Chloroquine Alone or in Combination for Malaria in Children in Malawi

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 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.

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.

Intervention(s) in this Clinical Trial

• 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.
• Drug: Artesunate
  • Artesunate: 4mg/kg once a day for 3 days, 50 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: CQ Monotherapy
  • N=160: treat with Chloroquine (CQ) alone.
• Experimental: CQ plus azithromycin
  • N=160: treat with CQ plus azithromycin.
• Experimental: CQ plus artesunate
  • N=160: treat with CQ plus artesunate.
• Experimental: CQ plus atovaquone proguanil
  • N=160: treat with CQ plus atovaquone proguanil.

Primary Measures

• Number of Clinical Malaria Episodes Per Year of Follow-up
  • Time Frame: 1 year
    Safety Issue?: No

Secondary Measures

• 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)
    Safety Issue?: No
• 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)
    Safety Issue?: No
• 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)
    Safety Issue?: No
• 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)
    Safety Issue?: No
• 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)
    Safety Issue?: No
• Number of Cases of Severe Malaria in Each Treatment Arm
  • Time Frame: 1 Year
    Safety Issue?: Yes
• 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
    Safety Issue?: Yes
• 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
    Safety Issue?: Yes
• Mean Creatinine in Each Treatment Arm (Renal Function)
  • Time Frame: Day 0 of initial malaria episode (Episode 0)
    Safety Issue?: Yes
• Mean Creatinine in Each Treatment Arm (Renal Function)
  • Time Frame: Day 14 of initial malaria episode (Episode 0)
    Safety Issue?: Yes
• Mean Creatinine in Each Treatment Arm (Renal Function)
  • Time Frame: Day 0 of first subsequent malaria episode (Episode 1)
    Safety Issue?: Yes
• Mean Creatinine in Each Treatment Arm (Renal Function)
  • Time Frame: Day 14 of first subsequent malaria episode (Episode 1)
    Safety Issue?: Yes
• Mean Creatinine in Each Treatment Arm (Renal Function)
  • Time Frame: Day 0 of second subsequent malaria episode (Episode 2)
    Safety Issue?: Yes
• Mean Creatinine in Each Treatment Arm (Renal Function)
  • Time Frame: Day 14 of second subsequent malaria episode (Episode 2)
    Safety Issue?: Yes
• Mean Creatinine in Each Treatment Arm (Renal Function)
  • Time Frame: Day 0 of third subsequent malaria episode (Episode 3)
    Safety Issue?: Yes
• Mean Creatinine in Each Treatment Arm (Renal Function)
  • Time Frame: Day 14 of third subsequent malaria episode (Episode 3)
    Safety Issue?: Yes
• Mean Creatinine in Each Treatment Arm (Renal Function)
  • Time Frame: Day 0 of fourth subsequent malaria episode (Episode 4)
    Safety Issue?: Yes
• Mean Creatinine in Each Treatment Arm (Renal Function)
  • Time Frame: Day 14 of fourth subsequent malaria episode (Episode 4)
    Safety Issue?: Yes
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
  • Time Frame: Day 0 of initial malaria episode (Episode 0)
    Safety Issue?: Yes
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
  • Time Frame: Day 14 of initial malaria episode (Episode 0)
    Safety Issue?: Yes
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
  • Time Frame: Day 0 of first subsequent malaria episode (Episode 1)
    Safety Issue?: Yes
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
  • Time Frame: Day 14 of first subsequent malaria episode (Episode 1)
    Safety Issue?: Yes
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
  • Time Frame: Day 0 of second subsequent malaria episode (Episode 2)
    Safety Issue?: Yes
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
  • Time Frame: Day 14 of second subsequent malaria episode (Episode 2)
    Safety Issue?: Yes
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
  • Time Frame: Day 0 of third subsequent malaria episode (Episode 3)
    Safety Issue?: Yes
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
  • Time Frame: Day 14 of third subsequent malaria episode (Episode 3)
    Safety Issue?: Yes
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
  • Time Frame: Day 0 of fourth subsequent malaria episode (Episode 4)
    Safety Issue?: Yes
• Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
  • Time Frame: Day 14 of fourth subsequent malaria episode (Episode 4)
    Safety Issue?: Yes
• Number of Participants in Each Treatment Arm Who Change From "Normal" to "Abnormal" on Any Questions of the Neurological Examination
  • Time Frame: 1 Year
    Safety Issue?: Yes
• 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
    Safety Issue?: No
• Incidence of Infections and Recrudescent Infections After Initial Treatment Per Treatment Arm.
  • Time Frame: 28 days to 1 year
    Safety Issue?: No
• Incidence of New and Recrudescent Infections After Subsequent New Episodes
  • Time Frame: 1 year
    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
    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
    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
    Safety Issue?: 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)

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 Investigator: National Institute of Allergy and Infectious Diseases (NIAID) NIH

Information obtained from ClinicalTrials.gov on February 12, 2012

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

Study ID Number: 06-0022

ClinicalTrials.gov Identifier: NCT00379821

Health Authority: Malawi: College of Medicine Research and Ethics Committee