P. Knowlesi Trial of Artesunate-mefloquine Versus Chloroquine

NCT01708876 | Completed Phase 3

• 1 other identifier: NMRR-12-89-11005
• Study Type: interventional
• Target: 250
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Uncomplicated Plasmodium Knowlesi Malaria

Keywords

uncomplicated; plasmodium; knowlesi; malaria; infection

Outcome Measures

Primary Outcomes (1)

• Parasite clearance

  The primary endpoint is the therapeutic efficacy of artesunate-mefloquine versus chloroquine, as defined by the assessment of microscopic P. knowlesi and P. vivax parasite clearance 24 hours after initiation of treatment.

  24 hours

Secondary Outcomes (6)

• Rates of recurrent infection / treatment failure at day 42.

  42 days

• Occurrence of anaemia at day 28 when using AS-MQ vs. CQ.

  28 days

• P. knowlesi and P. vivax gametocyte carriage throughout follow up when using AS-MQ vs. CQ.

  42 days

• Frequency of complications throughout follow up when using AS-MQ vs. CQ.

  42 days

• Utility of malaria rapid diagnostic tests in diagnosis of P. knowlesi infection.

  1 day

Study Arms (2)

Artesunate-mefloquine

ACTIVE COMPARATOR

3 doses artesunate-mefloquine - daily over 3 days (dosage according to bodyweight - 4mg/kg and 8.3mg/kg respectively).

Drug: Artesunate-mefloquine; Drug: Primaquine

Chloroquine

ACTIVE COMPARATOR

4 doses chloroquine over 3 days - total dose 25mg/kg. 10mg/kg at 0 hours, 5mg/kg at 6-8, 24, 48 hours.

Drug: Chloroquine; Drug: Primaquine

Interventions

Artesunate-mefloquine DRUG

Also known as: Artequin 600/1500, Artequin 300/750, Artequin Paed granules 50/125

Artesunate-mefloquine

Chloroquine DRUG

Also known as: Chloroquine; 1 tablet = 155mg base

Chloroquine

Primaquine DRUG

Given to P. vivax patients only. Delayed administration at day 28; 0.5mg/kg for children or 45mg for adults; normal G6PD activity (once daily administration for 14 days); moderate G6PD deficiency (once weekly for 8 weeks); severe G6PD deficiency (contraindicated / not given).

Artesunate-mefloquine; Chloroquine

Eligibility Criteria

• Age: 1 Year+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Menzies School of Health Research: lead
• Ministry of Health, Malaysia: collaborator

Study Sites (3)

Kota Marudu District Hospital

Kota Marudu, Sabah, 89108, Malaysia

Location

Kudat District Hospital

Kudat, Sabah, 89057, Malaysia

Location

Pitas District Hospital

Pitas, Sabah, Malaysia

Location

Related Publications (14)

• 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.

  PMID: 19284284 BACKGROUND

• 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.

  PMID: 21762577 BACKGROUND

• 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.

  PMID: 18439370 BACKGROUND

• 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.

  PMID: 20735938 BACKGROUND

• Vythilingam I. Plasmodium knowlesi in humans: a review on the role of its vectors in Malaysia. Trop Biomed. 2010 Apr;27(1):1-12.

  PMID: 20562807 BACKGROUND

• 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.

  PMID: 20350383 BACKGROUND

• 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.

  PMID: 18439369 BACKGROUND

• 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.

  PMID: 19747661 BACKGROUND

• Singh B, Daneshvar C. Plasmodium knowlesi malaria in Malaysia. Med J Malaysia. 2010 Sep;65(3):166-72.

  PMID: 21939162 BACKGROUND

• Cox-Singh J, Davis TM, Lee KS, Shamsul SS, Matusop A, Ratnam S, Rahman HA, Conway DJ, Singh B. Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clin Infect Dis. 2008 Jan 15;46(2):165-71. doi: 10.1086/524888.

  PMID: 18171245 RESULT

• Longley RJ, Grigg MJ, Schoffer K, Obadia T, Hyslop S, Piera KA, Nekkab N, Mazhari R, Takashima E, Tsuboi T, Harbers M, Tetteh K, Drakeley C, Chitnis CE, Healer J, Tham WH, Sattabongkot J, White MT, Cooper DJ, Rajahram GS, Barber BE, William T, Anstey NM, Mueller I. Plasmodium vivax malaria serological exposure markers: Assessing the degree and implications of cross-reactivity with P. knowlesi. Cell Rep Med. 2022 Jun 21;3(6):100662. doi: 10.1016/j.xcrm.2022.100662.

  PMID: 35732155 DERIVED

• Grigg MJ, William T, Menon J, Barber BE, Wilkes CS, Rajahram GS, Edstein MD, Auburn S, Price RN, Yeo TW, Anstey NM. Efficacy of Artesunate-mefloquine for Chloroquine-resistant Plasmodium vivax Malaria in Malaysia: An Open-label, Randomized, Controlled Trial. Clin Infect Dis. 2016 Jun 1;62(11):1403-1411. doi: 10.1093/cid/ciw121. Epub 2016 Apr 22.

  PMID: 27107287 DERIVED

• Grigg MJ, William T, Menon J, Dhanaraj P, Barber BE, Wilkes CS, von Seidlein L, Rajahram GS, Pasay C, McCarthy JS, Price RN, Anstey NM, Yeo TW. Artesunate-mefloquine versus chloroquine for treatment of uncomplicated Plasmodium knowlesi malaria in Malaysia (ACT KNOW): an open-label, randomised controlled trial. Lancet Infect Dis. 2016 Feb;16(2):180-188. doi: 10.1016/S1473-3099(15)00415-6. Epub 2015 Nov 19.

  PMID: 26603174 DERIVED

• Grigg MJ, William T, Dhanaraj P, Menon J, Barber BE, von Seidlein L, Rajahram G, Price RN, Anstey NM, Yeo TW. 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). BMJ Open. 2014 Aug 19;4(8):e006005. doi: 10.1136/bmjopen-2014-006005.

  PMID: 25138814 DERIVED

MeSH Terms

Conditions

Malaria; Infections

Interventions

Chloroquine; Alkalies; Primaquine

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Inorganic Chemicals

Study Officials

• Jayaram Menon, MBBS

  Sabah Ministry of Health

  STUDY DIRECTOR

• D Prabhakaran, MBBS

  Sabah Ministry of Health

  STUDY DIRECTOR

• Matthew J Grigg, MBBS

  Menzies School of Health Research

  STUDY DIRECTOR

• Tsin Yeo, MBBS

  Menzies School of Health Research

  STUDY DIRECTOR

• Lorenz von Seidlein, MBBS

  Menzies School of Health Research

  STUDY DIRECTOR

• Nicholas M Anstey, MBBS

  Menzies School of Health Research

  STUDY DIRECTOR

• Ric Price, MBBS

  Menzies School of Health Research

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 15, 2012
• First Posted: October 17, 2012
• Study Start: October 1, 2012
• Primary Completion: December 1, 2014
• Study Completion: December 1, 2014
• Last Updated: April 9, 2015

Record last verified: 2015-04

Locations

MY (3)