Chloroquine Alone or in Combination for Malaria in Children in Malawi

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00379821
• Collaborator: (none)
• Enrollment: 640
• Location: 1
• Arms: 4
• Duration (Months): 67
• Patients Per Site Per Month: 9.6

Study Details

Study Description

Brief Summary

Malaria is a sickness caused by a germ that can get into a person's body when a mosquito bites them. It can cause fever, headache, body aches and weakness. It can even cause death, especially in children. When malaria is treated with the appropriate medicine(s), it can be cured completely. The purpose of this study is to find out if it is better to use chloroquine alone or in combination with another drug to most effectively treat malaria. About 640 children with malaria, aged 6 months to 5 years of age, from the Blantyre Malaria Project Research Clinic at the Ndirande Health Center in Malawi will be in the study. They will be treated with either chloroquine alone or a combination of chloroquine plus another medication (azithromycin or artesunate or atovaquone-proguanil) every time they get malaria for a year. Blood samples will be collected and tested at least every 4 weeks. Participants will be involved in the study for 1 year.

Condition or Disease	Intervention/Treatment	Phase
Plasmodium Falciparum Infection	Drug: Atovaquone-proguanil; Drug: Artesunate; Drug: Azithromycin; Drug: Chloroquine	Phase 3

Detailed Description

Combination therapy is becoming the mainstay of malaria treatment. In general, the goal of combination therapy is to treat resistant infections successfully and to prevent the emergence and spread of resistance. The antimalarial combination therapies currently in use were not designed based on optimal pairing of drugs to deter the development and spread of parasite resistance to the individual partner drugs in settings of high malaria transmission. Careful studies are needed to identify the pharmacokinetic and pharmacodynamic properties of drug combinations that will deter resistance and prolong the useful therapeutic life of the next generation of antimalarial drug combinations. Current in vivo methods for measuring antimalarial drug efficacy in high-transmission areas use a 14 or 28-day follow-up period, but a single episode study misses several critical factors in assessing the efficacy and impact of antimalarial treatment. When follow-up is extended beyond 28 days, more cases of apparent resistance or treatment failure are found. Single-episode studies cannot assess the impact of therapy on the incidence of malaria over time. These limitations of standard in vivo studies have led the investigators to advocate longitudinal studies of drug efficacy. In addition to measuring efficacy of individual treatments, longitudinal studies measure sustained efficacy with repeated use of the same regimen over time, a scenario that more accurately reflects the real-life use of anti-malarial medication. The primary outcome of interest is the incidence of malaria episodes, as well as the secondary outcomes of anemia and severe malaria, are all highly relevant to public health policy-makers, as they reflect not only the burden of disease but also the utilization of health resources. Longitudinal studies also permit assessment of how pharmacokinetic properties of drugs affect the incidence of treatment episodes. This is a randomized, open-label, longitudinal drug efficacy trial. Participants will include 640 children, aged 6 months to 5 years, who are found to have uncomplicated malaria at the Blantyre Malaria Project Research Clinic at the Ndirande Health Centre in Blantyre, Malawi. After enrollment, participants will be randomized to one of four treatment arms: chloroquine alone or chloroquine in combination with artesunate, atovaquone-proguanil (AP), or azithromycin. The treatment outcome will be assessed through a standard 28-day efficacy study. Participants will subsequently be evaluated every 4 weeks and encouraged to return to the study clinic any time they are ill during the course of one year. If a new episode of uncomplicated malaria is diagnosed, the participant will receive the same therapy as assigned on enrollment. Polymerase chain reaction-corrected 28-day efficacy will be evaluated for each treatment episode. The primary study objective is to compare annual incidence of malaria clinical episodes. Secondary objectives are to: assess anti-malarial drug efficacy at first administration, by treatment arm; assess anti-malarial drug efficacy during subsequent episodes of malaria, by treatment arm; measure prevalence of chloroquine resistant parasites during the trial, by treatment arm; assess effect of each treatment arm on anemia at the end of study participation; assess safety of these drugs with repeated use; determine the chloroquine blood levels at which chloroquine sensitive and resistant parasites are able to cause infection; assess the effect of population movements on the risk of malaria infection; and assess the spatial patterns and the environmental determinants of malaria infection. Participants will be involved in study rela

Study Design

• Study Type: Interventional
• Actual Enrollment: 640 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Longitudinal Study of Chloroquine as Monotherapy or in Combination With Artesunate, Azithromycin or Atovaquone-Proguanil to Treat Malaria in Children in Blantyre, Malawi
• Study Start Date: Feb 1, 2007
• Actual Primary Completion Date: Aug 1, 2009
• Actual Study Completion Date: Sep 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CQ Monotherapy N=160: treat with Chloroquine (CQ) alone.	Drug: Chloroquine; Chloroquine: 10 mg/kg on days 0 and 1, 5 mg/kg/day on day 2, 100 mg tablet.
Experimental: CQ plus atovaquone proguanil N=160: treat with CQ plus atovaquone proguanil.	Drug: Atovaquone-proguanil; Atovaquone-proguanil: once a day for 3 days, Pediatric tablet: 62.5 mg/25 mg, Full strength tablet: 250 mg/100 mg; Drug: Chloroquine; Chloroquine: 10 mg/kg on days 0 and 1, 5 mg/kg/day on day 2, 100 mg tablet.
Experimental: CQ plus artesunate N=160: treat with CQ plus artesunate.	Drug: Artesunate; Artesunate: 4mg/kg once a day for 3 days, 50 mg tablet; Drug: Chloroquine; Chloroquine: 10 mg/kg on days 0 and 1, 5 mg/kg/day on day 2, 100 mg tablet.
Experimental: CQ plus azithromycin N=160: treat with CQ plus azithromycin.	Drug: Azithromycin; Azithromycin 30 mg/kg once a day for 3 days, 200 mg/5cc suspension; Drug: Chloroquine; Chloroquine: 10 mg/kg on days 0 and 1, 5 mg/kg/day on day 2, 100 mg tablet.

Outcome Measures

Primary Outcome Measures

1. Number of Clinical Malaria Episodes Per Year of Follow-up [1 year]

   Clinical malaria episode was defined as at least one symptom of malaria and a positive malaria smear. The number of clinical malaria episodes (not including the initial malaria episode) reported by participants during follow up is presented as the number per Person Years at Risk (PYAR).

Secondary Outcome Measures

1. Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm [Day 28 of initial malaria episode (Episode 0)]

   Adequate clinical and parasitologic response (ACPR) was defined as the absence of parasitemia at Day 28 and without previously meeting any of the criteria of early treatment or late clinical failure.

2. Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm [Day 28 of first subsequent malaria episode (Episode 1)]

   Adequate clinical and parasitologic response (ACPR) was defined as the absence of parasitemia at Day 28 and without previously meeting any of the criteria of early treatment or late clinical failure.

3. Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm [Day 28 of second subsequent malaria episode (Episode 2)]

   Adequate clinical and parasitologic response (ACPR) was defined as the absence of parasitemia at Day 28 and without previously meeting any of the criteria of early treatment or late clinical failure.

4. Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm [Day 28 of third subsequent malaria episode (Episode 3)]

   Adequate clinical and parasitologic response (ACPR) was defined as the absence of parasitemia at Day 28 and without previously meeting any of the criteria of early treatment or late clinical failure.

5. Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm [Day 28 of fourth subsequent malaria episode (Episode 4)]

   Adequate clinical and parasitologic response (ACPR) was defined as the absence of parasitemia at Day 28 and without previously meeting any of the criteria of early treatment or late clinical failure.

6. Number of Cases of Severe Malaria in Each Treatment Arm [1 Year]

   A case of severe malaria included one or more of the following: Hemoglobin ≤5 g/dL; prostration; respiratory distress; bleeding; recent seizures, coma or obtundation (Blantyre coma score < 5); inability to drink, or persistent vomiting. All cases were then adjudicated by a panel of investigators prior to analysis.

7. Mean Hemoglobin at the Last Study Visit in Each Treatment Arm for the Age Group of Participants 3 Years of Age or Younger. [1 year]

   Hemoglobin values were assessed from blood collected at the last study visit at one year after enrollment. Group means are stratified by participants 3 years of age and under, and over 3 to 5 years of age.

8. Mean Hemoglobin at the Last Study Visit in Each Treatment Arm for the Age Group of Participants Greater Than 3 Years to 5 Years of Age. [1 year]

   Hemoglobin values were assessed from blood collected at the last study visit at one year after enrollment. Group means are stratified by participants 3 years of age and under, and over 3 to 5 years of age.

9. Mean Creatinine in Each Treatment Arm (Renal Function) [Day 0 of initial malaria episode (Episode 0)]

   Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.

10. Mean Creatinine in Each Treatment Arm (Renal Function) [Day 14 of initial malaria episode (Episode 0)]

    Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.

11. Mean Creatinine in Each Treatment Arm (Renal Function) [Day 0 of first subsequent malaria episode (Episode 1)]

    Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.

12. Mean Creatinine in Each Treatment Arm (Renal Function) [Day 14 of first subsequent malaria episode (Episode 1)]

    Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.

13. Mean Creatinine in Each Treatment Arm (Renal Function) [Day 0 of second subsequent malaria episode (Episode 2)]

    Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.

14. Mean Creatinine in Each Treatment Arm (Renal Function) [Day 14 of second subsequent malaria episode (Episode 2)]

    Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.

15. Mean Creatinine in Each Treatment Arm (Renal Function) [Day 0 of third subsequent malaria episode (Episode 3)]

    Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.

16. Mean Creatinine in Each Treatment Arm (Renal Function) [Day 14 of third subsequent malaria episode (Episode 3)]

    Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.

17. Mean Creatinine in Each Treatment Arm (Renal Function) [Day 0 of fourth subsequent malaria episode (Episode 4)]

    Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.

18. Mean Creatinine in Each Treatment Arm (Renal Function) [Day 14 of fourth subsequent malaria episode (Episode 4)]

    Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.

19. Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [Day 0 of initial malaria episode (Episode 0)]

    ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.

20. Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [Day 14 of initial malaria episode (Episode 0)]

    ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.

21. Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [Day 0 of first subsequent malaria episode (Episode 1)]

    ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.

22. Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [Day 14 of first subsequent malaria episode (Episode 1)]

    ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.

23. Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [Day 0 of second subsequent malaria episode (Episode 2)]

    ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.

24. Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [Day 14 of second subsequent malaria episode (Episode 2)]

    ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.

25. Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [Day 0 of third subsequent malaria episode (Episode 3)]

    ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.

26. Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [Day 14 of third subsequent malaria episode (Episode 3)]

    ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.

27. Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [Day 0 of fourth subsequent malaria episode (Episode 4)]

    ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.

28. Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [Day 14 of fourth subsequent malaria episode (Episode 4)]

    ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.

29. Number of Participants in Each Treatment Arm Who Change From "Normal" to "Abnormal" on Any Questions of the Neurological Examination [1 Year]

    A basic age-appropriate neurological examination was conducted on Day 28 of each malaria illness episode and also at Days 112 and 224, and at 1 year. Subjects were were counted as a "change from 'normal' to 'abnormal' " if they had the 'normal' (or not-applicable) response for the initial day 28 exam and an 'abnormal' response at their last exam. If a subject did not have an exam at 1 year then the last available exam that was not associated with an illness episode (either Day 112 or 224) was used.

30. Number of Participants Infected With Parasites With the Mutation Pfcrt 76T on Day 0 of the Initial Episode of Malaria [Day 0 of initial episode of malaria]

    The presence of parasites with the mutation pfCRT 76T was measured with filter paper specimens collected at the time of enrollment and with successful parasite DNA amplification using pyrosequencing.

31. Number of Participants Infected With Parasites With the Mutation Pfcrt 76T at Recrudescent Episodes of Malaria [Recrudescent episodes of malaria within one year of enrollment]

    Participants were enrolled in the study at the time of the initial episode of malaria. If the participant presented with a subsequent episode of malaria at any time during the one year of follow-up, the presence of parasites with the mutation pfCRT 76T was measured with filter paper specimens collected at the time of enrollment and with successful parasite DNA amplification using pyrosequencing.

32. Number of Participants With New and Recrudescent Malaria Infections After Initial Treatment [28 days to 1 year]

    Participants were enrolled at the time of initial malaria episode and treated. Subsequent to treatment, subjects were monitored for the occurrence of new and recrudescent malaria infections, which were distinguished by analysis of the infecting parasites using merozoite surface protein-2 polymorphic gene length variation.

33. Number of Participants With New and Recrudescent Infections After Subsequent New Episodes [Day 28 to 1 year]

    Participants were enrolled at the time of initial malaria episode and treated. Subsequent to treatment, participants who subsequently suffered new malaria episodes were monitored for the additional occurrence of new and recrudescent malaria infections, which were distinguished by analysis of the infecting parasites using merozoite surface protein-2 polymorphic gene length variation.

34. Time to First Malaria Episode in Participants Who Travelled and Slept Outside the City Versus Those Who Did Not Travel and Sleep Outside the City. [Days 0 - 420]

    The cumulative hazard of having a malaria attack within one year for those participants who travelled and slept in rural areas (outside the city) versus those who did not was calculated and is presented as a life table to display the number of subjects at risk, the number with first clinical episode and the number censored at each time point. Participants are right-censored at the time of first malaria episode. Participants who did not develop malaria during follow-up or were lost to follow-up were censored at the time of their last visit.

35. Nearest Neighbor Index as a Measure of Spatial Pattern of the Distribution of Malaria Cases in Ndirande [1 year]

    The Global Positioning System (GPS) was used to establish the coordinates of participants' homes. The distribution of these coordinates was analyzed for evidence of clustering, or occurring closer together than would be expected on the basis of chance. Nearest Neighbor Index is a ratio of the observed mean distance over the expected mean distance. If the index is less than 1, the pattern exhibits clustering. If the index is greater than 1, the trend is toward dispersion.

36. Pharmacokinetics of Chloroquine Represented by Time of Maximal Concentration (Tmax) and Chloroquine Half-life [Day 0 - Day 28]

    1727 non-zero concentration measurements from 479 participants were pooled and used for population pharmacokinetic modeling in Monolix413s. Compartmental population pharmacokinetic modeling was used due to highly sparse data. The model was parameterized in terms of absorption rate constant for chloroquine (Ka), apparent clearance for chloroquine (CL/F, with F as the unknown oral bioavailability), apparent volume of distribution of the central and peripheral compartments for chloroquine (Vd/F), and the inter-compartmental clearance for chloroquine (Q/F). Only these primary population pharmacokinetic parameters could be estimated using the type of data collected. The best-fit population PK model was then used to estimate individual parameter estimates to derive Tmax and half-life.

37. Pharmacokinetics of Chloroquine Represented by Maximum Concentration (Cmax) [Day 0 - Day 28]

    1727 non-zero concentration measurements from 479 participants were pooled and used for population pharmacokinetic modeling in Monolix413s. Compartmental population pharmacokinetic modeling was used due to highly sparse data. The model was parameterized in terms of absorption rate constant for chloroquine (Ka), apparent clearance for chloroquine (CL/F, with F as the unknown oral bioavailability), apparent volume of distribution of the central and peripheral compartments for chloroquine (Vd/F), and the inter-compartmental clearance for chloroquine (Q/F). Only these primary population pharmacokinetic parameters could be estimated using the type of data collected. The best-fit population PK model was then used to estimate individual parameter estimates to derive Cmax in nanograms per milliliter (ng/mL).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months to 5 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects aged greater than or equal to 6 months to 5 years presenting to Ndirande Health Centre with signs or symptoms consistent with malaria including, but not limited to, one or more of the following:

1. fever at the time of evaluation (axillary temperature greater than or equal to 37.5 degrees Celsius by digital thermometer)

2. report of fever within the last two days

3. clinically profound anemia (conjunctival or palmar pallor)

4. headache

5. body aches

6. abdominal pain

7. decreased intake of food or fluids

8. weakness

• Weight greater than or equal to 5kg.

• Positive malaria smear for P. falciparum mono-infection with parasite density 2,000-200,000/mm^3.

• Planning to remain in the study area for 1 year.

• Willingness to return for four-weekly routine visits, as well as unscheduled sick visits.

• Parental/guardian consent for each participant.

Exclusion Criteria:

• Signs of severe malaria: One or more of the following:

1. hemoglobin less than or equal to 5 g/dL

2. prostration

3. respiratory distress

4. bleeding

5. recent seizures, coma or obtundation (Blantyre coma score < 5)

6. inability to drink

7. persistent vomiting

• Known allergy or history of adverse reaction to chloroquine (CQ), artesunate, azithromycin, erythromycin or atovaquone-proguanil (AP)

• Chronic medication with any antibiotic or anti malarial medication

• Previous enrollment in this study

• Alanine aminotransferase (ALT) more than 5x the upper limit of normal or creatinine greater than 3x the upper limit of normal

• Evidence of chronic disease or physical stigmata of severe malnutrition (i.e., loss of muscle mass or subcutaneous tissue, edema, or skin or hair findings consistent with severe malnutrition)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Blantyre Malaria Project - Ndirande Health Centre	Blantyre		Malawi

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Laufer MK, Thesing PC, Dzinjalamala FK, Nyirenda OM, Masonga R, Laurens MB, Stokes-Riner A, Taylor TE, Plowe CV. A longitudinal trial comparing chloroquine as monotherapy or in combination with artesunate, azithromycin or atovaquone-proguanil to treat malaria. PLoS One. 2012;7(8):e42284. doi: 10.1371/journal.pone.0042284. Epub 2012 Aug 17.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00379821
• Other Study ID Numbers: 06-0022
• First Posted: Sep 25, 2006
• Last Update Posted: Aug 11, 2014
• Last Verified: Jul 1, 2014

• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): chloroquine, malaria, Plasmodium falciparum, Malawi, children
• Additional relevant MeSH terms: Malaria; Azithromycin; Artesunate; Chloroquine; Atovaquone; Proguanil; Atovaquone, proguanil drug combination

Study Results

Participant Flow

Recruitment Details	Children who were brought to the Ndirande Health Centre with symptoms suggestive of malaria were recruited from February 19, 2007 to August 13, 2008.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Period Title: Overall Study
STARTED	160	160	160	160
COMPLETED	87	71	93	81
NOT COMPLETED	73	89	67	79

Baseline Characteristics

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy	Total
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.	Total of all reporting groups
Overall Participants	160	160	160	160	640
Age (Count of Participants)
<=18 years	160 100%	160 100%	160 100%	160 100%	640 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	2.7 (1.2)	2.7 (1.2)	2.8 (1.1)	2.7 (1.2)	2.7 (1.2)
Sex: Female, Male (Count of Participants)
Female	70 43.8%	82 51.3%	73 45.6%	77 48.1%	302 47.2%
Male	90 56.3%	78 48.8%	87 54.4%	83 51.9%	338 52.8%
Region of Enrollment (participants) [Number]
Malawi	160 100%	160 100%	160 100%	160 100%	640 100%

Outcome Measures

1. Primary Outcome

Title	Number of Clinical Malaria Episodes Per Year of Follow-up
Description	Clinical malaria episode was defined as at least one symptom of malaria and a positive malaria smear. The number of clinical malaria episodes (not including the initial malaria episode) reported by participants during follow up is presented as the number per Person Years at Risk (PYAR).
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The intention to treat (ITT) population was used for the primary outcome.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	157	155	160	156
Number [Episodes per PYAR]	0.61	0.68	0.64	0.59

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chloroquine Plus Artesunate, CQ Monotherapy
	Comments	Number of clinical malaria episodes per PYAR was compared using Poisson regression assuming null hypothesis that the number of malaria episodes are the same in both groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8097
	Comments	The a priori threshold for statistical significance is 0.05/3.
	Method	Poisson regression
	Comments	No adjustments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.0413
	Confidence Interval	(2-Sided) 95%; 0.7497 to 1.4463
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1746
	Estimation Comments	The denominator for the risk ratio is the CQ Monotherapy arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Chloroquine Plus Atovaquone-Proguanil, CQ Monotherapy
	Comments	Number of clinical malaria episodes per PYAR was compared using Poisson regression assuming null hypothesis that the number of malaria episodes are the same in both groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3767
	Comments	The a priori threshold for statistical significance is 0.05/3.
	Method	Poisson regression
	Comments	No adjustments.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.1623
	Confidence Interval	(2-Sided) 95%; 0.8333 to 1.6211
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1973
	Estimation Comments	The denominator for the risk ratio is the CQ Monotherapy arm.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	CQ Plus Azithromycin, CQ Monotherapy
	Comments	Number of clinical malaria episodes per PYAR was compared using Poisson regression assuming null hypothesis that the number of malaria episodes are the same in both groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6277
	Comments	The a priori threshold for statistical significance is 0.05/3.
	Method	Poisson regression
	Comments	No adjustments.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.0707
	Confidence Interval	(2-Sided) 95%; 0.7708 to 1.4872
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1795
	Estimation Comments	The denominator for the risk ratio is the CQ Monotherapy arm.

2. Secondary Outcome

Title	Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm
Description	Adequate clinical and parasitologic response (ACPR) was defined as the absence of parasitemia at Day 28 and without previously meeting any of the criteria of early treatment or late clinical failure.
Time Frame	Day 28 of initial malaria episode (Episode 0)

Outcome Measure Data

Analysis Population Description

This analysis was per protocol, which excludes participants who did not have p. falciparum or who did not receive all 3 doses of treatment.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	144	133	138	135
Number [Participants]	143 89.4%	133 83.1%	137 85.6%	135 84.4%

3. Secondary Outcome

Title	Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm
Description	Adequate clinical and parasitologic response (ACPR) was defined as the absence of parasitemia at Day 28 and without previously meeting any of the criteria of early treatment or late clinical failure.
Time Frame	Day 28 of first subsequent malaria episode (Episode 1)

Outcome Measure Data

Analysis Population Description

This analysis was per protocol, which includes participants who had at least 1 subsequent malaria episode, but excludes participants who did if that episode was not caused by p. falciparum or if the participant did not receive all 3 doses of treatment for the first subsequent episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	46	42	39	41
Number [Participants]	46 28.8%	42 26.3%	37 23.1%	39 24.4%

4. Secondary Outcome

Title	Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm
Description	Adequate clinical and parasitologic response (ACPR) was defined as the absence of parasitemia at Day 28 and without previously meeting any of the criteria of early treatment or late clinical failure.
Time Frame	Day 28 of second subsequent malaria episode (Episode 2)

Outcome Measure Data

Analysis Population Description

This analysis was per protocol, which which includes participants who had at least 2 subsequent malaria episodes, but excludes participants if the second episode was not caused by p. falciparum or if the participant did not receive all 3 doses of treatment for the second episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	17	14	12	6
Number [Participants]	17 10.6%	14 8.8%	12 7.5%	6 3.8%

5. Secondary Outcome

Title	Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm
Description	Adequate clinical and parasitologic response (ACPR) was defined as the absence of parasitemia at Day 28 and without previously meeting any of the criteria of early treatment or late clinical failure.
Time Frame	Day 28 of third subsequent malaria episode (Episode 3)

Outcome Measure Data

Analysis Population Description

This analysis was per protocol, which includes participants who had at least 3 subsequent malaria episodes, but excludes participants if the third episode was not caused by p. falciparum or if the participant did not receive all 3 doses of treatment for the third episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	4	4	7	1
Number [Participants]	4 2.5%	4 2.5%	6 3.8%	0 0%

6. Secondary Outcome

Title	Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm
Description	Adequate clinical and parasitologic response (ACPR) was defined as the absence of parasitemia at Day 28 and without previously meeting any of the criteria of early treatment or late clinical failure.
Time Frame	Day 28 of fourth subsequent malaria episode (Episode 4)

Outcome Measure Data

Analysis Population Description

This analysis was per protocol, which includes participants who had 4 subsequent malaria episodes, but excludes participants if the fourth episode was not caused by p. falciparum or if the participant did not receive all 3 doses of treatment for the fourth episode.

Arm/Group Title	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin
Arm/Group Description	Subjects receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Subjects receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.
Measure Participants	2	1
Number [Participants]	2 1.3%	1 0.6%

7. Secondary Outcome

Title	Number of Cases of Severe Malaria in Each Treatment Arm
Description	A case of severe malaria included one or more of the following: Hemoglobin ≤5 g/dL; prostration; respiratory distress; bleeding; recent seizures, coma or obtundation (Blantyre coma score < 5); inability to drink, or persistent vomiting. All cases were then adjudicated by a panel of investigators prior to analysis.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

The safety cohort includes all participants.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	160	160	160	160
Number [Cases of severe malaria]	0	2	2	6

8. Secondary Outcome

Title	Mean Hemoglobin at the Last Study Visit in Each Treatment Arm for the Age Group of Participants 3 Years of Age or Younger.
Description	Hemoglobin values were assessed from blood collected at the last study visit at one year after enrollment. Group means are stratified by participants 3 years of age and under, and over 3 to 5 years of age.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The safety population includes all participants. The number of participants is limited to those who attended the final 1-year visit.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	44	35	50	48
Mean (95% Confidence Interval) [Grams/Deciliter]	11.6	11.7	12.2	11.8

9. Secondary Outcome

Title	Mean Hemoglobin at the Last Study Visit in Each Treatment Arm for the Age Group of Participants Greater Than 3 Years to 5 Years of Age.
Description	Hemoglobin values were assessed from blood collected at the last study visit at one year after enrollment. Group means are stratified by participants 3 years of age and under, and over 3 to 5 years of age.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The safety population includes all participants. The number of participants is limited to those who attended the final 1-year visit.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	39	34	40	29
Mean (95% Confidence Interval) [Grams/Deciliter]	12.5	12.3	12.1	12.5

10. Secondary Outcome

Title	Mean Creatinine in Each Treatment Arm (Renal Function)
Description	Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.
Time Frame	Day 0 of initial malaria episode (Episode 0)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	160	160	158	160
Mean (95% Confidence Interval) [Micromole/Liter]	44.2	44.2	44.2	44.3

11. Secondary Outcome

Title	Mean Creatinine in Each Treatment Arm (Renal Function)
Description	Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.
Time Frame	Day 14 of initial malaria episode (Episode 0)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	144	138	143	141
Mean (95% Confidence Interval) [Micromole/Liter]	44.2	44.2	44.2	44.2

12. Secondary Outcome

Title	Mean Creatinine in Each Treatment Arm (Renal Function)
Description	Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.
Time Frame	Day 0 of first subsequent malaria episode (Episode 1)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	54	49	47	52
Mean (95% Confidence Interval) [Micromole/Liter]	43.9	44.2	43.7	43.6

13. Secondary Outcome

Title	Mean Creatinine in Each Treatment Arm (Renal Function)
Description	Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.
Time Frame	Day 14 of first subsequent malaria episode (Episode 1)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	53	43	45	46
Mean (95% Confidence Interval) [Micromole/Liter]	44.2	44.2	44.2	44.2

14. Secondary Outcome

Title	Mean Creatinine in Each Treatment Arm (Renal Function)
Description	Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.
Time Frame	Day 0 of second subsequent malaria episode (Episode 2)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	17	15	18	9
Mean (95% Confidence Interval) [Micromole/Liter]	44.2	44.2	44.2	46.4

15. Secondary Outcome

Title	Mean Creatinine in Each Treatment Arm (Renal Function)
Description	Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.
Time Frame	Day 14 of second subsequent malaria episode (Episode 2)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	17	14	16	8
Mean (95% Confidence Interval) [Micromole/Liter]	44.2	44.2	44.2	44.2

16. Secondary Outcome

Title	Mean Creatinine in Each Treatment Arm (Renal Function)
Description	Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.
Time Frame	Day 0 of third subsequent malaria episode (Episode 3)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	4	4	7	1
Mean (95% Confidence Interval) [Micromole/Liter]	44.2	44.2	44.2	44.2

17. Secondary Outcome

Title	Mean Creatinine in Each Treatment Arm (Renal Function)
Description	Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.
Time Frame	Day 14 of third subsequent malaria episode (Episode 3)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	3	4	6	1
Mean (95% Confidence Interval) [Micromole/Liter]	44.2	44.2	44.2	44.2

18. Secondary Outcome

Title	Mean Creatinine in Each Treatment Arm (Renal Function)
Description	Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.
Time Frame	Day 0 of fourth subsequent malaria episode (Episode 4)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin
Arm/Group Description	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.
Measure Participants	2	1
Mean (95% Confidence Interval) [Micromole/Liter]	44.2	44.2

19. Secondary Outcome

Title	Mean Creatinine in Each Treatment Arm (Renal Function)
Description	Creatine values were assessed from blood draws at Day 0 and Day 14 of each malaria episode. Samples that were below the limit of detection were reported as 44.2 micromoles/liter, equivalent to the lower limit of detection.
Time Frame	Day 14 of fourth subsequent malaria episode (Episode 4)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Atovaquone-Proguanil
Arm/Group Description	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.
Measure Participants	1
Mean (95% Confidence Interval) [Micromole/Liter]	44.2

20. Secondary Outcome

Title	Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
Description	ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
Time Frame	Day 0 of initial malaria episode (Episode 0)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	160	160	158	160
Mean (95% Confidence Interval) [International Units/Liter]	27.2	32.1	27.5	26.2

21. Secondary Outcome

Title	Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
Description	ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
Time Frame	Day 14 of initial malaria episode (Episode 0)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	144	138	143	142
Mean (95% Confidence Interval) [International Units/Liter]	14.3	16.2	17.8	15.5

22. Secondary Outcome

Title	Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
Description	ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
Time Frame	Day 0 of first subsequent malaria episode (Episode 1)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	54	49	47	52
Mean (95% Confidence Interval) [International Units/Liter]	24.2	21.7	22.4	25.3

23. Secondary Outcome

Title	Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
Description	ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
Time Frame	Day 14 of first subsequent malaria episode (Episode 1)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	53	43	45	46
Mean (95% Confidence Interval) [International Units/Liter]	14.5	14.2	18.3	17.2

24. Secondary Outcome

Title	Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
Description	ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
Time Frame	Day 0 of second subsequent malaria episode (Episode 2)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	17	15	18	9
Mean (95% Confidence Interval) [International Units/Liter]	26.1	23.0	23.3	23.5

25. Secondary Outcome

Title	Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
Description	ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
Time Frame	Day 14 of second subsequent malaria episode (Episode 2)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	17	14	16	8
Mean (95% Confidence Interval) [International Units/Liter]	116	14.7	17.3	16.3

26. Secondary Outcome

Title	Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
Description	ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
Time Frame	Day 0 of third subsequent malaria episode (Episode 3)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	4	4	7	1
Mean (95% Confidence Interval) [International Units/Liter]	26.4	20.7	18.6	16.2

27. Secondary Outcome

Title	Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
Description	ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
Time Frame	Day 14 of third subsequent malaria episode (Episode 3)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	3	4	6	1
Mean (95% Confidence Interval) [International Units/Liter]	17.8	13.6	15.3	14.3

28. Secondary Outcome

Title	Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
Description	ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
Time Frame	Day 0 of fourth subsequent malaria episode (Episode 4)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin
Arm/Group Description	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.
Measure Participants	2	1
Mean (95% Confidence Interval) [International Units/Liter]	27.3	24.9

29. Secondary Outcome

Title	Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
Description	ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
Time Frame	Day 14 of fourth subsequent malaria episode (Episode 4)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who have laboratory results reported at the time point for the episode.

Arm/Group Title	Chloroquine Plus Atovaquone-Proguanil
Arm/Group Description	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.
Measure Participants	1
Mean (95% Confidence Interval) [International Units/Liter]	13.9

30. Secondary Outcome

Title	Number of Participants in Each Treatment Arm Who Change From "Normal" to "Abnormal" on Any Questions of the Neurological Examination
Description	A basic age-appropriate neurological examination was conducted on Day 28 of each malaria illness episode and also at Days 112 and 224, and at 1 year. Subjects were were counted as a "change from 'normal' to 'abnormal' " if they had the 'normal' (or not-applicable) response for the initial day 28 exam and an 'abnormal' response at their last exam. If a subject did not have an exam at 1 year then the last available exam that was not associated with an illness episode (either Day 112 or 224) was used.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

Subjects who did not have an initial exam, or who did not have a subsequent exam at a routine visit are excluded.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	132	111	124	121
Number [Participants]	6 3.8%	4 2.5%	3 1.9%	12 7.5%

31. Secondary Outcome

Title	Number of Participants Infected With Parasites With the Mutation Pfcrt 76T on Day 0 of the Initial Episode of Malaria
Description	The presence of parasites with the mutation pfCRT 76T was measured with filter paper specimens collected at the time of enrollment and with successful parasite DNA amplification using pyrosequencing.
Time Frame	Day 0 of initial episode of malaria

Outcome Measure Data

Analysis Population Description

All participants from whom samples were successfully collected and DNA successfully amplified were included.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	159	159	159	158
Number [participants]	1 0.6%	0 0%	0 0%	0 0%

32. Secondary Outcome

Title	Number of Participants Infected With Parasites With the Mutation Pfcrt 76T at Recrudescent Episodes of Malaria
Description	Participants were enrolled in the study at the time of the initial episode of malaria. If the participant presented with a subsequent episode of malaria at any time during the one year of follow-up, the presence of parasites with the mutation pfCRT 76T was measured with filter paper specimens collected at the time of enrollment and with successful parasite DNA amplification using pyrosequencing.
Time Frame	Recrudescent episodes of malaria within one year of enrollment

Outcome Measure Data

Analysis Population Description

The analysis population is limited to participants who presented with subsequent episodes of malaria from whom samples were successfully collected and DNA successfully amplified.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	75	70	74	63
Number [participants]	0 0%	0 0%	1 0.6%	0 0%

33. Secondary Outcome

Title	Number of Participants With New and Recrudescent Malaria Infections After Initial Treatment
Description	Participants were enrolled at the time of initial malaria episode and treated. Subsequent to treatment, subjects were monitored for the occurrence of new and recrudescent malaria infections, which were distinguished by analysis of the infecting parasites using merozoite surface protein-2 polymorphic gene length variation.
Time Frame	28 days to 1 year

Outcome Measure Data

Analysis Population Description

All subjects completing the initial treatment were included in the analysis population.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	155	148	157	151
New infections	0 0%	0 0%	1 0.6%	0 0%
Recrudescent infections	1 0.6%	0 0%	0 0%	0 0%

34. Secondary Outcome

Title	Number of Participants With New and Recrudescent Infections After Subsequent New Episodes
Description	Participants were enrolled at the time of initial malaria episode and treated. Subsequent to treatment, participants who subsequently suffered new malaria episodes were monitored for the additional occurrence of new and recrudescent malaria infections, which were distinguished by analysis of the infecting parasites using merozoite surface protein-2 polymorphic gene length variation.
Time Frame	Day 28 to 1 year

Outcome Measure Data

Analysis Population Description

The analysis population is limited to participants who had new episodes of malaria during the follow-up period after treatment.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	71	64	67	56
New infections	0 0%	0 0%	1 0.6%	1 0.6%
Recrudescent infections	0 0%	0 0%	2 1.3%	1 0.6%

35. Secondary Outcome

Title	Time to First Malaria Episode in Participants Who Travelled and Slept Outside the City Versus Those Who Did Not Travel and Sleep Outside the City.
Description	The cumulative hazard of having a malaria attack within one year for those participants who travelled and slept in rural areas (outside the city) versus those who did not was calculated and is presented as a life table to display the number of subjects at risk, the number with first clinical episode and the number censored at each time point. Participants are right-censored at the time of first malaria episode. Participants who did not develop malaria during follow-up or were lost to follow-up were censored at the time of their last visit.
Time Frame	Days 0 - 420

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Participants Who Traveled and Slept Outside the City	Participants Who Did Not Travel and Sleep Outside the City
Arm/Group Description	At enrollment, participants were asked if they travelled and slept outside the city within the previous 4 weeks. This group indicated yes.	At enrollment, participants were asked if they travelled and slept outside the city within the previous 4 weeks. This group indicated no.
Measure Participants	432	201
Days 0-27 - Number At Risk	432 270%	201 125.6%
Days 0-27 - Number with Malaria	0 0%	0 0%
Days 0-27 - Number Censored	63 39.4%	28 17.5%
Days 28-55 - Number At Risk	369 230.6%	173 108.1%
Days 28-55 - Number with Malaria	13 8.1%	4 2.5%
Days 28-55 - Number Censored	26 16.3%	10 6.3%
Days 56-83 - Number At Risk	330 206.3%	159 99.4%
Days 56-83 - Number with Malaria	11 6.9%	9 5.6%
Days 56-83 - Number Censored	21 13.1%	16 10%
Days 84-111 - Number At Risk	298 186.3%	134 83.8%
Days 84-111 - Number with Malaria	12 7.5%	12 7.5%
Days 84-111 - Number Censored	16 10%	10 6.3%
Days 112-139 - Number At Risk	270 168.8%	112 70%
Days 112-139 - Number with Malaria	13 8.1%	4 2.5%
Days 112-139 - Number Censored	17 10.6%	5 3.1%
Days 140-167 - Number At Risk	240 150%	103 64.4%
Days 140-167 - Number with Malaria	3 1.9%	2 1.3%
Days 140-167 - Number Censored	22 13.8%	7 4.4%
Days 168-195 - Number At Risk	215 134.4%	94 58.8%
Days 168-195 - Number with Malaria	3 1.9%	1 0.6%
Days 168-195 - Number Censored	16 10%	3 1.9%
Days 196-223 - Number At Risk	196 122.5%	90 56.3%
Days 196-223 - Number with Malaria	4 2.5%	4 2.5%
Days 196-223 - Number Censored	16 10%	9 5.6%
Days 224-251 - Number At Risk	176 110%	77 48.1%
Days 224-251 - Number with Malaria	12 7.5%	1 0.6%
Days 224-251 - Number Censored	4 2.5%	6 3.8%
Days 252-279 - Number At Risk	160 100%	70 43.8%
Days 252-279 - Number with Malaria	12 7.5%	1 0.6%
Days 252-279 - Number Censored	8 5%	5 3.1%
Days 280-307 - Number At Risk	140 87.5%	64 40%
Days 280-307 - Number with Malaria	7 4.4%	4 2.5%
Days 280-307 - Number Censored	4 2.5%	3 1.9%
Days 308-335 - Number At Risk	129 80.6%	57 35.6%
Days 308-335 - Number with Malaria	8 5%	5 3.1%
Days 308-335 - Number Censored	8 5%	2 1.3%
Days 336-363 - Number At Risk	113 70.6%	50 31.3%
Days 336-363 - Number with Malaria	8 5%	3 1.9%
Days 336-363 - Number Censored	2 1.3%	7 4.4%
Days 364-391 - Number At Risk	103 64.4%	40 25%
Days 364-391 - Number with Malaria	2 1.3%	0 0%
Days 364-391 - Number Censored	100 62.5%	38 23.8%
Days 392 - 420 - Number At Risk	1 0.6%	2 1.3%
Days 392 - 420 - Number with Malaria	0 0%	0 0%
Days 392 - 420 - Number Censored	1 0.6%	2 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chloroquine Plus Artesunate, Chloroquine Plus Atovaquone-Proguanil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.79
	Comments	Not adjusted, 0.05
	Method	Regression, Cox
	Comments	There are no adjustments.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.68 to 1.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.17
	Estimation Comments	The reference category is those who did not travel.

36. Secondary Outcome

Title	Nearest Neighbor Index as a Measure of Spatial Pattern of the Distribution of Malaria Cases in Ndirande
Description	The Global Positioning System (GPS) was used to establish the coordinates of participants' homes. The distribution of these coordinates was analyzed for evidence of clustering, or occurring closer together than would be expected on the basis of chance. Nearest Neighbor Index is a ratio of the observed mean distance over the expected mean distance. If the index is less than 1, the pattern exhibits clustering. If the index is greater than 1, the trend is toward dispersion.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The analysis included all participants for whom the GPS coordinates of the home were established.

Arm/Group Title	All Groups
Arm/Group Description	Participants Receiving Any Treatment in the Study
Measure Participants	343
Number [Index]	0.328

37. Secondary Outcome

Title	Pharmacokinetics of Chloroquine Represented by Time of Maximal Concentration (Tmax) and Chloroquine Half-life
Description	1727 non-zero concentration measurements from 479 participants were pooled and used for population pharmacokinetic modeling in Monolix413s. Compartmental population pharmacokinetic modeling was used due to highly sparse data. The model was parameterized in terms of absorption rate constant for chloroquine (Ka), apparent clearance for chloroquine (CL/F, with F as the unknown oral bioavailability), apparent volume of distribution of the central and peripheral compartments for chloroquine (Vd/F), and the inter-compartmental clearance for chloroquine (Q/F). Only these primary population pharmacokinetic parameters could be estimated using the type of data collected. The best-fit population PK model was then used to estimate individual parameter estimates to derive Tmax and half-life.
Time Frame	Day 0 - Day 28

Outcome Measure Data

Analysis Population Description

All participants with non-zero concentration measures suitable for pharmacokinetic analysis were included.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	125	118	120	116
Time of maximal concentration (Tmax)	5.6	5.6	5.5	5.6
Chloroquine half-life	41.6	46.2	41.3	44.5

38. Secondary Outcome

Title	Pharmacokinetics of Chloroquine Represented by Maximum Concentration (Cmax)
Description	1727 non-zero concentration measurements from 479 participants were pooled and used for population pharmacokinetic modeling in Monolix413s. Compartmental population pharmacokinetic modeling was used due to highly sparse data. The model was parameterized in terms of absorption rate constant for chloroquine (Ka), apparent clearance for chloroquine (CL/F, with F as the unknown oral bioavailability), apparent volume of distribution of the central and peripheral compartments for chloroquine (Vd/F), and the inter-compartmental clearance for chloroquine (Q/F). Only these primary population pharmacokinetic parameters could be estimated using the type of data collected. The best-fit population PK model was then used to estimate individual parameter estimates to derive Cmax in nanograms per milliliter (ng/mL).
Time Frame	Day 0 - Day 28

Outcome Measure Data

Analysis Population Description

All participants with non-zero concentration measures suitable for pharmacokinetic analysis were included.

Arm/Group Title	Chloroquine Plus Artesunate	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Measure Participants	125	118	120	116
Median (95% Confidence Interval) [ng/mL chloroquine]	351.0	345.1	353.1	384.2

Adverse Events

Time Frame	Participants were evaluated for adverse events every four weeks through one year after enrollment.
Arm/Group Title	Chloroquine Plus Artesunate		Chloroquine Plus Atovaquone-Proguanil		CQ Plus Azithromycin		CQ Monotherapy
Arm/Group Description	Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.		Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.		Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.		Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
All Cause Mortality
	Chloroquine Plus Artesunate		Chloroquine Plus Atovaquone-Proguanil		CQ Plus Azithromycin		CQ Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Chloroquine Plus Artesunate		Chloroquine Plus Atovaquone-Proguanil		CQ Plus Azithromycin		CQ Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/160 (5%)		14/160 (8.8%)		7/160 (4.4%)		20/160 (12.5%)
Blood and lymphatic system disorders
Anaemia	0/160 (0%)	0	0/160 (0%)	0	0/160 (0%)	0	2/160 (1.3%)	2
Lymphadenitis	0/160 (0%)	0	1/160 (0.6%)	1	0/160 (0%)	0	0/160 (0%)	0
Congenital, familial and genetic disorders
Phimosis	0/160 (0%)	0	0/160 (0%)	0	0/160 (0%)	0	1/160 (0.6%)	1
Gastrointestinal disorders
Inguinal hernia	1/160 (0.6%)	1	0/160 (0%)	0	0/160 (0%)	0	0/160 (0%)	0
Rectal prolapse	1/160 (0.6%)	1	0/160 (0%)	0	0/160 (0%)	0	0/160 (0%)	0
Vomiting	0/160 (0%)	0	1/160 (0.6%)	1	0/160 (0%)	0	2/160 (1.3%)	2
General disorders
Pyrexia	0/160 (0%)	0	0/160 (0%)	0	1/160 (0.6%)	1	0/160 (0%)	0
Infections and infestations
Abscess	0/160 (0%)	0	1/160 (0.6%)	1	0/160 (0%)	0	0/160 (0%)	0
Cerebral malaria	0/160 (0%)	0	0/160 (0%)	0	0/160 (0%)	0	1/160 (0.6%)	1
Gastroenteritis	0/160 (0%)	0	2/160 (1.3%)	2	1/160 (0.6%)	1	1/160 (0.6%)	1
HIV infection	0/160 (0%)	0	1/160 (0.6%)	1	0/160 (0%)	0	1/160 (0.6%)	1
Malaria	1/160 (0.6%)	1	3/160 (1.9%)	3	2/160 (1.3%)	2	4/160 (2.5%)	4
Pneumonia	1/160 (0.6%)	1	1/160 (0.6%)	1	1/160 (0.6%)	1	1/160 (0.6%)	1
Pneumonia primary atypical	1/160 (0.6%)	1	0/160 (0%)	0	0/160 (0%)	0	0/160 (0%)	0
Upper respiratory tract infection	0/160 (0%)	0	0/160 (0%)	0	0/160 (0%)	0	1/160 (0.6%)	1
Viral infection	0/160 (0%)	0	0/160 (0%)	0	0/160 (0%)	0	1/160 (0.6%)	1
Injury, poisoning and procedural complications
Laceration	0/160 (0%)	0	0/160 (0%)	0	1/160 (0.6%)	1	0/160 (0%)	0
Metabolism and nutrition disorders
Kwashiorkor	0/160 (0%)	0	1/160 (0.6%)	1	0/160 (0%)	0	1/160 (0.6%)	1
Malnutrition	1/160 (0.6%)	1	0/160 (0%)	0	0/160 (0%)	0	1/160 (0.6%)	1
Musculoskeletal and connective tissue disorders
Limb discomfort	0/160 (0%)	0	0/160 (0%)	0	1/160 (0.6%)	1	0/160 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Central nervous system neoplasm	0/160 (0%)	0	0/160 (0%)	0	0/160 (0%)	0	1/160 (0.6%)	1
Nervous system disorders
Encephalopathy	0/160 (0%)	0	0/160 (0%)	0	0/160 (0%)	0	2/160 (1.3%)	2
Febrile convulsion	2/160 (1.3%)	2	2/160 (1.3%)	2	0/160 (0%)	0	0/160 (0%)	0
Surgical and medical procedures
Elective surgery	0/160 (0%)	0	1/160 (0.6%)	1	0/160 (0%)	0	0/160 (0%)	0
Other (Not Including Serious) Adverse Events
	Chloroquine Plus Artesunate		Chloroquine Plus Atovaquone-Proguanil		CQ Plus Azithromycin		CQ Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	144/160 (90%)		140/160 (87.5%)		143/160 (89.4%)		145/160 (90.6%)
Blood and lymphatic system disorders
Haemorrhagic anaemia	26/160 (16.3%)	32	28/160 (17.5%)	32	32/160 (20%)	36	38/160 (23.8%)	41
Neutropenia	1/160 (0.6%)	1	4/160 (2.5%)	4	8/160 (5%)	8	1/160 (0.6%)	1
Thrombocytopenia	11/160 (6.9%)	11	6/160 (3.8%)	6	6/160 (3.8%)	6	5/160 (3.1%)	6
Eye disorders
Conjunctivitis	27/160 (16.9%)	29	19/160 (11.9%)	21	31/160 (19.4%)	39	31/160 (19.4%)	38
Gastrointestinal disorders
Abdominal pain	12/160 (7.5%)	15	8/160 (5%)	9	16/160 (10%)	20	10/160 (6.3%)	10
Diarrhoea	42/160 (26.3%)	53	25/160 (15.6%)	33	26/160 (16.3%)	33	35/160 (21.9%)	49
Stomatitis	6/160 (3.8%)	6	5/160 (3.1%)	5	5/160 (3.1%)	5	14/160 (8.8%)	14
Vomiting	4/160 (2.5%)	4	7/160 (4.4%)	7	11/160 (6.9%)	11	7/160 (4.4%)	8
General disorders
Pyrexia	31/160 (19.4%)	35	22/160 (13.8%)	22	29/160 (18.1%)	31	28/160 (17.5%)	30
Infections and infestations
Body tinea	14/160 (8.8%)	14	10/160 (6.3%)	10	9/160 (5.6%)	10	6/160 (3.8%)	6
Bronchitis	1/160 (0.6%)	1	3/160 (1.9%)	3	5/160 (3.1%)	5	11/160 (6.9%)	11
Conjunctivitis bacterial	2/160 (1.3%)	2	2/160 (1.3%)	2	7/160 (4.4%)	7	9/160 (5.6%)	9
Dysentery	17/160 (10.6%)	24	8/160 (5%)	8	12/160 (7.5%)	14	11/160 (6.9%)	14
Gastroenteritis	46/160 (28.8%)	53	38/160 (23.8%)	41	34/160 (21.3%)	39	40/160 (25%)	44
Helminthic infection	8/160 (5%)	8	11/160 (6.9%)	12	21/160 (13.1%)	22	10/160 (6.3%)	11
Impetigo	46/160 (28.8%)	61	42/160 (26.3%)	62	31/160 (19.4%)	37	44/160 (27.5%)	56
Nasopharyngitis	128/160 (80%)	358	114/160 (71.3%)	297	120/160 (75%)	340	119/160 (74.4%)	335
Oral herpes	8/160 (5%)	9	5/160 (3.1%)	5	2/160 (1.3%)	2	4/160 (2.5%)	4
Otitis media	12/160 (7.5%)	12	11/160 (6.9%)	18	11/160 (6.9%)	13	15/160 (9.4%)	20
Parotitis	8/160 (5%)	8	1/160 (0.6%)	1	4/160 (2.5%)	4	7/160 (4.4%)	7
Pneumonia	36/160 (22.5%)	50	18/160 (11.3%)	23	29/160 (18.1%)	39	40/160 (25%)	50
Tinea capitis	23/160 (14.4%)	27	10/160 (6.3%)	11	14/160 (8.8%)	17	14/160 (8.8%)	15
Varicella	17/160 (10.6%)	17	11/160 (6.9%)	11	5/160 (3.1%)	5	16/160 (10%)	16
Injury, poisoning and procedural complications
Excoriation	10/160 (6.3%)	10	6/160 (3.8%)	6	6/160 (3.8%)	6	6/160 (3.8%)	6
Thermal burn	9/160 (5.6%)	9	7/160 (4.4%)	7	5/160 (3.1%)	5	6/160 (3.8%)	6
Investigations
Alanine aminotransferase increased	6/160 (3.8%)	6	4/160 (2.5%)	4	10/160 (6.3%)	10	7/160 (4.4%)	7
Respiratory, thoracic and mediastinal disorders
Cough	26/160 (16.3%)	31	28/160 (17.5%)	36	28/160 (17.5%)	32	30/160 (18.8%)	37
Skin and subcutaneous tissue disorders
Pruritus	5/160 (3.1%)	5	23/160 (14.4%)	25	32/160 (20%)	34	21/160 (13.1%)	23
Rash papular	18/160 (11.3%)	20	24/160 (15%)	26	20/160 (12.5%)	21	19/160 (11.9%)	20
Rash pruritic	9/160 (5.6%)	10	4/160 (2.5%)	4	4/160 (2.5%)	5	2/160 (1.3%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.