A study protocol for a randomised open-label clinical trial of artesunate-mefloquine versus chloroquine in patients with non-severe Plasmodium knowlesi malaria in Sabah, Malaysia (ACT KNOW trial)

Matthew Grigg, Timothy Williams, Prabakaran Dhanaraj, Jayaram Menon, Bridget Barber, Lorenz Von Seidlein, Giri Rajahram, Ric Price, Nicholas Anstey, Tsin Yeo

Research output: Contribution to journalArticleResearchpeer-review

6 Downloads (Pure)

Abstract

Introduction: Malaria due to Plasmodium knowlesi is reported throughout South-East Asia, and is the commonest cause of it in Malaysia. P. knowlesi replicates every 24 h and can cause severe disease and death. Current 2010 WHO Malaria Treatment Guidelines have no recommendations for the optimal treatment of non-severe knowlesi malaria. Artemisinin-combination therapies (ACT) and chloroquine have each been successfully used to treat knowlesi malaria; however, the rapidity of parasite clearance has not been prospectively compared. Malaysia's national policy for malaria pre-elimination involves mandatory hospital admission for confirmed malaria cases with discharge only after two negative blood films; use of a more rapidly acting antimalarial agent would have health cost benefits. P. knowlesi is commonly microscopically misreported as P. malariae, P. falciparum or P. vivax, with a high proportion of the latter two species being chloroquine-resistant in Malaysia. A unified ACT-treatment protocol would provide effective blood stage malaria treatment for all Plasmodium species.

Methods and analysis: ACT KNOW, the first randomised controlled trial ever performed in knowlesi malaria, is a two-arm open-label trial with enrolments over a 2-year period at three district sites in Sabah, powered to show a difference in proportion of patients negative for malaria by microscopy at 24 h between treatment arms (clinicaltrials.gov #NCT01708876). Enrolments started in December 2012, with completion expected by September 2014. A total sample size of 228 is required to give 90% power (? 0.05) to determine the primary end point using intention-to-treat analysis. Secondary end points include parasite clearance time, rates of recurrent infection/treatment failure to day 42, gametocyte carriage throughout follow-up and rates of anaemia at day 28, as determined by survival analysis.

Ethics and dissemination: This study has been approved by relevant institutional ethics committees in Malaysia and Australia. Results will be disseminated to inform knowlesi malaria treatment policy in this region through peer-reviewed publications and academic presentations. Trial registration number: NCT01708876.
Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalBMJ Open
Volume4
Issue number8
DOIs
Publication statusPublished - 2014

Fingerprint

Plasmodium knowlesi
Plasmodium malariae
Mefloquine
Malaysia
Chloroquine
Malaria
Clinical Trials
Therapeutics
Parasites
artesunate
artemisinine
Ethics Committees
Intention to Treat Analysis
Plasmodium
Far East
Falciparum Malaria
Antimalarials
Insurance Benefits
Survival Analysis
Clinical Protocols

Cite this

@article{5a32417d3cf94a488898a7c586a63fe2,
title = "A study protocol for a randomised open-label clinical trial of artesunate-mefloquine versus chloroquine in patients with non-severe Plasmodium knowlesi malaria in Sabah, Malaysia (ACT KNOW trial)",
abstract = "Introduction: Malaria due to Plasmodium knowlesi is reported throughout South-East Asia, and is the commonest cause of it in Malaysia. P. knowlesi replicates every 24 h and can cause severe disease and death. Current 2010 WHO Malaria Treatment Guidelines have no recommendations for the optimal treatment of non-severe knowlesi malaria. Artemisinin-combination therapies (ACT) and chloroquine have each been successfully used to treat knowlesi malaria; however, the rapidity of parasite clearance has not been prospectively compared. Malaysia's national policy for malaria pre-elimination involves mandatory hospital admission for confirmed malaria cases with discharge only after two negative blood films; use of a more rapidly acting antimalarial agent would have health cost benefits. P. knowlesi is commonly microscopically misreported as P. malariae, P. falciparum or P. vivax, with a high proportion of the latter two species being chloroquine-resistant in Malaysia. A unified ACT-treatment protocol would provide effective blood stage malaria treatment for all Plasmodium species. Methods and analysis: ACT KNOW, the first randomised controlled trial ever performed in knowlesi malaria, is a two-arm open-label trial with enrolments over a 2-year period at three district sites in Sabah, powered to show a difference in proportion of patients negative for malaria by microscopy at 24 h between treatment arms (clinicaltrials.gov #NCT01708876). Enrolments started in December 2012, with completion expected by September 2014. A total sample size of 228 is required to give 90{\%} power (? 0.05) to determine the primary end point using intention-to-treat analysis. Secondary end points include parasite clearance time, rates of recurrent infection/treatment failure to day 42, gametocyte carriage throughout follow-up and rates of anaemia at day 28, as determined by survival analysis. Ethics and dissemination: This study has been approved by relevant institutional ethics committees in Malaysia and Australia. Results will be disseminated to inform knowlesi malaria treatment policy in this region through peer-reviewed publications and academic presentations. Trial registration number: NCT01708876.",
keywords = "artesunate plus mefloquine, chloroquine, glucose 6 phosphate dehydrogenase, hemoglobin, antimalarial agent, artemisinin derivative, artesunate, mefloquine, analysis, article, clinical protocol, controlled study, drug bioavailability, drug efficacy, drug safety, drug treatment failure, female, follow up, gametocyte, health care cost, human, human tissue, length of stay, Malaysia, male, parasite clearance, Plasmodium knowlesi malaria, randomized controlled trial, recurrent infection, comparative study, malaria, methodology, parasitology, Plasmodium knowlesi, severity of illness index, Antimalarials, Artemisinins, Chloroquine, Female, Humans, Malaria, Male, Mefloquine, Research Design, Severity of Illness Index",
author = "Matthew Grigg and Timothy Williams and Prabakaran Dhanaraj and Jayaram Menon and Bridget Barber and {Von Seidlein}, Lorenz and Giri Rajahram and Ric Price and Nicholas Anstey and Tsin Yeo",
year = "2014",
doi = "10.1136/bmjopen-2014-006005",
language = "English",
volume = "4",
pages = "1--10",
journal = "BMJ Open",
issn = "2044-6055",
publisher = "British Medical Journal Publishing Group (BMJ Publishing)",
number = "8",

}

A study protocol for a randomised open-label clinical trial of artesunate-mefloquine versus chloroquine in patients with non-severe Plasmodium knowlesi malaria in Sabah, Malaysia (ACT KNOW trial). / Grigg, Matthew; Williams, Timothy; Dhanaraj, Prabakaran; Menon, Jayaram; Barber, Bridget; Von Seidlein, Lorenz; Rajahram, Giri; Price, Ric; Anstey, Nicholas; Yeo, Tsin.

In: BMJ Open, Vol. 4, No. 8, 2014, p. 1-10.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A study protocol for a randomised open-label clinical trial of artesunate-mefloquine versus chloroquine in patients with non-severe Plasmodium knowlesi malaria in Sabah, Malaysia (ACT KNOW trial)

AU - Grigg, Matthew

AU - Williams, Timothy

AU - Dhanaraj, Prabakaran

AU - Menon, Jayaram

AU - Barber, Bridget

AU - Von Seidlein, Lorenz

AU - Rajahram, Giri

AU - Price, Ric

AU - Anstey, Nicholas

AU - Yeo, Tsin

PY - 2014

Y1 - 2014

N2 - Introduction: Malaria due to Plasmodium knowlesi is reported throughout South-East Asia, and is the commonest cause of it in Malaysia. P. knowlesi replicates every 24 h and can cause severe disease and death. Current 2010 WHO Malaria Treatment Guidelines have no recommendations for the optimal treatment of non-severe knowlesi malaria. Artemisinin-combination therapies (ACT) and chloroquine have each been successfully used to treat knowlesi malaria; however, the rapidity of parasite clearance has not been prospectively compared. Malaysia's national policy for malaria pre-elimination involves mandatory hospital admission for confirmed malaria cases with discharge only after two negative blood films; use of a more rapidly acting antimalarial agent would have health cost benefits. P. knowlesi is commonly microscopically misreported as P. malariae, P. falciparum or P. vivax, with a high proportion of the latter two species being chloroquine-resistant in Malaysia. A unified ACT-treatment protocol would provide effective blood stage malaria treatment for all Plasmodium species. Methods and analysis: ACT KNOW, the first randomised controlled trial ever performed in knowlesi malaria, is a two-arm open-label trial with enrolments over a 2-year period at three district sites in Sabah, powered to show a difference in proportion of patients negative for malaria by microscopy at 24 h between treatment arms (clinicaltrials.gov #NCT01708876). Enrolments started in December 2012, with completion expected by September 2014. A total sample size of 228 is required to give 90% power (? 0.05) to determine the primary end point using intention-to-treat analysis. Secondary end points include parasite clearance time, rates of recurrent infection/treatment failure to day 42, gametocyte carriage throughout follow-up and rates of anaemia at day 28, as determined by survival analysis. Ethics and dissemination: This study has been approved by relevant institutional ethics committees in Malaysia and Australia. Results will be disseminated to inform knowlesi malaria treatment policy in this region through peer-reviewed publications and academic presentations. Trial registration number: NCT01708876.

AB - Introduction: Malaria due to Plasmodium knowlesi is reported throughout South-East Asia, and is the commonest cause of it in Malaysia. P. knowlesi replicates every 24 h and can cause severe disease and death. Current 2010 WHO Malaria Treatment Guidelines have no recommendations for the optimal treatment of non-severe knowlesi malaria. Artemisinin-combination therapies (ACT) and chloroquine have each been successfully used to treat knowlesi malaria; however, the rapidity of parasite clearance has not been prospectively compared. Malaysia's national policy for malaria pre-elimination involves mandatory hospital admission for confirmed malaria cases with discharge only after two negative blood films; use of a more rapidly acting antimalarial agent would have health cost benefits. P. knowlesi is commonly microscopically misreported as P. malariae, P. falciparum or P. vivax, with a high proportion of the latter two species being chloroquine-resistant in Malaysia. A unified ACT-treatment protocol would provide effective blood stage malaria treatment for all Plasmodium species. Methods and analysis: ACT KNOW, the first randomised controlled trial ever performed in knowlesi malaria, is a two-arm open-label trial with enrolments over a 2-year period at three district sites in Sabah, powered to show a difference in proportion of patients negative for malaria by microscopy at 24 h between treatment arms (clinicaltrials.gov #NCT01708876). Enrolments started in December 2012, with completion expected by September 2014. A total sample size of 228 is required to give 90% power (? 0.05) to determine the primary end point using intention-to-treat analysis. Secondary end points include parasite clearance time, rates of recurrent infection/treatment failure to day 42, gametocyte carriage throughout follow-up and rates of anaemia at day 28, as determined by survival analysis. Ethics and dissemination: This study has been approved by relevant institutional ethics committees in Malaysia and Australia. Results will be disseminated to inform knowlesi malaria treatment policy in this region through peer-reviewed publications and academic presentations. Trial registration number: NCT01708876.

KW - artesunate plus mefloquine

KW - chloroquine

KW - glucose 6 phosphate dehydrogenase

KW - hemoglobin

KW - antimalarial agent

KW - artemisinin derivative

KW - artesunate

KW - mefloquine

KW - analysis

KW - article

KW - clinical protocol

KW - controlled study

KW - drug bioavailability

KW - drug efficacy

KW - drug safety

KW - drug treatment failure

KW - female

KW - follow up

KW - gametocyte

KW - health care cost

KW - human

KW - human tissue

KW - length of stay

KW - Malaysia

KW - male

KW - parasite clearance

KW - Plasmodium knowlesi malaria

KW - randomized controlled trial

KW - recurrent infection

KW - comparative study

KW - malaria

KW - methodology

KW - parasitology

KW - Plasmodium knowlesi

KW - severity of illness index

KW - Antimalarials

KW - Artemisinins

KW - Chloroquine

KW - Female

KW - Humans

KW - Malaria

KW - Male

KW - Mefloquine

KW - Research Design

KW - Severity of Illness Index

UR - http://www.scopus.com/inward/record.url?scp=84924278427&partnerID=8YFLogxK

U2 - 10.1136/bmjopen-2014-006005

DO - 10.1136/bmjopen-2014-006005

M3 - Article

VL - 4

SP - 1

EP - 10

JO - BMJ Open

JF - BMJ Open

SN - 2044-6055

IS - 8

ER -