Clinical trial NCT00379821: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Plasmodium Falciparum Infection
Keywords: chloroquine, malaria, Plasmodium falciparum, Malawi, children
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2006-09-25
Enrollment: 640
Sex: ALL
Minimum age (years): 6
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Eligibility criteria: 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)

Primary outcomes:
measure: Number of Clinical Malaria Episodes Per Year of Follow-up
timeFrame: 1 year
Secondary outcomes:
measure: Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm
timeFrame: Day 28 of initial malaria episode (Episode 0)
measure: Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm
timeFrame: Day 28 of first subsequent malaria episode (Episode 1)
measure: Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm
timeFrame: Day 28 of second subsequent malaria episode (Episode 2)
measure: Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm
timeFrame: Day 28 of third subsequent malaria episode (Episode 3)
measure: Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm
timeFrame: Day 28 of fourth subsequent malaria episode (Episode 4)
measure: Number of Cases of Severe Malaria in Each Treatment Arm
timeFrame: 1 Year
measure: Mean Hemoglobin at the Last Study Visit in Each Treatment Arm for the Age Group of Participants 3 Years of Age or Younger.
timeFrame: 1 year
measure: 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.
timeFrame: 1 year
measure: Mean Creatinine in Each Treatment Arm (Renal Function)
timeFrame: Day 0 of initial malaria episode (Episode 0)
measure: Mean Creatinine in Each Treatment Arm (Renal Function)
timeFrame: Day 14 of initial malaria episode (Episode 0)
measure: Mean Creatinine in Each Treatment Arm (Renal Function)
timeFrame: Day 0 of first subsequent malaria episode (Episode 1)
measure: Mean Creatinine in Each Treatment Arm (Renal Function)
timeFrame: Day 14 of first subsequent malaria episode (Episode 1)
measure: Mean Creatinine in Each Treatment Arm (Renal Function)
timeFrame: Day 0 of second subsequent malaria episode (Episode 2)
measure: Mean Creatinine in Each Treatment Arm (Renal Function)
timeFrame: Day 14 of second subsequent malaria episode (Episode 2)
measure: Mean Creatinine in Each Treatment Arm (Renal Function)
timeFrame: Day 0 of third subsequent malaria episode (Episode 3)
measure: Mean Creatinine in Each Treatment Arm (Renal Function)
timeFrame: Day 14 of third subsequent malaria episode (Episode 3)
measure: Mean Creatinine in Each Treatment Arm (Renal Function)
timeFrame: Day 0 of fourth subsequent malaria episode (Episode 4)
measure: Mean Creatinine in Each Treatment Arm (Renal Function)
timeFrame: Day 14 of fourth subsequent malaria episode (Episode 4)
measure: Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
timeFrame: Day 0 of initial malaria episode (Episode 0)
measure: Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
timeFrame: Day 14 of initial malaria episode (Episode 0)
measure: Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
timeFrame: Day 0 of first subsequent malaria episode (Episode 1)
measure: Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
timeFrame: Day 14 of first subsequent malaria episode (Episode 1)
measure: Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
timeFrame: Day 0 of second subsequent malaria episode (Episode 2)
measure: Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
timeFrame: Day 14 of second subsequent malaria episode (Episode 2)
measure: Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
timeFrame: Day 0 of third subsequent malaria episode (Episode 3)
measure: Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
timeFrame: Day 14 of third subsequent malaria episode (Episode 3)
measure: Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
timeFrame: Day 0 of fourth subsequent malaria episode (Episode 4)
measure: Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)
timeFrame: Day 14 of fourth subsequent malaria episode (Episode 4)
measure: Number of Participants in Each Treatment Arm Who Change From "Normal" to "Abnormal" on Any Questions of the Neurological Examination
timeFrame: 1 Year
measure: Number of Participants Infected With Parasites With the Mutation Pfcrt 76T on Day 0 of the Initial Episode of Malaria
timeFrame: Day 0 of initial episode of malaria
measure: Number of Participants Infected With Parasites With the Mutation Pfcrt 76T at Recrudescent Episodes of Malaria
timeFrame: Recrudescent episodes of malaria within one year of enrollment
measure: Number of Participants With New and Recrudescent Malaria Infections After Initial Treatment
timeFrame: 28 days to 1 year
measure: Number of Participants With New and Recrudescent Infections After Subsequent New Episodes
timeFrame: Day 28 to 1 year
measure: 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.
timeFrame: Days 0 - 420
measure: Nearest Neighbor Index as a Measure of Spatial Pattern of the Distribution of Malaria Cases in Ndirande
timeFrame: 1 year
measure: Pharmacokinetics of Chloroquine Represented by Time of Maximal Concentration (Tmax) and Chloroquine Half-life
timeFrame: Day 0 - Day 28
measure: Pharmacokinetics of Chloroquine Represented by Maximum Concentration (Cmax)
timeFrame: Day 0 - Day 28
Other outcomes:
Locations:
city: Blantyre
country: Malawi
facility: Blantyre Malaria Project - Ndirande Health Centre
Study officials:
References:
citation: 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.