Chloroquine Alone or in Combination for Malaria in Children in Malawi
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Purpose
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 | Intervention | Phase |
|---|---|---|
|
Plasmodium Falciparum Malaria |
Drug: Chloroquine Drug: Atovaquone-proguanil Drug: Artesunate Drug: Azithromycin |
Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: 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 |
- Number of Clinical Malaria Episodes Per Year of Follow-up [ Time Frame: 1 year ] [ Designated as safety issue: No ]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) ] [ Designated as safety issue: No ]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) ] [ Designated as safety issue: No ]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) ] [ Designated as safety issue: No ]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) ] [ Designated as safety issue: No ]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) ] [ Designated as safety issue: No ]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 ] [ Designated as safety issue: Yes ]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 ] [ Designated as safety issue: Yes ]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 ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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) ] [ Designated as safety issue: Yes ]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 ] [ Designated as safety issue: Yes ]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.
- 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 ] [ Designated as safety issue: No ]
- Incidence of Infections and Recrudescent Infections After Initial Treatment Per Treatment Arm. [ Time Frame: 28 days to 1 year ] [ Designated as safety issue: No ]
- Incidence of New and Recrudescent Infections After Subsequent New Episodes [ Time Frame: 1 year ] [ Designated as 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 ] [ Designated as 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 ] [ Designated as 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 ] [ Designated as safety issue: No ]
| Enrollment: | 640 |
| Study Start Date: | February 2007 |
| Study Completion Date: | August 2009 |
| Primary Completion Date: | August 2009 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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
|
|
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
|
|
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
|
|
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.
|
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| Ages Eligible for Study: | 6 Months to 5 Years |
| Genders Eligible for Study: | Both |
| 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:
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)
Contacts and Locations More Information
Publications:
| Responsible Party: | National Institute of Allergy and Infectious Diseases (NIAID) |
| ClinicalTrials.gov Identifier: | NCT00379821 History of Changes |
| Other Study ID Numbers: | 06-0022 |
| Study First Received: | September 21, 2006 |
| Results First Received: | June 30, 2011 |
| Last Updated: | March 28, 2013 |
| Health Authority: | Malawi: College of Medicine Research and Ethics Committee United States: Federal Government United States: Food and Drug Administration United States: Institutional Review Board |
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
|
chloroquine, malaria, Plasmodium falciparum, Malawi, children |
Additional relevant MeSH terms:
|
Malaria Malaria, Falciparum Protozoan Infections Parasitic Diseases Chloroquine Artesunate Chloroquine diphosphate Proguanil Atovaquone Malarone Azithromycin Amebicides Antiprotozoal Agents Antiparasitic Agents Anti-Infective Agents |
Therapeutic Uses Pharmacologic Actions 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 Central Nervous System Agents |
ClinicalTrials.gov processed this record on May 21, 2013