Malariaandhealth.com

Combination Therapy for Uncomplicated
Falciparum Malaria in Ugandan Children
A Randomized Trial
Context Combination therapy is now widely advocated as first-line treatment for
uncomplicated malaria in Africa. However, it is not clear which treatment regimens are optimal or how to best assess comparative efficacies in highly endemic areas.
Objective To compare the efficacy and safety of 3 leading combination therapies
for the treatment of uncomplicated malaria.
Design, Setting, and Participants Single-blind randomized clinical trial, con-
ducted between November 2004 and June 2006, of treatment for all episodes of un- complicated malaria in children in an urban community in Kampala, Uganda. A totalof 601 healthy children (aged 1-10 years) were randomly selected and were followed up for 13 to 19 months, receiving all medical care at the study clinic.
Interventions Study participants were randomized to receive 1 of 3 combination
therapies (amodiaquine plus sulfadoxine-pyrimethamine, amodiaquine plus artesu-
MALARIAISONEOFTHE nate,orartemether-lumefantrine)whendiagnosedwiththeirfirstepisodeofuncom- plicated malaria. The same assigned treatment was given for all subsequent episodes.
Main Outcome Measure 28-Day risk of parasitological failure (unadjusted and ad-
justed by genotyping to distinguish recrudescence from new infection) for each epi- of death in children in Africa.1 The con- sode of uncomplicated malaria treated with study drugs.
Results Of enrolled children, 329 of 601 were diagnosed with at least 1 episode of
increasing resistance of Plasmodium fal- uncomplicated malaria, and 687 episodes of Plasmodium falciparum malaria were treated ciparum to antimalarial drugs, particu- with study drugs. The 28-day risk of treatment failure (unadjusted by genotyping) for individual episodes of malaria were 26.1% (95% CI, 21.1%-32.1%) for amodiaquine plus sulfadoxine-pyrimethamine, 17.4% (95% CI, 13.1%-23.1%) for amodiaquine plus artesunate, and 6.7% (95% CI, 3.9%-11.2%) for artemether-lumefantrine (PϽ.05 for all pairwise comparisons). When only recrudescent treatment failures were con-sidered, the risks of failure were 14.1% (95% CI, 10.3%-19.2%), 4.6% (95% CI, 2.5%- 8.3%), and 1.0% (95% CI, 0.3%-4.0%) for the same order of study drugs, respec- tively (PՅ.008 for all pairwise comparisons, except amodiaquine plus artesunate vs artemether-lumefantrine, P=.05). There were no deaths or cases of severe malaria.
Significant reductions in anemia (9.3% [95% CI, 7.0%-12.0%] at enrollment vs 0.6% [95% CI, 0.1%-2.2%] during the last 2 months of follow-up; PϽ.001) and asymp- tomatic parasitemia (18.6% [95% CI, 15.5%-22.1%] at enrollment vs 2.3% [95% CI, 1.5%-3.5%] during the last 2 months of follow-up; PϽ.001) were observed ac- Conclusions Artemether-lumefantrine was the most efficacious treatment for un-
complicated malaria in the study population. With all study regimens, the provision of prompt and reasonably effective facility-based treatment was associated with good outcomes in long-term health measures.
Trial Registration isrctn.org Identifier: ISRCTN37517549
Author Affiliations: Department of Medicine, San Fran-
University Medical School, Kampala, Uganda (Drs Njama- cisco General Hospital, University of California, San Fran- Meya, Nzarubara, Maiteki-Sebuguzi, and Kamya).
cisco (Drs Dorsey and Rosenthal, Ms Clark, and Mr Doko- Corresponding Author: Grant Dorsey, MD, PhD, Uni-
majilar); London School of Hygiene and Tropical versity of California, San Francisco, Box 0811, San Fran- Medicine, London, England (Dr Staedke); and Makerere cisco, CA 94143 (gdorsey@medsfgh.ucsf.edu).
2210 JAMA, May 23/30, 2007—Vol 297, No. 20 (Reprinted)
2007 American Medical Association. All rights reserved.
COMBINATION ANTIMALARIAL THERAPY IN UGANDA cently been adopted as first-line therapy supplies, difficulties in distribution, and Follow-up of Study Participants
Study Area and Recruitment
of Cohort
in the Mulago III parish from July to Oc- children for recruitment and to gather ba- physicians recruited children if they ful- filled all the following eligibility crite- acceptable alternatives were available.
Treatment Allocation
and Study Drug Administration
efficacies of antimalarial regimens is the larial regimens at their first episode of dinal studies also offer the advantage of evaluating long-term health outcomes.
2007 American Medical Association. All rights reserved.
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COMBINATION ANTIMALARIAL THERAPY IN UGANDA Malaria Follow-up
and Outcome Classification
tive of its suspected relationship to the Laboratory Methods
plicated malaria or failure to adequately early treatment failure or late parasito- logical failure), late parasitological fail- ϩ sulfadoxine-pyrimethamine and ure (asymptomatic parasitemia on days review of 100 high-powered fields. Theamodiaquine ϩ artesunate groups also ment, late clinical, or late parasitologi- cebo was given to the participant’s par- tive blood smear result after the quality- ferred for treatment with parenteral qui- Adverse Event Monitoring
stepwise fashion with msp-2, msp-1, and 4 microsatellites.13 If, for any of the 6 2212 JAMA, May 23/30, 2007—Vol 297, No. 20 (Reprinted)
2007 American Medical Association. All rights reserved.
COMBINATION ANTIMALARIAL THERAPY IN UGANDA Figure 1. Trial Profile
42 Did Not Provide Informed Consent28 Planning to Move Out of Study Area27 Weighed <10 kg15 Not Willing to Come to Clinic for All Care11 Not Aged 1-10 y 7 History of Serious Chronic Illness6 Severe Malnutrition3 Sickle Cell Disease2 Life-threatening Screening Laboratory 1 History of Adverse Effects to Study Drugs 226 With No Episodes of Uncomplicated Malaria 4 With Only Episodes of Complicated Malaria 42 Children Withdrawn Prior to Randomization 9 Withdrew Consent7 Lost to Follow-up for >60 Days1 Inability to Adhere to Study Schedule 253 Treatments Included in Safety Analysis 232 Treatments Included in Safety Analysis 202 Treatments Included in Safety Analysis 2007 American Medical Association. All rights reserved.
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COMBINATION ANTIMALARIAL THERAPY IN UGANDA rence at all 6 loci, the infection was clas- intention-to-treat analysis including all Statistical Analysis
were randomized to study drug therapy.
day risk for recurrent parasitemia (early treatment, late clinical, or late parasi- i n f e r i o r t o t h e a m o d i a q u i n e ϩ ter potential drug-related adverse events, relation and robust standard errors.
sis of treatment efficacy, we included the terim analysis, the data and safety moni- Treatment Outcomes for Individual
household. PϽ.05 was considered sta- Episodes of Malaria
early, given their potential public health Trial Profile
tient age, temperature, parasite density, ment arms (TABLE 1).
(FIGURE 1). We enrolled 601 children
follow-up are presented in TABLE 2 and
TABLE 3. Complete treatment out-
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2007 American Medical Association. All rights reserved.
COMBINATION ANTIMALARIAL THERAPY IN UGANDA Table 1. Baseline Characteristics of All Uncomplicated Malaria Episodes Due to Plasmodium
falciparum Treated With Study Drugs Treatment Group
and occurred in 8 of 253 (3.2%) chil-dren treated with amodiaquine ϩ sul- Amodiaquine ϩ
Sulfadoxine-
Amodiaquine ϩ
Artemether-
Pyrimethamine
Artesunate
Lumefantrine
Characteristic
Parasite density, geometric mean, per µL Mixed infection with other Plasmodium TABLE 4). More rapid parasite clear-
ance in the ACT treatment groups did
not translate into a clear clinical ben-
Table 2. Treatment Outcomes After 28 Days for Episodes of Uncomplicated Falciparum
Treatment Group, No. (%)
ver clearance between the 3 treatmentgroups (Table 4).
Amodiaquine ϩ
Sulfadoxine-
Amodiaquine ϩ
Artemether-
Pyrimethamine
Artesunate
Lumefantrine
Treatment Outcome
treatment failure after 28 days of follow- the 3 treatment groups. The risk of fail- mether-lumefantrine (PϽ.05 for all Table 3. Comparative Efficacies at 28 Days for Treatment of Uncomplicated Falciparum Malaria
Risk of Treatment Failure, %
Hazard Ratio
P
(95% Confidence Interval)
(95% Confidence Interval)*
*Adjusted for repeated measures in the same patient.
†Treatment failure defined as any early treatment, late clinical, or late parasitological failure; episodes with no outcomes and recurrent malaria caused by non-falciparum species ‡Treatment failure defined as any early treatment failure and only late clinical or late parasitological failure caused by recrudescence; episodes with no outcome, recurrent malaria caused by non-falciparum species, and new infections censored.
2007 American Medical Association. All rights reserved.
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COMBINATION ANTIMALARIAL THERAPY IN UGANDA t r e a t m e n t g r o u p s , r e s p e c t i v e l y ϩ artesunate treatment group (on day infection generally increased at a con- (PՅ.008 for all pairwise comparisons, we were able to assess the risk of recur- tively (FIGURE 2).
treatment group, 4 additional cases of re- ment prophylactic effects of the drugs.
21, and 23 days after initiation of therapy hemoglobin levels from day 0 to day 14were similar among the 3 treatmentarms (Table 4); only 12% of children Table 4. Secondary Outcomes for Episodes of Uncomplicated Falciparum Malaria
Treatment Group
Amodiaquine ϩ
Safety and Tolerability
Sulfadoxine-
Amodiaquine ϩ Artemether-
Pyrimethamine
Artesunate
Lumefantrine
of Study Drugs
safe and generally well tolerated. In the sodes in 14 patients. The majority of sei- Adverse events of any severity, days 1-14, No. (%)|| 1 Salmonella bacteremia). The other se- *Subjective fever during previous 24 hours or temperature Ն38.0°C.
†Amodiaquine ϩ sulfadoxine-pyrimethamine vs amodiaquine ϩ artesunate, PϽ.05 (adjusted for repeated measures in the ‡Amodiaquine ϩ sulfadoxine-pyrimethamine vs artemether-lumefantrine, PϽ.05 (adjusted for repeated measures in the §Change from day 0 to day 14 or day of clinical failure.
||Amodiaquine ϩ artesunate vs artemether-lumefantrine, PϽ.05 (adjusted for repeated measures in the same patient).
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2007 American Medical Association. All rights reserved.
COMBINATION ANTIMALARIAL THERAPY IN UGANDA Longitudinal Outcomes
for malaria after the first treatment with throughout the study (FIGURE 3). At en-
amine (1.24 vs 1.74; P = .02). Children low-up (PϽ.001). At enrollment, 52 of vision of health facility–based care and P = .10). There was no significant dif- ference in the incidence of malaria treat- ACT regimens (1.24 vs 1.34; P = .53).
The overall health of the children in this met WHO criteria for severe malaria.
Figure 2. Cumulative Risk of Recurrent Malaria Due to Recrudescence and New Infections Calculated With the Kaplan-Meier Product Limit
Formula
Pairwise comparisons of survival curves using Cox proportional hazards model with adjustment for repeated measures in the same patient. Recrudescence: amodia-quine ϩ sulfadoxine-pyrimethamine vs amodiaquine ϩ artesunate (P=.02), amodiaquine ϩ sulfadoxine-pyrimethamine vs artemether-lumefantrine (PϽ.001), amo-diaquine ϩ artesunate vs artemether-lumefantrine (P=.09). New infections: amodiaquine ϩ sulfadoxine-pyrimethamine vs amodiaquine ϩ artesunate (P=.60), amo-diaquine ϩ sulfadoxine-pyrimethamine vs artemether-lumefantrine (P=.19), amodiaquine ϩ artesunate vs artemether-lumefantrine (P=.40).
2007 American Medical Association. All rights reserved.
(Reprinted) JAMA, May 23/30, 2007—Vol 297, No. 20 2217
COMBINATION ANTIMALARIAL THERAPY IN UGANDA safety, tolerability, cost, and availabil- have typically focused on individual epi- tion therapies.20,21 Rather, important dif- sidual parasites. As resistance to a part- followed up for at least 28 days and that Figure 3. Prevalence of Asymptomatic Parasitemia and Anemia at Enrollment (November 2004–April 2005) and at Monthly Intervals During
Follow-up
Enroll Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr Enroll Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr 559 396 491 400 467 512 469 541 499 493 505 441 464 493 559 82 184 148 139 164 160 181 159 162 161 129 161 170 Error bars indicate 95% confidence intervals.
2218 JAMA, May 23/30, 2007—Vol 297, No. 20 (Reprinted)
2007 American Medical Association. All rights reserved.
COMBINATION ANTIMALARIAL THERAPY IN UGANDA 5. Dorsey G, Njama D, Kamya MR, et al. Sulfadoxine/
pyrimethamine alone or with amodiaquine or artesu-
nate for treatment of uncomplicated malaria: a lon- gitudinal randomised trial. Lancet. 2002;360: logical failures by day 28. Extending fol- dent’s Malaria Initiative, it seems that 2031-2038.
6. Rwagacondo CE, Niyitegeka F, Sarushi J, et al. Ef-
ficacy of amodiaquine alone and combined with sul- fadoxine-pyrimethamine and of sulfadoxine pyrimeth-amine combined with artesunate. Am J Trop Med Hyg.
7. Staedke SG, Mpimbaza A, Kamya MR, Nzarubara
BK, Dorsey G, Rosenthal PJ. Combination treatments
for uncomplicated falciparum malaria in Kampala, Uganda: randomised clinical trial. Lancet. 2004;364: 1950-1957.
8. Yeka A, Banek K, Bakyaita N, et al. Artemisinin ver-
sus nonartemisinin combination therapy for uncom- plicated malaria: randomized clinical trials from foursites in Uganda. PLoS Med. 2005;2:e190.
9. Mutabingwa TK, Anthony D, Heller A, et al. Amo-
diaquine alone, amodiaquine ϩ sulfadoxine-pyrimethamine, amodiaquine ϩ artesunate, and ar- Author Contributions: Dr Dorsey had full access to all
temether-lumefantrine for outpatient treatment of of the data in the study and takes responsibility for malaria in Tanzanian children: a four-arm ran- the integrity of the data and the accuracy of the data domised effectiveness trial. Lancet. 2005;365: participants suggest that even in the set- Study concept and design: Dorsey, Staedke, Kamya, 10. Davis JC, Clark TD, Kemble SK, et al. Longitudi-
nal study of urban malaria in a cohort of Ugandan chil- Acquisition of data: Dorsey, Staedke, Clark, dren: description of study site, census and recruitment.
facility–based treatment, ensuring good 11. World Health Organization. Assessment and
Analysis and interpretation of data: Dorsey, Clark, Monitoring of Antimalarial Drug Efficacy for the Treat- ment of Uncomplicated Falciparum Malaria. Geneva, Drafting of the manuscript: Dorsey, Staedke, Clark, Switzerland: WHO; 2003. Technical document WHO/ Njama-Meya, Nzarubara, Maiteki-Sebuguzi, Kamya, 12. World Health Organization. Susceptibility of Plas-
Critical revision of the manuscript for important intel- modium falciparum to antimalarial drugs: report on lectual content: Dorsey, Staedke, Clark, Njama-Meya, global monitoring: 1996-2004. Geneva, Switzer- land: WHO; 2005. Technical document WHO/HTM/ rural areas, the incidence of malaria may Statistical analysis: Dorsey.
Obtained funding: Dorsey, Staedke, Rosenthal.
13. Greenhouse B, Myrick A, Dokomajilar C, et al. Vali-
Administrative, technical, or material support: Dorsey, dation of microsatellite markers for use in genotyp- Clark, Njama-Meya, Nzarubara, Maiteki-Sebuguzi, ing polyclonal Plasmodium falciparum infections. Am J Trop Med Hyg. 2006;75:836-842.
Study supervision: Dorsey, Staedke, Clark, Kamya, 14. Montori VM, Devereaux PJ, Adhikari NK, et al.
Randomized trials stopped early for benefit: a system- Financial Disclosures: None reported.
atic review. JAMA. 2005;294:2203-2209.
Funding/Support: The study received financial sup-
15. Fanello CI, Karema C, van Doren W, Rwaga-
port from the National Institutes of Health (U01 condo CE, D’Alessandro U. Tolerability of amodia- AI052142) and the Doris Duke Charitable Founda- quine and sulphadoxine-pyrimethamine, alone or in tion (Dr Rosenthal is a Doris Duke Charitable Foun- combination for the treatment of uncomplicated Plas- dation Distinguished Clinical Scientist).
modium falciparum malaria in Rwandan adults. Trop Role of the Sponsor: The funding agencies had no role
Med Int Health. 2006;11:589-596.
in the design and conduct of the study; collection, man- 16. Karema C, Fanello CI, Van Overmeir C, et al. Safety
agement, analysis, and interpretation of the data; and and efficacy of dihydroartemisinin/piperaquine (Artekin preparation, review, or approval of the manuscript.
((R))) for the treatment of uncomplicated Plasmo- Acknowledgment: We are grateful to all the parents
dium falciparum malaria in Rwandan children. Trans and guardians for kindly giving their consent and the R Soc Trop Med Hyg. 2006;100:1105-1111.
study participants for their cooperation. We thank all 17. Zongo I, Dorsey G, Rouamba N, et al. Artemether-
the members of the study team in Uganda.
lumefantrine versus amodiaquine plus sulfadoxine- pyrimethamine for the treatment of uncomplicated fal- REFERENCES
ciparum malaria in Burkina Faso: a randomized controlled trial. Lancet. 2007;369:491-498.
limit the availability of drugs for treat- 1. Breman JG, Alilio MS, Mills A. Conquering the in-
18. Giao PT, Binh TQ, Kager PA, et al. Artemisinin for
tolerable burden of malaria: what’s new, what’s treatment of uncomplicated falciparum malaria: is there needed: a summary. Am J Trop Med Hyg. 2004; a place for monotherapy? Am J Trop Med Hyg. 2001; 2. Attaran A, Barnes KI, Curtis C, et al. WHO, the
19. Adjuik M, Babiker A, Garner P, Olliaro P, Taylor
Global Fund, and medical malpractice in malaria W, White N. Artesunate combinations for treatment treatment. Lancet. 2004;363:237-240.
of malaria: meta-analysis. Lancet. 2004;363:9-17.
3. Kremsner PG, Krishna S. Antimalarial combinations.
20. Stepniewska K, Taylor WR, Mayxay M, et al. In
vivo assessment of drug efficacy against Plasmo- 4. World Health Organization. WHO Guidelines for
dium falciparum malaria: duration of follow-up. An- the Treatment of Malaria. Geneva, Switzerland: WHO; timicrob Agents Chemother. 2004;48:4271-4280.
21. White NJ. The assessment of antimalarial drug
efficacy. Trends Parasitol. 2002;18:458-464.
2007 American Medical Association. All rights reserved.
(Reprinted) JAMA, May 23/30, 2007—Vol 297, No. 20 2219

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