<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01708876</url>
  </required_header>
  <id_info>
    <org_study_id>NMRR-12-89-11005</org_study_id>
    <nct_id>NCT01708876</nct_id>
  </id_info>
  <brief_title>P. Knowlesi Trial of Artesunate-mefloquine Versus Chloroquine</brief_title>
  <acronym>ACT KNOW</acronym>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Menzies School of Health Research</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ministry of Health, Malaysia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Menzies School of Health Research</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Preliminary studies have supported the background efficacy of local standard anti-malarial&#xD;
      medications in the treatment of uncomplicated knowlesi malaria, however this has not been&#xD;
      tested systematically and there are no current WHO treatment guidelines for this infection.&#xD;
      There are both health cost benefits to a more rapidly acting agent, and due to difficulties&#xD;
      with microscopic identification there may be more effective treatment for all malaria species&#xD;
      if an aligned treatment guideline could be supported. In addition, no therapeutic efficacy&#xD;
      monitoring of current first line anti-malarials used for the treatment of P. vivax malaria&#xD;
      have been conducted in Malaysia.&#xD;
&#xD;
      The investigators aim to test whether the fixed combination of artesunate-mefloquine is&#xD;
      superior to chloroquine in order to define the optimal treatment for both uncomplicated P.&#xD;
      knowlesi and P. vivax infection in both adults and children in this region.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      1.1 Background&#xD;
&#xD;
      Naturally acquired infections with Plasmodium knowlesi, the fifth human malaria, are growing&#xD;
      [1]. Since 2004 increasing numbers of cases have been reported from residents and returned&#xD;
      travelers predominantly from Malaysia and other countries in South-East Asia including&#xD;
      Thailand, Vietnam, Myanmar, Singapore, Indonesia and the Philippines [2-8]. Cases coincide&#xD;
      with the geographic distribution of its natural simian hosts (long-tailed and pig-tailed&#xD;
      macaques) and Anopheles leucosphyrus group mosquito vector [9, 10], with potential&#xD;
      human-to-human transmission unknown. Eastern Malaysia appears to be the epicentre, with&#xD;
      around 1400 PCR-confirmed P. knowlesi human mono-infections reported in 2009, comprising 41%&#xD;
      of 2,189 total malaria cases in Sarawak [11] and 343 cases from selected samples sent to&#xD;
      Sabah's State Reference Laboratory [12]. P. knowlesi is also now the most common cause of&#xD;
      malaria in different contrasting regions, including 70% of malaria admissions in the heavily&#xD;
      forested area of Kapit in Sarawak [1, 13], 63% of samples from the interior division of Sabah&#xD;
      [14], and in 87% of malaria admissions in the deforested coastal area of Kudat in Sabah,&#xD;
      where it is also the major cause of malaria in children [15].&#xD;
&#xD;
      Despite the increase in reported incidence, difficulties with microscopic diagnosis and a&#xD;
      lack of PCR based epidemiological surveillance studies throughout South-East Asia mean the&#xD;
      true disease burden is underestimated. P. knowlesi is microscopically misidentified as P .&#xD;
      falciparum and P. malariae due to morphological similarities in the early trophozoite, and&#xD;
      late trophozoite and schizont life stages respectively, with studies showing up to 80% of P.&#xD;
      malariae [16-19] and 7-12% of P. falciparum [1, 16] in this region are actually P. knowlesi&#xD;
      when definitively evaluated with PCR. Current rapid diagnostic tests (RDT) for malaria can&#xD;
      distinguish falciparum Current rapid diagnostic tests (RDT) for malaria can distinguish&#xD;
      falciparum from other Plasmodium species with a sensitivity of up to 99% at parasite counts &gt;&#xD;
      1,000/ μL [20], but a knowlesi specific antigen has not been developed and current antibody&#xD;
      panels are unable to differentiate between P. knowlesi and other mixed Plasmodium spp.&#xD;
      infections [21]. Misdiagnosis has concerning treatment implications, as unlike P. malariae,&#xD;
      knowlesi malaria has a rapid 24-hour replication rate and can cause hyperparasitaemia, severe&#xD;
      complications and fatal outcomes [13, 17, 18], while the inadvertent use of chloroquine for&#xD;
      widely chloroquine-resistant P. falciparum may also have fatal consequences.&#xD;
&#xD;
      1.2 Treatment&#xD;
&#xD;
      Initial observational and retrospective studies have suggested both chloroquine and&#xD;
      artemisinin combination therapy (ACT) are effective therapy for uncomplicated P. knowlesi&#xD;
      infection [15, 16, 22, 23]. Justification for treatment selection for this trial is based on&#xD;
      this literature review. Case reports predominantly from returned travelers to South-East Asia&#xD;
      also document uncomplicated knowlesi malaria responding well to conventional anti-malarials&#xD;
      such as chloroquine, mefloquine, atovaquone with proguanil, doxycycline and quinine [4, 24-&#xD;
      31], supporting its zoonotic and drug naïve origin. However to date there have been no&#xD;
      prospective randomised trials to compare chloroquine and ACT as the anti-malarials currently&#xD;
      used for uncomplicated P. knowlesi infection in Malaysia, and there are no current&#xD;
      recommendations on how to treat P. knowlesi infection in the WHO 2010 malaria treatment&#xD;
      guidelines. As ACTs are already being used for treating P. falciparum and are recommended for&#xD;
      the increasingly chloroquine-resistant P. vivax found in the surrounding countries in South&#xD;
      East Asia [32], the potential benefit of a unified treatment policy to facilitate prompt and&#xD;
      effective treatment of all Plasmodium species needs evidence of ACT as the optimal treatment&#xD;
      for P. knowlesi infection also.&#xD;
&#xD;
      Malaysian Ministry of Health guidelines currently recommend chloroquine and primaquine as&#xD;
      first line treatment for the erythrocytic and hypnozoite life stages of uncomplicated P.&#xD;
      vivax malaria respectively. While resistance to chloroquine has previously been documented in&#xD;
      Sabah [35] and Peninsular Malaysia [36-38], the unstable transmission dynamics and recent&#xD;
      reduction in P. vivax incidence due to public health measures mean the current risk of&#xD;
      chloroquine-resistant P.vivax transmission is likely to be low. Despite this, due to&#xD;
      increasing resistance in surrounding countries including Indonesia, Thailand, Vietnam, and&#xD;
      PNG [39], transient populations of migrant workers, and recent concerns of the failing&#xD;
      efficacy of hypnozoite eradication by primaquine [40], the need for ongoing therapeutic&#xD;
      efficacy monitoring is recommended [41].&#xD;
&#xD;
      1.3 Artesunate-mefloquine&#xD;
&#xD;
      Artesunate-mefloquine (AS-MQ) is a common and widely available ACT, and along with&#xD;
      artemether-lumefantrine (A-L) is one of only 2 first line WHO recommended options for the&#xD;
      treatment of uncomplicated P. falciparum infection which are registered in Malaysia and&#xD;
      produced according to international good manufacturing practice (GMP) standards. ACTs are the&#xD;
      current mainstay of malaria elimination efforts [33], with a mechanism of action resulting&#xD;
      both in a rapid reduction in parasite mass and resolution of clinical features, while the&#xD;
      long acting component eliminates residual parasites and delays the development of de novo&#xD;
      resistance [34, 35]. Safety and tolerability of all ACTs are dependent on their partner drug&#xD;
      [36], and while gastro-intestinal and self-limiting neuro-psychiatric adverse events have&#xD;
      been reported with mefloquine, multiple safety and efficacy trials have recommended its use&#xD;
      in both adults and children for uncomplicated falciparum malaria [37-40]. Due to concerns&#xD;
      over the safety of mefloquine in the first trimester of pregnancy [41], and its use in&#xD;
      patients with pre-existing psychiatric disorders or those who have previously had cerebral&#xD;
      malaria, it is currently not advised for these groups [36].&#xD;
&#xD;
      The only reported use of ACT for knowlesi malaria is from our retrospective study at a&#xD;
      tertiary referral hospital in Sabah, where a small sample size of 8 out of 34 patients with&#xD;
      PCR- confirmed uncomplicated P. knowlesi infection were treated with oral artemether-&#xD;
      lumefantrine. Median microscopic parasite clearance time was 1 day (range 0-3), which was&#xD;
      significantly faster than those receiving chloroquine (median 2.5 days, range 1-3, p = 0.01)&#xD;
      [23]. There are no published reports of other ACTs used in the treatment of P. knowlesi&#xD;
      infection, although currently both AS-MQ and A-L are being used in Sabah for uncomplicated P.&#xD;
      knowlesi and P. falciparum malaria, including in children &gt;5kg, as recommended by local&#xD;
      guidelines.&#xD;
&#xD;
      Mefloquine as a single agent has also been used in the successful treatment of a Swedish&#xD;
      traveller returning from Sarawak, Malaysia with PCR confirmed uncomplicated P. knowlesi&#xD;
      infection in 2009 [24]. The long half life of mefloquine of around 14 days also means when&#xD;
      used as the partner drug in an ACT for uncomplicated malaria caused by other Plasmodium&#xD;
      species such as P. vivax, there is a significant reduction compared to A-L in the day 42&#xD;
      treatment failure rate [42].&#xD;
&#xD;
      1.4 Chloroquine&#xD;
&#xD;
      Chloroquine with primaquine was initially suggested to have favourable treatment outcomes for&#xD;
      uncomplicated P. knowlesi human infections after a retrospective review of patients from&#xD;
      Kapit Hospital in Sarawak in 2004 [16]. Following this a single prospective observational&#xD;
      study conducted at the same site between 2006-7 administered chloroquine as a total base dose&#xD;
      of 25mg/kg and primaquine as a gametocidal agent to 73 patients with uncomplicated&#xD;
      PCR-confirmed P. knowlesi malaria, with results showing median fever clearance of 26 hours,&#xD;
      mean times to 50% and 90% microscopic parasite clearance of 3.1 and 10.3 hours respectively,&#xD;
      and a median PCR adjusted clearance time of 3 days. None of the 60 patients who completed the&#xD;
      28-day follow up demonstrated any evidence of resistance, re-infection or recrudescence [22].&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">December 2014</completion_date>
  <primary_completion_date type="Actual">December 2014</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Parasite clearance</measure>
    <time_frame>24 hours</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Rates of recurrent infection / treatment failure at day 42.</measure>
    <time_frame>42 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Occurrence of anaemia at day 28 when using AS-MQ vs. CQ.</measure>
    <time_frame>28 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>P. knowlesi and P. vivax gametocyte carriage throughout follow up when using AS-MQ vs. CQ.</measure>
    <time_frame>42 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of complications throughout follow up when using AS-MQ vs. CQ.</measure>
    <time_frame>42 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Utility of malaria rapid diagnostic tests in diagnosis of P. knowlesi infection.</measure>
    <time_frame>1 day</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rates of P. knowlesi and P. vivax recurrence in a 1 year follow up period.</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">250</enrollment>
  <condition>Uncomplicated Plasmodium Knowlesi Malaria</condition>
  <arm_group>
    <arm_group_label>Artesunate-mefloquine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>3 doses artesunate-mefloquine - daily over 3 days (dosage according to bodyweight - 4mg/kg and 8.3mg/kg respectively).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Chloroquine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>4 doses chloroquine over 3 days - total dose 25mg/kg. 10mg/kg at 0 hours, 5mg/kg at 6-8, 24, 48 hours.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Artesunate-mefloquine</intervention_name>
    <arm_group_label>Artesunate-mefloquine</arm_group_label>
    <other_name>Artequin 600/1500</other_name>
    <other_name>Artequin 300/750</other_name>
    <other_name>Artequin Paed granules 50/125</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Chloroquine</intervention_name>
    <arm_group_label>Chloroquine</arm_group_label>
    <other_name>Chloroquine; 1 tablet = 155mg base</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Primaquine</intervention_name>
    <description>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).</description>
    <arm_group_label>Artesunate-mefloquine</arm_group_label>
    <arm_group_label>Chloroquine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male and female patients at least 1 year of age and weighing more than 10kg&#xD;
&#xD;
          -  Microscopic diagnosis of Plasmodium species infection&#xD;
&#xD;
          -  Negative P. falciparum malaria rapid diagnostic test (histidine rich protein 2)&#xD;
&#xD;
          -  Fever (temperature 37.5°C) or history of fever in the last 48 hours&#xD;
&#xD;
          -  Able to participate in the trial and comply with the clinical trial protocol&#xD;
&#xD;
          -  Written informed consent to participate in trial; thumbprint is required for&#xD;
             illiterate patients, and written consent from parents/guardian for children below age&#xD;
             of consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Clinical or laboratory criteria for severe malaria, including warning signs, requiring&#xD;
             parenteral treatment according to modified WHO criteria (see Appendix 4)&#xD;
&#xD;
          -  Parasitaemia &gt; 20,000 /μL (P. knowlesi)&#xD;
&#xD;
          -  Inability to tolerate oral treatment&#xD;
&#xD;
          -  Concomitant infection with any other malaria species&#xD;
&#xD;
          -  Pregnancy or lactation&#xD;
&#xD;
          -  Unable or unwilling to use contraception during study period&#xD;
&#xD;
          -  Known hypersensitivity or allergy to artemisinin derivatives&#xD;
&#xD;
          -  Serious underlying disease (cardiac, renal or hepatic)&#xD;
&#xD;
          -  Received anti-malarials in last 2 months&#xD;
&#xD;
          -  Previous psychiatric illness or epilepsy&#xD;
&#xD;
          -  Previous episode of cerebral malaria&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jayaram Menon, MBBS</last_name>
    <role>Study Director</role>
    <affiliation>Sabah Ministry of Health</affiliation>
  </overall_official>
  <overall_official>
    <last_name>D Prabhakaran, MBBS</last_name>
    <role>Study Director</role>
    <affiliation>Sabah Ministry of Health</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Matthew J Grigg, MBBS</last_name>
    <role>Study Director</role>
    <affiliation>Menzies School of Health Research</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Tsin Yeo, MBBS</last_name>
    <role>Study Director</role>
    <affiliation>Menzies School of Health Research</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Lorenz von Seidlein, MBBS</last_name>
    <role>Study Director</role>
    <affiliation>Menzies School of Health Research</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Nicholas M Anstey, MBBS</last_name>
    <role>Study Director</role>
    <affiliation>Menzies School of Health Research</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Ric Price, MBBS</last_name>
    <role>Study Director</role>
    <affiliation>Menzies School of Health Research</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Kota Marudu District Hospital</name>
      <address>
        <city>Kota Marudu</city>
        <state>Sabah</state>
        <zip>89108</zip>
        <country>Malaysia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kudat District Hospital</name>
      <address>
        <city>Kudat</city>
        <state>Sabah</state>
        <zip>89057</zip>
        <country>Malaysia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pitas District Hospital</name>
      <address>
        <city>Pitas</city>
        <state>Sabah</state>
        <country>Malaysia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Malaysia</country>
  </location_countries>
  <reference>
    <citation>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.</citation>
    <PMID>19284284</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>21762577</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>18439370</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>20735938</PMID>
  </reference>
  <reference>
    <citation>Vythilingam I. Plasmodium knowlesi in humans: a review on the role of its vectors in Malaysia. Trop Biomed. 2010 Apr;27(1):1-12.</citation>
    <PMID>20562807</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>20350383</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>18439369</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>19747661</PMID>
  </reference>
  <reference>
    <citation>Singh B, Daneshvar C. Plasmodium knowlesi malaria in Malaysia. Med J Malaysia. 2010 Sep;65(3):166-72.</citation>
    <PMID>21939162</PMID>
  </reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>18171245</PMID>
  </results_reference>
  <verification_date>April 2015</verification_date>
  <study_first_submitted>October 15, 2012</study_first_submitted>
  <study_first_submitted_qc>October 16, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 17, 2012</study_first_posted>
  <last_update_submitted>April 7, 2015</last_update_submitted>
  <last_update_submitted_qc>April 7, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">April 9, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>uncomplicated</keyword>
  <keyword>plasmodium</keyword>
  <keyword>knowlesi</keyword>
  <keyword>malaria</keyword>
  <keyword>infection</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Malaria</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Artesunate</mesh_term>
    <mesh_term>Chloroquine</mesh_term>
    <mesh_term>Chloroquine diphosphate</mesh_term>
    <mesh_term>Primaquine</mesh_term>
    <mesh_term>Mefloquine</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01708876
org study id: NMRR-12-89-11005
nct id: NCT01708876
lead sponsor: 
collaborator: 
has dmc: No
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.
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].
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Parasite clearance
time frame: 24 hours
description: 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.
measure: Rates of recurrent infection / treatment failure at day 42.
time frame: 42 days
measure: Occurrence of anaemia at day 28 when using AS-MQ vs. CQ.
time frame: 28 days
measure: P. knowlesi and P. vivax gametocyte carriage throughout follow up when using AS-MQ vs. CQ.
time frame: 42 days
measure: Frequency of complications throughout follow up when using AS-MQ vs. CQ.
time frame: 42 days
measure: Utility of malaria rapid diagnostic tests in diagnosis of P. knowlesi infection.
time frame: 1 day
measure: Rates of P. knowlesi and P. vivax recurrence in a 1 year follow up period.
time frame: 1 year
arm group label: Artesunate-mefloquine
arm group type: Active Comparator
description: 3 doses artesunate-mefloquine - daily over 3 days (dosage according to bodyweight - 4mg/kg and 8.3mg/kg respectively).
arm group label: Chloroquine
arm group type: Active Comparator
description: 4 doses chloroquine over 3 days - total dose 25mg/kg. 10mg/kg at 0 hours, 5mg/kg at 6-8, 24, 48 hours.
intervention type: Drug
intervention name: Artesunate-mefloquine
arm group label: Artesunate-mefloquine
other name: Artequin 600/1500
other name: Artequin 300/750
other name: Artequin Paed granules 50/125
intervention type: Drug
intervention name: Chloroquine
arm group label: Chloroquine
other name: Chloroquine; 1 tablet = 155mg base
intervention type: Drug
intervention name: Primaquine
description: 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).
arm group label: Artesunate-mefloquine
arm group label: Chloroquine
criteria: 
gender: All
minimum age: 1 Year
maximum age: N/A
healthy volunteers: No
last name: Jayaram Menon, MBBS
role: Study Director
affiliation: Sabah Ministry of Health
last name: D Prabhakaran, MBBS
role: Study Director
affiliation: Sabah Ministry of Health
last name: Matthew J Grigg, MBBS
role: Study Director
affiliation: Menzies School of Health Research
last name: Tsin Yeo, MBBS
role: Study Director
affiliation: Menzies School of Health Research
last name: Lorenz von Seidlein, MBBS
role: Study Director
affiliation: Menzies School of Health Research
last name: Nicholas M Anstey, MBBS
role: Study Director
affiliation: Menzies School of Health Research
last name: Ric Price, MBBS
role: Study Director
affiliation: Menzies School of Health Research
facility: 
facility: 
facility: 
country: Malaysia
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PMID: 19284284
citation: 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
citation: 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
citation: 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
citation: 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
citation: 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
citation: 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
citation: 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
citation: Singh B, Daneshvar C. Plasmodium knowlesi malaria in Malaysia. Med J Malaysia. 2010 Sep;65(3):166-72.
PMID: 21939162
citation: 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
responsible party type: Sponsor
mesh term: Malaria
mesh term: Artesunate
mesh term: Chloroquine
mesh term: Chloroquine diphosphate
mesh term: Primaquine
mesh term: Mefloquine