Evaluation of Oral Activated Charcoal on Antimalarial Drug's Ability to Kill Parasites in Malian Children With Malaria
Evaluation of Oral Activated Charcoal on Antimalarial Drug's Ability to Kill Parasites in Malian Children With Malaria
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.
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.
-  INCLUSION CRITERIA

 1. Age 2 to 10 years, inclusive

 2. Resident of Kenieroba

 3. Uncomplicated malaria*

 4. P. falciparum density 10,000 70,000/micro L, inclusive

 5. Willingness to participate in the study as evidenced by informed consent of the
 child s parent or guardian

 6. Ability to swallow oral medication

 Uncomplicated malaria: axillary temperature >37.5oC or history of fever in the past few
 days and no criteria of SM (see next paragraph) and no other etiologies of febrile illness
 (e.g., respiratory tract infection) on clinical examination.

 Severe P. falciparum malaria: parasitemia of any density and any one of the following: coma
 (Blantyre coma score less than or equal to 2), convulsions (witnessed by investigator),
 severe prostration, severe anemia (hemoglobin less than or equal to 6 g/dl), respiratory
 distress, hypoglycemia (serum glucose less than or equal to 40 mg/dl), jaundice/icterus,
 shock (systolic blood pressure less than or equal to 70 mmHg, rapid pulse, cool
 extremities), cessation of eating and drinking, repetitive vomiting.

 EXCLUSION CRITERIA

 1. Severe malaria

 2. Any medical condition or history, including allergy to AS, AQ, artemether or
 lumefantrine, that poses a risk to the prospective participant

 3. Any condition that in the opinion of the investigator would render the participant
 unable to comply with the protocol (e.g., psychiatric disease)

 4. Any health condition that in the opinion of the investigator would confound data
 analysis or pose unnecessary risks to study participants (e.g., severe malnutrition,
 acquired or inherited immunodeficiency)

 5. Requirement for any medication for any concurrent illness or condition

 6. Participation on cohort study #13-I-N107

 7. Repetitive vomiting