Evaluation of Oral Activated Charcoal on Antimalarial Drug's Ability to Kill Parasites in Malian Children With Malaria
Condition: Malaria; Severe Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

      - Malaria is caused by small parasites carried by some mosquitoes. People can get malaria if
      an infected mosquito bites them. Malaria destroys red blood cells. Most malaria is mild, but
      some children develop severe malaria, which kills about 660,000 people annually. About 9 in
      10 who die of malaria are Sub-Saharan African children, most under 5 years old. Scientists
      can save many lives if they find out how to prevent or relieve severe malaria.

      Objective:

      - To know if a common medicine called activated charcoal can reduce severe malaria symptoms.

      Eligibility:

      - Children 2 to 11 years old with mild malaria who live in Kenieroba, Mali.

      Design:

        -  For the first 2 days and nights, participants will stay in the hospital.

        -  They will have their medical history taken, and a physical exam.

        -  Blood will be drawn from a thin tube inserted in their hand or forearm. This will be
           done 3 times overall. A drop of blood will be taken from a finger prick 12 times
           overall.

        -  An antimalarial drug will be injected into the tube in the arm 4 times. Each time the
           drug is given, participants will drink a small cup of either water or activated
           charcoal.

        -  For the following 3 days, participants will take an antimalarial pill.

        -  On day 7, participants will visit the hospital. A drop of blood from a finger prick will
           be tested for malaria parasites.
    

Detailed description: 
      While the incidence of Plasmodium falciparum malaria declines (1) the proportion of cases
      with severe malaria (SM) may increase (2). The mortality associated with SM in endemic
      countries remains high despite the use of artesunate (AS) (3). Safe, cheap, and effective
      adjunct therapies preventing the development of, or reducing the mortality from, SM could
      have considerable and rapid public health impact. We discovered that oral administration of
      activated charcoal (oAC), a safe treatment for acute poisoning (4), protects mice from
      experimental cerebral malaria and demonstrated in a randomized controlled trial (RCT) in
      African adults that oAC is safe and does not interfere with the pharmacokinetics of AS (5).
      Here, we propose the next step to evaluate the efficacy of adjunct treatment with oAC in
      Malian children and to explore its mode of action. Before testing adjunct treatment with oAC
      in children with SM, we will perform an open-label RCT in children with uncomplicated malaria
      (UM) to demonstrate non-inferiority of intravenous (IV) AS plus adjunct oAC vs. IV AS alone
      with regards to parasite clearance rate. This study will be conducted in African children,
      because they are the primary target population for such an intervention. Although the
      adequate standard-of-care treatment for UM is oral (PO) administration of an
      artemisinin-based combination therapy (ACT), we will treat participants with IV AS. Like ACT
      treatment of UM, AS is the WHO-recommended first-line treatment for SM (1). In order for the
      data obtained from UM cases to be meaningful for our future studies in children with SM, we
      will administer AS to the UM cases in this trial via the same IV route that is used to
      administer AS to SM cases. Exploratory objectives include: (i) to compare the kinetics of
      plasma cytokines in both groups, and (ii) to preserve RNA for gene transcription analysis for
      future studies into the mode of action of oAC. The study will be nested within an
      NIAID-funded study (Principal Investigators Drs. Fairhurst, Diakite) that assesses parasite
      clearance rates in response to AS treatment in Kenieroba (6). Children aged 2-10 years with
      UM and initial parasite densities 10,000 70,000 parasites per micro L will be enrolled.
      Parasite clearance rates will be expressed as the parasite half-life (Ph), estimated from
      parasite clearance curves using a formula that has been validated in this cohort (7).
      Children will be randomized 1:1 to receive IV AS+oAC or IV AS only, respectively, until
      complete specimen and data sets for 35 children per group are obtained. oAC will be
      administered as Actidose Aqua[registered] at 0, 6, 12, and 18 hours. AS will be administered
      IV following WHO recommendations for use of AS in SM (8), followed by 3 daily doses of
      amodiaquine (AQ). Subsequently and in a separate study, we plan a proof-of-concept RCT to
      determine whether adjunct oAC reduces disease severity and morbidity (assessed by scoring
      systems (9)) in hospitalized children with SM and to define the mode of action of oAC. Since
      oAC is a licensed, inexpensive drug without sophisticated storage requirements, which has an
      extremely long shelf life at room temperature and can be given orally or via nasogastric tube
      at high doses without major side effects (4, 10), this drug has an ideal profile for use at
      the primary health-care level to reduce mortality from SM, or even prevent the development of
      SM.
    

Intervention name(s): Actidose Aqua; Artesunate; Amodiaquine
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Actidose Aqua (oAC) (Paddock Laboratories is sold over the counter in the United States in bottles containing 25 g/120 mL (NDC # 0574-0121-04) or 50 g/240 mL (NDC # 0574-0121-08). oAC is stable at room temperature.; Artesunate (AS) obtained from Guilin Pharma (Shanghai), the only pharmaceutical company GMP pre-qualified by the WHO. The product artesunate for injection + 5% sodium carbonate inj + 0.9% sodium chloride inj will be delivered in vials of 30 mg and 60- mg vials, respectively, and will be dosed at 2.4 mg/kg as recommended for SM treatment by the WHO; Amodiaquine obtained from Pfizer (Dakar), is provided as 200-mg tablets or syrup (50 10 mg/mL), and will be provided as age-based doses per the manufacturer's directions.
Other intervention name(s): Oral activated charcoal; Artesunate for injection; Camoquine
Intervention MeSH terms: Artesunate; Amodiaquine; Charcoal
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Parasite Clearance Rate; Parasite Half Life; Actidose Aqua; Severe Malaria