Dataset Information

An open randomized clinical trial in comparing two artesunate-based combination treatments on Plasmodium falciparum malaria in Nigerian children: artesunate/sulphamethoxypyrazine/pyrimethamine (fixed dose over 24 hours) versus artesunate/amodiaquine (fixed dose over 48 hours).

ABSTRACT:

Background

Several studies have demonstrated the efficacy of artemisinin-combination therapy (ACT) across malaria zones of the world. Fixed dose ACT with shorter courses and fewer tablets may be key determinants to ease of administration and compliance.

Methods

Children aged one year to 13 years presenting with uncomplicated Plasmodium falciparum malaria were recruited in Ibadan, south-western Nigeria. A total of 250 children each were randomly assigned to receive three doses of artesunate/sulphamethoxypyrazine/pyrimethamine (AS + SMP) (12 hourly doses over 24 hours) or three doses of artesunate/amodiaquine (AS + AQ) (daily doses over 48 hours). Efficacy and safety of the two drugs were assessed using a 28-day follow-up and the primary outcome was PCR- corrected parasitological cure rate and clinical response.

Results

There were two (0.4%) early treatment failures, one in each treatment arm. The PCR corrected cure rates for day 28 was 97.9% in the AS + AQ arm and 95.6% in the AS + SMP arm (p = 0.15). The re-infection rate was 1.7% in the AS + AQ arm and 5.7% in the AS + SMP arm (p = 0.021). The fever clearance time was similar in the two treatment groups: 1 - 2 days for both AS + SMP and AS + AQ (p = 0.271). The parasite clearance time was also similar in the two treatment groups with 1 - 7 days for AS + SMP and 1 - 4 days for AS + AQ (p = 0.941). The proportion of children with gametocytes over the follow-up period was similar in both treatment groups. Serious Adverse Events were not reported in any of the patients and in all children, laboratory values (packed cell volume, liver enzymes, bilirubin) remained within normal levels during the follow-up period but the packed cell volume was significantly lower in the AS + SMP group.

Conclusions

This study demonstrates that AS + SMP FDC given as three doses over 24 hours (12-hour intervals) has similar efficacy as AS + AQ FDC given as three doses over 48 hours (24-hour interval) for the treatment of uncomplicated Plasmodium falciparum malaria in children in Nigeria. Both drugs also proved to be safe. Therefore, AS + SMP could be an alternative to currently recommended first-line ACT with continuous resistance surveillance.

SUBMITTER: Ayede IA

PROVIDER: S-EPMC3024282 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Publications

An open randomized clinical trial in comparing two artesunate-based combination treatments on Plasmodium falciparum malaria in Nigerian children: artesunate/sulphamethoxypyrazine/pyrimethamine (fixed dose over 24 hours) versus artesunate/amodiaquine (fixed dose over 48 hours).

Ayede Idowu Adejumoke IA Falade Adegoke Gbadegesin AG Sowunmi Akintunde A Jansen Frans Herwig FH

Malaria journal 20101231

<h4>Background</h4>Several studies have demonstrated the efficacy of artemisinin-combination therapy (ACT) across malaria zones of the world. Fixed dose ACT with shorter courses and fewer tablets may be key determinants to ease of administration and compliance.<h4>Methods</h4>Children aged one year to 13 years presenting with uncomplicated Plasmodium falciparum malaria were recruited in Ibadan, south-western Nigeria. A total of 250 children each were randomly assigned to receive three doses of a ...[more]

PMID: 21194422

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Project description:BackgroundPharmacokinetic (PK) and pharmacodynamic (PD) data are limited for artesunate (AS) and amodiaquine (AQ) in uncomplicated Plasmodium falciparum.MethodsFrom 2007-8, 54 P. falciparum-infected, Kenyan adults were assigned randomly fixed dose (FD) ASAQ (n?=?26) or non-fixed (NF) ASAQ (n?=?28). Total doses were 600 mg AS (both arms) + 1,620 mg (FD) or 1,836 mg (NF)AQ. Follow-up extended over 28 days. PK data were collected for AS, dihydroartemisinin (DHA), AS + DHA combined as DHA equivalents (DHAeq), AQ, desethylamodiaquine (DAQ),and their relationships assessed against the PD collected data consisting of parasitological efficacy, adverse events (AEs), and the Bazett's corrected QTinterval (QTcB).ResultsMean AUC 0-72 of dihydroartemisinin equivalents (DHAeq) when administered as a fixed dose (FD) compared to NF dose were similar: 24.2 ±4.6 vs 26.4±6.9 µmol*h/L (p?=?0.68) Parasite clearance rates were also similar after 24 hrs: 17/25 (68%) vs 18/28(64.3%) (p?=?0.86),as well as at 48 hrs: 25/8 (100%)vs 26 (92.9%)/28 (p?=?0.49). Mean FD vs NF DAQ AUC0-28 were 27.6±3.19 vs 32.7±5.53 mg*h/L (p?=?0.0005). Two PCR-proven new infections occurred on Day (D) 28 for estimated, in vivo, DAQ minimum inhibitory concentrations of 15.2 and 27.5 ng/mL. Combining the FD and NF arms, the mean QTcB at D2+4 hrs increased significantly (p?=?0.0059) vs baseline: 420 vs410 ms (??=?9.02 (95% confidence interval 2.72-15.31 ms), explained by falling heart rates, increasing DAQ concentrations and female sex in a general linear mixed effects model. Ten of 108 (9.26%) AEs (5/arm) reported by 37/54 (68.5%) patients were possibly or probably drug related. Severe, asymptomatic neutropaenia developed in 2/47 (4.25%) patients on D28: 574/µL (vsD0: 5,075/µL), and 777/µL (vsD0: 3,778/µL).ConclusionsTolerability of both formulations was good. For QTcB, a parameter for ECG modifications, increases were modest and due to rising DAQ concentrations and falling heart rates as malaria resolved. Rapid parasite clearance rates and no resistant infections suggest effective pharmacokinetics of both formulations.

Project description:The use of artemisinin-based combination therapy (ACT) is currently recommended for treating uncomplicated malaria. The objective was to assess the efficacy and safety of repeated administrations of two fixed-dose presentations of ACT--artesunate plus amodiaquine (ASAQ) and artemether-lumefantrine (AL)--in subsequent episodes of Plasmodium falciparum malaria.A randomized comparative study was conducted in a rural community of central Senegal from August 2007 to January 2009. Children and adults with uncomplicated P. falciparum malaria were randomized to receive open-label ASAQ once daily or AL twice daily for three days. Drug doses were given according to body weight. Treatments for first episodes were supervised. For subsequent episodes, only the first intake of study drug was supervised. ECGs and audiograms were performed in patients ? 12 years of age. Primary outcome was adequate clinical and parasitological response rate (ACPR) after polymerase chain reaction (PCR) correction on day 28 for the first episode.A total of 366 patients were enrolled in the two groups (ASAQ 184, AL 182) and followed up during two malaria transmission seasons. In the intent-to-treat population, PCR-corrected ACPRs at day 28 for the first episode were 98.4% and 96.2%, respectively, in the ASAQ and AL groups. For the per-protocol population (ASAQ 183, AL 182), PCR-corrected ACPRs at day 28 for the first episode were 98.9% and 96.7%, respectively. A 100% ACPR rate was obtained at day 28 in the 60 and four patients, respectively, who experienced second and third episodes. Treatment-related adverse events were reported in 11.7% of the patients, without significant differences between the two groups. A better improvement of haemoglobin at day 28 was noted in the ASAQ versus the AL group (12.2 versus 11.8 g/dL; p = 0.03). No sign of ototoxicity was demonstrated. A prolongation of the QTc interval was observed in both groups during treatment with no clinical consequence.Study results confirmed the satisfactory efficacy and safety profile of ASAQ and AL. Moreover, in patients who were treated at least twice, repeated administration of ASAQ or AL did not identify any major safety issues.ClinicalTrials.gov identifier NCT00540410.

Project description:Intermittent preventive treatment for malaria in children (IPTc) involves the administration of a full course of an anti-malarial treatment to children under 5 years old at specified time points regardless of whether or not they are known to be infected, in areas where malaria transmission is seasonal. It is important to determine the costs associated with IPTc delivery via community based volunteers and also the potential savings to health care providers and caretakers due to malaria episodes averted as a consequence of IPTc.Two thousand four hundred and fifty-one children aged 3-59 months were randomly allocated to four groups to receive: three days of artesunate plus amodiaquine (AS+AQ) monthly, three days of AS+AQ bimonthly, one dose of sulphadoxine-pyrimethamine (SP) bi-monthly or placebo. This paper focuses on incremental cost effectiveness ratios (ICERs) of the three IPTc drug regimens as delivered by community based volunteers (CBV) in Hohoe, Ghana compared to current practice, i.e. case management in the absence of IPTc. Financial and economic costs from the publicly funded health system perspective are presented. Treatment costs borne by patients and their caretakers are also estimated to present societal costs. The costs and effects of IPTc during the intervention period were considered with and without a one year follow up. Probabilistic sensitivity analysis was undertaken to account for uncertainty.Economic costs per child receiving at least the first dose of each course of IPTc show SP bimonthly, at US$8.19, is the cheapest to deliver, followed by AS+AQ bimonthly at US$10.67 and then by AS+AQ monthly at US$14.79. Training, drug delivery and supervision accounted for approximately 20-30% each of total unit costs. During the intervention period AS & AQ monthly was the most cost effective IPTc drug regimen at US$67.77 (61.71-74.75, CI 95%) per malaria case averted based on intervention costs only, US$64.93 (58.92-71.92, CI 95%) per malaria case averted once the provider cost savings are included and US$61.00 (54.98, 67.99, CI 95%) when direct household cost savings are also taken into account. SP bimonthly was US$105.35 (75.01-157.31, CI 95%) and AS & AQ bimonthly US$211.80 (127.05-399.14, CI 95%) per malaria case averted based on intervention costs only. The incidence of malaria in the post intervention period was higher in children who were <1 year old when they received AS+AQ monthly compared to the placebo group leading to higher cost effectiveness ratios when one year follow up is included. The cost per child enrolled fell considerably when modelled to district level as compared to those encountered under trial conditions.We demonstrate how cost-effective IPTc is using three different drug regimens and the possibilities for reducing costs further if the intervention was to be scaled up to the district level. The need for effective training, drug delivery channels and supervision to support a strong network of community based volunteers is emphasised.

Project description:BackgroundThe use of artemisinin derivative-based combination therapy (ACT) such as artesunate plus amodiaquine is currently recommended for the treatment of uncomplicated Plasmodium falciparum malaria. Fixed-dose combinations are more adapted to patients than regimens involving multiple tablets and improve treatment compliance. A fixed-dose combination of artesunate + amodiaquine (ASAQ) was recently developed. To assess the efficacy and safety of this new combination and to define its optimum dosage regimen (once or twice daily) in the treatment of uncomplicated P. falciparum malaria, a multicentre clinical study was conducted.MethodsA multicentre, randomized, controlled, investigator-blinded, parallel-group study was conducted in five African centers in Cameroon, Madagascar, Mali and Senegal from March to December 2006. Efficacy and safety of ASAQ were assessed compared to those of artemether + lumefantrine (AL). The WHO protocol with a 28-day follow-up for assessing the drug therapeutic efficacy was used. Patients suffering from uncomplicated P. falciparum malaria were randomized to receive ASAQ orally once daily (ASAQ1), ASAQ twice daily (ASAQ2) or AL twice daily (AL) for three days. The primary outcome was PCR-corrected parasitological cure rate and clinical response.ResultsOf 941 patients initially randomized and stratified into two age groups (<5 years, and >or=5 years), 936 (99.5%) were retained for the intent to treat (ITT) analysis, and 859 (91.3%) patients for the per protocol (PP) analysis. Among ITT population, up to D28, PCR-corrected adequate parasitological and clinical response rates were 95.2% in the ASAQ1 group, 94.9% in the ASAQ2 group and 95.5% in the AL group. Moreover, the cure rate evaluated among PP population was >or=98.5% in both ASAQ therapeutic arms. Therapeutic response rates did not display any significant differences between age groups or between one geographical site and another. Altogether, this demonstrates the non-inferiority of ASAQ1 regimen compared to both ASAQ2 and AL regimens. During follow-up mild and moderate adverse events including gastrointestinal and/or nervous disorders were reported in 29.3% of patients, with no difference between groups in the nature, frequency or intensity of adverse events.ConclusionThe non-inferiority of ASAQ compared with AL was demonstrated. The fixed-dose combination artesunate + amodiaquine (ASAQ) is safe and efficacious even in young children under 5 years of age. Whilst administration on a twice-a-day basis does not improve the efficacy of ASAQ significantly, a once-a-day intake of this new combination clearly appears as an effective and safe therapy in the treatment of uncomplicated P. falciparum malaria both in adults and children. Implications of such findings are of primary importance in terms of public health especially in African countries. As most national policies plan to strengthen malaria control to reach the elimination of this disease, anti-malarial drugs such as the artesunate + amodiaquine fixed-dose ACT will play a pivotal role in this process.Trial registrationThe protocol was registered with the www.clinicaltrials.gov open clinical trial registry under the identifier number NCT00316329.

Dataset Information

An open randomized clinical trial in comparing two artesunate-based combination treatments on Plasmodium falciparum malaria in Nigerian children: artesunate/sulphamethoxypyrazine/pyrimethamine (fixed dose over 24 hours) versus artesunate/amodiaquine (fixed dose over 48 hours).

Background

Methods

Results

Conclusions

Publications

An open randomized clinical trial in comparing two artesunate-based combination treatments on Plasmodium falciparum malaria in Nigerian children: artesunate/sulphamethoxypyrazine/pyrimethamine (fixed dose over 24 hours) versus artesunate/amodiaquine (fixed dose over 48 hours).

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