TES of Chloroquine for Pv in the Philippines in 2016
Condition: Malaria; Vivax Malaria; Recrudescence
MeSH terms: Malaria; Malaria, Vivax; Recurrence
Study type: Observational

Summary: 
      Chloroquine (CQ) is officially used as a first-line drug of Plasmodium vivax malaria in the
      Philippines. In this study, the therapeutic efficacy of CQ for the treatment of uncomplicated
      P. vivax malaria in three (3) municipalities (Bataraza, Brooke's Point and Rizal) of Palawan
      was evaluated using the World Health Organization protocol with a follow-up of 28 days and
      additional 2 days (Day 31 and 34) for hemoglobin monitoring after primaquine treatment. Study
      subjects were febrile individuals between > 6 months old and 59 years old with confirmed
      uncomplicated P. vivax infections. Chloroquine was 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 1 year period that
      this report covers, there were 8,305 individuals were screened.
    

Detailed description: 
      In 2002, the Philippines changed its antimalarial drug policy to a combination treatment,
      CQ+SP as the 1st-line treatment and artemether-lumefantrine as the 2nd-line treatment. The
      DOH prescribed the use of an 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. Furthermore, in the
      2013-2014 study, recurrence of parasitemia was observed in two of 75 enrolled patients in
      Palawan. This study updates the drug efficacy for P. vivax malaria in the country.

      STUDY OBJECTIVES The general objective of this study is to assess the therapeutic efficacy
      and safety of chloroquine for the treatment of P. vivax infections in Palawan province, the
      Philippines in 2016.

      The specific objectives are:

        1. 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 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
      vivax malaria. Individuals with vivax malaria who met the study inclusion criteria were
      enrolled, treated on-site with CQ+PQ, and monitored for a period of 28 days. 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
      distinguishes 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, P. vivax; (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 trial, and security.

      STUDY PARTICIPANTS. The population of interest consisted of patients aged between > 6 months
      to 59 years old diagnosed with uncomplicated vivax 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.

      SAMPLE SIZE. Treatment failure to CQ 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.
      vivax patients need to be included and a maximum of 75 Plasmodium vivax were enrolled.

      SAMPLING TECHNIQUE. All individuals who consulted at the selected rural health units met the
      inclusion criteria and had none of the exclusion criteria 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 into 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 the
      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): Chloroquine; Primaquine
Intervention type(s): Drug; Drug
Intervention description(s): 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; 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.
Intervention MeSH terms: Chloroquine; 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 vivax 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 vivax; Chloroquine