TES of Artemether-lumefantrine for Pf in the Philippines in 2015
Condition: Malaria,Falciparum; Malaria Recrudescence
MeSH terms: Malaria; Malaria, Falciparum; Recurrence
Study type: Observational

Summary: 
      Artemether-lumefantrine has been used as a first-line treatment for uncomplicated Plasmodium
      falciparum infection since 2009 in the Philippines. The 28 day therapeutic efficacy study was
      conducted between February 2015 and December 2015, in accordance with WHO guidelines in the
      three (3) municipalities (Bataraza, Brookes and Rizal) of Palawan. Attempt was made to
      include Panglima-Sugala, Tawi-Tawi; however, due to the decline in the number of malaria
      cases, no evaluable subject was enrolled. The study subjects were febrile individuals between
      > 6 months old and 59 years old with confirmed uncomplicated P. falciparum. They were treated
      with artemether-lumefantrine (20 mg and 120 mg, respectively) administered 3 days (Days 0, 1
      and 2) according to body weight. Primaquine (0.75 mg base/kg body weight single dose) was
      given on Day 3. Outcomes were classified as early treatment failure (ETF), late clinical
      failure (LCF), late parasitological failure (LPF) and adequate clinical and parasitological
      response (ACPR).
    

Detailed description: 
      In 2002, the Philippines changed its antimalarial drug policy to the combination treatment,
      CQ+SP as 1st-line treatment and artemether-lumefantrine as 2nd-line treatment. The DOH
      prescribed the use of artemether-lumefantrine (AL) combination as the second-line drug,
      limiting its use only in the treatment of confirmed Plasmodium falciparum until a further
      study on its efficacy was done before making it the first-line treatment. Consequently, AL
      became the first-line drug for falciparum malaria in the 2009 revised drug policy. The DOH in
      the past 6 years (2002-2007) adopted the use of AL in the highly endemic areas of the country
      and conducted therapeutic efficacy studies (TES) in 3 sentinel sites: Kalinga-Isabela,
      Palawan, and several Mindanao provinces showing 97-100% efficacy. Whereas CQ+SP showed
      variability and declining efficacy, results ranged from 70%-95% (CARAGA region). In Sultan
      Kudarat province, results in 2006-2007 showed 90% efficacy of CQ+SP and 96% for AL for
      falciparum malaria.

      In the 2009 drug policy, chloroquine (CQ) remains the primary treatment for P. vivax malaria,
      with primaquine as an anti-relapse drug. Previous studies (1999-2005) elsewhere in the
      country have shown 100% efficacy of CQ or the CQ+PQ combination. However, in 2011, a
      recurrence of parasitemia was observed in one of 117 enrolled patients in Palawan. The last
      TES of AL as a first-line drug of choice for falciparum malaria was made in 2007. This study
      will update this drug's efficacy for this parasite.

      STUDY OBJECTIVES The general objective of this study is to assess the therapeutic efficacy
      and safety of artemether-lumefantrine for the treatment of uncomplicated P. falciparum
      infections in Palawan province, the Philippines in 2015.

      The specific objectives are:

        1. To measure the clinical and parasitological efficacy of artemether-lumefantrine (AL)
           among patients aged between > 6 months and 59 years old suffering from uncomplicated
           falciparum malaria, by determining the proportion of patients with Early Treatment
           Failure (ETF), Late Clinical Failure (LTF), Late Parasitological Failure (LPF), or with
           an Adequate Clinical and Parasitological Response (ACPR) as indicators of efficacy;

        2. To evaluate the incidence of adverse events;

        3. To formulate recommendations to enable the Department of Health to make informed
           decisions about the possible need for updating of the current national antimalarial
           treatment guidelines.

      MATERIALS AND METHODS. The design of this surveillance study is a one-arm, prospective
      evaluation of the clinical and parasitological response to directly observed treatment for
      uncomplicated falciparum. Individuals with uncomplicated malaria who met the study inclusion
      criteria were enrolled, treated on-site with AL, and monitored for a period of 28 days if
      they had falciparum malaria. The follow-up consisted of a fixed schedule of check-up visits
      and corresponding clinical and laboratory examinations. Study patients had been classified as
      therapeutic failures (early or late) or adequate responders based on the results of these
      assessments. The proportion of patients experiencing a therapeutic failure during the
      follow-up period had been used to estimate the efficacy of the study drug(s). Polymerase
      Chain Reaction (PCR) analysis will also help distinguish between a true recrudescence due to
      treatment failure and episodes of re-infection.

      Barangay Health Workers and Barangay Malaria Microscopists were mobilized to recruit febrile
      patients (patients with body temperature ≥37.5 °C). Screened individuals were re-examined at
      the main health center for malaria symptoms, body temperature, and weight. All laboratory
      procedures and tests were carried out by trained staff.

      STUDY AREA / SETTINGS. The study was conducted in the Rural Health Units (RHU) of Rizal,
      Bataraza, and Brookes Point. Several factors influenced the selection of sites: (a) adequate
      numbers of patients with symptomatic, uncomplicated P. falciparum; (b) willingness and
      availability of the selected healthcare facility staff to participate in the trial and to
      support the work with laboratory space; (c) access of patients to the health facility for
      weekly follow-ups; and (d) willingness of the Municipality Health Officer (MHO), the nurse
      and a trained Medical Technologist to take responsibility for conducting the trail, and
      security.

      An attempt was made to include Panglima-Sugala, Tawi-Tawi as a TES site. Health staff was
      trained in malaria microscopy and TES procedures. However, no evaluable subject was enrolled
      for a period of seven months. Arrangements were made to conduct a limited survey to confirm
      the low number of cases. In the end, it was decided that the site be closed.

      STUDY PARTICIPANTS. The population of interest consisted of patients aged between > 6 months
      to 59 years old diagnosed with uncomplicated falciparum malaria attending the study health
      clinic and having given, or whose parents or legal guardians had given informed consent for
      study inclusion and assent in children as appropriate.

      ETHICAL CONSIDERATIONS Participants were recruited after the study received favorable
      approval of the protocol, participant information sheet, and written informed consent form
      from RITM Institutional Review Board (IRB). The study document versions given written
      approval by the IRB were used. The study was carried out according to the ethical guidelines
      in the Declaration of Helsinki (version 2008), applicable guidelines of ICH-GCP (E6); and
      applicable regulations of the Department of Health, Manila. The participant's written
      informed consent was secured before enrolment and prior to initiating procedures specific to
      this study. For potential participants below 18 years old, this consent was obtained from
      either parent or a legally accepted guardian. An independent witness was present during the
      process of obtaining informed consent from a participant or parents/legal guardian who was
      illiterate.
    

Intervention name(s): Artemether-lumefantrine; Primaquine
Intervention type(s): Drug; Drug
Intervention description(s): Artemether-lumefantrine will be administered for 3 days according to body weight (Days 0 and 8 hours after, 1 and 2). Dosage depending on body weight or age if weight cannot be determined.
Dosage: 1 tablet contains 20 mg artemether and 120 mg lumefantrine Dosage per weight: 1 tablet (5 to <16kg); 2 tablets (15 to <25kg); 3 tablets (25 to <35kg), 4 tablets for >35 kg) Dosage per age, if weight cannot be determined: 1 tablet (6 months old to 3 years old); 2 tablets (4 to 8 years old); 3 tablets (9-13 years old), 4 tablets (>13 years old); For Pf patients, primaquine at 0.75 mg base/kg body weight single dose will be given on Day 3 for Pf patients; For Pv patients primaquine will be withheld for 28 days and will be given after Day 28 follow-up, at 0.25 mg base/kg per day for 14 days.
Other intervention name(s): Coartem
Intervention MeSH terms: Lumefantrine; Artemether; Primaquine; Artemether, Lumefantrine Drug Combination
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        The population of interest consists of patients aged between > 6 months to 59 years old
        diagnosed with uncomplicated falciparum malaria attending the study health clinic, and
        having given, or whose parents or legal guardians have given informed consent for study
        inclusion and assent in children as appropriate.
      
Biospecimen description: 
      Capillary blood (malaria blood film and filter paper)
    
Keywords: MALARIA; TES; Plasmodium falciparum; Artemether-lumefantrine