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Chloroquine Alone or in Combination for Malaria in Children in Malawi

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ClinicalTrials.gov Identifier: NCT00379821
Recruitment Status : Completed
First Posted : September 25, 2006
Results First Posted : July 27, 2011
Last Update Posted : August 11, 2014
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Study Description
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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
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Study Type : Interventional  (Clinical Trial)
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 : February 2007
Actual Primary Completion Date : August 2009
Actual Study Completion Date : September 2012

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

Arms and Interventions
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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
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Primary Outcome Measures :
  1. Number of Clinical Malaria Episodes Per Year of Follow-up [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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. [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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
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Ages Eligible for Study:   6 Months to 5 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00379821


Locations
Malawi
Blantyre Malaria Project - Ndirande Health Centre
Blantyre, Malawi
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
More Information
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Publications:

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00379821     History of Changes
Other Study ID Numbers: 06-0022
First Posted: September 25, 2006    Key Record Dates
Results First Posted: July 27, 2011
Last Update Posted: August 11, 2014
Last Verified: July 2014

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
chloroquine, malaria, Plasmodium falciparum, Malawi, children

Additional relevant MeSH terms:
Malaria
Protozoan Infections
Parasitic Diseases
Artesunate
Chloroquine
Artemisinins
Chloroquine diphosphate
Atovaquone
Proguanil
Atovaquone, proguanil drug combination
Amebicides
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antimalarials
 Antirheumatic Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Filaricides
Antinematodal Agents
Anthelmintics
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites