P. Knowlesi Trial of Artemether-lumefantrine vs Chloroquine (CAN KNOW)

July 5, 2017 updated by: Menzies School of Health Research

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

123

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Malaysia
    • Sabah
      • Kota Marudu, Sabah, Malaysia
        • Kota Marudu District Hospital
      • Kudat, Sabah, Malaysia, 89057
        • Kudat District Hospital
      • Pitas, Sabah, Malaysia
        • Pitas District Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Male and female patients at least 1 year of age and weighing more than 10kg.
  • Microscopic diagnosis P. knowlesi (including diagnosis as P. malariae) or P. falciparum infection (any parasitaemia).
  • 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
  • Inability to tolerate oral treatment
  • Concomitant infection with any other malaria species
  • Positive for P. falciparum histidine-rich-protein-2 by malaria rapid diagnostic test
  • 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 previous 2 months
  • Previous psychiatric illness or epilepsy
  • Previous episode of cerebral malaria

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Artemether-lumefantrine

Artemether-lumefantrine.

1 tablet = 20mg arthemether and 120mg lumefantrine. Dosing at 0, 8, 24, 36, 48 and 60 hours. Dose according to bodyweight; >35kg = 2 tablets, 26-35kg = 3 tablets, 16-25kg = 2 tablets, >10-15kg = 1 tablet.
Drug: Artemether-lumefantrine combination
Other Names:
  • Riamet
  • Co-Artem
Active Comparator: Chloroquine

Chloroquine.

1 tablet contains 155mg chloroquine base. Adult dose (>35kg); 620mg (4 tablets) at 0 hours, and 310mg (2 tablets) at 6-8, 24 and 48 hours.

Child dose (>10-35kg); 10mg/kg at 0 hours, and 5mg/kg at 6-8, 24 and 48 hours.
Drug: Chloroquine
Other Names:
  • Chloroquine; 1 tablet = 155mg base

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Parasite clearance
Time Frame: 24 hours
The primary endpoint is the therapeutic efficacy of artemether-lumefantrine versus chloroquine, as defined by the assessment of microscopic P. knowlesi parasite clearance 24 hours after initiation of treatment.
24 hours

Secondary Outcome Measures

Outcome Measure
Time Frame
Rates of recurrent infection / treatment failure at day 42.
Time Frame: 42 days
42 days
Occurrence of anaemia at day 28 when using AL vs. CQ.
Time Frame: 28 days
28 days
P. knowlesi and gametocyte carriage throughout follow up when using AL vs. CQ.
Time Frame: 42 days
42 days
Frequency of complications throughout follow up when using AL vs. CQ.
Time Frame: 42 days
42 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Menzies School of Health Research

Collaborators

Ministry of Health, Malaysia

Investigators

  • Study Director: Bridget Barber, MBBS, Menzies School of Health Research
  • Study Director: Matthew Grigg, MBBS, Menzies School of Health Research
  • Study Director: Prabakaran Dhanaraj, MBBS, Sabah Ministry of Health
  • Study Director: Nicholas Anstey, MBBS, Menzies School of Health Research

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2014

Primary Completion (Actual)

January 1, 2015

Study Completion (Actual)

March 1, 2015

Study Registration Dates

First Submitted

November 27, 2013

First Submitted That Met QC Criteria

November 27, 2013

First Posted (Estimate)

December 4, 2013

Study Record Updates

Last Update Posted (Actual)

July 7, 2017

Last Update Submitted That Met QC Criteria

July 5, 2017

Last Verified

July 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NMRR-13-18375

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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