Uncomplicated Knowlesi Malaria Clinical Trial
Official title:
Artemether-lumefantrine vs Chloroquine in Patients With Acute Uncomplicated P. Knowlesi Malaria: a Randomized Open Label Trial in Sabah, Malaysia (CAN KNOW Trial)
Preliminary studies have supported the background efficacy of local standard anti-malarial
medications in the treatment of uncomplicated knowlesi malaria, however there are no current
WHO treatment guidelines for this infection. There are both health cost benefits to a more
rapidly acting agent, and due to difficulties with microscopic identification there may be
more effective treatment for all malaria species if an aligned treatment guideline could be
supported. We are currently conducting a separate RCT using a similar protocol evaluating
artesunate-mefloquine versus chloroquine for uncomplicated P. knowlesi malaria. However
artemether-lumefantrine should also be compared against chloroquine due to the fact it is
also a first line anti-malarial recommended in Malaysia, and there are potential differences
in efficacy due to the different administration, absorption and half-life of
artemether-lumefantrine.
The investigators aim to test whether the fixed combination of artesunate-mefloquine is
superior to chloroquine in order to define the optimal treatment for both uncomplicated P.
knowlesi infection in both adults and children in this region.
Naturally acquired infections with Plasmodium knowlesi, the fifth human malaria, are growing
[1]. Since 2004 increasing numbers of cases have been reported from residents and returned
travelers predominantly from Malaysia and other countries in South-East Asia including
Thailand, Vietnam, Myanmar, Singapore, Indonesia and the Philippines [2-8]. Cases coincide
with the geographic distribution of its natural simian hosts (long-tailed and pig-tailed
macaques) and Anopheles leucosphyrus group mosquito vector [9, 10], with potential
human-to-human transmission unknown. Eastern Malaysia appears to be the epicentre, with
around 1400 PCR-confirmed P. knowlesi human mono-infections reported in 2009, comprising 41%
of 2,189 total malaria cases in Sarawak [11] and 343 cases from selected samples sent to
Sabah's State Reference Laboratory [12]. P. knowlesi is also now the most common cause of
malaria in different contrasting regions, including 70% of malaria admissions in the heavily
forested area of Kapit in Sarawak [1, 13], 63% of samples from the interior division of Sabah
[14], and in 87% of malaria admissions in the deforested coastal area of Kudat in Sabah,
where it is also the major cause of malaria in children [15].
Despite the increase in reported incidence, difficulties with microscopic diagnosis and a
lack of PCR based epidemiological surveillance studies throughout South-East Asia mean the
true disease burden is underestimated. P. knowlesi is microscopically misidentified as P .
falciparum and P. malariae due to morphological similarities in the early trophozoite, and
late trophozoite and schizont life stages respectively, with studies showing up to 80% of P.
malariae [16-19] and 7-12% of P. falciparum [1, 16] in this region are actually P. knowlesi
when definitively evaluated with PCR. Misdiagnosis has concerning treatment implications, as
unlike P. malariae, knowlesi malaria has a rapid 24-hour replication rate and can cause
hyperparasitaemia, severe complications and fatal outcomes [13, 17, 18], while the
inadvertent use of chloroquine for widely chloroquine-resistant P. falciparum may also have
fatal consequences.
Naturally acquired infections with Plasmodium knowlesi, the fifth human malaria, are growing
[1]. Since 2004 increasing numbers of cases have been reported from residents and returned
travelers predominantly from Malaysia and other countries in South-East Asia including
Thailand, Vietnam, Myanmar, Singapore, Indonesia and the Philippines [2-8]. Cases coincide
with the geographic distribution of its natural simian hosts (long-tailed and pig-tailed
macaques) and Anopheles leucosphyrus group mosquito vector [9, 10], with potential
human-to-human transmission unknown. Eastern Malaysia appears to be the epicentre, with
around 1400 PCR-confirmed P. knowlesi human mono-infections reported in 2009, comprising 41%
of 2,189 total malaria cases in Sarawak [11] and 343 cases from selected samples sent to
Sabah's State Reference Laboratory [12]. P. knowlesi is also now the most common cause of
malaria in different contrasting regions, including 70% of malaria admissions in the heavily
forested area of Kapit in Sarawak [1, 13], 63% of samples from the interior division of Sabah
[14], and in 87% of malaria admissions in the deforested coastal area of Kudat in Sabah,
where it is also the major cause of malaria in children [15].
Despite the increase in reported incidence, difficulties with microscopic diagnosis and a
lack of PCR based epidemiological surveillance studies throughout South-East Asia mean the
true disease burden is underestimated. P. knowlesi is microscopically misidentified as P .
falciparum and P. malariae due to morphological similarities in the early trophozoite, and
late trophozoite and schizont life stages respectively, with studies showing up to 80% of P.
malariae [16-19] and 7-12% of P. falciparum [1, 16] in this region are actually P. knowlesi
when definitively evaluated with PCR. Current rapid diagnostic tests (RDT) for malaria can
distinguish falciparum Current rapid diagnostic tests (RDT) for malaria can distinguish
falciparum from other Plasmodium species with a sensitivity of up to 99% at parasite counts >
1,000/ μL [20], but a knowlesi specific antigen has not been developed and current antibody
panels are unable to differentiate between P. knowlesi and other mixed Plasmodium spp.
infections [21]. Misdiagnosis has concerning treatment implications, as unlike P. malariae,
knowlesi malaria has a rapid 24-hour replication rate and can cause hyperparasitaemia, severe
complications and fatal outcomes [13, 17, 18], while the inadvertent use of chloroquine for
widely chloroquine-resistant P. falciparum may also have fatal consequences.
Artemether-lumefantrine (A-L) is a common and widely available ACT, and along with
artesunate-mefloquine (AS-MQ) is one of only 2 first line WHO recommended options for the
treatment of uncomplicated P.falciparum infection which are registered in Malaysia and
produced according to international good manufacturing practice (GMP) standards. ACTs are the
current mainstay of malaria eradication efforts 28, with a mechanism of action resulting both
in a rapid reduction in parasite mass and resolution of clinical features, while the long
acting component eliminates residual parasites and delays the development of de novo
resistance 29,30.
Initial reported use of A-L for knowlesi malaria was from our retrospective study at a
tertiary referral hospital in Sabah, where a small sample size of 8 out of 34 patients with
PCR confirmed uncomplicated P.knowlesi infection were treated with oral
artemether-lumefantrine. Median microscopic parasite clearance time was 1 day (range 0-3),
which was significantly faster than those receiving chloroquine (median 2.5 days, range 1-3),
while this also resulted in fewer days of hospitalization and health sector associated costs.
The proportion remaining parasitaemic at day 1 was 33% 16. Our subsequent prospective study
at the same site documented 109 knowlesi malaria patients successfully treated with A-L, with
no recurrences identified. Unpublished data from this study showed that of the patients with
uncomplicated P. knowlesi malaria enrolled, 51 received A-L monotherapy, with a median
parasite clearance time of 2 days31.
Evaluation of A-L is required in addition to AS-MQ, as there are a number of pharmacokinetic
and pharmacodynamic differences that may affect clinical outcomes. In contrast to AS-MQ,
adequate oral absorption of A-L requires co-adminstration with fatty foods, with twice daily
dosing28. The longer acting partner drug in A-L is lumefantrine, which has a half life of 3
days compared to mefloquine in AS-MQ which is 21 days. Therefore there may be differences in
P. knowlesi recurrence at day 28 or 42 as the follow up time recommended by WHO for
anti-malarial efficacy monitoring studies 32.
Chloroquine with primaquine was initially suggested to have favourable treatment outcomes for
uncomplicated P. knowlesi human infections after a retrospective review of patients from
Kapit Hospital in Sarawak in 2004 15. Following this a single prospective observational study
conducted at the same site between 2006-7 administered chloroquine as a total base dose of
25mg/kg and primaquine as a gametocidal agent to 73 patients with uncomplicated PCR-confirmed
P. knowlesi malaria, with results showing median fever clearance of 26 hours, mean times to
50% and 90% microscopic parasite clearance of 3.1 and 10.3 hours respectively, and a median
PCR adjusted clearance time of 3 days. The proportion remaining parasitaemic at day 1 was
55%. None of the 60 patients who completed the 28-day follow up demonstrated any evidence of
resistance, re-infection or recrudescence 25.
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