Safety Experience During Real-World Use of Injectable Artesunate in Public Health Facilities in Ghana and Uganda: Outcomes of a Modified Cohort Event Monitoring Study (CEMISA)

Abstract

Introduction: Injectable artesunate (Inj AS) is the World Health Organization (WHO)-recommended product for treating severe malaria. However, despite widespread usage, there are few published safety studies involving large populations in real-world settings. In this study, we sought to assess the incidence of common adverse events (AEs) following the intake of Inj AS in real-life settings.

Methods: This is a modified cohort event monitoring study involving patients who were administered with Inj AS at eight sites (four each in Ghana and Uganda) between May and December 2016. Patients were eligible for inclusion if they had severe/complicated malaria and were able and willing to participate in the study. Eligible patients were followed up by telephone or hospital or home visit on Days 7, 14, 21 and 28 after drug administration to document AEs and serious AEs (SAEs). Patients were also encouraged to report all AEs at any time during the study period. The Kaplan-Meier method was used to estimate the proportion of patients with any AEs by end of Day 28. Causality assessment was made on all AEs/SAEs using the WHO/UMC (Uppsala Monitoring Centre) causality method.

Results: A total of 1103 eligible patients were administered Inj AS, of which 360 patients were in Ghana and 743 in Uganda. The incidence of any AE by the end of follow-up among patients treated with AS was estimated to be 17.9% (197/1103) (95% confidence interval [CI] 15.8-20.3). The median time-to-onset of any AEs was 9 days (interquartile range (IQR) = 4, 14). The top five AEs recorded among patients treated with AS were pyrexia (3.5%), abdominal pain (2.5%), diarrhoea (1.7%), cough (1.5%) and asthenia (1.5%). Most of these top five AEs occurred in the first 14 days following treatment. Regarding the relatedness of these AEs to Inj AS, 78.9% of pyrexia (30/38), 63.0% of pain (17/27), 68.4% of diarrhoea (13/19), 85.5% of cough (14/16) and 75.0% of asthenia (12/16) were assessed as 'possibly' related. There were 17 SAEs including 13 deaths. Two of the deaths are 'possibly' related to Inj AS, as were three non-fatal SAEs: severe abdominal pain, failure of therapy and severe anaemia.

Conclusion: The incidence of common AEs among patients treated with Inj AS in real-world settings was found to be relatively low. Future studies should consider larger cohorts to document rare AEs as well. CLINICALTRIALS.

Gov identifier: NCT02817919.

Conflict of interest statement

Conflicts of interest

H. Hilda Ampadu, Alexander N.O. Dodoo, Samuel Bosomprah, Helga Gardarsdottir, H.G.M. Leufkens, Dan Kajungu and Kwaku Poku Asante have no conflicts of interest. Samantha Akakpo and Pierre Hugo are full-time employees of Medicines for Malaria Venture (MMV).

Funding

Medicines for Malaria Venture provided funding for this study.

Ethical approval

The study received ethical approval from the Ghana Health Service Ethics Review Committee and the Uganda National Council for Science and Technology (UNCST). It was also registered on ClinicalTrials.gov with the ClinicalTrials.gov identifier NCT02817919. The study was conducted under Good Clinical Practice (GCP) guidelines taking into consideration the Declaration of Helsinki (as amended in October 2013) and local rules and regulations of participating countries and health facilities. All personnel involved in the study undertook and successfully passed an online GCP course prior to study initiation unless they already had a valid GCP certificate.

Patient consent

Written informed consent was obtained from the patients for publication of this study. A copy of the written consent may be requested for review from the corresponding author.

Consent for publication

Consent for publication was obtained as part of the informed consent process.

Figures

Fig. 1

Patient flow. AE adverse event, AR artemether, AS artesunate, GH Ghana, Q quinine, UG Uganda

Fig. 2

Proportion of patients with any adverse events by time, 2016: Kaplan–Meier failure estimate. AE adverse event, CI confidence interval

Fig. 3

Adverse events among patients treated with injectable artesunate at all sites, 2016