The Artemisinin Combination Therapies (ACT) Asia Baseline Study Group has begun gathering and curating data shared with WWARN by participating investigators. The data analysis will start in June 2015 and a manuscript is expected to be submitted for publication by March 2016.

The ACT Asia Baseline Study Group was first formed in October 2013, with an open invitation to interested researchers with relevant data sets. Potential Study Group participants met at the November 2013 ASTMH Annual Meeting to discuss the project including governance and publication policy. 

Slow clinical and parasitological response after artemisinin therapy for uncomplicated falciparum malaria has emerged in western Cambodia. Subsequently, similar responses have been identified in western Thailand and southern Vietnam. Spread of these slow-clearing parasites poses a major global public health threat, with the greatest potential impact in sub-Saharan Africa where disease burdens are greatest. If resistance to artemisinin compounds spreads, it will likely propagate from the Mekong region through South Asia and into Eastern Africa. Alternatively, artemisinin drug resistance may develop de novo in South Asia or Africa before these parasites spread from the Mekong.

It is critical to establish baseline parasitological responses to ACT in areas of Asia and the Pacific outside the Mekong region where slow parasite clearance has been described. Identifying changes in parasitological responses following ACTs will inform malaria control and elimination efforts and allow effective strategies to be devised accordingly. However, clinical studies are difficult to compare over time and between sites since both host (e.g., age and immunity) and parasite (e.g., baseline parasite density) or partner drug factors can significantly influence parasite clearance.

• Define the spectrum of early parasitological response following ACT in Asian clinical trials especially those conducted outside the Mekong region, and to define the cofactors affecting early and late treatment outcomes
• Investigate geographical and temporal trends in early parasitological outcomes which, after controlling for confounding factors, may indicate declining artemisinin efficacy.

Recently, studies have been conducted in the Mekong region to define the longer parasite clearance phenotype following artemisinin therapy. Results from these trials will be published in early 2014. These studies have adopted artesunate monotherapy with frequent sampling of parasitemia during the first three days of treatment. This protocol is more difficult to conduct than the standard therapeutic efficacy studies and requires significant revision of current practices that may not be easily applied to an outpatient care setting.

As a first step, we will conduct a pooled analysis of individual patients’ early parasitological response after ACT treatment in regions of Asia outside the Mekong.

• Clinical trials including artemisinin combination therapy 
  Individual patient data including:
  • A minimum of once daily sampling of parasitemia in the first 3 days or at least on day 2 and day 3 following treatment
  • Details of treatment regimens including manufacturer and dosage based on weight or age
  • Baseline characteristics of the patient, including age and sex
• Ethical clearance of study protocol

• Time of administration of medicines and collection of blood smears
• Dosing variables including target dose, mg/kg administered, dosing scheme, tablet counts treatment adherence, and supervised or unsupervised drug intake
• Variables related to microscopy used for estimating parasitemia (count based on WBC/RBC, minimum limit of detection)
• PCR-corrected treatment outcomes
• Malaria transmission intensity at study sites

Proportion of patients remaining parasitemic on day 1, day 2, and day 3 (parasite positivity rate, or PPR)

• Parasite clearance on day 1 and day 2
• Reduction in parasitemia between day 0, day 1 and day 2 (parasite reduction rate, or PRR)
• PCR-confirmed recrudescence (i.e., treatment failure)

After upload to the WWARN Data Repository, WWARN will standardize data sets according to the WWARN Clinical Data Management and Statistical Analysis Planand pool into a single database of quality-assured individual patient data.

The analyses will document the parasitological and clinical response following treatment with a recommended ACT, and how these vary between regimens, geospatially and temporarily after controlling for confounding factors. This information will help investigators plan targeted prospective clinical trials using rich parasitological sampling methods to better define the degree of resistance to the artemisinin derivatives.

The Study Group comprises of participating investigators who will or have contribute 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 will identify one or two people to coordinate activities including data analysis and drafting of publications and reports for group review.

Once the data are uploaded into the WWARN Data Repository, they will be curated and standardized into a single format using the WWARN Clinical Data Management and Statistical Analysis Plan and pooled into a single database of quality-assured individual patient data. WWARN statisticians will be responsible for statistical analyses.

For further information contact clinical@wwarn.org