Transcript Longitudinal trial of therapy for uncomplicated

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.