Longitudinal comparison of antimalarial treatment efficacy (U01 Mulago III Cohort Study)

Co-Principal Investigators: Philip Rosenthal, MD and Moses Kamya, MBChB, MMed, MPH

Co-investigator: Grant Dorsey, MD, PhD, Sarah Staedke, MD, Jeffrey N. Martin, MD, MPH, Lisa Butler, PhD, Bryan Greenhouse, MD, Chandy John, MD, MS

ClinicalTrials.gov Identifier: NCT00123552

Sponsored by: The National Institutes of Health / Division of Microbiology and Infectious Diseases (NIH/DMID)

Start Date: November 1, 2004

End Date: December 15, 2008

This randomized, single-blinded, longitudinal clinical trial was designed to compare the safety, tolerability and efficacy of three different combination antimalarial regimens for the treatment of uncomplicated malaria. These three regimens were amodiaquine + sulfadoxine-pyrimethamine (AQ+SP), amodiaquine + artesunate (AQ+AS) and co-artemether (AL). Beginning July – September 2004, a census project was carried out in Mulago III parish of Kampala near Mulago Hospital to identify and enumerate all households within this area. Probability sampling was used to select a random sample of 601 Ugandan children between the ages of 1 to 10 years from 322 households from this area between November 2004 and May 2005. In May 2006, the study began Phase II, a randomized open label longitudinal clinical trial comparing two antimalarial regimens only, AQ+AS and AL and all participants received an insecticide treated bed net (ITN). At this time, enrollment was reopened to children aged 1- 10 yrs belonging to a household already in the study and an additional 89 children were enrolled.

Participants were followed from time of enrollment until the study ended on December 15, 2008 for all routine medical care in our study clinic at Mulago Hospital. All patients presenting to our study clinic with a new episode of fever underwent standard evaluation (history, physical examination and Giemsa-stained blood smear) for the diagnosis of malaria. Participants were randomized to one of three combination regiments at the time of their first diagnosis of uncomplicated malaria and all subsequent episodes of uncomplicated malaria were treated with each participant’s assigned treatment regimen. Children randomized to AQ+SP were re-randomized to either AQ+AS or AL during Phase II. Beginning on February 1, 2008 (Phase IIa), AQ+AS will be dropped due to the discontinuation of the AS product and all episodes of uncomplicated malaria will be treated with AL. All clinical treatment failures occurring within 14 days of diagnosis of malaria and for all episodes of complicated malaria were treated with quinine, the standard therapy for malaria after treatment failure in Uganda. All episodes diagnosed more than 14 days after a previous episode were considered new episodes for treatment purposes. Routine visits included history, temperature and blood smear/filter paper taken every 30 days and blood draw for CBC and ALT tests every 90 days. Home visits were made for any participant not seen in our study clinic after any consecutive 30-day period.

Treatment incidence was been highly variable by month and year (Figure 1). Generally there were two periods of increased incidence, occurring in December to February and April to June. Distribution of bed nets in Phase II of the study was implemented in May – June 2006. Incidence markedly decreased in the past year as compared to previous years, probably due to a number of factors, including ITN use, aging of our study population, and the cumulative benefits of prompt effective treatment of all episodes of malaria.

Figure 1. Treatment incidence density by month
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A total of 1464 treatments for malaria were given, resulting in a treatment incidence density of 0.74 per person year.

 

Malaria Incidence (November 1, 2004 – December 15, 2008)

Study Summary # malaria episodes* Person-years Incidence density
STUDY TOTAL 1464 1986 0.74
TOTAL PHASE I 731 740 0.99
TOTAL PAHSE II 733 1246 0.59


*Unadjusted for recrudence by genotyping

Of the 1464 episodes of malaria, 1381 episodes were classified as new infections and 83 episodes were classified as recrudences based on parasite genotyping. The treatment failure rate for all study drugs combined was 14.3% (clinical and parasitological failures) at day 28.

Antimalarial drug N ETF LCF LPF ACPR LOST
AQ+SP
(Nov 1, 2004– Mar 5, 2007)
359 9 (2.5%) 45 (12.5%) 36 (10.0%) 258 (71.9%) 11 (3.1%)
AQ+AS
(Nov 1, 2004– Jan 31, 2008)
423 3 (0.7%) 36 (8.5%) 25 (5.9%) 346 (81.8%) 13 (3.1%)
AL
(Nov 1, 2004- Dec 15, 2008)
568 2 (0.3%) 14 (2.5%) 19 (3.3%) 517 (91.0%) 16 (2.8%)
QNN
(Nov 1, 2004- Dec 15, 2008)
30 2 (6.7%) 6 (20.0%) 1 (3.3%) 20 (66.7%) 1 (3.3%)
QNN/CLIND
(Nov 1, 2004- Dec 15, 2008)
1 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (100%) 0 (0.0%)
TOTAL 1381 16 (1.2%) 101 (7.3%) 81 (5.9%) 1142 (82.7%) 41 (3.0%)

 

CLINICAL OUTCOME CLASSIFICATION

ETF (Early Treatment Failure): Days 0, 1, 2, and 3

  • Development of danger signs or severe malaria on Days 0-3 in the presence of parasitemia
  • Parasitemia on Day 2 higher than on Day 0, irrespective of temperature
  • Parasitemia on Day 3 with temperature > 38.0°C (tympanic)
  • Parasitemia on Day 3 > 25% of count on Day 0

 

LCF (Late Clinical Failure): Days 4 To 14

  • Development of danger signs or severe malaria after Day 3 in the presence of parasitemia, without previously meeting any of the criteria of early treatment failure
  • Temperature > 38.0°C (tympanic), or history of fever in past 24 hours, on Days 4 to 14 in the presence of parasitemia, without previously meeting any of the criteria of early treatment failure

 

LPF (Late Parasitological Failure): Day 14

  • Presence of parasitemia on Day 14 and temperature < 38.0°C (tympanic), without previously meeting any of the criteria of early or late treatment failure

 

ACPR (Adequate Clinical and Parasitological Response)

  • Absence of parasitemia on Day 14, irrespective of temperature, without previously meeting any of the criteria of early or late treatment failure