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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)
Article  in  Drug Safety · April 2018
DOI: 10.1007/s40264-018-0667-x
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Drug Saf
https://doi.org/10.1007/s40264-018-0667-x
ORIGINAL RESEARCH ARTICLE
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)
H. Hilda Ampadu1,2 • Alexander N. O. Dodoo1,7 • Samuel Bosomprah3 •
Samantha Akakpo4 • Pierre Hugo4 • Helga Gardarsdottir2 • H. G. M. Leufkens2 •
Dan Kajungu5 • Kwaku Poku Asante6
 The Author(s) 2018
Abstract 7, 14, 21 and 28 after drug administration to document AEs
Introduction Injectable artesunate (Inj AS) is the World and serious AEs (SAEs). Patients were also encouraged to
Health Organization (WHO)-recommended product for report all AEs at any time during the study period. The
treating severe malaria. However, despite widespread Kaplan–Meier method was used to estimate the proportion
usage, there are few published safety studies involving of patients with any AEs by end of Day 28. Causality
large populations in real-world settings. In this study, we assessment was made on all AEs/SAEs using the WHO/
sought to assess the incidence of common adverse events UMC (Uppsala Monitoring Centre) causality method.
(AEs) following the intake of Inj AS in real-life settings. Results A total of 1103 eligible patients were administered
Methods This is a modified cohort event monitoring study Inj AS, of which 360 patients were in Ghana and 743 in
involving patients who were administered with Inj AS at Uganda. The incidence of any AE by the end of follow-up
eight sites (four each in Ghana and Uganda) between May among patients treated with AS was estimated to be 17.9%
and December 2016. Patients were eligible for inclusion if (197/1103) (95% confidence interval [CI] 15.8–20.3). The
they had severe/complicated malaria and were able and median time-to-onset of any AEs was 9 days (interquartile
willing to participate in the study. Eligible patients were range (IQR) = 4, 14). The top five AEs recorded among
followed up by telephone or hospital or home visit on Days 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 asAlexander N. O. Dodoo
adodoo@gsa.gov.gh ‘possibly’ related. There were 17 SAEs including 13
deaths. Two of the deaths are ‘possibly’ related to Inj AS,
1 African Collaborating Centre for Pharmacovigilance, as were three non-fatal SAEs: severe abdominal pain,
P. O. Box LT282, Accra, Ghana
failure of therapy and severe anaemia.
2 Utrecht Institute for Pharmaceutical Sciences, Utrecht Conclusion The incidence of common AEs among patients
University, Utrecht, The Netherlands
treated with Inj AS in real-world settings was found to be
3 Department of Biostatistics, School of Public Health, relatively low. Future studies should consider larger
University of Ghana, Accra, Ghana
cohorts to document rare AEs as well.
4 Medicines for Malaria Venture, Geneva, Switzerland ClinicalTrials.gov Identifier NCT02817919.
5 Makerere University Centre for Health and Population
Research, Kampala, Uganda
6 Kintampo Health Research Centre, Kintampo, Ghana
7 University of Ghana School of Medicine and Dentistry,
Accra, Ghana
H. Hilda Ampadu et al.
slowly as a constant intravenous (IV) infusion, a process
Key Points which is difficult in most settings. It may also be given
intramuscularly (IM) but IM administration is associated
Injectable artesunate (Inj AS) is a life-saving with erratic availability and poor clinical outcomes. In
medicine used to treat severe malaria. addition to these, the use of quinine is associated with
several AEs including cinchonism, rashes, rare cardiotox-
There are few data on the safety of Inj AS when used icity, deafness, hypoglycaemia, dizziness, blindness and
in real-world settings, though it has been shown to be even death [9, 10]. These factors prompted the WHO
well-tolerated in clinical trials. policy change and subsequent recommendation for the use
Safety data obtained from public health facilities in of Inj AS for treating severe malaria.
Ghana and Uganda support the safety findings from The current data on the efficacy and clinical safety of Inj
clinical trials and provide additional evidence for AS have all been obtained in well-controlled clinical trials
continued use of Inj AS in severe malaria. or during operational research [6, 11–15]. The recruitment
of patients in such settings is controlled and patient follow-
up and management is stringent in these studies; hence,
safety information obtained may not reflect what occurs in
real life. There is a dearth of information on the safety of
Inj AS when used in real-world (post-approval, routine
1 Introduction
healthcare practice) settings even though a signal—post-
artesunate delayed haemolysis (PADH)—has been raised
Severe malaria is a life-threatening condition responsible
following identification of a number of delayed haemolysis
for a significant part of the 445,000 global malaria deaths
cases after treatment with Inj AS [16–18].
that occurred in 2016 alone [1]. When not treated, the case
Inj AS is an extremely important life-saving product in
fatality rate for severe malaria can be very high. Severe
the treatment of severe malaria across all 91 malaria-en-
malaria is the harshest form of the disease. In addition to
demic countries and across all malaria transmission zones
the symptoms of uncomplicated malaria such as fever,
[1, 19]. It is used extensively in imported or traveller’s
parasitaemia and malaise, severe malaria also manifests
malaria in non-endemic countries, where it has been
with one or more of the following: severe anaemia, acute
associated with very high reduction in mortality with few
renal failure, respiratory oedema, hypoglycaemia or coma.
reports of drug-related AEs [20]. Despite the assurance
Published fatality rates for severe malaria vary widely due
given by the available studies on the safety of Inj AS, the
to study design, treatment practices and patient types.
absence of strong pharmacovigilance systems in countries
Fatality rates are typically around 16–20% but rates as low
that use millions of doses of the product annually makes it
as 2% and high as 100% have been reported [2]. With
necessary to undertake appropriate post-authorisation
prompt and effective treatment, case fatality rates can fall
studies in order to better understand its actual safety profile
as low as 10% [2] or below. The current edition of the
when used in real-world settings. This study was therefore
World Health Organization (WHO) Guidelines for the
conceived to obtain safety data in relation to Inj AS when
Treatment of Malaria (2015, third edition) [3] recommends
used in real-world settings in public health facilities in two
injectable artesunate (Inj AS) (ATC [Anatomical Thera-
African countries where severe malaria may or may not be
peutic Chemical] code P01BE03) as the treatment of
properly diagnosed (microscopy; rapid diagnostic tests
choice for severe malaria. The SEAQUAMAT (South East
[RDTs]; laboratory measurement of haemoglobin [Hb])
Asian Quinine Artesunate Malaria Trial) [4] and AQUA-
and where facilities for monitoring and follow-up are
MAT (Artesunate Versus Quinine in the Treatment of
variable.
Severe Falciparum Malaria in African Children) [5] studies
The specific objective of the study was to determine the
showed reductions in fatality of 34.7% and 22.5%,
incidence of any AEs that occur up to 28 days after
respectively, when Inj AS was used to treat severe malaria
administration of Inj AS for the treatment of severe/com-
instead of injectable quinine. In these studies, the use of Inj
plicated malaria during the normal course of clinical
AS was also associated with fewer adverse events (AEs)
practice in the participating health facilities. The findings
than quinine. Systematic reviews [6, 7] have also demon-
from this study should contribute to the WHO global
strated lower case fatality rates and lower AE profiles with
individual case safety report (ICSR) database VigiBaseTM
Inj AS than with quinine. For years, parenteral quinine
and facilitate quicker identification of safety signals. Cur-
remained the main drug for treating severe malaria, but its
rently, VigiBaseTM has very little data from Africa that
usage is associated with problems in reconstitution and
includes data on antimalarials [21, 22].
administration [8]. Quinine needs to be administered
Safety of injectable artesunate: outcomes of a modified cohort event monitoring study in Sub-Saharan Africa (CEMISA)
2 Methods data quality checks is then prepared for entry into the study
database.
2.1 Study Design, Sites and Patient Recruitment Patients were followed up to document the occurrence
of any AEs using standard questions on the follow-up
This was a prospective, longitudinal, modified cohort event CRFs. Patients were followed up by telephone or hospital
monitoring study in sub-Saharan Africa (CEMISA) which or home visit, when possible, on Days 7, 14, 21 and 28
utilises the principles of prescription event monitoring [23] after drug intake (index date) and were asked to report all
but with cohorts smaller than the minimum 10,000 patients. AEs at any time during the 28-day follow-up period. The
The study recruits patients in secondary care settings 28-day follow-up period was adopted in line with the fol-
similar to the approach adopted in specialised cohort event low-up period adopted for malaria clinical trials [25] as
monitoring [24]. In this study, the cohort consisted of well as previous studies on the safety of antimalarials [26].
patients who were prescribed Inj AS for presumed or No attempt was made to intervene in routine care of any of
diagnosed severe malaria between May 2016 and Decem- the recruited patients in the study apart from monitoring the
ber 2016 in two countries (Ghana and Uganda). The study safety of the antimalarial agents administered by the
was undertaken in four public health facilities in Ghana treating clinicians by collecting data from consenting
(Princess Marie Louise Hospital and Ridge Hospital, patients directly and sometimes also from their clinical
Accra; Kintampo Municipal Hospital, Kintampo and notes. Hb levels, when measured, were also recorded. Any
Agogo Medical Research Hospital, Agogo) and four public patient with AEs was managed in line with existing stan-
health facilities in Uganda (Mubende Regional Referral dard of care in each of the participating facilities.
Hospital, Mubende; Jinja Referral Hospital, Jinja; Lira
Regional Referral Hospital, Lira and Kagadi Hospital, 2.2 Definitions
Kagadi).
Patients were eligible for inclusion if they had sev- The following definitions are based on the European
ere/complicated malaria (Plasmodia of any species) pre- Union’s Guidelines on Good Pharmacovigilance Practice.
sumed or diagnosed as per national policies and health
facility practice/protocol [3]; if they were able and willing 2.2.1 Adverse Event (AE)
to participate in the study; and if they agreed to the
schedule for follow-up contact or home visits. Patients An AE is any untoward medical occurrence in a clinical
were excluded if they had a serious concurrent illness. All investigation participant temporally associated with the use
eligible patients gave informed consent. For children, of a medicinal product, whether or not considered related
informed consent was obtained from parents or a to the medicinal product. An AE can therefore be any
caregiver/guardian. unfavourable and unintended sign (including an abnormal
Case Report Forms (CRFs) were used to record data on laboratory finding), symptom or disease (new or exacer-
each study subject during the study as defined by the bated) temporally associated with the use of a medicinal
protocol. All events that happened in the study were fully product.
documented in the CRF. The CRFs consisted of the day 1A
form, drug administration form, follow-up forms (Days 7, 2.2.2 Serious AE (SAE)
14, 21 and 28), AE form, SAE form and the end of study
form. The day 1A form served as the enrolment form on An SAE means an AE that results in death, is life-threat-
the first day of the study. It was the form used after the ening, requires in-patient hospitalisation or prolongation of
participant or representative signed the informed consent to existing hospitalisation, results in persistent or significant
record demographic, medical history and laboratory data. disability or incapacity, or is a congenital anomaly/birth
The drug administration form was used to record the drug defect.
under investigation administered to the participant and all
other concomitant medications. The AE form was used to 2.3 Data Collection, Drug Prescription and Dosing
record all AEs and the SAE form was used to record events
that met the seriousness criteria. The Day 7 to Day 28 Routine clinical practice in malaria-endemic countries
follow-up forms were used to record the participant’s requires immediate treatment of patients with suspected
current health status and any new concomitant medications. clinical malaria in line with WHO Guidelines for the
Finally, the end of study form was used to record the pri- Treatment of Malaria [3]. Treatment of severe malaria
mary reason for the termination from the study. A com- occurs usually in in-patient settings. All study participants
pleted CRF after going through the various validations and were recruited from hospitals. The implication for this
study, therefore, was that most patients had started
H. Hilda Ampadu et al.
treatment before being recruited into the study. IM/IV patients produces a two-sided 95% CI with a width equal to
artesunate was administered as per normal practice in the 0.050 when the incidence of any AE is 20% as we have
treating institutions. The actual dosage and duration of assumed.
treatment as well as any concomitant medications were
extracted from the patient’s clinical notes and recorded on 2.6 Data Analysis
the study CRFs. The WHO recommendation [3] for treat-
ing severe malaria is to ‘‘treat all adults and children with We summarized patients’ characteristics using proportion
severe malaria (including infants, pregnant women in all (nominal scale variables) and mean or median (interval
trimesters, lactating women) with intravenous or intra- scale variables). We calculated the incidence of any AEs as
muscular artesunate for at least 24 h. Once a patient has the total number of any AEs recorded by end of follow-up
received at least 24 h of parenteral therapy and can tolerate divided by the total number of patients treated with AS and
oral therapy, complete treatment with 3 days of ACT who completed the study. The Kaplan–Meier method was
[artemisinin-based combination therapy]’’. We also col- used to estimate the proportion of patients with any AEs by
lected data on mode of malaria diagnosis (i.e. clinically, the end of Day 28. The date of treatment was considered as
microscopically or by the use of RDTs). Other co-variables the origin (i.e. the date the patient was at risk of any AE).
collected included laboratory investigations conducted The patient was censored at the date the patient was last
(including Hb measurements). Data were entered, managed seen (i.e. lost to follow-up) or at the end of the study
and stored in a specially created version of MedSpinaTM, without any AE.
an in-house electronic health records system that allows Since the study was designed to have a cumulative
clinicians and other health workers to collect patients’ data, sample size of 1000 patients on Inj AS from all partici-
including laboratory results, to facilitate patient care. pating countries (Part 1), with the eventual number of 3164
expected in Part 2, we considered site (country) as a fixed
2.4 Outcome and Causality Measurement effect and therefore we did not present results for each
country. All analyses were performed using STATA 14
The outcomes measured in the study were all AEs tem- MP (StataCorp, College Station, TX, USA). Case sum-
porarily associated with the intake of Inj AS, including maries were also presented for all SAEs, including deaths
deaths and other SAEs. Assessment of causality included, and their relatedness to Inj AS as well as the causality
where available, the level of parasitaemia as well as any assessment gradings.
concomitant medications administered. Since this was a
non-interventional study, there was no systematic labora-
tory investigation to document AEs. However, all events
reported or available in the patient’s notes, including lab- 1262 (GH-403, UG-859) 
46 (GH-3, UG-43)
oratory data, were extracted and recorded in the CRFs. screened
Using the WHO/UMC (Uppsala Monitoring Centre) excluded because they 
causality method, a physician and a pharmacist not declined to parcipate 
involved in the direct care of the participants assessed the 1216 (GH-400, UG-816) in the study
relatedness and causal link of the medicine to the AEs. treated with AS or AR 
or Q
2.5 Sample Size Calculation 25 (GH-9, UG-16)
The study was powered to estimate the incidence of AEs 1191 (GH-391, UG-800) lost to follow up
with a certain level of precision in Ghana and Uganda. We treated with AS or AR or 
assumed that the incidence of any AEs in the Ghanaian and Q and completed the 
Ugandan population was, on average, 20%. We therefore study
required a total of 3164 patients in the two countries to
produce a two-sided 95% confidence interval (CI) for the
ratio of population proportions with a width that is equal to
1103 (GH-360, UG-743) 
0.200 when the estimated sample proportion decreases to
treat with AS and 
0.12 and the ratio of the sample proportions is 0.60. Due to
completed the study
available funding, we planned to enrol a cumulative sample
size of 1000 patients receiving Inj AS from all participating
countries in the first part of this study with the additional Fig. 1 Patient flow. AE adverse event, AR artemether, AS artesunate,
number of 2164 expected in the second part. The 1000 GH Ghana, Q quinine, UG Uganda
Safety of injectable artesunate: outcomes of a modified cohort event monitoring study in Sub-Saharan Africa (CEMISA)
3 Results visits and 63 (5.7%) by hospital visits. In 58 (5.3%) follow-
ups, the mode was not indicated. In relation to Day 14
3.1 Characteristics of Participants and Treatment follow-ups, 874 (79.2%) were by telephone calls, with 88
Received (8.0%) and 82 (7.4%) being by way of home visits or in
hospital, respectively. Day 21 follow-ups followed a sim-
A total of 1262 patients were screened, of whom 46 were ilar pattern, with 932 (84.5%) by telephone calls, 82 (7.4%)
excluded for declining to participate in the study (Fig. 1). by home visits and 38 (3.4%) by hospital visits. In relation
Of the 1216 eligible patients, 25 were lost to follow-up and to Hb readings, there was marked differences between
88 were treated with either artemether or quinine, making Ghana and Uganda. In the Ghana sites, baseline Hb was
them ineligible for analysis. There were 1103 patients who measured for 327 of the 360 patients, representing 90.8%
were treated with Inj AS (360 in Ghana and 743 in Uganda) of the patients. Seven patients in Ghana had Hb values
(Table 1) and completed the study. The median age of recorded on both Day 0 and Day 14, and in all these cases
patients was 3.9 years (interquartile range [IQR] = 2.1, 9) the Hb values rose from baseline, indicating remission of
and the median weight was 13 kg (IQR = 10, 20) anaemia. In Uganda, only 106 (14.3%) of the 743 patients
(Table 1). had Day 0 Hb recorded and only one patient had Day 14
Hb recorded.
3.2 Patient Follow-Up and Recording
of Haemoglobin Readings 3.3 Incidence of Any AEs
Most patients were followed-up by way of telephone calls. The incidence of any AE by the end of follow-up among
Of the 1103 individuals treated with Inj AS, 894 (81.1%) patients treated with Inj AS was estimated to be 17.9 (i.e.
were followed up by telephone calls, 88 (8.0%) by home 197 of 1103) (95% CI 15.8–20.3) (Table 1 and Fig. 2). The
Table 1 Incidence of any adverse events by baseline characteristics of patients, 2016
Characteristics Median (IQR) Number of patients (% of total) n (%) who had any AE 95% CI
Sex
Female 540 (49.0) 96 (17.8) 14.8–21.2
Male 563 (51.0) 102 (18.1) 15.1–21.5
Age (years) 3.9 (2, 9)
\5 654 (59.3) 115 (17.6) 14.8–20.7
5–9 186 (16.9) 24 (12.9) 8.8–18.5
10–19 61 (5.5) 10 (16.4) 9.0–27.9
15–19 40 (3.6) 10 (25.0) 14.0–40.6
20–24 46 (4.2) 10 (21.7) 12.1–35.9
25? 114 (10.3) 29 (25.4) 18.3–34.2
Missing 2 (0.2)
Weight (kg) 13 (10, 20)
\10 255 (23.1) 49 (19.2) 14.8–24.5
10–19 470 (42.6) 72 (15.3) 12.3–18.9
20–29 105 (9.5) 14 (13.3) 8.1–21.3
30? 184 (16.7) 36 (19.6) 14.4–25.9
Missing 89 (8.1)
Time-to-onset of AE (days) 9 (4, 14)
Site
Ghana 360 (32.6) 125 (16.8) 14.3–19.7
Uganda 743 (67.4) 73 (20.3) 16.4–24.8
Pregnant
No 1067 (96.7) 193 (18.1) 15.9–20.5
Yes 68 (3.3) 5 (13.9) 5.9–29.3
Total 1103 (100) 197 (17.9) 15.8–20.3
AE adverse event, CI confidence interval, IQR interquartile range
H. Hilda Ampadu et al.
Fig. 2 Proportion of patients
with any adverse events by
time, 2016: Kaplan–Meier
failure estimate. AE adverse
event, CI confidence interval
Table 2 Top five adverse events by sex and time-to-onset among patients treated with injectable artesunate at all sites, 2016
Number of patients treated with Inj AS AE [n (%)]
Pyrexia Abdominal pain Diarrhoea Cough Asthenia
Sex 1103
Female 540 16 (3.0) 13 (2.4) 6 (1.1) 9 (1.7) 8 (1.5)
Male 563 22 (3.9) 14 (2.5) 13 (2.3) 7 (1.2) 8 (1.4)
Time-to-onset of AE (days) 198
0–7 77 11 (14.3) 12 (15.6) 6 (7.8) 5 (6.5) 9 (11.7)
8–14 58 12 (20.7) 4 (6.9) 8 (13.8) 5 (8.6) 6 (10.3)
15–21 27 7 (25.9) 2 (7.4) 3 (11.1) 4 (14.8) 1 (3.7)
22–28 36 8 (22.2) 9 (25.0) 2 (5.6) 2 (5.6) 0 (0.0)
Total 1103 38 (3.5) 27 (2.5) 19 (1.7) 16 (1.5) 16 (1.5)
AE adverse event, Inj AS injectable artesunate
median time-to-onset of any AEs was 9 days (IQR = 4, 14) are described in Table 3. Four of the deaths occurred in
(Table 1). The top five AEs recorded among patients seriously ill patients who were transferred from the hospital
treated with Inj AS were pyrexia (3.5%), abdominal pain to their home with no further follow-up information due to
(2.5%), diarrhoea (1.7%), cough (1.5%) and asthenia the reluctance of carers/guardians and/or family members
(1.5%) (Table 2 and Fig. 3). Most of these top five AEs to provide any further information. Two others had no post-
occurred in the first 14 days following treatment (Table 2). mortem information even though follow-up information
Regarding the relatedness of these AEs to Inj AS, 78.9% of with family members confirmed death.
pyrexia (30/38), 63.0% of abdominal 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. 4 Discussion
3.4 SAEs Including Deaths This is the first large-scale post-approval safety study on
Inj AS. It involved over 1100 patients who were exposed to
During the study, 17 AEs were considered to be serious; 13 at least one dose of Inj AS in the participating public health
of these led to death. The deaths and the four other SAEs facilities in Ghana and Uganda. The majority of the
Safety of injectable artesunate: outcomes of a modified cohort event monitoring study in Sub-Saharan Africa (CEMISA)
Fig. 3 Adverse events among
patients treated with
injectable artesunate at all sites,
2016
Table 3 Deaths and other serious adverse events reported in patients treated with injectable artesunate
Event n Relationship to Inj AS intake
type
Deaths 13 4 of the 13 deaths did not have SAE specified and patients died outside the hospital with little information on follow-up. These
reports are classified as ‘unassessable’. 2 of the remaining 9 fatal SAEs (severe anaemia in a 22-month-old female and severe
anaemia in a 20-month-old female) are causally assessed as ‘possible’ in relation to Inj AS intake. These SAEs are classified
as ‘related’ to Inj AS, though disease and other conditions could also explain these SAEs. The remaining 7 fatal SAEs (multi-
organ failure, severe respiratory distress, abdominal distension, asthenia, sickle cell disease, severe anaemia, pulmonary
tuberculosis) are unrelated to Inj AS intake
Other 4 3 of the 4 SAEs—severe abdominal pain in a 42-year-old female; failure of therapy and severe anaemia in a sickle cell disease
SAEs patient—are causally assessed as ‘possible’ in relation to Inj AS intake and thus related to Inj AS. 1 case—threatened
abortion—is considered to be causally assessed as ‘unlikely’ to be attributable Inj AS intake and is thus unrelated
Inj AS injectable artesunate, SAE serious adverse event
participants were children, with 59.3% being less than SEAQUAMAT and AQUAMAT studies. The overall
5 years old. Inj AS was very well-tolerated among the incidence of AE is similar to that listed in the public
study population even though nearly one-fifth of partici- assessment reports (PARs; Part 4: Summary of Product
pants reported at least one mild to moderate AE. The most Characteristics) for Inj AS, as published by the WHO [27].
common AEs reported in both countries included pyrexia The PAR lists the following among the possible common
(3.5%), abdominal pain (2.5%), diarrhoea (1.7%), cough (1–10 in 100 patients) AEs related to Inj AS: cough,
(1.5%) and asthenia (1.5%). The relationship between Inj diarrhoea, abdominal pain and ‘flu-like’ effects (including
AS and most of these events were classified as ‘possible’ fever, tiredness, bone and muscle pain). These AEs are,
following case causality assessment. There were 13 all- however, also symptoms of malaria and severe malaria,
cause deaths reported in this study, giving an all-cause making case causality assessment complex. Nonetheless,
death rate of 1.2% (13/1103). Two of the deaths could be the study findings provide validation for the safety profile
‘possibly’ related to Inj AS. There were four other SAEs in of Inj AS as recorded in the PAR. This study recorded a
addition to the deaths. Three of the non-fatal SAEs were lower proportion of deaths than the AQUAMAT and
‘possibly’ related to Inj AS. Overall, the safety profile of SEAQUAMAT studies. In the AQUAMAT study, 8.5% of
Inj AS in the study population was favourable and com- the 2712 patients in the artesunate arm died (230 African
parable to that documented in the SEAQUAMAT and children), whilst 15% of the 730 patients in the artesunate
AQUAMAT studies. arm of the SEAQUAMAT study died (107 Asian patients)
The results obtained from this study are similar to the [4, 5]. It is important to state that, in contrast to our study,
findings from clinical trials of Inj AS, including the the SEAQUAMAT and AQUAMAT studies involved
H. Hilda Ampadu et al.
patients who had been clinically diagnosed with severe powered to detect rare AEs since the sample size of 1103
malaria. In our study we did not apply a strict definition of can only detect common AEs. It will be important to
diagnosis of severe malaria as the aim was to follow expand the study further in order to capture rare AEs in
patients who had been administered Inj AS in the ‘normal real-world settings. However, this follow-up study should,
course of clinical practice’. It is, therefore, possible that as a matter of ethics and for public health considerations,
several of the cases in our study are not necessarily severe include a revision in the protocol for Hb readings to be
malaria, a serious disease with relatively high mortality. made at baseline or soon thereafter and also at Day 14 to
The lower mortality of 1.1% obtained in this study com- capture essential data to address the issue of PADH, which
pares with a similar study [28] in Africa where an overall is a signal that has been raised in association with Inj AS
mortality of 1.03% (2/194) was recorded, though it must be use.
stressed that reported mortality in severe malaria varies This study has provided additional information on the
widely due to differences in practices, including not safety of Inj AS to that given in the pivotal studies that led
applying strict criteria for the definition of severe malaria to the WHO recommendation for its use as the medicine of
[29]. Our study had two reports of severe anaemia which choice in severe malaria. The incidence and types of AEs
may be potential cases of PADH. PADH occurs 14 days and SAEs observed in this study validates the WHO
after artesunate intake and has other features. However, the recommendation.
absence of pre-Day 14 Hb readings in the two cases made a
definite diagnosis of PADH fundamentally impossible.
This work has provided evidence indicating a favourable 5 Conclusion
toxicity profile of Inj AS in real-world settings and one that
is similar to that observed in earlier studies. However, it The incidence of common AEs among patients treated with
suffered from the limitations of most real-world studies. Inj AS in real-world settings was relatively low. The
For instance, patients were enrolled if they had been overall safety profile of Inj AS among the treatment cohort
administered at least one dose of Inj AS, presumably for was favourable. An interventional study to address PADH
the treatment of severe malaria. However, the majority of would be useful. Future studies should consider larger
the patients were enrolled without any Hb readings and cohort to document rare AEs as well.
diagnosis of severe malaria was purely based on RDT and/
or microscopy. Even in cases where microscopy or RDT Acknowledgements The authors would like to thank the following
for their support for the CEMISA research in the roles indicated:
showed absence of malaria parasites, the patients were still
African Collaborating Centre Accra, Ghana Team Members: Pro-
administered Inj AS. The safety profile of Inj AS would not ject Manager: Bernice Owusu-Boakye; IT Lead and Support: Danny
necessarily be expected to be different in patients with the Kofi-Armah and FelixJones Addo-Quaye; Site Coordinator: Alex
potentially deadly severe malaria than in patients without Martey; Data Managers: Leticia Toffah and Prince N. Teye; Data
Entry Operators: Samuel Larbi, Richard Narh Teye, Sandra Ampadu,
severe malaria, though the outcomes of treatment may
Marilyn Amoama-Dapaah, Lawrencia Abrafi Osei and Richard
differ. Another limitation of the study was the absence of Opata-Teye.
baseline and Day 14 Hb values. Whilst there were 327 Sub Principal Investigators: Mame Yaa Nyarko (Princess Marie
(91%) Day 0 Hb readings in Ghana, there were only seven Louise Hospital, Ghana); Adriana Asante (Ridge Hospital, Ghana);
Theresa Retigg (Agogo, Ghana); Madira Kefa (Kagadi Hospital,
(1.8%) Day 14 Hb readings in this same cohort. In Uganda,
Uganda); Daniel Aguma (Lira Hospital, Uganda) Kizito John (Jinja
there were only 106 (14.3%) Day 0 Hb readings and one Hospital, Uganda); and Komaketch Amal Denis (Mubende Regional
(0.1%) Day 14 Hb reading. Thus, in most of the partici- Referral Hospital, Uganda)
pating facilities, most patients did not have more than one Site Coordinators: Steven Tuure (Princess Marie Louise Hospital,
Ghana); Mariam Mohammed (Ridge Hospital & Princess Marie
recorded Hb reading from the time of administration of Inj
Louise Hospital, Ghana); Anthony Kwarteng (Kintampo Ghana);
AS to the time the patient exited the study. This made it Martin Ssebidandi (Mubende Regional Referral Hospital, Uganda);
impossible to know whether there had been any drug-re- Isaac Okorie (Lira Hospital, Uganda); Kabahuma Violet (Kagadi
lated changes in Hb values post-administration. Thus, even Hospital, Uganda); and Oboke Margaret (Jinja Hospital, Uganda).
Site Manager: Patrick Buabeng (Agogo, Ghana).
though very low levels of Hb were recorded in a few
Advisor on Protocol and Study: Dr Stephan Duparc, Medicines for
patients on Day 14, it was impossible to know whether this Malaria Venture.
represented an existing severe anaemia or an actual fall due
to Inj AS and which could thus have been a potential case Compliance with Ethical Standards
of PADH. Another challenge in this real-world study was
Conflicts of interest H. Hilda Ampadu, Alexander N.O. Dodoo,
not being able to obtain follow-up information on four Samuel Bosomprah, Helga Gardarsdottir, H.G.M. Leufkens, Dan
patients who died at home. The family/carers were not Kajungu and Kwaku Poku Asante have no conflicts of interest.
willing to provide any information, making it impossible to Samantha Akakpo and Pierre Hugo are full-time employees of
make any causal relationship. Finally, this study was not Medicines for Malaria Venture (MMV).
Safety of injectable artesunate: outcomes of a modified cohort event monitoring study in Sub-Saharan Africa (CEMISA)
Funding Medicines for Malaria Venture provided funding for this imported malaria: comparative analysis of adverse events
study. focussing on delayed haemolysis. Malar J. 2013;15(12):241.
https://doi.org/10.1186/1475-2875-12-241.
Ethical approval The study received ethical approval from the 12. Eder M, Farne H, Cargill T, Abbara A, Davidson RN. Intravenous
Ghana Health Service Ethics Review Committee and the Uganda artesunate versus intravenous quinine in the treatment of severe
National Council for Science and Technology (UNCST). It was also falciparum malaria: a retrospective evaluation from a UK centre.
registered on ClinicalTrials.gov with the ClinicalTrials.gov identifier Pathog Glob Health. 2012;106(3):181–7. https://doi.org/10.1179/
NCT02817919. The study was conducted under Good Clinical 2047773212Y.0000000032.
Practice (GCP) guidelines taking into consideration the Declaration of 13. Krudsood S, Wilairatana P, Vannaphan S, Treeprasertsuk S,
Helsinki (as amended in October 2013) and local rules and regula- Silachamroon U, Phomrattanaprapin W, et al. Clinical experience
tions of participating countries and health facilities. All personnel with intravenous quinine, intramuscular artemether and intra-
involved in the study undertook and successfully passed an online venous artesunate for the treatment of severe malaria in Thailand.
GCP course prior to study initiation unless they already had a valid Southeast Asian J Trop Med Public Health. 2003;34(1):54–61.
GCP certificate. 14. Ferrari G, Ntuku HM, Burri C, Tshefu AK, et al. An operational
comparative study of quinine and artesunate for the treatment of
Patient consent Written informed consent was obtained from the severe malaria in hospitals and health centres in the Democratic
patients for publication of this study. A copy of the written consent Republic of Congo: the MATIAS study. Malar J.
may be requested for review from the corresponding author. 2015;30(14):226. https://doi.org/10.1186/s12936-015-0732-1.
15. Ntuku HM, Ferrari G, Burri C, Tshefu AK, Kalemwa DM,
Consent for publication Consent for publication was obtained as Lengeler C. Feasibility and acceptability of injectable artesunate
part of the informed consent process. for the treatment of severe malaria in the Democratic Republic of
Congo. Malar J. 2016;8(15):18. https://doi.org/10.1186/s12936-
Open Access This article is distributed under the terms of the 015-1072-x.
Creative Commons Attribution-NonCommercial 4.0 International 16. Aldámiz-Echevarrı́a Lois T, López-Polı́n A, Norman FF, Monge-
License (http://creativecommons.org/licenses/by-nc/4.0/), which per- Maillo B, López-Vélez R, Perez-Molina JA. Delayed haemolysis
mits any noncommercial use, distribution, and reproduction in any secondary to treatment of severe malaria with intravenous arte-
medium, provided you give appropriate credit to the original sunate: report on the experience of a referral centre for tropical
author(s) and the source, provide a link to the Creative Commons infections in Spain. Travel Med Infect Dis. 2017;15:52–6.
license, and indicate if changes were made. 17. Rolling T, Agbenyega T, Issifou S, Adegnika AA, Sylverken J,
Spahlinger D, et al. Delayed hemolysis after treatment with
parenteral artesunate in African children with severe malaria—a
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