The AS-AQ Dose Impact Study Group formed in October 2011, with an open invitation to interested researchers with relevant data sets. Potential study group participants met at the December 2011 ASTMH Annual Meeting to discuss the Study Group governance and publication policy. The study group closed in March 2013. The latest results were presented at the 2014 RSTMH biannual Meeting in Oxford, UK.

The Study Group pooled 45 studies (10,821 patients) conducted between 1999 and 2012. This includes nine unpublished studies and 36 published studies representing 65% of the targeted published literature on this treatment regimen. Out of the 45 studies, 43 (9,106 patients) were included in the final analysis. Of those patients included in the final analysis, 93.7% were from Africa, 5.7% from Asia and 0.5% from South America.

The publication: The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data was published in March 2015

Download a presentation from the AS-AQ Dose Impact Study Group.

Artemisinin Combination Therapies (ACTs) efficacy is influenced by both the artemisinin derivative and the partner drug. The drugs should cure patients and also prevent the survival and spread of artemisinin resistant strains of Plasmodium. One of the most common partner drugs currently prescribed for uncomplicated malaria is amodiaquine. The dosage of partner drugs must be sufficient to ensure that blood concentrations exceed the minimum inhibitory concentration of the parasite until all parasites have been killed. A fixed dose combination of artesunate-amodiaquine was introduced in 2007 to optimise the AS:AQ ratio and improve adherence. Although target doses are usually given as a total mg/kg over three days, in practice, manufacturers’ recommendations are often pragmatic and based upon weight ‘banding’. This approach inevitably results in some patients at the margins receiving either lower or higher dosages. Young children are particularly vulnerable to extreme total dosages especially when drug administration is based on tablets rather than paediatric formulations or suspensions. The problem is further confounded when dosing is recommended according to age bands rather than actual body weight. Preliminary modelling of dosing strategies according to known ‘weight for age’ demographics in malaria patients, suggests that the wide range of mg/kg dosing used may impact significantly on treatment efficacy and possibly safety. 

• Determine the mg/kg dosing range of the clinically-adopted ACT partner drug amodiaquine
• Investigate the effects of amodiaquine mg/kg dosing on clinical outcome 

• Prospective clinical efficacy studies of P. falciparum (either alone or mixed infections);
• Artesunate-amodiaquine treatment with a minimum of 28 days follow up; and, 
• Individual patient data on exact dosage of amodiaquine received by patients (dosage per tablets, number of tablets given per dose and duration of treatment).

• Drug manufacturer
• Whether all doses were supervised
• Whether drugs were administered with fat

After upload to the WWARN Data Repository, WWARN standardised data sets according to the WWARN Clinical Data Management and Statistical Analysis Plan were pooled into a single database of quality-assured individual patient data. Analyses (subject to Study Group approval) included: 

• Dosing strategies adopted by different studies will be reviewed and the profile of total mg/kg dose of amodiaquine defined. In those patients for whom exact treatment dosage was recorded, adherence to study protocols will be assessed
• Clinical outcome (Pf PCR adjusted and unadjusted treatment failure at day 28 and 42) will be defined and significant baseline risk factors, for example age and parasitaemia, identified; and
• The effect of mg/kg dosing on clinical outcome will be analysed after controlling for other known confounding factors, including drug source

Kaplan Meier survival analysis will be used to define treatment efficacy for both univariate and multivariate analyses. 

This analysis aimed to determine whether differences in current dosing strategies, particularly fixed-dose vs. non fixed dose formulations, affect the assessment of efficacy of artesunate-amodiaquine, one of the most important ACTs currently being deployed.

The Study Group comprised participating investigators who contributed relevant data sets to the pooled analysis. Data sets remain the property of the investigator. The Study Group collectively makes decisions with respect to including additional studies, data analysis and plans for publication, in line with the WWARN Publication Policy. The Study Group identified one or two people to coordinate activities including data analysis, and drafting of publications and reports for group review. It is proposed that Prof Philippe Guérin would lead the Study Group.  

WWARN thanks the investigators who contributed individual patient data from published or unpublished clinical studies to the AS-AQ Dose Impact Study Group (see Related Documents for listing).

For further information, or to learn about the latest results of the Study Group, contact WWARN@wwarn.org.

AS-AQ Study Group. The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data. BMC Medicine. March 31, 2015.