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”

Malaria is a sickness caused by a parasite that people can get from mosquito bites. If it is not treated, malaria can make people very sick and even cause death, especially in children.

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study

Combination therapy is becoming the mainstay of malaria treatment. In general, the goal of combination therapy is to successfully 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, 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 involving approximately 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 (Malarone® or AP), or azithromycin. The treatment outcome will be assessed through a standard 28-day efficacy study. Participants subsequently will be evaluated every four 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.

Intervention(s) in this Clinical Trial

• Drug: Artesunate
  • Artesunate: 4 mg/kg once a day for 3 days, 50 mg tablet
• Drug: Atovaquone-proguanil
  • Atovaquone-proguanil (Malarone® or AP) once a day for 3 days, Pediatric tablet (PT): 62.5 mg/25 mg Full strength tablet (FST):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
• Drug: Azithromycin
  • Azithromycin 30 mg/kg once a day for 3 days, 200 mg/5cc suspension

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • CQ + Artesunate: 4 mg/kg once a day for 3 days.
• Experimental: 2
  • CQ + Atovaquone-proguanil (Malarone® or AP) once a day for 3 days
• Experimental: 3
  • CQ + Azithromycin 30 mg/kg once a day for 3 days.
• Experimental: 4
  • Chloroquine: 10 mg/kg on days 0 and 1, 5 mg/kg/day on day 2 Participants will be randomized to receive chloroquine alone or in combination with one of the other study products.

Primary Measures

• The number of clinical malaria episodes.
  • Time Frame: Per year of follow-up.
    Safety Issue?: No

Secondary Measures

• To measure the prevalence of chloroquine resistant parasites, by treatment arm.
  • Time Frame: Duration of study.
    Safety Issue?: No
• To assess the antimalarial drug efficacy, by treatment arm.
  • Time Frame: At first administration and during subsequent episodes of malaria.
    Safety Issue?: No
• To assess the effect of each treatment arm on anemia.
  • Time Frame: At the end of study participation.
    Safety Issue?: No
• To determine the chloroquine blood levels at which chloroquine sensitive and resistant parasites are able to cause infection.
  • Time Frame: Analysis.
    Safety Issue?: No
• Assess the spatial patterns and the environmental determinants of malaria infection.
  • Time Frame: Analysis.
    Safety Issue?: No
• Assess the effect of population movements on the risk of malaria infection.
  • Time Frame: Analysis.
    Safety Issue?: No
• To assess the safety of repeated use of the drugs in each of the study arms.
  • Time Frame: Duration of study.
    Safety Issue?: Yes

Inclusion Criteria:

• Patients aged >/= 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:
• fever at the time of evaluation (axillary temperature >/= 37.5 degrees C by digital thermometer)
• report of fever within the last two days
• clinically profound anemia (conjunctival or palmar pallor)
• headache
• body aches
• abdominal pain
• decreased intake of food or fluids
• weakness Weight >/= 5kg Positive malaria smear for P. falciparum mono-infection with parasite density 2,000-200,000/cubic millimeter 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:

• hemoglobin </= 5 g/dL
• prostration
• respiratory distress
• bleeding
• recent seizures, coma or obtundation (Blantyre coma score < 5)
• inability to drink
• persistent vomiting Known allergy or history of adverse reaction to chloroquine, artesunate, azithromycin or atovaquone-proguanil 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)

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 6 Months

Maximum Age for this Clinical Trial: 5 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Overall Clinical Trial Officials and Contacts

Overall Contact: Christopher Plowe (410) 706-5328 

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00379821

Study ID Number: 06-0022

ClinicalTrials.gov Identifier: NCT00379821

Health Authority: United States: Federal Government