Chloroquine Alone or in Combination for Malaria in Children in Malawi

A Longitudinal Study of Chloroquine as Monotherapy or in Combination With Artesunate, Azithromycin or Atovaquone-Proguanil to Treat Malaria in Children in Blantyre, Malawi

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00379821

Enrollment

640

Registered

2006-09-25

Start date

2007-02-28

Completion date

2012-09-30

Last updated

2014-08-11

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Plasmodium Falciparum Infection

Keywords

chloroquine, malaria, Plasmodium falciparum, Malawi, children

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

Interventions

DRUGAtovaquone-proguanil

Atovaquone-proguanil: once a day for 3 days, Pediatric tablet: 62.5 mg/25 mg, Full strength tablet: 250 mg/100 mg

DRUGArtesunate

Artesunate: 4mg/kg once a day for 3 days, 50 mg tablet

DRUGAzithromycin

Azithromycin 30 mg/kg once a day for 3 days, 200 mg/5cc suspension

DRUGChloroquine

Chloroquine: 10 mg/kg on days 0 and 1, 5 mg/kg/day on day 2, 100 mg tablet.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

6 Months to 5 Years

Healthy volunteers

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)

Design outcomes

Primary

Measure	Time frame	Description
Number of Clinical Malaria Episodes Per Year of Follow-up	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

Measure	Time frame	Description
Number of Cases of Severe Malaria in Each Treatment Arm	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.	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.	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)	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 Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)	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.
Number of Participants in Each Treatment Arm Who Change From Normal to Abnormal on Any Questions of the Neurological Examination	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	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 With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm	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 New and Recrudescent Malaria Infections After Initial Treatment	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	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.
Nearest Neighbor Index as a Measure of Spatial Pattern of the Distribution of Malaria Cases in Ndirande	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.
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.	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.
Pharmacokinetics of Chloroquine Represented by Time of Maximal Concentration (Tmax) and Chloroquine Half-life	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)	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).
Number of Participants Infected With Parasites With the Mutation Pfcrt 76T at Recrudescent Episodes of Malaria	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.

Countries

Malawi

Participant flow

Recruitment details

Children who were brought to the Ndirande Health Centre with symptoms suggestive of malaria were recruited from February 19, 2007 to August 13, 2008.

Participants by arm

Arm	Count
Chloroquine Plus Artesunate Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.	160
Chloroquine Plus Atovaquone-Proguanil Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; \>30 kg, 3 FST.	160
CQ Plus Azithromycin Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.	160
CQ Monotherapy Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.	160
Total	640

Baseline characteristics

Characteristic	Chloroquine Plus Atovaquone-Proguanil	CQ Plus Azithromycin	Chloroquine Plus Artesunate	CQ Monotherapy	Total
Age, Categorical <=18 years	160 Participants	160 Participants	160 Participants	160 Participants	640 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Continuous	2.7 years STANDARD_DEVIATION 1.2	2.8 years STANDARD_DEVIATION 1.1	2.7 years STANDARD_DEVIATION 1.2	2.7 years STANDARD_DEVIATION 1.2	2.7 years STANDARD_DEVIATION 1.2
Region of Enrollment Malawi	160 participants	160 participants	160 participants	160 participants	640 participants
Sex: Female, Male Female	82 Participants	73 Participants	70 Participants	77 Participants	302 Participants
Sex: Female, Male Male	78 Participants	87 Participants	90 Participants	83 Participants	338 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	144 / 160	140 / 160	143 / 160	145 / 160
serious Total, serious adverse events	8 / 160	14 / 160	7 / 160	20 / 160

Outcome results

Primary

Number of Clinical Malaria Episodes Per Year of Follow-up

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).

Time frame: 1 year

Population: The intention to treat (ITT) population was used for the primary outcome.

Arm	Measure	Value (NUMBER)
Chloroquine Plus Artesunate	Number of Clinical Malaria Episodes Per Year of Follow-up	0.61 Episodes per PYAR
Chloroquine Plus Atovaquone-Proguanil	Number of Clinical Malaria Episodes Per Year of Follow-up	0.68 Episodes per PYAR
CQ Plus Azithromycin	Number of Clinical Malaria Episodes Per Year of Follow-up	0.64 Episodes per PYAR
CQ Monotherapy	Number of Clinical Malaria Episodes Per Year of Follow-up	0.59 Episodes per PYAR

Comparison: Number of clinical malaria episodes per PYAR was compared using Poisson regression assuming null hypothesis that the number of malaria episodes are the same in both groups.p-value: 0.809795% CI: [0.7497, 1.4463]Poisson regression

Secondary