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Download Longitudinal trial of therapy for uncomplicated
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Longitudinal trial of chloroquine monotherapy and combination therapy for uncomplicated falciparum malaria in children in Blantyre, Malawi Presenter: Patricia Mawindo Clinical Research Coordinator, Blantyre Malaria Project, Ndirande Research Clinic, Malawi. BACKGROUND • Malawi was the first country to stop using chloroquine as the first line treatment of malaria due to high rates of resistance. • The decline in the prevalence of genetic marker of Chroloquine-resistance malaria began immediately following the switch to Sulfadoxine-Pyrimethamine in 1993 and was undetectable in 2001. • In 2005, BMP conducted a study demonstrating 99% effectiveness of Chroloquine in uncomplicated malaria in children RATIONALE • Reintroduction of Chroloquine, whether for routine treatment or targeted prevention with a partner drug would protect against the re-emergence of resistance. • Combination therapy is recommended to effectively treat individual infections and to prevent the emergence and spread of resistance. • Rather, our hope was to answer the question: for how long does a partner drug need to be active to protect against resistance? OBJECTIVES Primary: • Compare annual incidence of malaria clinical episodes. Secondary: • Assess antimalarial drug efficacy at first and subsequent administrations by treatment arm. • Measure the effect of each treatment arm on anaemia. Objectives • Measure the prevalence of chloroquine resistance . • Assess the safety of each study arm with repeated use. METHODS • Ndirande H/Centre serving a population of 200,000. • Targeted children aged 6 months to 5 years (attending the pediatric clinic). Studied Chloroquine: • as monotherapy • in combination with drugs with different halflives; Artesunate, azithromycin and atovaquineproguanil. STUDY DESIGN & DURATION • Ppts identified at the time of first episode of uncomplicated malaria. • 640 children randomized to one of the four treatment arms. • Treatment outcome assessed through the standard 28-day efficacy study. • Subsequently, evaluated every 4wks and encouraged to return when sick. DESIGN & DURATION • Offered same therapy as assigned at enrollment incases of a new episode of uncomplicated malaria. • PCR-corrected 28-day efficacy evaluated at each treatment episode. • Primary endpoint: annual incidence of malaria. • Study duration was 1.5 years. RESULTS • Out of 640 children, 628 included in the intention-to-treat analysis. • Malaria incidence (95% confidence interval) was 0.59 (0.46-.74), .61 (.49-.76), .63 (.50.79) and .68 (.54-.86) episodes/person-year. • Treatment efficacy for 1st episodes was 100% for CQ monotherapy, 97% for subsequent episodes. Similar results in combination groups. RESULTS • The incidence of pfcrt T76 in pure form was 0%; mixed infections with both K76 and T76 were found in 2 out of 911 infections. • Young children treated with chloroquineazithromycin had higher hemoglobin concentrations at the study’s end than did those in the chloroquine monotherapy. Conclusions and next steps • chloroquine is once again an effective drug for treatment of malaria in Malawi. • with its excellent safety profile, low cost and long post-treatment prophylactic effect, an attractive candidate for prevention in vulnerable groups, typically women and infants, in areas where resistance to SP is high. Conclusions and next steps • Clinical efficacy of chloroquine was maintained with repeated use in a clinical trial. • Evidence of resistance on a molecular level will be evaluated. • PK-PD modeling in susceptible and resistant parasites. Acknowledgements • Study leadership: – – – – – Chris Plowe Miriam Laufer Terrie Taylor Fraction Dzinjalamala Phil Thesing • Blantyre Malaria Project staff, led by • Data management and biostatistical support EMMES Corp. • We are grateful to the children and their parents who participated in this study and continue to welcome us at the research clinic in Ndirande. – Osward Nyirenda – Rhoda Masonga – Joseph Kanyangalika • Administrative support – Esther Gondwe, BMP – Nicole Eddington, UMB Funded by NIH: U01AI044824 and K23AI059316 Zithromax (azithromycin) donated by Pfizer Inc.
