.
University of California, San Francisco
Principal Yale Investigator:
Sunil Parikh, M.D., MPH
Yale School of Public Health
Principal MU Investigator:  
Norah Mwebaza, MBChB, DPPM, PhD
Makerere University
Study Co-Chairs:  
Sunil Parikh, M.D., MPH
Yale School of Public Health
Norah Mwebaza, MBChB, DPPM, PhD.
Makerere University
Francesca Aweeka, Pharm.D.
University of California, San Francisco
UCSF-CHR Number:
17-22578
SOMREC Number:
2017-117
UNCST Number: 
  HS2323
Yale HIC Number:
2000021248
National Clinical Trial (NCT) Number:
Version Number: v.1.3
Version Date: 19 July 2018
NCT03453840

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Table of Contents
PROTOCOL TEAM ROSTER..................................................................................................................5
GLOSSARY................................................................................................................................................7
EXALT TRIAL SCHEMA...........................................................................................................................9
I.0 INTRODUCTION................................................................................................................................12
1.1 Background ....................................................................................................................................12
1.2 Rationale.........................................................................................................................................15
2.0 STUDY OBJECTIVES......................................................................................................................17
2.1 Primary Objectives:.......................................................................................................................17
2.2 Secondary Objectives:..................................................................................................................17
3.0 STUDY DESIGN................................................................................................................................17
3.1 Overview of Pharmacokinetic Sampling Design.......................................................................17
3.2 Overview of study groups.............................................................................................................19
3.3 Study sites......................................................................................................................................21
4.0 SELECTION AND ENROLLMENT OF SUBJECTS.....................................................................21
4.1 Inclusion Criteria............................................................................................................................21
4.2 Exclusion Criteria ..........................................................................................................................22
4.3 Identification and recruitment of study participants..................................................................22
4.4 Screening .......................................................................................................................................23
4.5 Study informed consent and enrollment ....................................................................................24
5.0 MALARIA and HIV TREATMENT ...................................................................................................24
5.1 Artemether-lumefantrine (Coartem®).........................................................................................24
6.0 CLINICAL AND LABORATORY EVALUATIONS.........................................................................28
6.1 Schedule of Evaluations...............................................................................................................28
6.2 Malaria Diagnosis..........................................................................................................................28
6.3 Classification of Uncomplicated Malaria ....................................................................................29
6.4 Management and Follow-up of Malaria......................................................................................29
6.5 Anthropometric measurements to assess nutritional status. ..................................................32
6.6 Clinical Laboratory Studies ..........................................................................................................32

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6.7 Pharmacology Laboratory Studies..............................................................................................32
6.8 Parasitology Laboratory Studies .................................................................................................34
6.9 Blood volumes ...............................................................................................................................35
6.10 Electrocardiogram (ECG) monitoring.......................................................................................36
7.0 TOXICITY MANAGEMENT .............................................................................................................36
7.1 Antiretroviral toxicity......................................................................................................................36
7.2 Artemether-lumefantrine toxicity .................................................................................................36
7.3 Toxicity management by grade ...................................................................................................37
8.0 MONITORING OF ADVERSE EVENTS AND MANAGEMENT.................................................37
9.0 Statistical considerations..................................................................................................................39
9.1 General Design Issues.................................................................................................................40
9.2 Outcome Measures.......................................................................................................................40
9.3 Nutritional Status ...........................................................................................................................40
9.4 Intensive PK study ........................................................................................................................41
9.5 Population PK study......................................................................................................................42
10.0 DATA COLLECTION AND MONITORING..................................................................................43
10.1 Record Keeping...........................................................................................................................43
10.2 Data Quality Assurance and Monitoring ..................................................................................44
11.0 HUMAN SUBJECTS.......................................................................................................................44
11.1 Risks and Benefits ......................................................................................................................44
11.2 Treatment and Compensation for Injury ..................................................................................44
11.3 Costs to the Subjects..................................................................................................................45
11.4 Reimbursement of Subjects ......................................................................................................45
11.5 Institutional Review Board (IRB) Review and Informed Consent.........................................45
11.6 Study Discontinuation.................................................................................................................45
11.7 Definition of Parent/Guardianship.............................................................................................45
12.0 PUBLICATION OF RESEARCH FINDINGS...............................................................................46
13.0 BIOHAZARD CONTAINMENT......................................................................................................46
14.0 REFERENCES................................................................................................................................47
APPENDIX A. Schedule of Evaluations: Intensive PK StudY...........................................................55
APPENDIX B. Schedule of Evaluations: Population PK Study.........................................................57
APPENDIX C. Information Sheet ..........................................................................................................60

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APPENDIX D. WHO Criteria for Severe Malaria/Danger Signs........................................................61
APPENDIX E. WHO Malaria Treatment Outcome Classification System.......................................62
APPENDIX F. Guidelines for Adverse Event Grading (DAIDS AE grading table) .........................63
APPENDIX G. HIV-INFECTED CHILDREN CONSENT....................................................................64
APPENDIX H. HIV-UNINFECTED CHILDREN CONSENT ..............................................................64
APPENDIX I. ASSENT............................................................................................................................64
APPENDIX J. FUTURE USE OF BIOLOGICAL SPECIMENS CONSENT.....................................64
APPENDIX J. FUTURE USE OF BIOLOGICAL SPECIMENS CONSENT…………………….....62

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PROTOCOL TEAM ROSTER
Investigators:
Principal UCSF Investigator: 
Francesca Aweeka, Pharm.D., Department of Clinical Pharmacy, University of 
California, San Francisco
Address:  Parnassus Avenue Box 0622, San Francisco, CA 94143, U.S.A.
Phone number: 01-415 476-0339; Fax Number:  415 476-0307
Email:  fran.aweeka@ucsf.edu 
Principal Yale Investigator: 
Sunil Parikh, M.D., MPH, Yale School of Public Health
Address: Laboratory of Epidemiology and Public Health, 60 College Street, Room 724
Phone Number: 01-203-737-7906; Fax Number: 01-203-737-1662
Email: sunil.parikh@yale.edu 
Principal MU Investigator:  
Norah Mwebaza, MBChB, DPPM, PhD. Makerere University, Kampala, Uganda
Address:  Department of Pharmacology and Therapeutics
Phone number: +256782589889
Email: mwebno@yahoo.com 
Study Co-Investigators:
Liusheng Huang, Ph.D. Department of Clinical Pharmacy, University of California, San 
Francisco
Address:  Parnassus Avenue Box 0622, San Francisco, CA 94143, U.S.A.
Phone number: 01-415 502-2594; Fax Number:  415 476-0307
Email:  Liusheng.huang@ucsf.edu 
Rada Savic, Ph.D. Department of Bioengineering and Therapeutic Sciences
University of California, San Francisco 
Address: 1700 4th Street, Rm 503C; UCSF Box 2552
San Francisco, CA 94158
Phone: +1 415 502-0640; Fax: +1 415 514-4361
Email: rada.savic@ucsf.edu 
Arthur Mpimbaza, MBChB, MMed; Assistant Lecturer
Address: Department of Pediatrics and Child Health, School of Medicine. 
Makerere University
Email: ampimbaza@idrc-uganda.org or arthurwakg@yahoo.com]
Richard Kajubi, MBChB, Infectious Diseases Research Collaboration (IDRC)

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Address:  IDRC, 2C Nakasero Hill Road, P.O. Box 7475, Kampala, Uganda
Phone number: +256776211591
Email: rkajubi@gmail.com 
Martina Wade; Research Technician
Address: Yale School of Public Health, New Haven, CT USA
Email: martina.wade@yale.edu 
Sponsor:
NICHD Sponsoring Investigator:  Nahida Chakhtoura, M.D.
Address:  6710B ROCKLEDGE DRIVE Room 2155, MSC 7002
Bethesda, MD 20817
For Fed-Ex use: Rockville, MD  20852
Phone:  301-435-6872 
Email: nahida.chakhtoura@nih.gov  

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GLOSSARY
ACT
Artemisinin-combination therapy
AE
Adverse event 
AL 
Artemether-lumefantrine 
ALT 
Alanine transaminase (SGPT) 
ART 
Antiretroviral therapy 
AS/AQ
Artesunate-amodiaquine
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the curve 
BID 
Twice a day 
CAB 
Community Advisory Board 
CBC 
Complete blood count 
CDC 
Center for Disease Control 
CI 
Confidence Interval 
Cmax 
Maximum plasma concentration of a drug 
Cmin 
Trough serum concentration of a drug 
Cr 
Creatinine 
CRF 
Case report form 
CYP3A4
Cytochrome p450 3A4 
CYP2B6
Cytochrome p450 2B6
DAIDS 
Division of AIDS 
DHA
Dihydroartemisinin
DMC 
Data Management Centre 
DP
Dihydroartemisinin-piperaquine
DSMB 
Data and Safety Monitoring Board 
ECG
Electrocardiogram
EFV
Efavirenz 
H 
Hour 
HFA
Height for age
Hg 
Hemoglobin 
HIV 
Human Immunodeficiency Virus
HRPP & IRB Human Research Protection Program and Institutional Review Board
HS-RDT 
High sensitive rapid diagnostic test
IDRC
Infectious Disease Research Center
IPT 
Intermittent preventive therapy (for malaria) 
IRB 
Institutional review board 
ITN 
Insecticide treated net 
LAMP
Loop-mediated isothermal amplification
LBW 
Low birth weight (<2500g) 
LPV 
Lopinavir 
LPV/r 
Lopinavir/ritonavir
LR
Lumefantrine 
MGH             Masafu General Hospital
MOH 
Ministry of Health 
MU 
Makerere University 

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NDA 
Uganda National Drug Authority 
NICHD 
National Institute of Child Health and Human Development 
NIH 
National Institutes of Health 
NLME
Non-linear mixed effects
NNRTI 
Nonnucleoside reverse transcriptase inhibitor 
NRTI 
Nucleoside reverse transcriptase inhibitor 
NVP 
Nevirapine 
OR 
Odds ratio 
PCR 
Polymerase chain reaction
PD
Pharmacodynamics 
PI 
Protease inhibitor 
PK
Pharmacokinetics
PO 
Oral 
PQ
Piperaquine
PROMOTE
Prevention of Malaria and HIV Disease in Tororo
Q
Every 
QTc
Corrected QT interval
QTcB
Corrected QT interval using Bazzett’s correction
QTcF
Corrected QT interval using Fridericia’s correction
QD 
Once every day 
RR 
Relative Risk 
SD 
Single dose 
SP 
Sulfadoxine-pyrimethamine 
TASO 
The AIDS Support Organization 
TDH 
Tororo District Hospital 
TS 
Trimethoprim-sulfamethoxazole 
UCSF 
University of California, San Francisco 
ULN
Upper limit of normal
UNAIDS 
Joint United Nations Program of HIV AIDS
UNCST 
Ugandan National Council for Science and Technology 
WFA
Weight for age
WFH
Weight for height
WHO 
World Health Organization 

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EXALT TRIAL SCHEMA
DESIGN: 
Randomized open-label prospective pharmacokinetic and pharmacodynamic study of 
extended duration artemether-lumefantrine in HIV-infected children on EFV-based ART 
and HIV-uninfected children
SAMPLE SIZE: 
1) HIV-infected children with uncomplicated malaria on EFV-based ART

Up to 60 children enrolled into an intensive PK study of 3-day vs 5-day AL 
with 30 needed for each regimen*.  

Up to 100 children enrolled into a population PK study of 3-day AL and 5-
day AL with 50 needed for each regimen*. 
2) HIV-uninfected children with uncomplicated malaria

Up to 100 children enrolled into an intensive PK study of 3-day vs 5-day 
AL with 50 needed for each regimen*.

Up to 120 children enrolled into a population PK study of 3-day AL and 5-
day AL with 60 needed for each regimen*.
* participants will be enrolled from study sites in Uganda, including Tororo District 
Hospital (TDH) as the primary site, Masafu General Hospital (MGH) in Busia, and other 
centers.
* individual participants can be enrolled into the intensive PK study for 2 episodes of 
malaria and can be enrolled into the population PK studies for 2 episodes to minimize 
the number of total participants needed.
POPULATION: 
1) HIV-infected children on EFV-based ART aged 3 to 18 years.
2) HIV-uninfected children aged 6 months to 18 years.
STUDY REGIMENS FOR PARTICIPANTS: 
1) HIV-infected participants must be on efavirenz (EFV) + 2NRTI
2) All participants will be given either 6-dose or 10-dose AL over the course of 
the study for individual episodes of uncomplicated malaria.  The order of 
administration will be via randomization. 
MALARIA CASE DEFINITION: 
Uncomplicated malaria (all of the following) 

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
Fever (> 38.0ºC tympanic) or history of fever in the previous 24 hours 

Positive thick blood smear 

Absence of complicated malaria 
Complicated malaria (any of the following) 

Evidence of severe malaria and parasitemia 

Danger signs present and parasitemia 

Parasite density > 500,000/μl
STUDY DURATION: 
Up to 42 days for treatment of each malaria episode. 

Children will be eligible to participate in intensive PK sampling for up to two 
episodes of malaria. Children will be randomly assigned to either 3-day or 5-day 
regimens for each episode of malaria for the intensive PK sampling.

Children will also be eligible to participate in the population PK sampling and 
again will be randomized to 3-day or 5-day regimens for each subsequent 
episode of malaria.

Each child can participate in intensive and/or population PK evaluations for up to 
a total of 4 malaria episodes
HYPOTHESES:
1) 5-day AL will provide superior PK exposure and improved treatment outcomes 
compared to 3-day AL in HIV-infected EFV-treated children
2) 5-day AL in HIV-infected EFV-treated children will provide comparable PK 
exposure and outcomes to 3-day AL in HIV-uninfected children.
3) 5-day AL in HIV-uninfected children will provide superior PK exposure and 
improved treatment outcomes as compared to 3-day AL in HIV-uninfected 
children. 
PRIMARY OBJECTIVES: 
1) To evaluate and compare the PK exposure between 5-day AL treatment and 3-
day al treatment in HIV-infected children on EFV-based ART 
2) To evaluate and compare the PK exposure of 3-day and 5-day AL treatment in 
HIV-infected children on EFV-based ART to 3-day AL treatment in HIV-
uninfected children not on ART.
3) To evaluate and compare the PK exposure of 3-day and 5-day AL treatment in 
HIV-uninfected children not on ART.
4) To evaluate the pharmacodynamics of AL in the context of extended dose 
regimens and HIV infection.
SECONDARY OBJECTIVES: 

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1) To assess the comparative safety of 5-day vs 3-day AL
2) To assess the impact of 3-day vs 5-day AL on the prevalence of gametocytemia 
following treatment
3) To evaluate the association of anthropomorphic indicators of malnutrition on PK 
exposure and outcomes of AL in HIV-infected and HIV-uninfected children.
4) To compare the diagnostic sensitivity of LAMP, HS-RDT, and microscopy for the 
detection of recurrent parasitemia.
5) To assess the comparative metabolomic profile of HIV-infected and HIV-
uninfected children following treatment with 3-day and 5-day AL to assess
6) To assess the relationship between molecular markers of drug resistance and 
recurrent malaria

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I.0 INTRODUCTION
1.1 Background
1.1.1 Malaria and artemisinin-combination therapy in sub-Saharan Africa. 
Plasmodium falciparum malaria in Africa remains one of the most challenging infectious 
diseases in the world causing roughly 198 million cases and 584,000 deaths in 2013.(1) 
Sub-Saharan Africa has the heaviest burden, bearing >90% of deaths, primarily in 
young children <5 years of age for whom antimalarial dosing guidelines are not yet 
optimized.(1, 2) Treatment of uncomplicated malaria in children relies solely upon the 
artemisinin-combination therapies (ACTs).(1) The artemisinins rapidly reduce parasite 
load while the long-acting partner drugs eliminate residual parasites and protect against 
artemisinin resistance and recurrent infection. In 2013 alone, an estimated 392 million 
ACT courses were procured by malaria-endemic countries(3) with artemether-
lumefantrine (AL), artesunate-amodiaquine (AS-AQ), and dihydroartemisinin-
piperaquine (DP) stipulated as first-line according to the World Health Organization 
(WHO).(3, 4) While AL is the most widely utilized ACT, DP use is on the rise as it protects 
best against recurrent infections, due to the longer half-life of piperaquine (PQ; 1 month) 
as compared to lumefantrine (3 to 5 days).(1, 5-8) 
1.1.2 HIV and antiretroviral treatment (ART) in sub-Saharan Africa. Sub-Saharan 
Africa is also home to 25 million people with HIV; 2.9 million of whom are children <15 
years,(9) and all of whom are eligible for ART under new WHO guidelines.(9-11) First-line 
ART includes lopinavir/ritonavir (LPV/r)-based ART for children <3 years, and efavirenz 
(EFV)-based ART for children >3 years(10) with 86% of 58 WHO focus countries adopting 
EFV-based ART as their preferred 1st-line regimen.(12) We will study AL given as malaria 
treatment in 3 vs 5-day regimens to HIV-infected children stabilized on EFV-based ART 
to delineate its impact of previously described drug-drug interactions.(10) Nevirapine 
(NVP), another non-nucleoside reverse transcriptase inhibitor (NNRTI), has less 
pharmacokinetic (PK) alterations in the setting of AL, and will not be a subject of this 
study.(13, 14)
1.1.3 Malaria and HIV in Uganda. Uganda bears a heavy burden of both malaria and 
HIV. Although malaria prevention and control programs have reduced infections and 
mortality overall, Uganda still has one of the highest malaria transmission intensities in 
the world.(1, 15) In Tororo, the site of this proposal, children experience up to 2 to 6 malaria 
episodes per year, despite usage of bed nets and trimethoprim-sulfamethoxazole (TS) 
for those HIV-infected.(15-19) For HIV, Uganda is lauded for prior success in stemming the 
HIV epidemic, but new infections are now on the rise.(9) It is estimated that 2 million HIV-
infected children will reside in sub-Saharan African in 2020.(9, 20) Thus, HIV-malaria co-
infection remains common, with treatment complicated by multiple pharmacological 
factors that require field-based studies, such as those currently proposed in this 
renewal.(21, 22)
1.1.4 Significant drug interactions occur between ART and ACT. Both components 
of AL are extensively metabolized.(5) Artemether undergoes rapid demethylation by 
cytochrome p450 3A4 (CYP3A4) and CYP2B6 to the active metabolite, 

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dihydroartemisinin (DHA), which undergoes further metabolism via UDP-
glucuronosyltransferases (UGT).(23-25) CYP3A4 is also responsible for metabolizing 
lumefantrine to desbutyl-lumefantrine (desbutyl-LR), and was shown by our group to be 
the major pathway for PQ 
metabolism.(26-28) In the setting of 
HIV-malaria co-infection, ritonavir 
and EFV cause potent CYP3A4 
inhibition and induction, 
respectively.(29-31) For AL, a marked 
increase in lumefantrine exposure 
(defined by the area under the 
concentration curve, AUC) 
occurred during LPV/r-based ART 
co-administration, contrasting with 
a highly significant decrease in 
artemether, DHA, and 
lumefantrine when given with 
EFV-based ART, resulting in a 10-fold variance in lumefantrine exposure in HIV-infected 
children with malaria.(5, 32-34)  
1.1.5 ACT-ART interactions significantly alter clinical outcomes. The change in AL 
exposure with EFV-based ART was associated with a ~4-fold higher risk of recurrent 
malaria compared to the change in AL exposure with LPV/r. These results, and our 
earlier findings of unexpected toxicity with AS-AQ and EFV, have impacted HIV and 
malaria treatment guidelines; specifically, AQ and EFV co-administration is to be 
avoided and AL and EFV co-administration should be used with caution.(3, 33, 35, 36) 
However, no data are available on alternate ways to administer AL in the setting of the 
EFV-based ART so that optimized treatment guidelines can be developed. 
1.1.6 ACT PK exposure is also affected by childhood development. The PK 
disposition of drugs in children differs substantially from that in adults.(37-39) For 
metabolism, UGTs mature from 0-6 months of age while CYPs mature over 12 months 
of age.(40, 41) Children >1 year from resource-rich settings often exhibit higher drug 
clearance compared to adults, which can reduce PK exposure and warrant higher 
doses (per kg).(42-44) Our group and others showed that lumefantrine PK is lower in 
Ugandan children compared to U.S. adults, also suggesting higher clearance in 
children.(45, 46) 
1.1.7 Suboptimum dosing of ACTs in the context of EFV-based ART has important 
implications for the emergence and spread of ACT resistance. Systematic under-
dosing, whether due to ART, malnutrition or other factors, is a concerning factor in the 
development and spread of antimalarial drug resistance.(47) This was suggested for 
sulfadoxine-pyrimethamine,(47, 48) and recently for DP, where 36% of patients in Cambodia 
who failed to clear infection had PQ concentrations below in vitro target levels.(49)  We 
have now shown that a) EFV-treated children have ~2-fold reduced exposure to AL with 
similar changes expected for DP and b) underweight children have reduced exposure to 
Comparison of  AL PK exposure in HIV-infected 
children on ART compared to HIV-uninfected children 
(controls)
HIV-uninfected 
HIV-infected 
AL alone (control)
AL+EFV
Table 1
GM; 95%CI (n=52)
GM; 95%CI 
(n=31)
GMR, 
EFV/Control
AR_AUC0-8
120 (97.6-147)a
48.5 (37.2, 63.1)
0.40***
DHA_AUC0-8
212 (176, 256)a
62.9 (49.2, 80.3)
0.30***
LR_AUC0-
270 (232, 313)
130 (107, 157)
0.48***
LR Half-lifeb
64.3 (52.0, 121)
23.7 (21.8, 46.0)
0.37***
Intensive and sparse PK (n=363 episodes)
Median (IQR), 
n=186
Median (IQR), 
n=48
MR, 
EFV/Control
LR C7d
340 (257, 531)
111 (63, 192)
0.30***
LR C14d
86 (59, 137)
BLQ (BLQ,BLQ)
<1***
LR C21d
BLQ (BLQ, 63)
BLQ (BLQ,BLQ)
<1**

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AL and DP compared to children with normal WFA.(17, 28, 34, 50-53) For the ~3 million sub-
Saharan African children with HIV, EFV is first-line (when >3years).(9) For sub-Saharan 
African children with malaria, AL is the most common ACT, with DP use increasing. For 
all children in sub-Saharan Africa, 28 and 56 million are estimated to be underweight 
and stunted, respectively.(54) Thus, with the spread of artemisinin and DP resistance in 
Southeast Asia,(55-58) and emerging concerns for Africa,(59, 60) there is mounting concern that 
suboptimal AL and DP dosing in HIV-infected children on EFV-based ART or children 
will contribute to the emergence and selection of ACT resistant parasites.(47) 
1.1.8 Lumefantrine exhibits dose-limited absorption. Low exposure to AL is of 
concern, and various strategies to increase lumefantrine exposure have been proposed. 
These include an 1) increase in mg/kg dose, 2) increase in dosing frequency (ie. 3 
doses per day), and 3) an extended duration of treatment. A notable study by Ashley E, 
et al. found that doubling of the dose (once to twice daily) yielded only a 30% increase 
in lumefantrine AUC, and no change in Cmax.
(61) Based on these and other data, 
absorption of lumefantrine is felt to be dose-limited, and thus, an increase in mg/kg dose 
or frequency are not felt to be an effective solution. Thus, WWARN and others have 
suggested that extended dosing regimens be evaluated.(62-65) In silico modeling (Tarning 
J, personal communication) also suggest that an increase in mg/kg twice daily dosing in 
young children does not reach similar concentrations as adults, whereas three daily 
doses reaches equivalent concentrations, and a 5-day regimen results in the highest 
exposure. In addition, with growing concern over the emergence of artemisinin 
resistance, alternative strategies for ACT use have been proposed in SE Asia, including 
use of triple ACTs (artemisinin + 2 long-acting partner drugs) and the use of longer 
regimen durations.(66) An added potential benefit of the extended regimen is the 
exposure of parasites for 2-complete life cycles (each is 48 hours) to the artemisinin 
component, as compared to only 1 full cycle with current regimens. Importantly, we 
have shown that higher exposure to lumefantrine is well tolerated with no increase in 
adverse events.(17, 67) More specifically, we recently evaluated the impact of another 
antiretroviral, lopinavir/ritonavir, on levels of lumefantrine in children with malaria.(67) 
Importantly, in contrast to EFV, lopinavir/ritonavir is a potent inhibitor of CYP3A4, and 
therefore expected to increase levels of lumefantrine. In our study, day 7 levels in 
children on lopinavir/ritonavir-based ART had 10-fold higher day 7 levels of lumefantrine 
and >2-fold higher AUC, as compared to those on EFV-based ART, while exhibiting no 
increase in toxicity.(17, 67). Thus, we do not expect an increase in toxicity with a 5-day 
duration of AL.
1.1.9 Malnutrition is prevalent in African children and may impact ACT 
pharmacology. Malnutrition can include a) chronic protein-calorie malnutrition resulting 
in slow linear growth (decreased height-for-age: HFA; stunting), b) acute protein-calorie 
malnutrition resulting in weight loss or slow weight gain (decreased weight-for-height: 
WFH; wasting) and c) micronutrient deficiencies in iron, zinc, and vitamin A that can be 
difficult to detect clinically.(68) Underweight (decreased weight-for-age: WFA) status 
reflects the combination of chronic and acute protein-calorie malnutrition, and is the 
most clinically utilized indicator of nutritional status. Grading of malnutrition depends on 
anthropomorphic measures where z-scores > 2 standard deviations (SD) below the 

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mean of the reference population denote moderate to severe malnutrition.(69) In Africa, an 
estimated 36% and 18% of children <5 years are classified as stunted or underweight, 
respectively (39% and 16% for Uganda, respectively).(54, 70, 71)  Malnutrition can alter drug 
absorption due to changes in gut integrity and gastric emptying;(72) plasma binding of 
drugs;(73) drug activation;(74) and drug clearance.(75, 76) The net impact on overall PK 
exposure depends on both the drug and type of malnutrition. Clear specification of 
malnutrition indices and their relationship to 
PK evaluations are needed to optimize drug protocols for malnourished children.  
Dosing of AL in malnourished children using weight-based guidelines that ignore 
nutritional status and a child’s maturational age, may result in mg/kg doses that are too 
low in malnourished children.(51, 53, 79) and worsen treatment outcomes. 
1.1.10 Strategies for completing field-based pharmacology studies. The conduct of 
antimalarial PK/PD studies in field settings must consider blood volume. Intensive PK 
studies require serial sampling of blood volumes that must be minimized in children. 
Small volume methods for venous samples or capillary samples via a finger prick can 
measure drugs using as little as 100-200 μl of plasma (81-83). Small volume methods 
permit easy collection of samples in large populations, permitting optimum population 
PK designs to investigate relationships between drug exposure, patient and disease 
covariates, and clinical outcomes (84, 85).  These studies will include utilization of small 
volume assay methods for ACT and ART to optimize PK/PD study and our group will 
employ small volume capillary methods that will be easily incorporated into subjects’ 
existing visits/blood draws. 
1.2 Rationale
This study is designed to directly address antimalarial PK and PD objectives in children, 
primarily HIV infected children, one of the most vulnerable populations to malaria in the 
world. This study will focus on the pharmacology of the most widely prescribed 
antimalarial treatment regimen, AL, primarily in the context of EFV-based ART but also 
in HIV uninfected children who will serve as a control group. Therefore, results from this 
study will inform specific dosing guidelines for treatment of uncomplicated malaria in 
children, both HIV infected and uninfected. Traditionally, studies have focused on HIV-
uninfected, non-pregnant adults, largely ignoring the effects of childhood maturation and 
ART interactions on drug disposition. This gap in research is specified as a priority by 
NIAID and leaders of the WorldWide Antimalarial Resistance Network (WWARN), who 
emphasize the importance of proper PK and PD study in relevant populations to reduce 
the threat of ACT drug resistance and treatment failure (84-87). This study will allow 
optimization of ACT regimens, especially in the setting of HIV co-infection and inform 
the best use of AL with EFV-based ART, in the setting of malaria, with the goal of 
improving clinical outcomes. 
ACT
Modifying 
factor
Mode of 
modification
Change in PK 
exposure 
Reinfection risk
Selected 
References
EFV
Induce CYP/UGT
↓↓↓ AL
↑↑↑ AL
(17, 34, 63, 77, 78)
Under-weight
↓ F, CYP
↓↓ AL
↑↑ AL
(51, 53, 64, 79)
AL
Stunted
↓ F, CYP
No data
Likely ↑
(80)
Table 1.  
Impact of  
factors on 
ACT PK and 
outcomes 
based on 
Limited Data
F: bioavailability, CYP: cytochrome p450, UGT:  UDP-glucuronosyltransferases; 

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The ACTs are the most important drugs for the treatment of uncomplicated malaria. 
Despite their widespread use globally, fundamental questions remain for assuring their 
optimal use in our most vulnerable populations, especially for children in the context of 
interacting medications or malnutrition. Our results to on ACT drug interactions are 
striking and reveal that HIV-infected children treated with AL have a wide range of 
antimalarial exposure depending on their ART. Compared to no ART, lopinavir/ritonavir 
(LPV/r)-based ART increased lumefantrine PK exposure >2-fold, while efavirenz (EFV)-
based ART, first-line for children >3 years of age, dramatically reduced exposure to 
artemether, the active dihydroartemisinin metabolite, and lumefantrine. Importantly, 
these PK changes were associated with a 4-fold higher risk of recurrent malaria after 
treatment with AL in children receiving EFV compared to those receiving LPV/r. These 
findings suggest that AL dosing should be modified for children receiving EFV. We 
propose that extending AL dosing from 3 to 5 days will offset these changes. We will 
study an extended AL regimen, rather than a higher dose, as we know lumefantrine 
absorption is dose-limited (Section 1.1.8). This strategy should be useful for other 
conditions causing low exposure, such as pregnancy, and in the setting of emerging 
resistance. 
We will conduct our study in the malaria-endemic region of Eastern Uganda in both 
Tororo and Busia where our team has long standing experience directing field-based 
PK/PD studies in the most relevant populations. We will utilize a combination of state-of-
the-art intensive and population PK designs and drug assay methods to determine drug 
exposure and study associations between exposure and specific malaria outcomes 
including recurrent malaria. 
Rationale for this study is summarized below:

Dosing guidelines for children have historically relied on studies carried out in adults
despite knowledge that children exhibit distinct physiological characteristics that
impact how drugs are handled by their body

Improper dosing may compromise care of acute infection but more importantly
contribute to develop of resistance

We have shown that interactions between AL and EFV greatly altered levels to
BOTH artemether and lumefantrine, and put patients at risk for treatment failure.

Extended dosing intervals of AL may overcome lower exposure that is found in
patients concomitantly taking EFV.

Higher exposure to AL is not expected to increase toxicity

Extending dosing intervals in HIV-uninfected children may reduce the likelihood of
emergence of artemisinin resistance.

Intensive PK design resulting in determination of a precise AUC will permit robust
comparisons so that results will inform treatment guidelines and policy for HIV-
infected children.

Population PK designs will provide additional data to assess covariates that may
impact exposure as well as enhance PK-outcome assessments

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2.0 STUDY OBJECTIVES
2.1 Primary Objectives: 
1) To evaluate and compare the PK exposure between 5-day AL treatment and 3-
day al treatment in HIV-infected children on EFV-based ART
2) To evaluate and compare the PK exposure of 3-day and 5-day AL treatment in
HIV-infected children on EFV-based ART to 3-day AL treatment in HIV-
uninfected children not on ART.
3) To evaluate and compare the PK exposure of 3-day and 5-day AL treatment in
HIV-uninfected children not on ART.
4) To evaluate the pharmacodynamics of AL in the context of extended dose
regimens and HIV infection.
2.2 Secondary Objectives:
1) To assess the comparative safety of 5-day vs 3-day AL
2) To assess the impact of 3-day vs 5-day AL on the prevalence of gametocytemia
following treatment
3) To evaluate the association of anthropomorphic indicators of malnutrition on PK
exposure and outcomes of AL in HIV-infected and HIV-uninfected children.
4) To compare the diagnostic sensitivity of LAMP, HS-RDT, and microscopy for the
detection of recurrent parasitemia.
5) To assess the comparative metabolomic profile of HIV-infected and HIV-
uninfected children following treatment with 3-day and 5-day AL to assess
6) To assess the relationship between molecular markers of drug resistance and
recurrent malaria
3.0 STUDY DESIGN
This is a prospective randomized multi-site study to evaluate the PK/PD of extended 
duration AL in HIV-infected children on EFV-based ART and HIV-uninfected children not 
on ART. AL is the first-line treatment for malaria in Uganda. No change in standard of 
care treatment will be made for the purposes of this study except for the extension of AL 
to 5-day dosing. Figure 1 summarizes the design. This study will enroll a) HIV-infected 
children, and b) HIV-uninfected children. All participants may be enrolled through Tororo 
District Hospital (TDH) or Masafu General Hospital (MGH) in Busia, or other referral 
centers the area.
3.1 Overview of Pharmacokinetic Sampling Design
3.1.1   Intensive PK study.  
Intensive PK study entails multiple venous blood collections in a smaller sample of 
individuals to accurately estimate drug exposure over time. These studies will be 

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conducted in both HIV-infected and HIV-uninfected participants and will allow us to 
investigate extended duration AL PK exposure in the context of EFV-based ART and in 
HIV-uninfected children. This will be accomplished through a design where children will 
be randomized to either 3-day or 5-day AL and then be re-randomized for subsequent 
episodes of malaria, should they occur.  Comparisons of AL PK exposure will be made 
among and between a) HIV-infected children with malaria receiving EFV-based ART 
and b) HIV-uninfected children who are not on ART. Comparisons will be based on an 
intensive PK design for AL AUC estimations. Conservatively, assuming each enrolled 
child participates for only a single episode of malaria, up to 60 (30 HIV-infected on 3-
day and 30 HIV-infected on 5-day) and 100 (50 HIV-uninfected on 3-day and 50 HIV-
uninfected on 5-day) subjects will be enrolled for each of the intensive study groups. 
The generation of an AUC will permit robust comparisons so that results will inform 
treatment guidelines and policy.  
Figure 1—Overview of Study Design
3.1.2   Population PK study. 

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Population PK study involves having few PK samples drawn over time which are ideally 
combined with intensive PK studies to allow for optimal PK-outcomes assessments.  
These studies will also be conducted in both HIV-infected and HIV-uninfected 
participants where a randomized design will also be employed where children will be 
randomized to either 3-day or 5-day AL and then re-randomized for a subsequent 
episode of malaria, should it occur.  The preference will be that children will first have 
participated in the intensive PK evaluations (for both 3-day and 5-day regimens for two 
sequential episodes of malaria until the sample size has been reached) before 
continuing onto the population PK assessments.  In total, each child may participate in 
intensive and/or population PK assessments for a total of 4 malaria episodes.
3.2 Overview of study groups
Both HIV-infected and HIV-uninfected children will be enrolled from Tororo District 
Hospital (TDH) or other referral centers in Tororo and at Masafu General Hospital in the 
Busia District. As children can be enrolled for multiple episodes of malaria, these 
sample sizes represent the maximum numbers of children enrolled in each study arm. 
Consenting will be done once in each child to cover the potential for enrollment for 
multiple episodes of malaria and in both intensive and population PK studies.
Conservatively, assuming each enrolled child has only a single episode of malaria, the 
maximum total number enrolled will be 380 children, as follows:

HIV-infected 3-day AL regimen (80 total)
o
30 intensive PK participants
o
50 population PK participants

HIV-infected 5-day AL regimen (80 total)
o
30 intensive PK participants
o
50 population PK participants

HIV-uninfected 3-day AL regimen (110 total)
o
50 intensive PK participants
o
60 population PK participants

HIV-uninfected 5-day AL regimen (110 total)
o
50 intensive PK participants
o
60 population PK participants
3.2.1   HIV-infected participants 
This protocol will study the clinical pharmacology of AL in HIV-infected participants on 
EFV-based ART regimens, specifically children aged 3 to 18 years. Up to 60 children 
will be enrolled for intensive PK studies and up to 100 children will be enrolled for 
population PK studies. All children will be enrolled at the time they present with 
uncomplicated malaria and will undergo intensive PK sampling during 42 days of follow-
up.  Some of the same children will 1) re-randomized for a subsequent episode of 
malaria, thus providing two intensive PK datasets and, potentially, 2) undergo 
population PK assessments for either or both 3-day and 5-day regimens.

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3.2.2   HIV-uninfected participants
This protocol will also study the clinical pharmacology of AL in HIV-uninfected children 
aged 6 months to 18 years. Up to 100 HIV-uninfected subjects will be enrolled for 
intensive PK studies and up to 120 children will be enrolled for population PK studies. 
HIV-uninfected children will primarily serve as controls for comparison with HIV-infected 
children but will also be assessed for the effects of age on PK (see note). Children will 
be enrolled at the time they present with uncomplicated malaria and will undergo 
population PK sampling during 42 days of follow-up. Some of the same children will 1) 
undergo crossover to the alternate regimen, thus providing intensive PK data for both 
regimens, and, potentially, 2) undergo population PK assessments for either or both 3-
day and 5-day regimens. 
Note: the larger sample size of 100 for intensive PK and 120 for population PK in HIV-
uninfected children will permit assessment of the impact of age on the PK of AL in these 
regimens over a range of developmental maturation (6 months to 18 years) 
3.2.3   All children

If a child has multiple episodes of malaria, they will be randomized for each 
episode into a 3-day or 5-day regimen. For example, a child could be randomized 
to a 3-day regimen for episode #1 and then randomized to either a 3-day or 5-
day regimen for episode #2, or vice-versa. 

All sample sizes refer to “evaluable” PK participants, in other words, those that 
have completed follow-up sufficiently to obtain all required PK study samples 
(see Note*).   

If a child does not complete PK sampling procedures for the intensive study for 
any reason (they are not “evaluable”), the child may be re-enrolled in the 
intensive PK study for subsequent episode(s) of malaria, if they meet eligibility 
requirements. 

All children can be enrolled into the intensive study for a maximum of two 
“evaluable” episodes of malaria.  
o
*Note: Up to 2 PK samples can be missing to still be considered 
“evaluable” for intensive PK.  More than 2 missing PK samples will permit 
a child to either repeat a specific intensive study for a subsequent episode 
or be replaced.  They may also be eligible to transition from the intensive 
study into the population PK sampling study, provided enrolment criteria 
are met. For any malaria episodes beyond the 4th episode, a child will be 
referred to the local health center for management.

At least 28 days must separate each PK study malaria episode. 

All children will preferentially undergo intensive PK studies until the maximum of 
two episodes in the intensive sampling scheme has been reached

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
A child may be enrolled for a maximum of 4 episodes of malaria over the study
period whether deemed “evaluable” or not. For any malaria episodes beyond the
4th episode, a child will be referred to the local health center for management.

If participation in the intensive study is not feasible for any reason or if the
desired intensive sampling size has been an achieved, a child can be directly
enrolled into the population studies.
3.3 Study sites
The primary study site is the study clinic at the TDH campus situated in Tororo, Eastern 
Uganda, an area of high malaria transmission. This was the primary study site for the 
initial RO1. Participants will receive all routine and acute medical care at the TDH study 
clinic, open 7 days a week from 8 a.m. to 5 p.m. If medical care is needed after hours, 
parents/guardians/participants will be instructed to go to the TDH premises (where the 
study clinic is located) and request that a study physician on-call be contacted. 
The secondary study site is at the MGH campus situated in the Busia District, also in 
Eastern Uganda, approximately 50 km south of the TDH site. Busia is currently the site 
of several active NIH-funded malaria studies by the IDRC and other collaborators. As 
with TDH, the study clinic in Busia will remain open 7 days a week from 8 a.m. to 5 p.m.  
Similar to our previous RO1 PK study, we will allow for referrals from neighboring health 
centers in the Tororo and Busia districts, provided that entry criteria are met.
4.0 SELECTION AND ENROLLMENT OF SUBJECTS
4.1 Inclusion Criteria
4.1.1   All participants:
1) Residency within 60 km of the study clinics either at TDH or at MGH
2) Agreement to come to clinic for all follow-up clinical and PK evaluations
3) Provision of informed consent
4) Weight ≥6 kg
5) Presentation with uncomplicated P. falciparum malaria, or mixed infection with
the presence of P. falciparum species, as indicated by positive smear for malaria
parasites along with clinical evidence of infection (fever or history of fever in the
past 24 hours)
6) Willingness to undergo intensive PK sampling and/or population PK sampling
during episode(s) of malaria.
4.1.2   HIV-infected participants: 
1) Confirmed HIV infection (positive rapid HIV test to be confirmed by Western Blot
or HIV RNA after enrollment)

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2) On stable EFV-based ART for at least 10 days prior to enrollment
3) Age 3 years to 18 years
4.1.3   HIV-uninfected participants: 
1) Confirmed HIV negative test (negative rapid HIV test to be confirmed by Western 
Blot or HIV RNA after enrollment)
2) Age 6 months to 18 years
4.2 Exclusion Criteria
1) History of significant comorbidities such as malignancy, active tuberculosis or 
other WHO stage 4 disease
2) Current infection without the presence of P. falciparum species
3) Receipt of any medications known to affect CYP450 metabolism (except ART) 
within 14 days of study enrollment (see 4.2.2)
4) Hemoglobin < 7.0 g/dL 
5) Prior treatment for malaria within 28 days of enrollment 
6) Signs or evidence of complicated malaria, defined as unarousable coma OR 
ANY TWO OF THE FOLLOWING SYMPTOMS: Recent febrile convulsions, 
altered consciousness, lethargy, unable to drink, unable to stand/sit due to 
weakness, severe anemia (Hb < 5.0 gm/dL), respiratory distress, jaundice (see 
Appendix D)
7) History of toxicity to AL
4.2.2 Disallowed Medication Guidelines
The following medications are disallowed within 3 weeks prior to receiving study drug:
•
Carbamazepine
•
Clarithromycin
•
Erythromycin (oral)
•
Ketoconazole
•
Phenobarbital
•
Phenytoin
•
Rifabutin 
•
Rifampin 
•
Halofantrine
•
Any other medication known to significantly affect CYP450 metabolism.
•
Grapefruit juice should be avoided during the study due to its potential 
effects on CYP3A4.
4.3 Identification and recruitment of study participants
Children will be enrolled from TDH or other referral site or MGH in the Busia District as 
described below (Section 4.3.1). Parents/guardians of children will be approached for 
their willingness to participate in intensive PK studies and/or population PK studies for 

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one of more episodes of malaria. All children will undergo 42 days of follow-up around 
each malaria episode for which they will have PK sampling carried out. Participants may 
be recruited through multiple referral mechanisms including those primary sites 
described below.
4.3.1   Primary Referral Sites
1. Tororo District Hospital (TDH). Tororo District Hospital Pediatric, Antenatal 
and Adult Clinics and Wards:  HIV-infected and HIV-uninfected children 
presenting with uncomplicated malaria to the TDH clinics or wards.  
2. The AIDS Service Organization (TASO, Tororo). TASO has been providing 
care to HIV-infected children and adults in Tororo since 1989.  HIV-infected 
children presenting with uncomplicated malaria.
3.
Masafu General Hospital, Busia District. HIV-infected and HIV-uninfected 
children presenting with uncomplicated malaria to the clinics or wards. 
4.4 Screening 
HIV-infected and HIV-uninfected children will be screened for study eligibility at the time 
they present with uncomplicated malaria at TDH or MGH. Children referred from sites 
other than TDH or MGH will be screened upon their arrival to the study clinics at either 
TDH/MGH by study staff. Parents/guardians will be asked about their willingness to 
have their child participate in intensive and/or population PK studies involving standard 
42-day follow-up for up to 4 episodes of uncomplicated malaria.  It will be explained to 
the child and parent or guardian that participation can be during as few as one or as 
many as four episodes of malaria, depending on their preference. For any malaria 
episodes beyond the 4th episode, it will be explained that referral/care will be directed to 
the local health center for management. It will also be explained that children will only 
be part of the study during the 42-days of malaria follow-up, but not during periods in 
between episodes of malaria. If the initial verbal screening criteria assessed by 
interview are met, the child and parent or guardian will be asked to provide informed 
consent for laboratory screening and study participation. Consenting for intensive and 
population PK procedures will be made together in a single consent form, as well as 
consent for future use of biologic specimens. Assent will be obtained following Ugandan 
guidelines.  
4.4.1   Confirmation of malaria status
All children must have confirmed uncomplicated P. falciparum malaria in order to meet 
criteria for entry into the study. Details on the definition of uncomplicated malaria and 
how it is diagnosed are detailed in Sections 6.2 and 6.3. All laboratory procedures, 
including those for screening, will only be conducted after informed consent/assent have 
been obtained.
4.4.2   HIV Testing of HIV-uninfected children

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HIV counseling and testing will be done on all HIV-uninfected children presenting to the 
clinics or wards in Tororo or Busia as part of study enrolment screening.  Based on 
results of testing, children will be referred appropriately to study staff and clinical care 
(in the event they test positive for HIV for the first time). All children ≥ 6 months will have 
serology testing performed as per Ugandan policy. Initially, a Determine rapid test is 
performed. If it is negative, the participant is declared negative. If Determine is positive, 
the Stat pak rapid test will be done for confirmation. If Stat pak is positive, then the 
participant is confirmed positive. If Stat pak is negative, then a Unigold rapid test is run. 
If Unigold is positive, then the participant is positive for HIV. If Unigold test is negative 
then the participant is negative for HIV. For children who are 6 months to 18 months of 
age with positive serologic tests, they will be referred to an HIV clinic for confirmatory 
virologic testing (PCR). HIV testing protocol may be modified to be in-line with Ugandan 
policy if changes occur over the course of the study.
4.5 Study informed consent and enrollment
Study physicians will conduct the informed consent discussion in the study clinic in the 
appropriate language for the adult or the parents/guardians; translators will be used if 
necessary. Following the informed consent discussion, parents/guardians/participants 
will be asked by the study physicians to sign a research participation informed consent 
form or assent form (Appendices G, H, and I) approved by the UCSF Committee for 
Human Research (UCSF CHR), Yale Human Investigations Committee, Makerere 
University College of Health Sciences Ethics Committee, and the Uganda National 
Council for Science and Technology (UNCST) that will be available in 6 languages 
(Jopadhola, Teso, Swahili, Luganda, Samia, and English). The informed consent form 
will contain information and permission for specimen banking and future use of 
biological specimens. If the parent/guardian/participant is unable to read or write, their 
fingerprint will substitute for a signature, and a signature from a witness to the informed 
consent procedures will be obtained. The witness may be a family member, clinic staff 
not conducting the informed consent discussions, or a translator. 
Subjects who fulfill verbal eligibility criteria and have provided informed consent, will 
undergo a series of evaluations including a detailed history and physical examination, 
measurement of temperature, height, and weight. Blood will then be collected by finger 
prick for hemoglobin testing, as well as for malaria thick and thin smear, if not already 
available (see Section 6.2). 
5.0 MALARIA AND HIV TREATMENT
5.1 Artemether-lumefantrine (Coartem®)
Participants enrolling in the study will receive AL as dispersible Coartem® (Novartis 
Pharmaceuticals, Switzerland) tablets treatment for each episode of uncomplicated 
malaria. Coartem® has been FDA-approved for the treatment of malaria in the U.S 
since 2009, and is a first-line treatment for malaria by the WHO. Importantly, 

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participants would have received AL for treatment of malaria if they were not in the 
study, and it is provided at no charge by the Ugandan Ministry of Health. However, as 
there may be many generic brands of AL available in Uganda, we will provide AL as 
dispersible Coartem® for all malaria episodes associated with this study to ensure 
consistency.  
AL is generally considered very effective for treatment of malaria.  Dosing in children is 
primarily based on weight-based adjustments to adult dosing.  The artemisinins 
(artemether in the case of AL) are generally well tolerated in humans.  In a clinical 
safety review of 108 studies including 9241 patients, no serious adverse events or 
significant toxicities were reported (88).  Of minimal concern is the potential for artemisinin 
associated auditory toxicity. However, in a study based in Thailand, there was no 
evidence of auditory toxicity reported(89). Longer acting lumefantrine is also generally well 
tolerated.  The drug is chemically similar to halofantrine, a drug associated with cardiac 
arrhythmogenic potential, but no cardiac issues have been identified in children 
receiving lumefantrine.  In 713 lumefantrine treated patients, serial ECG monitoring 
indicated no adverse cardiac events(90). There have been no reports associating elevated 
AL drug levels with toxicity.  There is no evidence of harm in infants exposed to AL.  
Specifically, in our prior study evaluating AL with lopinavir/ritonavir based ART, AUC 
estimated for lumefantrine were increased close to 3-fold, without evidence of untoward 
effects(67)
AL is typically dosed twice daily for 3 days for a total of 6 doses for treatment of 
uncomplicated malaria.  In this study, we will also study when AL is dosed twice daily for 
5 days for a total of 10 doses. 
5.1.1   Dosing schedule for intensive and population PK studies 
Of note, in malaria studies, it is standard practice to refer to the 1st day of treatment as 
study day 0.  This nomenclature is used universally in the clinical care of malaria 
patients, and has been the standard for all our studies in Uganda. We will use the study 
day nomenclature throughout this protocol.
The primary focus of the intensive PK studies involves PK sampling around the last 
dose of the AL regimen. To ensure that we can begin intensive sampling around the last 
dose or AL, a modest alteration in the dosing schedule will be made so that the last 
dose falls in morning. This alteration does not affect treatment efficacy or safety and we 
have used this approach for our prior intensive PK studies of AL.(67, 91) The dosing 
schedule specified in Table 4 will be used to assure a) adequate AL treatment and b) 
the scheduling of intensive PK sampling during the day, rather than during the night. 

AL treatment for the 3-day regimen will be 6 doses of Coartem® administered
over 4 days (Study Days 0, 1, 2 and 3) as per weight-based dosing guidelines.
Sampling will begin in the morning of day 3. The 6-dose regimen is the standard
of care for the treatment of malaria

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
AL treatment for the 5-day regimen will be 10 doses of Coartem® administered
over 6 days (Study Days 0, 1, 2, 3, 4, and 5) as per weight-based dosing
guidelines. Sampling will begin in the morning of day 5.

Children will be presenting for care at various times of the day.  Therefore, the
precise timing of the 1st and 2nd dose on Day 0 will be left to the discretion of the
medical officer.

However, spacing between the 1st and 2nd doses of AL should be a minimum of 7
hours and maximum of 10 hours.
Table 4. Coartem® dosing for intensive PK study ONLY
*spacing between the 1st and 2nd doses of AL on study day 0 should be at a minimum of 7 hours, and maximum of 10 hours. 
3-day AL 
regimen
STUDY DAY 1
STUDY DAY 2
STUDY 
DAY 3
Dose 1
Dose 2
Dose 3
Dose 4
Dose 5
Dose 6
(11AM -
5PM) (C)
(9PM -1AM)
(H)
(1PM -3PM)
(C)
(8AM -
10AM)
(C)
(8PM-
10PM)
(H)
(8AM-
10AM)
(C)
5-day AL 
regimen
STUDY DAY 0
STUDY DAY 1
STUDY DAY 2
STUDY DAY 3
STUDY DAY 4
STUDY DAY 5
Dose 1
Dose 2
Dose 3
Dose 4
Dose 5
Dose 6
Dose 7
Dose 8
Dose 9
Dose 10
(11AM -
5PM) (C)
(9PM -1AM)
(H)
(1PM -3PM)
(C)
(8AM -
10AM)
(C)
(8PM-
10PM)
(H)
(8AM-
10AM)
(C)
(8PM-
10PM)
(H)
8AM-
10AM)
(C)
(8PM-
10PM)
(H)
8AM-10AM)
(C)
For population PK studies, AL will be administered as per standard dosing schedules 
(twice daily for 3 days) or as the extended regimen (twice daily for 5 days) with the twice 
daily dosing unaltered during the population PK studies. 
5.1.2   Drug Administration
Every dose of AL should be administered with whole milk as specified below since 
ingestion with fat-containing food and drinks greatly improves lumefantrine absorption.(92) 
Although risk of treatment failure is very small, subjects who remain averse to food 
during treatment should be closely monitored. At the time of study entry, subjects and/or 
subjects’ families will be provided with container(s) of whole milk or vouchers to 
purchase whole milk to be administered with study drug.  Adherence of AL will be 
assured by recording each treatment dose time.  Doses will be administered either in 
the clinic and observed by a study nurse or at the subject’s home and observed by the 
caregiver.
Dosage: Children will receive the dispersible formulation of AL with contains 20 mg 
artemether, 120 mg of lumefantrine (Coartem® Dispersible). Dispersible tablet(s) 
composing 1 dose should be completely dispersed in a small amount of water 
(approximately 10 mL per tablet). Stir gently and administer immediately to the subject. 
Rinse the glass with an additional small amount of water (approximately 10 mL) and 
give immediately to the subject. Weight-based dosing will be as below (Table 5).
Table 5. Weight-based dosing guidelines for AL
Weight
Coartem® Dispersible 20mg /120 mg 
tabs
<15 kg
 1

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≥15 to <25 kg
 2
≥25 to <35 kg
 3
≥35 kg
 4
Efavirenz-based ART. This study will not initiate ART treatment.  Initiating and 
management of ART use will be carried out through the study subjects’ usual clinic.
HIV infected children will receive EFV-based ART as per prescription through their 
primary HIV clinic.  No changes in ART will be made for the purposes of this protocol.  
While receiving AL treatment for malaria, EFV-based ART administration in the morning 
will occur at the same time as AL administration and the timing will be documented. In 
order to meet eligibility, children will need to have been maintained on EFV-based ART 
for at least 10 days prior to enrollment.  
5.1.3   Missed Doses of AL
Missed doses due to vomiting:

If the episode of vomiting occurs ≤30 minutes post-administration of AL,
participants will be counseled to repeat the dose.  PK sampling will only continue
if the subject can be re-dosed with a full dose and vomiting occurred ≤30 minutes
post-administration of AL.

If the vomiting occurs more than 30 minutes but less than 2 hours post-
administration of AL, redosing of 50% of the dose should occur. The redosing will
be carefully noted on the study case report forms. Participants may not continue
in the intensive study if this occurs, but may be transitioned to the population PK
study.

Any patient who vomits repeatedly (> 3 times) will be recorded as having
complicated malaria and treated with quinine or artesunate, as is standard of
care.
Missed or late doses due to other reasons:  

If an AL dose was missed or late for any other reason, participants will be
counseled that the dose should be taken as soon as remembered.

Participants in intensive PK studies should have taken the 5th and 6th AL doses
(for the 3-day regimen) or the 9th and 10th AL doses (for the 5-day regimen) 12 ±
2 hours apart to participate in the intensive PK sampling.
5.1.4   Drug supply and distribution
Artemether-lumefantrine 
AL is the standard of care for malaria treatment in Uganda. However, to ensure 
consistency in drug preparation, this study will supply the AL for all participants, and will 
be purchased through Ugandan suppliers of the Novartis product (as per program 
pharmacist) Coartem®, which is brand name AL. At the time of AL initiation, participants 
will be provided doses for administration in the afternoon or evening only. All morning 
doses will be provided by and observed in the study clinic.

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Efavirenz-based antiretroviral therapy
Efavirenz-based ART is the WHO first-line ART regimen for all children > 3 years of 
age, adolescents, and adults.(10, 11, 93) EFV-based ART for HIV-infected participants will be 
administered and managed through their usual clinic at TDH, MGH, TASO or other 
referral site.  Those who are not yet followed by a clinic will be referred to the 
appropriate HIV clinic in Tororo or Busia for follow-up of HIV. This study will maintain a 
supply of EFV-based ART, either provided by the Uganda Ministry of Health or 
purchased by the study, to provide to study participants as necessary.  
5.1.5   Drug Accountability
The study pharmacist will maintain complete records of all study-related medications 
received in the study pharmacy. Lot number and number of pills given to each 
participant at each visit will be recorded. Patients will be requested to return all empty 
drug bottles and to bring any bottles in use to the clinic at follow-up visits. A registry of 
all medications, current product labels, and Certificates of Analysis, provided by 
suppliers will be maintained within the regulatory binder for the study. The date 
received, lot number, expiration date, and date used will be recorded for each of the 
medications. Monthly inventory of all medications will be conducted and a record log of 
medications will be kept at the study clinic. All unused drugs will be returned to the 
Tororo District hospital or MGH drug dispensaries after the study is completed or 
terminated.
6.0 CLINICAL AND LABORATORY EVALUATIONS
6.1 Schedule of Evaluations
See Appendices A and B for Schedule of Evaluation (SOE) Tables
6.2 Malaria Diagnosis 
All children will have their malaria diagnosis carried out through their usual clinic in 
Tororo/Busia or through the study clinic at the time of enrollment in this protocol. At the 
time of enrollment, parents/guardians/participants will be instructed to come to the study 
clinic for all medical care over the 42-day follow-up period.  For all participants, the 
study clinics in both Tororo and Busia remain open 7 days a week from 8 a.m. to 5 p.m.
Microscopy. Subjects may be enrolled following diagnosis of uncomplicated malaria if 
their malaria diagnosis is supported through documentation of thick blood smear results.  
For those subjects who have not already been diagnosed, but present 1) febrile 
(tympanic temperature > 38.0˚C) or 2) report history of fever in the past 24 hours, 
he/she will have blood obtained by finger prick for a thick blood smear (in very young 
children, heel sticks may be substituted for finger pricks). Thick blood slides will be read 
and counted by the laboratory technicians at the time of presentation. The parasite 
density of positive screening thick blood smears will be estimated by counting the 

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number of asexual parasites per 200 leukocytes, assuming a leukocyte count of 
8,000/μl (or per 500 leukocytes, if the count is <10 asexual parasites/200 leukocytes). 
Smears will be considered negative when examination of 100 high-power fields does 
not reveal parasites. If the thick blood smear is positive, the patient will be diagnosed 
with malaria. If the thick blood smear is negative, the patient will be managed by 
medical officers in their usual clinic or by study staff. Thin blood smears will be 
evaluated for parasite species. All subjects with a positive smear for P. falciparum, and 
a parasite density of ≤ 500,000/μL will be referred to the PK study medical officers to 
determine further eligibility for study enrollment which will involve additional screening 
tests (e.g. HIV test if serostatus not known via appropriate test results, hemoglobin 
testing) (see section 6.8).
Loop-mediated isothermal amplification (LAMP). LAMP is a recent field-adapted 
molecular technique to identify malaria parasites with an estimated lower limit of 
detection of 1-5 parasites/µL, which is below the limit of detection for microscopy (~100 
parasites/µL). LAMP will be performed on dried blood spot specimens permitting us to 
identify parasitemia at lower levels, and perhaps at earlier time points over the course of 
follow-up (see section 6.8).
Rapid Diagnostic Test (RDT). Alere Inc has recently developed the Alere™ Malaria Ag 
P.f., a highly sensitive RDT (HS-RDT) for the detection of P. falciparum. The RDT can
detect the parasite within 20 minutes from capillary whole blood and has a greater than
10-fold higher sensitivity than current RDTs (www.alera.ecom/malaria-POC).  The
estimated lower limit of detection is anticipated to be similar to LAMP, though head-to-
head comparisons have not been performed. In a subset of children, HS-RDT will be
performed to compare the sensitivity/specificity to that of LAMP and microscopy (see
section 6.8), and to determine the duration of time that the new RDT remains positive
after treatment.
6.3 Classification of Uncomplicated Malaria
All episodes of malaria will be classified as uncomplicated or complicated based on the 
following criteria:  
Uncomplicated malaria (all the following must be present)
1) Fever (> 38.0ºC tympanic) or history of fever in the previous 24 hours
2) Positive thick blood smear
3) Absence of complicated malaria
Complicated malaria (any of the following)
1) Evidence of severe malaria (Appendix D) and parasitemia
2) Danger signs present and parasitemia
3) Parasite density > 500,000/µl
6.4 Management and Follow-up of Malaria
6.4.1   3-day AL regimen

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Following diagnosis of malaria on Study Day 0, children managed with the 3-day AL 
regimen will be evaluated clinically on Study Days 1, 2, 3, (4*), 7 (8*), 10, 14, 21, 28, 35, 
42 and on any unscheduled day in which the patient is brought to the clinic (Appendix A 
and B).  Children who do not return for a scheduled visit will be visited by a study home 
visitor and, if necessary, transported to the study clinic.  Blood will be obtained by finger 
prick on Study Days 0, 1, 2, 3, (4*), 7, (8*), 10, 14, 21, 28, 35, 42 and on any 
unscheduled day in which the patient is brought to the clinic for thick blood smears (for 
parasite density and gametocytes) and filter paper collection (see section 6.8). 
6.4.2   5-day AL regimen
Following diagnosis of malaria on Study Day 0, children managed with the 5-day AL 
regimen will be evaluated clinically on Study Days 1, 2, 3, 4, 5 (6*), 7 (8*), 10, 14, 21, 
28, 35, 42 and on any unscheduled day in which the patient is brought to the clinic 
(Appendix A and B).  Children who do not return for a scheduled visit will be visited by a 
study home visitor and, if necessary, transported to the study clinic.  Blood will be 
obtained by finger prick on Study Days 0, 1, 2, 3, 4, 5 (6*), 7, (8*), 10, 14, 21, 28, 35, 42, 
and on any unscheduled day in which the patient is brought to the clinic for thick blood 
smears (for parasite density and gametocytes) and filter paper collection (see section 
6.8). 
*participants enrolled in the intensive PK study have F/U visits on Days 4 and 8 (instead of Day
7) if receiving 3-day AL or on Days 6 and 8 if receiving 5-day AL.
6.4.3   Timing of doses
The time of AL and EFV administration will be noted whether at home or in the clinic. It 
is critical for PK studies that the time of AL and EFV administration and the time of all 
PK sample collections be recorded on the Case Report Forms.  
All PK samples will be immediately placed on dry ice, processed for plasma separation, 
transferred to liquid nitrogen, and shipped at a later date on dry ice to our laboratory in 
San Francisco for analysis.
6.4.4   Unscheduled or After-Hours Visits
Blood will be obtained by finger prick on any unscheduled day, only when a fever is 
documented or reported in the previous 24 hours, for thick blood smears (for parasite 
density and gametocytes), filter paper collection, and potential additional studies. 
Parents/guardians will be encouraged to visit TDH or MGH when urgent care is needed 
for her or his child outside of study clinic hours. Parents/guardians will be instructed to 
inform hospital personnel of their child’s involvement in the study at the time of 
registration and to visit the study clinic on the following day. If a patient is diagnosed 
with uncomplicated malaria outside of clinic hours, he or she will receive treatment from 
a hospital supply of AL and the doctors will be instructed to refer patients to our study 
clinic when it opens at 8 am the following day. If a patient is diagnosed with severe 

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malaria, he or she will receive quinine following standard TDH or MGH treatment 
guidelines. Patients with non-malarial illnesses will be managed at the discretion of the 
TDH or MGH staff. Study personnel will visit TDH or MGH daily to inquire about visits 
from study subjects and facilitate follow-up in the study clinic.
6.4.5   Missed or late visits
Parents/guardians/participants will be instructed to return on specified follow-up days in 
all studies. If a participant fails to return on the appropriate follow-up day, a home visitor 
will be sent to assist them in returning to the clinic as soon as possible for follow-up.
6.4.6   Criteria and management of Early/Late Treatment Failure
Treatment outcomes will be based on 42-day treatment outcomes as per standard 
WHO classification system. Interim 28-day outcomes will also be assessed. The 
following criteria will be used for all participants participating in intensive and/or 
population PK studies.  Patients treated for uncomplicated malaria but classified as 
early or late clinical failures within 14 days of treatment will be treated with quinine. 
Clinical failures between days 15-42 will be treated as a new episode of malaria. 
Early Treatment Failure:  Study Days 0, 1, 2, and 3

Development of danger signs or severe malaria on study Days 0-3 in
the presence of parasitemia

Parasitemia on study Day 2 higher than on Day 0, irrespective of
temperature

Parasitemia on study Day 3 with temperature > 38.0º C (tympanic)

Parasitemia on study Day 3 > 25% of count on Day 0
LPF (Late Parasitological Failure): Days 4 to 42

Presence of parasitemia on Days 4-42 with temperature < 38.0 º C
(tympanic) and no history of fever in past 24 hours, without previously
meeting any of the criteria for early treatment failure
LCF (Late Clinical Failure): Days 4 to 42

Development of danger signs or severe malaria Days 4 to 42 in the
presence of parasitemia, without previously meeting any of the criteria
of early treatment failure or late parasitological failure

Temperature > 38.0 º C (tympanic) or history of fever in past 24 hours
on Days 4 to 42 in the presence of parasitemia, without previously
meeting any of the criteria of early treatment failure or late
parasitological failure
Adequate Clinical and Parasitological Response

Absence of parasitemia on study Day 42, with no prior requirement for
additional treatment other than the standard 6 dose regimen received
at time of presentation with malaria.

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
For subjects who experience treatment failure before study Day 3, PK
sampling will be discontinued.
Participants from TDH or MGH who experience recurrent malaria within 42 days will be 
evaluated for reenrollment eligibility (see Section 4.1 and 4.2). If eligible, they will be re-
enrolled into the appropriate study. For those not eligible or not willing to reenroll, effort 
will be made to follow them for 7 days (or longer if they remain sick) after the diagnosis 
of recurrent malaria. In addition, the most recent laboratory and clinical tests will be 
checked to assess for any grade 3 or 4 abnormalities. If present, repeat testing should 
be done until AE is resolved.
In the case of participant withdrawal (unless a participant cannot be located or refuses 
follow-up), attempt will be made to follow them until all AEs are resolved to grade 2 or 
below, AND until Day 7 of follow-up for treatment of current malaria episode. Attempt 
will also be made to obtain the Day 14 hematology and chemistry blood work for safety 
follow-up. 
6.5 Anthropometric measurements to assess nutritional status.   
All children will have nutritional status characterized at enrollment based on assessment 
of WHO 2009 growth indicators by staff trained in the proper assessment of growth 
measurements.  Specifically, measurements for height, weight, age and mid-upper-arm 
circumference (as a proxy for “weight for height, WFA”) will be collected and recorded at 
the time of first enrollment (for the first PK assessment around an episode of 
uncomplicated malaria) and at the time of each subsequent episode of uncomplicated 
malaria for which children will also undergo PK. 
6.6 Clinical Laboratory Studies
Blood will be collected on Study Day 0, 14, and 28 for CBC, differential, liver function 
tests (LFTs; AST, ALT).  Additional venipunctures may be performed, as appropriate, 
for laboratory testing to evaluate non-malarial medical illnesses at the discretion of 
study physicians.  Results will be made available to study physicians for patient 
management decision-making. HIV-infected children will have baseline CD4 and VL 
testing performed.
HIV-uninfected children will have HIV serostatus documented through rapid testing.    
All positive test results generated for the purpose of this study will be confirmed through 
Western Blot or HIV RNA.  If needed, HIV counseling and referral will be made. 
Children will not be notified of HIV testing results. Parents and guardians will be notified, 
and provided post-test counseling, and referred to the appropriate HIV clinic for care.  
HIV infected children will be expected to have HIV status confirmed through their clinic 
and will be required to be stabilized on at least 10 days of EFV-based ART to meet 
enrollment criteria.
6.7 Pharmacology Laboratory Studies
6.7.1   Intensive pharmacokinetic study 

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For children participating in the intensive PK sampling, Coartem® treatment will be on 
Study Days 0, 1, 2 and 3 (for the 6-dose regimen) or Study Days 0,1,2,3,4 and 5 (for the 
10-dose regimen).  Intensive PK samples for AL (artemether, DHA, and lumefantrine)
will be collected on Study Day 3 or 5, around the 6th or 10th (i.e. last) treatment dose for
all subjects enrolled in the study.  AL administration of the 6th or 10th dose will be
observed in the clinic, as well prior morning doses. In addition, two samples will be
collected on Study Days 0, 1 and 2 (for those randomized to 3-day AL) or on Study
Days 0, 1, 2, 3 and 4 (for those randomized to 5-day AL).
Sampling for artemether, dihydroartemisinin and lumefantrine. 
Capillary samples (200 μL each*) will be collected by finger stick at approximately 2 and 
4 hours post- each morning AL dose. A pre-1st dose sample will also be collected to 
confirm no residual antimalarial drug is detectable. On Study Day 1 (when a single dose 
is administered mid-day) capillary samples will also be collected at approximately 2 and 
4 hours post- this dose.  
Intensive venous sampling will occur via an indwelling catheter prior to and 0.5 1, 2, 3, 
4, 6 and 8 hours post-administration of the 6th or 10th dose (for the 3-day and 5-day AL 
regimens, respectively) for the determination of artemether, DHA, and lumefantrine 
concentrations in plasma (500 µL each*). Participants will remain in the clinic until 
completion of the 8-hour blood sampling on Study Day 3 or 5 (for the 3-day and 5-day 
AL regimens, respectively) and discharged home. They will then return to the clinic the 
next morning for the 24-hour sample. 
To determine the correlation between capillary and venous artemisinin exposure, a 
simultaneous capillary sample (200 µL) will be collected at the time of the 2 and 8-hour 
samples.
Sampling for lumefantrine 
Participants will be asked to return to the clinic on Study Days 8, 14, and 21 (venous or 
capillary sampling, 200 μL each). 
PK sampling will be discontinued in patients who do not meet laboratory eligibility 
criteria or do not complete treatment due to early failure. Subjects with repeat malaria 
infection during the 42-day follow-up will provide an additional PK sample and blood 
smear. 
*200 µL capillary samples will be collected by finger prick and can be used to
measure all 3 analytes but without the ability to do repeat analysis if necessary.
500µL venous samples permits repeat analysis as needed.
6.7.2   Population pharmacokinetic study 

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For children participating in the population PK sampling, AL treatment will be 6 or 10 
doses of Coartem® (provided by the study) administered over 3 or 5 days: Study Days 
0, 1, and 2 or Study Days 0,1,2,3 and 4, Capillary samples for lumefantrine only (200 
μL) will be collected on Study Day 0 (prior to AL administration).  Capillary samples for 
artemether/DHA and lumefantrine (200 μL*) will be collected by finger prick on Study 
Days 0-2 (3 day AL) or 0-4 (5 day AL) at approximately 2 and 4 hours post-dose. In a 
subset of children, capillary samples for artemether/DHA and lumefantrine (200 μL*) will 
be collected by finger prick on Day 2 in the 3-Day regimen and on Day 4 in the 5-Day 
regimen, prior to AL administration.  On Study Days 3 (3 day AL) or 5 (5 day AL) at 
approximately 24 hours post-last dose, an additional capillary sample will be taken. In 
addition, capillary or venous samples will be collected for lumefantrine only on Study 
Days 7, 14, 21.  Subjects with repeat infection during the 42-day follow-up will provide 
an additional PK sample at the time of repeat infection. 
*200 µL capillary samples will be collected by finger prick and can be used to
measure all 3 analytes but without the ability to do repeat analysis if necessary.
500µL venous samples permits repeat analysis as needed.
6.7.3   PK Sample collection and handling
For consistency, blood samples will be obtained from capillary or venous sources, as 
specified.  However, if venous PK samples cannot be obtained at desired times due to 
technical or other limitations, technicians may obtain blood from a capillary site.  Prior 
correlation studies between venous and capillary measurements for lumefantrine have 
confirmed the ratio of concentrations is 1:1. For the artemisininis, correlation studies will 
be carried out in the context of this protocol.
All samples will be immediately placed on dry ice, processed for plasma, transferred to 
liquid nitrogen, and shipped at a later date on dry ice to our laboratory for analysis. 
Liquid nitrogen will be obtained from Kampala.
6.7.4   Assays for artemether, DHA and lumefantrine
Artemether, DHA and lumefantrine and active desbutyl-lumefantrine will be measured 
using optimized methods validated in our laboratory. All methods will utilize liquid 
chromatography tandem mass spectrometry.
6.8 Parasitology Laboratory Studies 
Thick blood smears. Parasite counts (asexual stage and gametocyte counts) via blood 
smears will be collected in all participants on each day of clinical follow-up. In addition, 
in a subset of population PK participants, more frequent thick blood smears will be 
collected to document the rate of parasite clearance, as we have done in prior studies.(94, 
95)

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Thick blood smears will be stained with 2% Giemsa and read by experienced laboratory 
technologists who are not involved in direct patient care.  Parasite densities will be 
calculated by counting the number of asexual parasites per 200 leukocytes (or per 500 
leukocytes, if the count is <10 asexual parasites/200 leukocytes), assuming a leukocyte 
count of 8,000/µL. A blood smear will be considered negative when the examination of 
100 high power fields does not reveal asexual parasites. Gametocytemia will also be 
determined by thick blood smears. At varied time points, blood smears for the 
determination of parasitemia will be obtained by simultaneous venous and capillary 
blood draws. Parasitology studies will be performed in the laboratory of Dr. Sunil Parikh 
at Yale School of Public Health
LAMP will be done using a commercially available DNA amplification kit (such as the 
Loopamp Plasmodium Kit, Eiken, Japan). LAMP will be performed on dried blood spot 
specimens during each day of 42-day follow-up (See SOE). All LAMP will be run at our 
laboratory on the TDH clinic or Yale by those trained in LAMP.(96)
Rapid Diagnostic Test. The Alere™ Malaria Ag P.f., will be prepared and used per 
manufacturer’s instructions (www.alera.ecom/malaria-POC). A drop of capillary whole 
blood obtained by finger prick will be placed onto the RDT well, along with control 
buffers, and read according product insert. The total time for preparation and resulting is 
estimated at 20 minutes.
Molecular studies. Parasite genotyping using polymorphic markers will be conducted 
to assess genetic diversity using methods routine in our laboratory to determine the 
multiplicity of infection (MOI).(50, 67) Six polymorphic markers (merozoite surface protein 
(MSP)-1, MSP-2, and 4 microsatellites) will be typed using capillary electrophoresis. For 
drug resistance genotyping, extracted DNA will be amplified by PCR, and following 
amplification, multiplex LDR will be conducted with bead-specific oligonucleotides, 
followed by hybridization to magnetic beads, and fluorometric assessment of mutation 
prevalence on a Bio-Plex system (Bio-Rad, Hercules, CA).(97) RNA-based studies will 
also be performed for more sensitive detection of asexual blood stages and 
gametocytes. RNA-based studies will allow for the most sensitive quantification of 
parasite and gametocyte clearance between study regimens, as well as early detection 
of recurrent parasitemia.
Metabolomics studies. Metabolomics assays will be conducted using plasma and/or 
RBC pellets. 20uL of plasma will be placed in an ice-cold methanol solution, vortexed, 
and stored in -80°C. De-identified metabolomics study samples will be shipped on dry 
ice to the lab of Darren Creek, an expert in malaria metabolomics, at Monash University 
for analysis.
6.9 Blood volumes
Intensive PK study
The total blood volumes collected from intensive PK study participants during the 42-
day follow-up period for single episode of malaria will be no more than 28 mL (~6 
teaspoons). (Section 11.1). 

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Population PK study
The total blood volumes collected from participants in the population PK study during 
the 42-day follow-up period for each malaria episode will be approximately 21 mL (~4-5 
teaspoons).  (Section 11.1)
RNA and Metabolomic studies will not be performed in those under 10kg to assure 
blood volumes are not excessive in this weight range.
6.10 Electrocardiogram (ECG) monitoring
As noted in section 7.2, AL has an excellent safety profile. It was first registered as 
Coartem® in 1998, and is used in over 90 countries worldwide, including the U.S.  In 
2016, the WHO convened an Evidence Review Group (ERG) to assess the cardiac 
safety of antimalarials, with particular focus on the QT interval.(98) Of note, members of th 
The QT interval is associated with the risk of drug-induced torsades de pointes (TdP), a 
potentially lethal arrhythmia. The review followed the “ICH E14: The clinical evaluation 
of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic 
drugs”, guidelines set forth by the Food and Drug Administration (FDA). According to 
E14 guidelines, QT intervals should be corrected for heart rate, and Fridericia’s 
correction is considered sufficient (QTc = QT/RR0.5). In addition, an increase in QT or 
QTc > 500ms or >60ms above baseline are considered thresholds of particular concern. 
Categorical analysis and AE reporting are also recommended with absolute QT/QTc 
intervals of >450, >480, and >500, or increases of >30ms, and >60ms above baseline.
According to the review, no cases of sudden or unexplained cardiac death have been 
reported with AL up to the time of the ERG. Despite in vitro evidence of inhibition of 
hERG currents, which are associated with QT interval prolongation, no QTc interval 
prolongation was seen in vivo in dogs with AL, except at doses of 600mg/day, far 
exceeding the doses being administered in this study. In a thorough QT study, an 
increase of >10ms was excluded. In clinical trials, no pediatric patients aged <12 years 
had a post-baseline QTcF interval of >500ms, while 0.2% of the adult patients reported 
an interval of >500ms. In conclusion, the committee stated that “The small increase in 
QTc interval associated with AL does not appear to be associated with a significant risk 
of arrhythmia. The small number of adverse events affecting the cardiovascular system 
were almost all of mild intensity and resolved without intervention.”
In order to confirm the expected safety of an extended dosing regimen of AL, we will 
conduct ECGs in a sub-set of up to 50 children in each arm (3-Day and 5-Day) prior to 
the administration of the first dose of Coartem®, at the time of expected Cmax 
(maximum concentration), and at 2 time-points following recovery from malaria. ECGs 
will be performed in triplicate, with the average QTc (central tendency) used for 
analyses. Based on prior data from our group, the time of expected maximum 
concentration is 4-6 hours following the last dose of AL. ECGs are feasible at this time 
in the intensive study. However, due to the last dose occurring in the evening of day 2 
or 4 in population PK participants, ECGs will only be performed on the morning of day 3 
or 5 in the population PK arm, corresponding to an estimated 8-14 hours post-last dose.

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Specifically, ECGs will be performed in up to 50 participants in each arm (3-Day and 5-
Day) at the following time points:

Intensive PK study
o
3- day regimen

Day 0 – baseline, prior to the 1st dose of AL

Day 3 – prior to the last dose, and 4 to 6 hours after the last dose

Day 8

Day 28 or later
o
5- day regimen

Day 0 – baseline, prior to the 1st dose of AL

Day 5 – prior to the last dose, and 4 to 6 hours after the last dose

Day 8

Day 28 or later

Population PK study
o
3- day regimen

Day 0 – baseline, prior to the 1st dose of AL

Day 3 – 8-12 hours after the last dose

Day 7

Day 28 or later
o
5- day regimen

Day 0 – baseline, prior to the 1st dose of AL

Day 5 – 8-12 hours after the last dose

Day 7

Day 28 or later
7.0 TOXICITY MANAGEMENT
7.1 Antiretroviral toxicity
For HIV-infected children enrolled, ART management for HIV will be managed through 
the subject’s primary clinic.  This study is not designed to initiate ART treatment for 
study subjects.  ART regimens permitted for this study include only EFV-based 
regimens.
7.2 Artemether-lumefantrine toxicity
AL will be used to manage acute uncomplicated malaria. AL is the Ugandan first-line 
national regimen and would be the preferred treatment for all patients whether enrolled 
in this study or not. AL as a 3-day regimen is standard of care while AL as a 5-day 
regimen is being evaluated in this study and is a “study regimen”. Therefore, we will be 
assessing and recording data in relation to how participants tolerate AL. As noted in 
Section 1.1.8, we evaluated the impact of a cytochrome P450-inhibitor, 
lopinavir/ritonavir, on levels of lumefantrine in children with malaria.(67) Day 7 levels in 
children on lopinavir/ritonavir-based ART had 10-fold higher day 7 levels of lumefantrine 
and >2-fold higher AUC, as compared to those on EFV-based ART, while exhibiting no 
increase in toxicity.(17, 67). We will, however, be recording participants tolerance of AL 

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using the NIH Division of AIDS Adult and Pediatric Toxicity Tables (version 2.1, March 
2017; https://rsc.tech-res.com/docs/default-source/safety/daids-ae-grading-table-
mar2017.pdf).  This will be used to screen for eligibility and to evaluate adverse events 
for children. Study staff will receive extensive training in the identification and 
management of adverse events. In addition, participants will be informed by the study 
team about potential adverse events associated with AL and will be encouraged to 
present to the study clinic for all potential adverse events. Symptomatic screening for 
auditory AEs will be conducted at each visit. The study clinic will remain open 7 days a 
week so that participants may present with potential adverse events as they arise. 
Monitoring, reporting, and management of adverse events is described below, and will 
follow guidelines set forth by each respective institution.
7.3 Toxicity management by grade
Alternate explanations for clinical and laboratory abnormalities will be sought. 
Laboratory normal values will be those provided by the clinical laboratory used for this 
study. For each adverse event identified as grade 3 or higher AND serious or 
unexpected (See Section 8.0), an adverse event report form will be completed. Adverse 
events will be followed until they resolve to below a grade 3. 
Grade 1 and 2:
It is anticipated that some subjects may enter this study with grade 1 or 2 abnormalities 
already present (e.g. due to ART management).  The site physicians will manage the 
grade 1 or 2 events according to standard practice. An adverse event report form will 
not be completed for events classified as grade 1 or 2, as these events are common 
and difficult to distinguish from common childhood illnesses.
Grade 3 or 4 (non-life threatening):

Notify the study team.

Repeat observation within 72 hours; notify study team of results.

Subjects may continue taking AL pending clinic visit or repeat laboratory
tests.  The clinician has the option of immediately stopping the AL if the subject
cannot be examined in clinic, if a repeat laboratory test cannot be performed
within 72 hours, or if the clinician determines that continuation of AL is unsafe
while awaiting clinic exam or test results.

Work-up to exclude other causes.

For all confirmed Grade 3 or 4 toxicities supported by repeat clinical exam or
laboratory test results, stop AL until toxicity resolves to < Grade 3.

If drug is restarted with resolution of toxicity and toxicity recurs on re-challenge,
study drugs will be permanently discontinued.  If AL is discontinued the
participant will be withdrawn from the study.
Grade 4 life threatening:

Notify study team.

If still receiving AL, AL should be permanently discontinued.

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8.0 MONITORING OF ADVERSE EVENTS AND MANAGEMENT
An adverse event is defined as "unfavorable changes in health, including abnormal 
laboratory findings that occur in study participants during the study or within a specified 
period following the study”.  There are no “study drugs” in this study, and all therapies 
being studied for PK are the standard of care in Uganda and provided free of charge by 
the Ministry of Health outside of study participation. This study will be directly observing 
administration of AL (Coartem®) to participants for the treatment of malaria. Data 
regarding the tolerance of AL will be recorded. Study clinicians will assess patients at 
each scheduled and unscheduled visit to the clinic according to a standardized clinical 
record form using scales developed by the NIH Division of AIDS Adult and Pediatric 
Toxicity Tables version 2.1, March 2017. Guidelines for reporting of adverse events due 
to study participation provided by UCSF Human Research Protection Program and 
Institutional Review Board, Yale Human Investigations Committee, NICHD, Makerere 
University School of Medicine Research Ethics Committee (SOMREC), and the 
Ugandan National Council for Science and Technology will be followed as described 
below. 
Per UCSF HRPP & IRB guidelines as found on website updated April, 2017: Adverse 
events which are definitely, probably, or possibly related to study procedures or study 
participation AND serious
 or unexpected will be reported. AEs which do not meet those 
criteria will be documented, referenced, and retained in the study files for follow-up. Per 
UCSF HRPP & IRB guidelines, the following definitions for serious or unexpected 
adverse events will be followed:
*Serious Adverse Event (SAE) is any AE that results in any of the following outcomes:
• Death,
• Life-threatening adverse experience,
• Inpatient hospitalization or prolongation of existing hospitalization,
• Persistent or significant disability/incapacity,
• Congenital anomaly/birth defect, or cancer, or
• Any other experience that suggests a significant hazard, contraindication, side
effect or precaution that may require medical or surgical intervention to prevent
one of the outcomes listed above,
• Event occurring in a gene therapy study
• Event that changes the risk/benefit ratio of the study.
±Unexpected Adverse Event. An adverse event is defined as being unexpected if the 
event exceeds the nature, severity, or frequency described in the protocol, consent form 
and investigator brochure (when applicable). An unexpected AE also includes any AE 
that meets any of the following criteria:
• Results in subject withdrawal from study participation,
• Due to an overdose of study medication, or
• Due to a deviation from the study protocol

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Per UNCST National guidelines March 2007: “These guidelines give criteria for prompt 
reporting of certain categories of adverse events to an IRC and the UNCST.” “An 
adverse event is any unfavorable and unintended sign, symptom or condition temporally 
associated with the administration of a health-related intervention, whether or not 
considered related to the intervention. The requirement to report adverse events to 
regulatory authorities shall not apply to events that are observed among participants 
who are in observational studies in which no health-related intervention is being 
administered.” However, for consistency, we will report adverse events which are 
definitely, probably, or possibly related to study procedures or study participation AND 
serious
 or unexpected similarly to UNCST and SOMREC.
Table 7. Guidelines for reporting adverse events related to study participation
Institution
Type of Adverse Events
When to Report
NICHD

Definitely, Probably, or Possibly
related AND Serious or
Unexpected

Within 10 working days of
awareness
UCSF-
HRPP&IRB

Definitely, Probably, or Possibly
related AND Serious or
Unexpected

Within 5 working days of
awareness

Internal, related deaths
and life-threatening
events: report
immediately
Yale-HIC

Definitely, Probably or Possibly
related to participation in the
research AND Serious AND
Unexpected (in terms of nature,
specificity, severity, or
frequency)

Within 5 days of
awareness

Related Events not
meeting prompt reporting
requirements are
reportable in summary
form at time of continuing
review
MU-
SOMREC

All Serious and Unexpected
events irrespective of
relationship;

All serious adverse
events and unexpected
events must be reported
within 7 calendar days of
awareness

All other reportable
events should be
reported within 14
calendar days
UNCST

All Serious and Unexpected
events irrespective of
relationship;

Death and Life-
threatening events within
48-hours with written
report within 7-calendar
days of awareness

All other reportable

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events within 15-calendar 
days of awareness
9.0 STATISTICAL CONSIDERATIONS
9.1 General Design Issues. 
This is a prospective study to evaluate the PK and PD of extended dose AL in the 
context of EFV-based ART and in the context of HIV-uninfected children and to 
characterize the impact of a 5-day regimen on AL PK/PD as compared to the standard 
3-day regimen; the study will be conducted in Uganda.
The current proposal will study the PK/PD of AL in HIV-infected children on EFV-based 
ART and HIV-uninfected children not on ART either enrolled at TDH or MGH. We will 
compare the PK of 5-day AL in HIV-infected children on EFV-based ART to 1) 3-day AL 
in HIV-infected children on EFV-based ART, and 2) 3-day AL in HIV-uninfected children. 
In addition, we will compare the PK of 5-day AL in HIV-uninfected children to 3-day AL 
in HIV-uninfected children. Comparisons will be based on an intensive PK design for AL 
AUC estimations in 30 to 50 subjects for each of the study groups. Study group 
comparisons will be controlled for age (i.e. results for HIV infected children on EFV-
based ART who are 3-10 years of age, will be compared to results for HIV uninfected 
children who are also 3-10 years of age).  The proposal will also study the impact of AL 
exposure on treatment outcomes and adverse events using a population PK/PD design. 
This will involve population PK study of up to an additional 100 HIV-infected children 
and 120 HIV-uninfected children. 
Although an individual child is eligible to enroll in both the intensive PK study and the 
population PK study for separate episodes of malaria, there is no assurance that the 
same child will contribute to both study components. Thus, it is possible that the total 
number of subjects for all groups may be as high as 380.
9.2 Outcome Measures
9.2.1 Primary outcomes 
1) Area under the plasma concentration versus time curve for all drug analytes.
2) Recurrent malaria following treatment by day 42 (recrudescence or new
infection)
9.2.2 Secondary outcomes

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1) Safety of 5-day vs 3-day AL regimens
2) Prevalence of gametocytemia following treatment in 3-day vs 5-day AL regimens
3) Weight-for-age and Height-for-age associations with PK
4) Diagnostic sensitivity of LAMP, HS-RDT, and microscopy for the detection of
recurrent parasitemia.
5) Metabolomic measurements in HIV infected vs HIV uninfected children
6) Relationship between molecular markers of drug resistance and treatment failure
9.3 Nutritional Status
Using anthropometric measurements and for a secondary study aim to relate nutritional 
status to PK and clinical outcomes, children will be characterized as a) “stunted” but not 
underweight [i.e. height for age (HFA) z-score ≤-2 and weight for age (WFA) z-score>-
2); b) underweight, but not stunted (WFA z-score ≤-2 and HFA z-score>-2); or c) of 
normal nutritional status (WFA and HFA z-scores >-1)  
9.4 Intensive PK study
9.4.1   Sample Size
Using measures of mean AUC and its coefficients of variation (CV) from our studies and 
the literature, the intensive arms of the study are powered to detect differences in ACT 
AUC between all study groups (3-day AL vs 5-day AL) with n=30 for each group of HIV 
infected children. To assure adequate age-matched HIV uninfected children, n=50 is 
used for the group of HIV uninfected children.  Figure 1 and Table 8.  50 HIV-uninfected 
children provides for adequate subjects <3 years and ≥3 years of age as HIV-infected 
children receiving EFV-based ART is restricted to ≥ 3 years of age. In addition, the 
same size of 50 will permit PK/PD of the extended regimen in younger children <3 years 
of age. At least 30 HIV uninfected children must be between 3-10 years of age.
For comparisons where n=30 in both groups, there will be 80% power to detect a 
difference in AUC of 35% or more, given an overall Type I error of 0.05, a Bonferroni 
correction for multiple comparisons, and with assumption that the coefficient of variation 
(CV) for all AUC’s is 35-38%. For the HIV-uninfected children with n=50, further
distinctions based on age can be determined as well as further enhancement of
exposure-response analysis.
Although many children are likely to be studied for both the 3-day and 5-day regimens, it 
is not likely that all children will provide results for both. However, all analyses will 
account for repeated measures/correlated data that occur from participants enrolled into 
multiple arms.
9.4.2   Intensive PK Analysis
PK parameters for each subject will be estimated using non-compartmental analysis 
(NONCMP) and follow a linear up-log down trapezoidal rule in conjunction with first-
order input (WinNonlin). PK parameters, including the elimination rate constant λz and 
t1/2 will be estimated, with t1/2 calculated as ln2/λz. AUC will be estimated as the AUC0-8h
or AUC0-24h (as results permit) for artemether/DHA and the sum of AUClast (AUC to the 

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end of the sampling period) and AUClast- (from the end of sampling to infinity) for 
lumefantrine/ desbutyl-lumefantrine. PK parameters will be compared between groups 
of interest (Figure 1 and Table 8) using a two-sided unpaired t-test for two-group 
comparisons, and ANOVA for multi-group comparisons. If PK parameters are found to 
have skewed distributions and data transformations do not induce symmetry, rank-
based tests will be used. To enhance comparison between 3-day and 5-day AL, peak 
concentrations collected on Days 0-4 will be integrated using population methods. The 
following groups will be compared:
Table 8. Primary objectives and comparator groups for intensive PK study
Primary Objectives
Comparison Groups
Impact of 5-day vs 3-day AL on 
AL exposure in HIV-infected 
children on EFV-based ART 
HIV-infected children on EFV-based ART 3-day AL (n=30), 
vs.
HIV-infected children on EFV-based ART 5-day AL(n=30).
Impact on AL exposure of 5-
day AL in HIV-infected children 
on EFV-based ART vs 3-day 
AL in HIV-uninfected children
HIV-infected children on EFV-based ART 3-day AL (n=30),
Vs.
HIV-uninfected children 3-day AL (n=30, age 3-18years).
Impact of 5-day vs 3-day AL on 
AL exposure in HIV-uninfected 
children
HIV-uninfected children 5-day AL (n=50), 
vs.
HIV-uninfected children 3-day AL (n=50).
9.5 Population PK study
9.5.1   Sample Size
160 episodes of malaria in HIV-infected children and 220 episodes of malaria in HIV-
uninfected children (up to 4 episodes per child including up to 2 involving intensive 
sampling) are more than sufficient to obtain population PK parameter estimates for both 
groups of children with good precision. Outcomes will be assessed in children in both 
the intensive and population PK studies, as such, sample sizes reflect the sum of 
children enrolled in each arm for each type of PK sampling. Thus, total sample sizes will 
be 80 to 110 children per arm. Using WinPOPT®, the standard errors (SE) of all 
population PK parameters, including variability parameters, will be <20% of their means, 
except for the interindividual variability of ka, for which the SE is estimated to be 32% of 
its mean. Based on our recent study from Tororo, where a 42-day recurrence rate of 
47% was observed in those on EFV-based ART, we will have 80% power to detect a 
20% difference in recurrence rates between 3-day and 5-day arms.(67)  Notably, in our 
previous exposure-outcomes, with 50 to 70 children in each ART arm and 184 children 
not on ART, a 2.1-fold change in AUC between those on EFV and lopinavir/ritonavir 
translated to a 2.7-fold increase in risk for reinfection.  In other words, the anticipated 
increase in AUC between 5-day and 3-day AL of 1.7-fold increase in exposure is 
expected to translate to a clinically relevant change in risk in a similar number of 
subjects.
9.5.2   Population PK Analysis and Correlation of AL PK with treatment outcomes. 
Population PK analysis will utilize both intensive and sparse PK sampling data for both 
HIV infected and HIV uninfected children. Plasma concentrations will be transformed 

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into natural logarithms and concentration-time profiles will be analyzed using non-linear 
mixed effects (NLME). For NLME modeling, PK data will be analyzed using a standard 
PK model formalism. To analyze population data the PK model is embedded in a two-
stage NLME model, accounting for both intra- and inter-subject variability.(99, 100) The 
estimation of NLME parameters will be accomplished using the software NONMEM 
(version 7; Icon Development Solutions, Maryland), in particular the first order 
conditional estimation method with interaction that uses a linear approximation to the 
likelihood of the data. Diagnostic graphics and post-processing of NONMEM output and 
simulations will be performed using the statistical software R. Model development will 
be guided by exploratory analysis of the data, changes in the NONMEM objective 
function value, and diagnostic plots. Our recent lumefantrine modeling suggest a two- 
and three-compartment model provide the best fit, respectively, though additional 
models will be tested(101) Alternative models for intra-subject variability (proportional and 
constant plus proportional) will be explored as appropriate. To reinforce the primary 
objectives, base model building will also include quantification and formal test of the 
impact of EFV on PK of AL. Specifically, the impact of HIV treatment will be tested as 
potential covariate on clearance and/or bioavailability. Further stepwise covariate 
analysis will be performed to identify the impact of covariates on the PK of AL with 
special focus on the impact of markers of malnutrition, as measured by weight, BMI, 
and various Z scores and mid-arm circumference. Other covariates will include age, 
body size (weight, height), concomitant medications, parasitemia, hematocrit, and CD4 
count (for HIV-infected children). Both linear and nonlinear relationship between 
continuous covariates and model parameters will be investigated in a stepwise fashion. 
Subject-specific estimates of artemether, DHA, lumefantrine, and desbutyl-LR exposure 
will be obtained from individual PK analyses for subjects with intensive PK sampling 
(AUC) and a posteriori from population PK analysis (as given by dose/(CL/F)). These 
estimates will be used to test for a significant relationship between drug exposure and 
the primary treatment outcome (recurrent infection at day 28-42 using standard WHO 
treatment outcomes(3)) using Cox proportional hazard models with robust sandwich 
estimators that account for correlated data, as individuals may be enrolled for multiple 
episodes of malaria. A secondary outcome will be sub-patent infections detectable by 
LAMP, which will also be analyzed for associations with PK exposure using Cox 
models. Simultaneous PK/PD analysis will be performed to maximize the entire 
database. As for PK, we will investigate if there is any potential impact of indices of 
malnutrition, HIV status, age and other covariates on PD parameters. In other words, 
we will identify if target concentrations to prevent reinfection might be altered in different 
patient population due to known covariates. Once targets are identified, population PK 
models will be used to simulate different AL PK dosing approaches to identify optimized 
regimens that ensure concentrations are maintained within the concentration range 
necessary to maximize efficacy in all studied populations.
10.0 DATA COLLECTION AND MONITORING

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10.1 Record Keeping
All clinical data will be recorded onto standardized case record forms (CRFs) by study 
physicians. Laboratory data will be recorded in a laboratory record book by the study 
laboratory technologists and then transferred to the case record forms by study 
coordinators, who will review the case record forms frequently for completeness and 
accuracy. Data will be entered directly from CRFs into a computerized database or 
transferred from the CRFs onto standardized data extraction forms and then into a 
computerized database. All computerized data will be double entered to verify accuracy 
of entry. Electronic data including all study databases and supporting electronic 
documentation will be archived to large-scale digital tape on a daily basis. On a monthly 
basis, a complete backup tape will be transported off-site to the Kampala Data 
Management Center (DMC) for rotating secure storage. In addition, the database from 
the backup will be placed onto one of the Kampala DMC servers as a data mirror for 
read-only access in the event that the Tororo web-site becomes temporary unavailable.
10.2 Data Quality Assurance and Monitoring
In order to insure data quality, the study Data Manager will perform a quarterly data 
quality audit. For this audit a 1% random sample of study forms entered into the data 
management system from the previous 2 weeks will be selected and compared for 
accuracy with the original case-report forms and source documents. In addition, the 
study the Data Manager will perform monthly reviews of the 100% double data entry 
data verification logs and the data management system audit trail log to identify 
potential data quality issues.
11.0 HUMAN SUBJECTS
11.1 Risks and Benefits
There are minimal direct benefits to the study subject for participation in the study. Free 
medical treatment for malaria is provided in Uganda.  In Uganda, typical treatment for 
malaria involves the provision of medications, but no set schedule of follow-up after 
treatment.  In our study, we will provide an increased level of care, primarily through 
enhanced follow-up of participants.  However, we will not list this as a benefit on our 
informed consent documents. The risks have been reduced to a minimum.  Participants 
will already be requiring AL for their malaria therapy.  For children, we have consciously 
considered the guidelines set forth by the UCSF HRPP & IRB of 3ml/kg for blood 
sample collection and have optimized all assay requirements for accurate quantification 
of drug concentrations using the lowest amount of blood.  We have also consulted other 
recommendations.  The most conservative recommendations suggest no more than 
2.5% (~2 mL/kg) of total blood volume within a 24 hour period or 5% (~4 mL/kg) within a 
30 day period.  The NIH guidelines state that no more than 3 mL/kg are to be drawn in a 
single blood draw (24 hour period) and no more than 9.5 mL/kg are to be drawn over 
any eight week period for the purposes of research in children. We feel it is unlikely the 
participant would be harmed by taking the amount of blood required in this study.  For 
even children as small as 5 kg, the amount of blood that will be drawn in a 24 hour 

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period will not exceed 1.2 mL/kg.  For the total amount collected over 42 days of follow-
up the amount of blood that will be drawn will not exceed 5.3 mL/kg, which are well 
within these limits.   
There is small chance of infection from performing blood draws.  Additional risks include 
anxiety from HIV testing and learning of testing results.  Participants will be counseled 
regarding test results and referred for medical care if necessary.  
11.2 Treatment and Compensation for Injury
If the participant is injured as a result of being in this study, treatment will be available 
through TDH and MGH. Makerere University, UCSF, Yale, and NICHD do not normally 
provide any other form of compensation for injury.
11.3 Costs to the Subjects
There will be no cost to the participant or their parents/guardians/participants for 
participation in this study.
11.4 Reimbursement of Subjects
Participants will not be paid for their participation in the study. We will provide all routine 
medical care, including evaluations, medications available in our clinic, and cost of any 
transportation free of charge. On certain days, participants will have to be in the clinic 
for several hours. On those days, we will provide food and drink to participants 
(breakfast, dinner, and/or snacks) to ensure their well-being. In addition, we will 
reimburse the cost of consultation for referrals made by study physicians to other clinics 
and services within TDH or MGH using available funds when available. However, 
reimbursement of all diagnostic tests and treatment recommended outside the study 
clinic cannot be guaranteed in all circumstances.
11.5 Institutional Review Board (IRB) Review and Informed Consent
This protocol, all procedures and consent forms, and any subsequent modifications 
must be reviewed and approved by the IRBs of participating institutions in both the U.S. 
and in Uganda. This includes the UCSF Human Research Protection Program & 
Institutional Review Board (HRPP & IRB), the Yale Human Investigations Committee 
(HIC), the Makerere University School of Medicine Research Ethics Committee 
(SOMREC), and the Uganda National Council of Science and Technology (UNCST).
All consent forms will be translated into the local language (Jopadhola, Teso, Swahili, 
Luganda, Samia, and English) and back-translated into English to ensure correct use of 
language. Consent forms will be read aloud to parents by trained study interviewers. 
The informed consent will describe the purpose of the study, all the procedures 
involved, and the risks and benefits of participation. Interviewers will ask 
parents/guardians/participants to summarize the study and explain the reasons why 
they want to participate. Either a signature or a thumbprint (for parents/guardians who 

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cannot read) will be acceptable to confirm informed consent for participation in the 
study.
11.6 Study Discontinuation
This study may be discontinued at any time by the NIH, respective IRBs or other 
Governmental agencies in the United States or Uganda as part of their duties to ensure 
that research subjects are protected
11.7 Definition of Parent/Guardianship
For this project, we will define a parent as someone who attests that he/she is the 
biological parent of the potential participant. However, it has been found in Uganda that 
a high number of the HIV-infected children have lost one or both parents. These 
children live with caretakers who do not have documented formal guardianship status 
because there is no formal, legal guardian system in Uganda. In Uganda, orphan 
children are customarily cared for by one or more relatives; a single individual family 
member is not usually identified as the sole guardian or custodian of the child. We will 
define a guardian as someone who identifies him/herself as the primary caregiver who 
is able to make all health care decisions for the potential participant. A guardian must be 
at least 18 years of age, however; a parent may be less than 18 years of age. These 
definitions are currently approved for use in current research projects conducted in 
Uganda following extensive discussion with the Ugandan Ministry of Justice, the 
Uganda National Council of Science, the Makerere University College of Health 
Sciences, and the NIH in 2006.
12.0 PUBLICATION OF RESEARCH FINDINGS
The findings from this study may be published in a medical journal. No individual 
identities will be used in any reports or publications resulting from the study. The 
researchers will publish results of the trial in accordance with NICHD, UNCST, UCSF, 
Yale, and Makerere University guidelines.
13.0 BIOHAZARD CONTAINMENT
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel involved in the drawing of blood, 
exposure to blood and secretions, and shipping and handling of all specimens for this 
study. We will follow the current guidelines set forth by the Centers for Disease Control 
and Prevention and the NIH. All infectious specimens will be transported using 
packaging mandated in the Federal Code of Regulations, CDC 42 CFR Part 72.

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APPENDIX A. SCHEDULE OF EVALUATIONS: INTENSIVE PK STUDY
INTENSIVE PK STUDY
Study Day
01
1
2
3
        4
511
611
89
1015
14
21
28
35
42
Any 
other 
day10
ADMINISTRATIVE AND 
REGULATORY PROCEDURES
Screening and study participation 
informed consent 
X
HIV counseling and referral if 
necessary2
X
Collect locator information
X
CLINICAL AND LABORATORY 
EVALUATIONS
History3
X
X
X
X
X
X11
X11
X
X
X
X
X
X
X
Physical Examination4
X
X
X
X
X
X11
X11
X
X
X
X
X
X
X
HIV testing and documentation2
X
Hematology and Chemistries5
4mL
4mL
4mL
Rapid Diagnostic Test (RDT)
X
X
X
X
X
X
X
X
Thick Blood Smear13 and Filter 
Paper collection (finger stick) for 
LAMP
X
X
X
X
X
X11
X11
X
X
X
X
X
X
X
X
Thin Blood Smear6
X
X
Electrocardiogram (ECG)17
X
X
X
X
X
DRUG ADMINISTRATION
AL dosing for all study subjects7
X
X
X
X
X11
X11
Antiretroviral dosing for HIV- 
infected subjects8
X
X
X
X
X
X
X
X
X
INTENSIVE PHARMACOKINETIC 
STUDY SAMPLING (VENOUS OR 
CAPILLARY DRAWS AS PER 
SECTION 6.7)
3-day AL regimen
 Artemether and Lumefantrine
200μL
(pre-AL)
2 and 4 
hrs post-
dose
200μL
2 and 4 
hrs post-
dose
200μL
2 and 4 
hrs post-
dose
500 μL
(0, 0.5, 1, 
212, 3, 4, 6 
and 812 
hrs)
(additional 
200 μL at 
2 and 8 
hrs)
200μL
(24 hrs)
200μL
(120 hrs)
200μL
(288 hrs)
200μL
(456 hrs)
200μL

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5-day AL regimen 
Artemether and Lumefantrine11
200μL
(pre-AL)
2 and 4 
hrs post-
dose
200μL
2 and 4 
hrs post-
dose
200μL
2 and 4 
hrs post-
dose
200μL
2 and 4 
hrs post-
dose
200μL
2 and 4 
hrs post-
dose
500 μL
(0, 0.5, 1, 
2, 3, 4, 6 
and 8 
hrs)
200μL
(24 hrs)
200μL
(120 hrs)
200μL
(288 hrs)
200μL
(456 hrs)
200μL
Blood for metabolomics and 
molecular studies
1mL
X14
X14
X15
1mL
X14
1mL
X14
1mL
1mL
APPROXIMATE TOTAL BLOOD 
VOLUME (mL)16
5.6
0.6
0.6
0.6-4.8
0.4-0.6
0.2-4.2
0.4
0.6
0.3
5.4
0.6
5.2 
0.4
1.2
1.4
Explanation of Intensive PK schedule of events (Appendix A):
1
As is standard practice, study Day 0 stipulates the time of diagnosis of uncomplicated malaria and initiation of AL treatment.
2
Rapid HIV test will be performed to determine eligibility to enroll as either HIV infected or HIV uninfected participant, although 
children must be stabilized on EFV-based ART for 10 days prior to enrollment.  Positive HIV test results to be confirmed by Western 
Blot or HIV RNA after enrollment.
3
History will include general medical history, diagnosis, medication (including ingestion of herbs), allergies, and current symptoms.
4
Physical examination will include weight, height, and viral signs (temperature, pulse, blood pressure, respiratory rate), 
lymphadenopathy, hepatomegaly, splenomegaly, infections in ears, mouth, pharynx or skin and pulmonary, cardiac, neurologic or 
skeletal abnormalities and anthropometric assessments.   Mid-upper arm circumference will also be collected at time of first 
enrollment for each episode of malaria.
5
Hematology/chemistry draws entail a 4mL venous sample for CBC, differential, ALT/AST, and creatinine.  AST is incorporated as 
part of chemistries at all blood draws.
6
A thin smear is performed to assist in species identification.
7
Dosing of AL for all subjects undergoing intensive PK sampling will be scheduled to assure the last dose of a six or 10 dose regimen 
is given in the morning (Day 3 or 5).
8
On stable ART as per clinical management in TDH or MGH or other referral clinic; ART dosing permitted at home, but time of 
administration is recorded
9
For subjects participating in intensive PK evaluations, sampling for the 120 PK sample will occur on Day 8 since these subjects 
receive the 6th or 10th AL dose on Day 3 or 5.
10
Patients presenting on an unscheduled day for a sick visit will undergo sampling for lumefantrine PK if found to have a positive 
malaria thick 
11
Specifically, for children receiving 5-day AL
12
At 2 and 8 hours an additional 200µL will be drawn via a capillary stick to permit correlation of venous and capillary concentrations 
for the artemisinins.
13
At approximately 0, 24, 48, and 72, 84 and 96 hours post the first dose of AL or until blood smears are consistently negative. In a 
subset of participants, additional thick blood smears will be done on the days of AL doses to assess parasite clearance.
14
Additional 200uL capillary samples for RNA studies will be done on these days. RNA studies will not be done on participants under 
10kg.   

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15
Day 10 visit can be done in a subset of participants in either the clinic or by home visitor for collection of approximately 250uL for 
RNA and filter paper. Sampling will note will not be done on participants under 10kg.  
16
Total blood volume in either arm is between 5-6 teaspoons over 42-days of follow-up for scheduled visits
17
Perform ECG on subgroup of participants. ECGs will be performed at baseline (before the administration of first dose), prior to and 4-
6 hours post-last dose, Day 8, and Day 28. ECG will be performed on Day 3 for 3-day regimen and on Day 5 for 5-day regimen. 

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APPENDIX B. SCHEDULE OF EVALUATIONS: POPULATION PK STUDY
POPULATION PK STUDY
Study Day
01
1
2
3
        4
5
79
1014
14
21
28
35
42
Any other 
day10
ADMINISTRATIVE AND 
REGULATORY PROCEDURES
Screening and study participation 
informed consent 
X
HIV counseling and referral if 
necessary2
X
Collect locator information
X
CLINICAL AND LABORATORY 
EVALUATIONS
History3
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination4
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV testing and documentation2
X
Hematology and Chemistries5
4mL
4mL
4mL
Rapid Diagnostic Test (RDT)
X
X
X
X
X
X
X
X
Thick Blood Smear12 and Filter Paper 
collection (finger stick) for LAMP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Thin Blood Smear6
X
X
Electrocardiogram (ECG)16
X
X
X
X
X
DRUG ADMINISTRATION
AL dosing for all study subjects7
X
X
X
X11
X11
Antiretroviral dosing for HIV- infected 
subjects8
X
X
X
X
X
X
X
X
INTENSIVE PHARMACOKINETIC 
STUDY SAMPLING (VENOUS OR 
CAPILLARY DRAWS AS PER 
SECTION 6.7)
3-day AL regimen
 Artemether and Lumefantrine
200μL
(pre-AL, 2 
and 4 hrs 
post-dose)
200μL
2 and 4 
hrs post-
dose
200μL
Pre-dose17, 
2 and 4 hrs 
post-dose
200μL
(24 hrs)
200μL
(120 hrs)
200μL
(288 hrs)
200μL
(456 hrs)
200μL
5-day AL regimen 
Artemether and Lumefantrine11
200μL
(pre-AL, 2 
and 4 hrs 
post-dose)
200μL
2 and 4 
hrs post-
dose
200μL
2 and 4 hrs 
post-dose
200μL11
2 and 4 
hrs post-
dose
200μL11
Pre-
dose17, 2 
and 4 hrs 
post-
dose
200μL11
(24 hrs)
200μL
(120 hrs)
200μL
(288 hrs)
200μL
(456 hrs)
200μL
Blood for metabolomics and molecular 
studies
1mL
X13
X13
X14
1mL
X13
1mL
X13
1mL
1mL
APPROXIMATE TOTAL BLOOD 
VOLUME (mL)15
5.8
0.6
0.8
0.4-0.8
0.2-0.6
0.4
0.6
0.3
5.4
0.6
5.2
0.4
1.2
1.4

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Explanation of Population PK schedule of events (Appendix B):
1
As is standard practice, study Day 0 stipulates the time of diagnosis of uncomplicated malaria and initiation of AL treatment.
2
Rapid HIV test will be performed to determine eligibility to enroll as either HIV infected or HIV uninfected participant, although children 
must be stabilized on EFV-based ART for 10 days prior to enrollment.  Positive HIV test results to be confirmed by Western Blot or 
HIV RNA after enrollment.
3
History will include general medical history, diagnosis, medication (including ingestion of herbs), allergies, and current symptoms.
4
Physical examination will include weight, height, and viral signs (temperature, pulse, blood pressure, respiratory rate), 
lymphadenopathy, hepatomegaly, splenomegaly, infections in ears, mouth, pharynx or skin and pulmonary, cardiac, neurologic or 
skeletal abnormalities and anthropometric assessments.   Mid-upper arm circumference will also be collected at time of first 
enrollment for each episode of malaria.
5
Hematology/chemistry draws entail a 4mL venous sample for CBC, differential, ALT/AST, and creatinine.  AST is incorporated as part 
of chemistries at all blood draws.
6
A thin smear is performed to assist in species identification.
7
Dosing of AL for all subjects will not be adjusted as done for intensive study so the last dose will be occur in the evening of Day 2 (3 
day AL) or 4 (5 day AL)..
8
On stable ART as per clinical management in TDH or MGH or other referral clinic; ART dosing permitted at home, but time of 
administration is recorded
9
For subjects participating in population PK evaluations, sampling for the 120 PK sample will occur on Day 7 since these subjects will 
not have adjustments in their dosing
10 Patients presenting on an unscheduled day for a sick visit will undergo sampling for lumefantrine PK if found to have a positive malaria 
thick 
11 Specifically, for children receiving 5-day AL
12 At approximately 0, 24, 48, and 72, 84 and 96 hours post the first dose of AL or until blood smears are consistently negative.  In a 
subset of participants, additional thick blood smears will be done on the days of AL doses to assess parasite clearance.
13 Additional 200uL capillary samples for RNA studies will be done on these days. RNA studies will not be done on participants under 
10kg.   
14 Day 10 visit can be done in a subset of participants in either the clinic or by home visitor for collection of approximately 250uL for RNA 
and filter paper. Sampling will note will not be done on participants under 10kg.  
15 Total blood volume in either arm is between 4-5 teaspoons over 42-days of follow-up for scheduled visits
16 Perform ECG on subgroup of participants. ECGs will be performed at baseline (before the administration of first dose), the next 
morning following the last dose, Day 7, and Day 28. ECG will be performed on Day 3 for 3-day regimen and on Day 5 for 5-day 
regimen. 
17 A 200ul capillary draw will be done pre-dose on Day 2 in the 3-Day regimen and on Day 4 in the 5-Day regimen, in a subset of 
children, to look at AL drug level. This will inform the study team of drug adherence.

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APPENDIX C. INFORMATION SHEET                  
                                                                        
Information Sheet
A study on Antimalarial Pharmacology in HIV infected and uninfected
Makerere University, University of California, San Francisco, Yale University, and 
Tororo District Hospital are carrying out a study on artemether-lumefantrine (Coartem) 
uptake by the body and response to this malaria treatment in HIV-infected (receiving 
anti-HIV medications) and HIV-uninfected children.

Our clinics are located at Tororo District Hospital and Masafu General Hospital

We are comparing groups receiving Coartem, currently recommended 
uncomplicated malaria treatment by the Uganda Ministry of Health

We want the following to participate
o
HIV-infected (HIV+) children aged 3 to 10 years 
o
HIV-uninfected (HIV-) children aged 6 months to 10 years

Participants in this malaria study will receive medical care during the course of 
the study at the study clinic

We will provide transport to and from our clinic if needed

The clinic is open every day from Monday to Sunday, 8am to 5pm
For more information, come to Tororo District Hospital or Masafu General Hospital and 
ask for the malaria children’s clinic. The doctors will be happy to talk with you. 
UCSF

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APPENDIX D. WHO CRITERIA FOR SEVERE MALARIA/DANGER SIGNS 
Criteria for severe malaria 

Cerebral malaria - defined as unarousable coma not attributable to any 
other cause in a patient with falciparum malaria 

Generalized convulsions (≥ 3 convulsions over 24 hours period) 

Severe normocytic anemia (Hb < 5 gm/dL) 

Hypoglycemia 

Metabolic acidosis with respiratory distress 

Fluid and electrolyte disturbances 

Acute renal failure 

Acute pulmonary edema and adult respiratory distress syndrome (ARDS) 

Circulatory collapse, shock, septicemia ("algid malaria") 

Abnormal bleeding 

Jaundice 
Danger signs 

1-2 convulsions over a 24 hour period 

Inability to sit up or stand 

Vomiting everything 

Unable to breastfeed or drink 

Lethargy 

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APPENDIX F. GUIDELINES FOR ADVERSE EVENT GRADING (DAIDS 
AE GRADING TABLE)
Estimating Severity Grade
If the need arises to grade a clinical AE that is not identified in the DAIDS AE grading 
table, use the category “Estimating Severity Grade”.
Grading Adult and Pediatric AEs
The DAIDS AE grading table includes parameters for grading both Adult and Pediatric 
AEs. When a single set of parameters is not appropriate for grading specific types of 
AEs for both Adult and Pediatric populations, separate sets of parameters for Adult 
and/or Pediatric populations (with specified respective age ranges) are given in the 
table. If there is no distinction in the table between Adult and Pediatric values for a type 
of AE, then the single set of parameters listed is to be used for grading the severity of 
both Adult and Pediatric events of that type.
Determining Severity Grade
If the severity of an AE could fall under either one of two grades (e.g., the severity of an 
AE could be either Grade 2 or Grade 3), select the higher of the two grades for the AE.
Definitions
Basic Self-care Functions
Adult
Activities 
such 
as 
bathing, 
dressing, 
toileting, 
transfer/movement, continence, and feeding.
Young Children
Activities that are age and culturally appropriate (e.g., 
feeding self with culturally appropriate eating implement).
LLN
Lower limit of normal
Medical Intervention
Use of pharmacologic or biologic agent(s) for treatment 
of an AE.
NA
Not Applicable
Operative Intervention
Surgical OR other invasive mechanical procedures.
ULN
Upper limit of normal

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APPENDIX G. HIV-INFECTED CHILDREN CONSENT
APPENDIX H. HIV-UNINFECTED CHILDREN CONSENT
APPENDIX I. ASSENT
APPENDIX J. FUTURE USE OF BIOLOGICAL SPECIMENS CONSENT