P. Knowlesi Trial of Artemether-lumefantrine vs Chloroquine

NCT02001012 | Completed Phase 3

• 1 other identifier: NMRR-13-18375
• Study Type: interventional
• Target: 123
• 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 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.

Conditions

Uncomplicated Knowlesi Malaria

Keywords

uncomplicated; plasmodium; knowlesi; malaria; infection

Outcome Measures

Primary Outcomes (1)

• Parasite clearance

  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 Outcomes (4)

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

  42 days

• Occurrence of anaemia at day 28 when using AL vs. CQ.

  28 days

• P. knowlesi and gametocyte carriage throughout follow up when using AL vs. CQ.

  42 days

• Frequency of complications throughout follow up when using AL vs. CQ.

  42 days

Study Arms (2)

Artemether-lumefantrine

ACTIVE COMPARATOR

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

Chloroquine

ACTIVE COMPARATOR

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

Interventions

Artemether-lumefantrine combination DRUG

Also known as: Riamet, Co-Artem

Artemether-lumefantrine

Chloroquine DRUG

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

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 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.

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
• 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

Sponsors & Collaborators

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

Study Sites (3)

Kota Marudu District Hospital

Kota Marudu, Sabah, Malaysia

Location

Kudat District Hospital

Kudat, Sabah, 89057, Malaysia

Location

Pitas District Hospital

Pitas, Sabah, Malaysia

Location

Related Publications (7)

• 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 BACKGROUND

• 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

• 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

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

  PMID: 21939162 BACKGROUND

• Grigg MJ, William T, Barber BE, Rajahram GS, Menon J, Schimann E, Wilkes CS, Patel K, Chandna A, Price RN, Yeo TW, Anstey NM. Artemether-Lumefantrine Versus Chloroquine for the Treatment of Uncomplicated Plasmodium knowlesi Malaria: An Open-Label Randomized Controlled Trial CAN KNOW. Clin Infect Dis. 2018 Jan 6;66(2):229-236. doi: 10.1093/cid/cix779.

  PMID: 29020373 DERIVED

MeSH Terms

Conditions

Malaria; Infections

Interventions

Artemether, Lumefantrine Drug Combination; Chloroquine; Alkalies

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Artemether; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Lumefantrine; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sesquiterpenes; Terpenes; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Jayaram Menon, MBBS

  Sabah Ministry of Health

  STUDY DIRECTOR

• Matthew Grigg, MBBS

  Menzies School of Health Research

  STUDY DIRECTOR

• Prabakaran Dhanaraj, MBBS

  Sabah Ministry of Health

  STUDY DIRECTOR

• Tsin Yeo, MBBS

  Menzies School of Health Research

  STUDY DIRECTOR

• Bridget Barber, MBBS

  Menzies School of Health Research

  STUDY DIRECTOR

• Nicholas 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: November 27, 2013
• First Posted: December 4, 2013
• Study Start: January 1, 2014
• Primary Completion: January 1, 2015
• Study Completion: March 1, 2015
• Last Updated: July 7, 2017

Record last verified: 2017-07

Locations

MY (3)