P. Knowlesi Trial of Artesunate-mefloquine Versus Chloroquine
Information source: Menzies School of Health Research
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Uncomplicated Plasmodium Knowlesi Malaria
Intervention: Artesunate-mefloquine (Drug); Chloroquine (Drug); Primaquine (Drug)
Phase: Phase 3
Status: Completed
Sponsored by: Menzies School of Health Research Official(s) and/or principal investigator(s): Jayaram Menon, MBBS, Study Director, Affiliation: Sabah Ministry of Health D Prabhakaran, MBBS, Study Director, Affiliation: Sabah Ministry of Health Matthew J Grigg, MBBS, Study Director, Affiliation: Menzies School of Health Research Tsin Yeo, MBBS, Study Director, Affiliation: Menzies School of Health Research Lorenz von Seidlein, MBBS, Study Director, Affiliation: Menzies School of Health Research Nicholas M Anstey, MBBS, Study Director, Affiliation: Menzies School of Health Research Ric Price, MBBS, Study Director, Affiliation: Menzies School of Health Research
Summary
Preliminary studies have supported the background efficacy of local standard anti-malarial
medications in the treatment of uncomplicated knowlesi malaria, however this has not been
tested systematically and 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. In addition, no therapeutic
efficacy monitoring of current first line anti-malarials used for the treatment of P. vivax
malaria have been conducted in Malaysia.
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 and P. vivax infection in both adults and children in this region.
Clinical Details
Official title: Artesunate-mefloquine vs Chloroquine in Patients With Acute Uncomplicated P. Knowlesi and P. Vivax Malaria: a Randomized Open Label Trial in Sabah, Malaysia
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Parasite clearance
Secondary outcome: Rates of recurrent infection / treatment failure at day 42.Occurrence of anaemia at day 28 when using AS-MQ vs. CQ. P. knowlesi and P. vivax gametocyte carriage throughout follow up when using AS-MQ vs. CQ. Frequency of complications throughout follow up when using AS-MQ vs. CQ. Utility of malaria rapid diagnostic tests in diagnosis of P. knowlesi infection. Rates of P. knowlesi and P. vivax recurrence in a 1 year follow up period.
Detailed description:
1. 1 Background
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.
1. 2 Treatment
Initial observational and retrospective studies have suggested both chloroquine and
artemisinin combination therapy (ACT) are effective therapy for uncomplicated P. knowlesi
infection [15, 16, 22, 23]. Justification for treatment selection for this trial is based on
this literature review. Case reports predominantly from returned travelers to South-East
Asia also document uncomplicated knowlesi malaria responding well to conventional
anti-malarials such as chloroquine, mefloquine, atovaquone with proguanil, doxycycline and
quinine [4, 24- 31], supporting its zoonotic and drug naïve origin. However to date there
have been no prospective randomised trials to compare chloroquine and ACT as the
anti-malarials currently used for uncomplicated P. knowlesi infection in Malaysia, and there
are no current recommendations on how to treat P. knowlesi infection in the WHO 2010 malaria
treatment guidelines. As ACTs are already being used for treating P. falciparum and are
recommended for the increasingly chloroquine-resistant P. vivax found in the surrounding
countries in South East Asia [32], the potential benefit of a unified treatment policy to
facilitate prompt and effective treatment of all Plasmodium species needs evidence of ACT as
the optimal treatment for P. knowlesi infection also.
Malaysian Ministry of Health guidelines currently recommend chloroquine and primaquine as
first line treatment for the erythrocytic and hypnozoite life stages of uncomplicated P.
vivax malaria respectively. While resistance to chloroquine has previously been documented
in Sabah [35] and Peninsular Malaysia [36-38], the unstable transmission dynamics and recent
reduction in P. vivax incidence due to public health measures mean the current risk of
chloroquine-resistant P. vivax transmission is likely to be low. Despite this, due to
increasing resistance in surrounding countries including Indonesia, Thailand, Vietnam, and
PNG [39], transient populations of migrant workers, and recent concerns of the failing
efficacy of hypnozoite eradication by primaquine [40], the need for ongoing therapeutic
efficacy monitoring is recommended [41].
1. 3 Artesunate-mefloquine
Artesunate-mefloquine (AS-MQ) is a common and widely available ACT, and along with
artemether-lumefantrine (A-L) 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 elimination efforts [33], 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 [34, 35]. Safety and tolerability of all ACTs are dependent on their
partner drug [36], and while gastro-intestinal and self-limiting neuro-psychiatric adverse
events have been reported with mefloquine, multiple safety and efficacy trials have
recommended its use in both adults and children for uncomplicated falciparum malaria
[37-40]. Due to concerns over the safety of mefloquine in the first trimester of pregnancy
[41], and its use in patients with pre-existing psychiatric disorders or those who have
previously had cerebral malaria, it is currently not advised for these groups [36].
The only reported use of ACT for knowlesi malaria is 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, p = 0. 01)
[23]. There are no published reports of other ACTs used in the treatment of P. knowlesi
infection, although currently both AS-MQ and A-L are being used in Sabah for uncomplicated
P. knowlesi and P. falciparum malaria, including in children >5kg, as recommended by local
guidelines.
Mefloquine as a single agent has also been used in the successful treatment of a Swedish
traveller returning from Sarawak, Malaysia with PCR confirmed uncomplicated P. knowlesi
infection in 2009 [24]. The long half life of mefloquine of around 14 days also means when
used as the partner drug in an ACT for uncomplicated malaria caused by other Plasmodium
species such as P. vivax, there is a significant reduction compared to A-L in the day 42
treatment failure rate [42].
1. 4 Chloroquine
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 [16]. 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. None of the 60 patients who completed
the 28-day follow up demonstrated any evidence of resistance, re-infection or recrudescence
[22].
Eligibility
Minimum age: 1 Year.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Male and female patients at least 1 year of age and weighing more than 10kg
- Microscopic diagnosis of Plasmodium species infection
- Negative P. falciparum malaria rapid diagnostic test (histidine rich protein 2)
- Fever (temperature 37. 5°C) or history of fever in the last 48 hours
- Able to participate in the trial and comply with the clinical trial protocol
- Written informed consent to participate in trial; thumbprint is required for
illiterate patients, and written consent from parents/guardian for children below age
of consent
Exclusion Criteria:
- Clinical or laboratory criteria for severe malaria, including warning signs,
requiring parenteral treatment according to modified WHO criteria (see Appendix 4)
- Parasitaemia > 20,000 /μL (P. knowlesi)
- Inability to tolerate oral treatment
- Concomitant infection with any other malaria species
- Pregnancy or lactation
- Unable or unwilling to use contraception during study period
- Known hypersensitivity or allergy to artemisinin derivatives
- Serious underlying disease (cardiac, renal or hepatic)
- Received anti-malarials in last 2 months
- Previous psychiatric illness or epilepsy
- Previous episode of cerebral malaria
Locations and Contacts
Kota Marudu District Hospital, Kota Marudu, Sabah 89108, Malaysia
Kudat District Hospital, Kudat, Sabah 89057, Malaysia
Pitas District Hospital, Pitas, Sabah, Malaysia
Additional Information
Related publications: Putaporntip C, Hongsrimuang T, Seethamchai S, Kobasa T, Limkittikul K, Cui L, Jongwutiwes S. Differential prevalence of Plasmodium infections and cryptic Plasmodium knowlesi malaria in humans in Thailand. J Infect Dis. 2009 Apr 15;199(8):1143-50. doi: 10.1086/597414. Marchand RP, Culleton R, Maeno Y, Quang NT, Nakazawa S. Co-infections of Plasmodium knowlesi, P. falciparum, and P. vivax among Humans and Anopheles dirus Mosquitoes, Southern Vietnam. Emerg Infect Dis. 2011 Jul;17(7):1232-9. doi: 10.3201/eid1707.101551. Ng OT, Ooi EE, Lee CC, Lee PJ, Ng LC, Pei SW, Tu TM, Loh JP, Leo YS. Naturally acquired human Plasmodium knowlesi infection, Singapore. Emerg Infect Dis. 2008 May;14(5):814-6. doi: 10.3201/eid1405.070863. Jiang N, Chang Q, Sun X, Lu H, Yin J, Zhang Z, Wahlgren M, Chen Q. Co-infections with Plasmodium knowlesi and other malaria parasites, Myanmar. Emerg Infect Dis. 2010 Sep;16(9):1476-8. doi: 10.3201/eid1609.100339. Vythilingam I. Plasmodium knowlesi in humans: a review on the role of its vectors in Malaysia. Trop Biomed. 2010 Apr;27(1):1-12. Review. Figtree M, Lee R, Bain L, Kennedy T, Mackertich S, Urban M, Cheng Q, Hudson BJ. Plasmodium knowlesi in human, Indonesian Borneo. Emerg Infect Dis. 2010 Apr;16(4):672-4. doi: 10.3201/eid1604.091624. Luchavez J, Espino F, Curameng P, Espina R, Bell D, Chiodini P, Nolder D, Sutherland C, Lee KS, Singh B. Human Infections with Plasmodium knowlesi, the Philippines. Emerg Infect Dis. 2008 May;14(5):811-3. doi: 10.3201/eid1405.071407. Baird JK. Malaria zoonoses. Travel Med Infect Dis. 2009 Sep;7(5):269-77. doi: 10.1016/j.tmaid.2009.06.004. Epub 2009 Jul 14. Review. Singh B, Daneshvar C. Plasmodium knowlesi malaria in Malaysia. Med J Malaysia. 2010 Sep;65(3):166-72. Review.
Starting date: October 2012
Last updated: April 7, 2015
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