CQSP in Malawi: Chloroquine and Sulfadoxine-pyrimethamine Efficacy for the Treatment of Malaria in Malawi
CQSP in Malawi: Chloroquine and Sulfadoxine-pyrimethamine Efficacy for the Treatment of Malaria in Malawi
The purpose of this research study is to find out how well chloroquine works as a drug to
 treat malaria in children, compared to the standard malaria treatment in Malawi. In
 preparation for a longer study of the malaria treatment medication chloroquine alone and in
 combination with other drugs, a shorter pre-study will be done to compare the anti-malarial
 effectiveness of chloroquine versus sulfadoxine-pyrimethamine (SP), the standard treatment in
 Malawi. Two hundred ten children, ages 6 months to 12 years, around Blantyre, Malawi, will be
 given standard dosing of either chloroquine or SP when they come to the Ndirande Health
 Centre with signs or symptoms consistent with malaria. The first 30 participants in each
 treatment group will remain under continuous observation at the health center so that the
 researchers can monitor their response to the medication until the infection goes away. The
 participants will be followed for 28 days to see if the the treatment works or fails.
This study follows the observation that chloroquine-resistant malaria may have returned to
 Malawi, 10 years after its use was eliminated. There is growing consensus that combination
 chemotherapy should be the rule in malaria treatment to deter the development of drug
 resistance and possibly also decrease malaria transmission. As sulfadoxine-pyrimethamine (SP)
 failure rates increase, the reintroduction of chloroquine in Malawi in combination with
 highly effective rapidly acting drugs such as artesunate and chlorproguanil-dapsone should be
 considered, and would likely extend the useful life span of each of the drugs. In preparation
 for a longitudinal clinical trial of chloroquine alone and SP in combination with other
 drugs, a preliminary trial will be conducted to compare the anti-malarial efficacy of
 chloroquine versus SP, the standard treatment in Malawi. This is a randomized, open-label
 clinical trial to compare the antimalarial efficacy of chloroquine versus SP among children
 with uncomplicated malaria in Blantyre, Malawi. In this study, 210 peri-urban children will
 be randomly assigned to receive standard dosing of either chloroquine or SP. Follow up will
 consist of visits on days 2, 3, 7, 14, 21 and 28, according to the standard World Health
 Organization protocol. Because chloroquine has not been used to treat malaria in Malawi for
 over a decade, special safety precautions will be taken at the beginning of the study. The
 first 30 participants in each arm will remain at the Health Centre under continuous
 observation of the medical staff to monitor response to therapy until they are afebrile for
 12 hours and have two consecutive negative 12-hourly blood smears. Observation in an
 inpatient setting will also help to avoid potential bias due to more intense follow-up of the
 hospitalized group. A Safety Monitoring Committee (SMC) will meet after the first 30
 participants have been enrolled in each arm to determine if the study should stop continuous
 observation and proceed with out-patient follow up only. All participants will be followed
 for 28 days to monitor for late therapeutic or parasitologic failure. The primary study
 objective is to assess the efficacy of chloroquine compared with standard SP therapy, in
 treating malaria in Malawi, where chloroquine has not been used for over 10 years and to
 compare it to the efficacy of standard therapy with SP. The secondary study objective is to
 assess the effect of the re-introduction of chloroquine on the molecular markers associated
 with chloroquine resistance. The primary study endpoint is the rates of adequate clinical and
 parasitologic response to therapy. The secondary study endpoints are: (1) rates of early and
 late therapeutic failure; (2) rates of early and late parasitologic failure; (3) prevalence
 of chloroquine-resistance conferring pfcrt K76T mutation in pre-treatment infections; (4)
 rates of pre- and post-treatment pfcrt K76T mutation in cases of chloroquine treatment
 failure; (5) prevalence of SP-resistance conferring dhfr/dhps mutations in pre-treatment
 infections; (6) rates of pre- and post-treatment dhfr/dhps mutations in cases of SP treatment
 failure; (7) clearance time of parasitemia; (8) clearance time of fever; and (9) presence of
 post-treatment anemia.
Inclusion Criteria:

 1. Patients aged >= 6 months to 12 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 37.5° C by digital
 thermometer)

 -  report of fever within the last two days

 -  profound anemia (conjunctival or palmar pallor)

 -  headache

 -  body aches

 -  abdominal pain

 -  decreased intake of food or fluids

 -  weakness

 2. Positive malaria smear for P. falciparum mono-infection

 3. Parasite density of 2,000-200,000/microliter or < 10%

 4. Willingness to remain at the Health Centre under continuous observation until the
 resolution of the infection

 5. Parental consent for each participant, and child assent for children older than 5
 years

 Exclusion Criteria:

 1. Signs of severe malaria: One or more of the following:

 -  hemoglobin < 5 g/dl

 -  parasitemia > 10%

 -  prostration * as indicated by inability to drink or breastfeed

 -  respiratory distress (deep Kussmaul respirations)

 -  bleeding

 -  recent seizures*, coma* or mental obtundation* (Blantyre coma score less than 5)

 -  persistent vomiting*

 2. Presence of a severe disease

 3. Presence of a febrile condition caused by diseases other than malaria

 4. Known allergy or history of adverse reaction to sulfadoxine/pyrimethamine (SP), sulfa
 drugs or chloroquine

 5. Chronic medication with an antifolate drug

 6. Enrollment in this clinical study in the past 28 days *Each of these symptoms or signs
 is considered a "danger sign."