Harmonized AS/MQ Efficacy Study - Thailand
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 4

Summary: 
      The purposes of this study is to determine parasitological clearance rates by microscopy for
      the 72-hour period after first artesunate dose in subjects with uncomplicated P. falciparum
      malaria.
    

Detailed description: 
      Project Summary

      Objectives

      Primary Objective

      1. To determine parasitological clearance rates by microscopy for the 72-hour period after
      first artesunate dose in subjects with uncomplicated P. falciparum malaria

      Secondary Objectives

      2.1. To describe clinical and parasitological outcomes for subjects with uncomplicated P.
      falciparum malaria treated with AS-MQ administered sequentially.

      2.2. To measure the gametocyte carriage rate in subjects with uncomplicated malaria before
      and after treatment.

      2.3. To monitor drug levels associated with artesunate-mefloquine treatment failure.

      2.4. To determine in vitro drug sensitivity profiles for fresh parasites from
      malaria-infected subjects prior to artesunate-mefloquine treatment and at the time of
      parasite recurrence.

      2.5. To identify specific genetic determinants of artemisinin resistance derived from
      parasite populations.

      2.6. To correlate clinical outcomes from the in vivo study with in vitro antimalarial drug
      sensitivity responses and molecular genotyping.

      2.7. To compare P. falciparum malaria artemisinin resistance genotypes at three sites in
      three continents, using clinical and parasitological outcomes, in vitro drug sensitivity
      profiles, and molecular markers generated using harmonized methodologies.

      2.8. To determine the contribution of host immunity to parasitological and clinical outcomes.

      2.9. To create a catalog of parasite samples closely correlated to clinical datasets to
      longitudinally track resistance trends.

      Subject Population

      Subjects aged 5-65 years, who meet study entry criteria will be drawn from the local
      community.

      Study Site

      The study will be based at the Kwai River Christian Hospital (KRCH) in Sangklaburi District,
      Kanchanaburi Province, Thailand, which is located about 360km northwest of Bangkok near the
      Thailand-Myanmar border. Additional sites in Thailand, including in Sai Yok District,
      Kanchanaburi Province, may be added if enrolment at Sangklaburi is insufficient.

      Number of Subjects

      Up to 100 subjects will be enrolled to ensure a minimum of 59 subjects complete all study
      activities. This will allow for 40% subjects dropping out or being otherwise unevaluable. Up
      to 200 subjects may be screened to achieve the required number of evaluable subjects. A
      subject is considered evaluable at 72 hours from the commencement of artesunate treatment or
      once asexual parasites have been cleared from peripheral blood based on microscopy, whichever
      is longer.

      Treatment

      The antimalarial drug regimen being evaluated is: artesunate (AS) 4mg/kg by mouth once daily
      at 0, 24 and 48 hours; plus mefloquine (MQ) 15mg/kg by mouth once at 72 hours, and 10mg/kg
      once by mouth at 84-96 hours; plus primaquine (PQ) 0.5mg/kg single dose by mouth at 84-96
      hours.

      Study Design and Methodology

      This is an open-label, single-arm evaluation of AS-MQ combination for the treatment of
      uncomplicated P. falciparum malaria. Subjects will remain as in-patients until completion of
      antimalarial treatment and will then be followed up weekly to 42 days.

      Study Endpoints

      Primary Endpoint

      1. Parasite clearance rate as defined by the slope of the linear portion of the logarithm
      parasite clearance curve using microscopy to determine parasitemia

      Secondary Endpoints

      2.1. A description of the clinical and parasitological features of uncomplicated malaria in
      this setting (composite endpoint), including:

        -  Parasite clearance rate during the first 72 hours after artesunate administration as
           defined by the slope of the linear portion of the logarithm parasite clearance curve
           using qPCR to determine parasitemia

        -  Parasite reduction ratios at 24 and 48 hours assessed by microscopy and qPCR

        -  Time for parasite count to fall to 50%, 90%, 99% and 100% of initial parasite density

        -  Fever clearance time (i.e. the time taken for temperature to fall below 38.0˚C (tympanic
           method) or below 37.5˚C (axillary method) and remain there for at least 24 hours)

        -  42-day PCR-adjusted treatment efficacy using World Health Organization classification of
           outcome.

      2.2. Gametocyte carriage rates assessed in person weeks (up to 42 days) 2.3. Plasma levels of
      AS, DHA and MQ at selected time points 2.4. In vitro IC50, IC90, IC99 P. falciparum responses
      to a panel of antimalarial drugs, including dihydroartemisinin (DHA) and mefloquine.

      2.5. Parasite molecular markers of drug resistance as determined by GWAS, SNP analysis and
      other genotyping methodologies 2.6. A detailed characterization of drug-resistant malaria
      using integrated endpoints above, including clinical, in vitro and molecular 2.7. Comparison
      of clinical and parasitological outcomes and in vitro and molecular features of parasites
      between harmonized sites in Kenya and Peru.

      2.8. Identification of host factors that correlate with slow parasite clearance and other
      clinical outcomes 2.9. Creation of a well-characterised catalog of malaria parasites for
      future research
    

Intervention name(s): Artesunate/mefloquine (AS/MQ)
Intervention type(s): Drug
Intervention description(s): artesunate (AS) 4mg/kg by mouth once daily at 0, 24 and 48 hours
mefloquine (MQ) 15mg/kg by mouth once at 72 hours, and 10mg/kg once by mouth at 84-96 hours
primaquine (PQ) 0.5mg/kg single dose by mouth at 84-96 hours
Other intervention name(s): Mequin
Intervention MeSH terms: Artesunate; Mefloquine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: P.f Malaria, Artemisinin resistance, ACT treatment failure