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
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Condition or disease | Intervention/treatment | Phase |
---|---|---|
Plasmodium Falciparum Infection | Drug: Atovaquone-proguanil Drug: Artesunate Drug: Azithromycin Drug: Chloroquine | Phase 3 |
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 |

Arm | Intervention/treatment |
---|---|
Experimental: CQ Monotherapy
N=160: treat with Chloroquine (CQ) alone.
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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.
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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. |
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).

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Ages Eligible for Study: | 6 Months to 5 Years (Child) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | 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:
- fever at the time of evaluation (axillary temperature greater than or equal to 37.5 degrees Celsius 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 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:
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Signs of severe malaria: One or more of the following:
- hemoglobin less than or equal to 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 (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)

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
Malawi | |
Blantyre Malaria Project - Ndirande Health Centre | |
Blantyre, Malawi |
Responsible Party: | National Institute of Allergy and Infectious Diseases (NIAID) |
ClinicalTrials.gov Identifier: | NCT00379821 |
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 |
chloroquine, malaria, Plasmodium falciparum, Malawi, children |
Malaria Protozoan Infections Parasitic Diseases Infections Vector Borne Diseases Azithromycin Artesunate Chloroquine Atovaquone Proguanil Atovaquone, proguanil drug combination Anti-Bacterial Agents Anti-Infective Agents |
Antimalarials Antiprotozoal Agents Antiparasitic Agents Antineoplastic Agents Antiviral Agents Schistosomicides Antiplatyhelmintic Agents Anthelmintics Amebicides Antirheumatic Agents Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antimetabolites |