Discussion
diarrhoea, nausea, fever, abdominal pain, malaria, vomiting, pain, dizziness, anorexia
MALARIA, EVENTS, DISEASE, ANOREXIA
The overall number of symptoms reported in the IMPROV study varied significantly between sites, and this difference remained apparent after adjusting for demographics, disease severity estimated by presence of fever and parasite density at enrolment, and treatment arm. One site in Ethiopia reported almost 100% of study patients suffering from anorexia compared to other sites where less than 5% patients reported anorexia. There were less extreme but still relevant differences in the reporting of other symptoms including vomiting, diarrhoea, nausea, abdominal pain and dizziness. Critically the differences in symptom reporting were greater between study sites than between treatment arms, suggesting that symptoms are best interpreted in relation to the control arm.Differences in the circumstances under which symptoms were elicited may explain the variation between sites. Despite standardised training on how to complete the symptom questionnaire, the approach of study centres is likely to have differed in practice. At one extreme, investigators may have encouraged study participants to report every symptom, while in other sites the investigators may have been less explicit. This would be in line with previously reported differences showing that more specific questioning of study subjects resulted in more events reported compared to open-ended questioning [There are several alternative explanations for these findings. Cultural differences between study sites and countries may play a role. Observed differences could be explained by variations in expression and reporting of symptoms, such as pain, between different groups of people [Data on self-reporting of symptoms versus reporting by parents on behalf of a paediatric patient was not available and could have contributed. However, the proportion of children under the age of 5 was overall small and a sensitivity analysis excluding patients under 5 showed similar results. The effect of schizontocidal treatments on symptoms could not be assessed due to collinearity with study site. However, results remained heterogeneous on day 3–13, following cessation of the schizontocidal treatment.Gastro-intestinal tolerability of primaquine can be improved with food. While it was recommended to patients to take primaquine with food, patient level data on food uptake during treatment was not available and practices might have varied between sites. However, the difference in the proportion of patients reporting symptoms between the control arm and the treatment arms at each site were much smaller than between sites, suggesting that other explanations are more likely.Finally, a large number of patients in the placebo arm reported symptoms following drug administration, this could in part be explained by symptoms attributable to malaria. In addition it seems likely that the ‘nocebo’ effect (negative consequences following the administration of a placebo) may have played a role in the perception of symptoms by some participants [While the data collection tools for determining antimalarial efficacy have generally been well standardised [