TES of Artemether-lumefantrine for Pf and Chloroquine for Pv in the Philippines From 2013-2014
Condition: Malaria; Falciparum Malaria; Vivax Malaria; Malaria Recrudescence
MeSH terms: Malaria; Malaria, Falciparum; Malaria, Vivax; Recurrence
Study type: Observational

Summary: 
      An antimalarial drug efficacy trial was conducted for artemether-lumefantrine (AL) and
      chloroquine (CQ) in the three (3) municipalities (Bataraza, Brookes and Rizal) of Palawan.
      Study subjects are febrile individuals between > 6 months old and 59 years old with confirmed
      uncomplicated P. falciparum or P. vivax infections. Patients with P. falciparum was treated
      with Artemether-lumefantrine administered 3 days (Days 0, 1 and 2) according to body weight.
      Primaquine at 0.75 mg base/kg body weight single dose was given on Day 3. For Plasmodium
      vivax patients chloroquine were administered according to body weight at a total dose of 25
      mg/kg over 3 days (10 mg/kg on Day 0; 10 mg/kg on Day 1 and 5 mg/kg on Day 2), and primaquine
      following the National Treatment Guidelines.

      During the period that this report covers, 84 and 75 patients met the inclusion criteria for
      Pf and Pv respectively. Clinical and parasitological parameters were monitored over a 28-day
      follow-up period for both drugs.

      The presence of only 1 Late Clinical Failure (LCF) of P. falciparum parasitemia out of 84
      enrolled patients and 2 Late Parasitological Failure (LPF) of P. vivax patients out of 75
      enrolled patients within the 28 days follow up suggest that both drugs are still efficacious.
    

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 as 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, 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 and that of P. vivax.

      STUDY OBJECTIVES The general objective of this study is to assess the therapeutic efficacy
      and safety artemether-lumefantrine for the treatment of uncomplicated P. falciparum
      infections and of chloroquine for the treatment of P. vivax infections in Palawan province,
      the Philippines from 2013-2014.

      The specific objectives are:

        -  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;

        -  To measure the clinical and parasitological efficacy of Chloroquine among patients aged
           between > 6 months and 59 years old suffering from vivax malaria, by determining the
           proportion of patients with clinical and parasitological failure, or with an Adequate
           Clinical and Parasitological Response (ACPR) as indicators of efficacy;

        -  To evaluate the incidence of adverse events;

        -  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.

      STUDY DESIGN 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 and vivax malaria. Individuals with uncomplicated malaria who meet the study
      inclusion criteria will be enrolled, treated on-site with AL, and monitored for a period of
      28 days if they have falciparum malaria, and with chloroquine if with vivax malaria, and
      monitored for a period of 28 days. The follow-up consists of a fixed schedule of check-up
      visits and corresponding clinical and laboratory examinations. Study patients have 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 has 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.

      STUDY AREA The study was conducted in the Rural Health Units (RHU) of Bataraza, Brookes
      Point, and Rio Tuba Nickel Foundation Inc. Hospital (RTNFI). However, due to the difficulty
      of recruiting patients in RTNFI, recruitment was stopped in October 2013 and was replaced by
      the RHU of Rizal. Several factors influenced the selection of sites: adequate numbers of
      patients with symptomatic, uncomplicated P. falciparum or P. vivax malaria; willingness and
      availability of the selected health care facility staff to participate in the trial and to
      support the work with laboratory space; access of patients to the health facility for weekly
      follow-ups; availability of the Municipality Health Officer (MHO), the nurse and a trained
      Medical Technologist to take responsibility for conducting the trail, and security.

      SAMPLE SIZE Treatment failure to AL in the area being 0-5 %, 5% has been chosen as the
      estimated therapeutic failure rate of the drug. At a confidence level of 95% and with
      precision around the estimate of 10%, 18 patients will be needed. With a 20% increase to
      allow losses to follow-up and withdrawals during the 28-day follow-up period, 22 patients
      need to be included. But in order for the sample to be representative, a minimum of 50 P.
      falciparum and 50 P. vivax patients need to be included and a maximum of 75 patients for
      Plasmodium falciparum and 75 Plasmodium vivax will be enrolled.

      SAMPLING TECHNIQUE All individuals who consulted at the selected rural health units met the
      inclusion criteria and had none of the exclusion criteria were included in the study.

      DATA MANAGEMENT The principal investigator has ensured that the study protocol is strictly
      adhered to throughout and that all data are collected and recorded correctly on the CRF.
      Laboratory and clinical data have been recorded on a daily basis in the CRF designed for the
      study. Data that are derived from source documents are consistent with the source documents
      or the discrepancies were explained. Any changes or corrections to a CRF were dated and
      explained and did not obscure the original entry. All CRF was checked for completeness. After
      the study was completed, data were entered onto a database using double independent data
      entry. The data were stored in a computer database maintaining confidentiality in accordance
      with the national data legislation.

      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): Arthemeter-lumefantrine; Chloroquine; Primaquine
Intervention type(s): Drug; 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); Chloroquine will be administered according to body weight at a total dose of 25 mg base/kg over 3 days (10 mg base/kg on Day 0; 10 mg base/kg on Day 1 and 5 mg base/kg on Day 2). Correct drug dosage will be determined using the dosing chart (in accordance with national treatment guidelines); 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: Chloroquine; Lumefantrine; Primaquine
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 and vivax malaria attending the study health
        clinic, and having given, or whose parents or legal guardians have given an 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; Plasmodium vivax; Chloroquine