• Number of Clinical Malaria Episodes Per Year of Follow-up [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  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).
  
  

• Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm [ Time Frame: Day 28 of initial malaria episode (Episode 0) ] [ Designated as safety issue: No ]
  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.
  
  
• Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm [ Time Frame: Day 28 of first subsequent malaria episode (Episode 1) ] [ Designated as safety issue: No ]
  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.
  
  
• Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm [ Time Frame: Day 28 of second subsequent malaria episode (Episode 2) ] [ Designated as safety issue: No ]
  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.
  
  
• Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm [ Time Frame: Day 28 of third subsequent malaria episode (Episode 3) ] [ Designated as safety issue: No ]
  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.
  
  
• Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm [ Time Frame: Day 28 of fourth subsequent malaria episode (Episode 4) ] [ Designated as safety issue: No ]
  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.
  
  
• Number of Cases of Severe Malaria in Each Treatment Arm [ Time Frame: 1 Year ] [ Designated as safety issue: Yes ]
  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.
  
  
• Mean Hemoglobin at the Last Study Visit in Each Treatment Arm for the Age Group of Participants 3 Years of Age or Younger. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  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.
  
  
• 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. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  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.
  
  
• Mean Creatinine in Each Treatment Arm (Renal Function) [ Time Frame: Day 0 of initial malaria episode (Episode 0) ] [ Designated as safety issue: Yes ]
  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.
  
  
• Mean Creatinine in Each Treatment Arm (Renal Function) [ Time Frame: Day 14 of initial malaria episode (Episode 0) ] [ Designated as safety issue: Yes ]
  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.
  
  
• Mean Creatinine in Each Treatment Arm (Renal Function) [ Time Frame: Day 0 of first subsequent malaria episode (Episode 1) ] [ Designated as safety issue: Yes ]
  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.
  
  
• Mean Creatinine in Each Treatment Arm (Renal Function) [ Time Frame: Day 14 of first subsequent malaria episode (Episode 1) ] [ Designated as safety issue: Yes ]
  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.
  
  
• Mean Creatinine in Each Treatment Arm (Renal Function) [ Time Frame: Day 0 of second subsequent malaria episode (Episode 2) ] [ Designated as safety issue: Yes ]
  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.
  
  
• Mean Creatinine in Each Treatment Arm (Renal Function) [ Time Frame: Day 14 of second subsequent malaria episode (Episode 2) ] [ Designated as safety issue: Yes ]
  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.
  
  
• Mean Creatinine in Each Treatment Arm (Renal Function) [ Time Frame: Day 0 of third subsequent malaria episode (Episode 3) ] [ Designated as safety issue: Yes ]
  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.
  
  
• Mean Creatinine in Each Treatment Arm (Renal Function) [ Time Frame: Day 14 of third subsequent malaria episode (Episode 3) ] [ Designated as safety issue: Yes ]
  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.
  
  
• Mean Creatinine in Each Treatment Arm (Renal Function) [ Time Frame: Day 0 of fourth subsequent malaria episode (Episode 4) ] [ Designated as safety issue: Yes ]
  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.
  
  
• Mean Creatinine in Each Treatment Arm (Renal Function) [ Time Frame: Day 14 of fourth subsequent malaria episode (Episode 4) ] [ Designated as safety issue: Yes ]
  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.
  
  
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [ Time Frame: Day 0 of initial malaria episode (Episode 0) ] [ Designated as safety issue: Yes ]
  ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
  
  
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [ Time Frame: Day 14 of initial malaria episode (Episode 0) ] [ Designated as safety issue: Yes ]
  ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
  
  
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [ Time Frame: Day 0 of first subsequent malaria episode (Episode 1) ] [ Designated as safety issue: Yes ]
  ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
  
  
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [ Time Frame: Day 14 of first subsequent malaria episode (Episode 1) ] [ Designated as safety issue: Yes ]
  ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
  
  
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [ Time Frame: Day 0 of second subsequent malaria episode (Episode 2) ] [ Designated as safety issue: Yes ]
  ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
  
  
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [ Time Frame: Day 14 of second subsequent malaria episode (Episode 2) ] [ Designated as safety issue: Yes ]
  ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
  
  
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [ Time Frame: Day 0 of third subsequent malaria episode (Episode 3) ] [ Designated as safety issue: Yes ]
  ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
  
  
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [ Time Frame: Day 14 of third subsequent malaria episode (Episode 3) ] [ Designated as safety issue: Yes ]
  ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
  
  
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [ Time Frame: Day 0 of fourth subsequent malaria episode (Episode 4) ] [ Designated as safety issue: Yes ]
  ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
  
  
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function) [ Time Frame: Day 14 of fourth subsequent malaria episode (Episode 4) ] [ Designated as safety issue: Yes ]
  ALT values were assessed from blood draws at Day 0 and Day 14 of each malaria episode.
  
  
• Number of Participants in Each Treatment Arm Who Change From "Normal" to "Abnormal" on Any Questions of the Neurological Examination [ Time Frame: 1 Year ] [ Designated as safety issue: Yes ]
  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.
  
  
• Prevalence of Chloroquine Resistant Parasites, by Treatment Arm: Prevalence of Parasites With the Mutation Pfcrt 76T on Day 0 of Each Episode of Malaria, and in Cases of Recurrent Parasitemia After Therapy. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  
• Incidence of Infections and Recrudescent Infections After Initial Treatment Per Treatment Arm. [ Time Frame: 28 days to 1 year ] [ Designated as safety issue: No ]
  
• Incidence of New and Recrudescent Infections After Subsequent New Episodes [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  
• Effect of Population Movements on the Risk of Malaria Infection - Risk of Malaria in Children Who Travelled Outside the City vs Those That Did Not. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  
• Spatial Patterns and the Environmental Determinants of Malaria Infection: Distribution of Malaria Cases in Relation to Environmental Factors in Ndirande. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  
• Chloroquine Blood Levels at Which Chloroquine Sensitive and Resistant Parasites Are Able to Cause Infection: Chloroquine Pharmacokinetic Curve for the Population, and Drug Concentration at the Time of Parasitemia. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  

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 related procedures for 1 year.