Please select the eligibility criteria that correspond to the clinical trial below.
Title: Clinical Investigation of In-vivo Susceptibility of P.Falciparum to Artesunate in Western Cambodia
Brief Summary: There are worrying signs that parasitological responses to the artemisinin drugs for uncomplicated falciparum malaria are slower than elsewhere in the world.If responses to artesunate are poor it is essential to have characterised the blood concentration profile as well as the parasitological response to differentiate resistance from abnormal pharmacokinetics.

The primary objective of the study is to assess the level of resistance to artemisinin derivatives in Western Cambodia.

A detailed evaluation of 2 different artesunate containing regimens in patients with uncomplicated malaria will be performed. Patients will be randomised to receive either a) Artesunate 2mg/kg/day for 7 days or b) Artesunate 4mg/kg/day for 3 days plus mefloquine 15mg/kg on day 3 and 10mg/kg on day 4 The effect on parasite clearance and cure will be assessed in relation to blood concentrations of the antimalarial drugs ('PK-PD').


Options:
A: Inclusion Criteria:

* Children \>5yrs and adults presenting with acute falciparum malaria (N=40) to Pailin hospital will be eligible for inclusion in this study provided that

  * They or their parents/guardians give fully informed consent.
  * They are not pregnant.
  * They have not received antimalarial drugs in the previous 48 hours.
  * P.falciparum parasitaemia exceeds 10,000/uL

Exclusion Criteria:

* Mixed infection (such as vivax malaria), history of allergy to artesunate or mefloquine, any sign of severe disease according to WHO criteria
B: Inclusion Criteria:

* Male or female patients between the age of 3 and 60 years, inclusive.
* Body weight between 20 kg and 90 kg with no clinical evidence of severe malnutrition.
* Presence of acute uncomplicated P. falciparum mono-infection confirmed by:

  1. Fever, as defined by axillary/tympanic temperature ≥ 37.5°C or oral/rectal temperature ≥ 38°C, or documented history of fever in the previous 24 hours and,
  2. Positive microscopy of P. falciparum with parasite density between 1,000 and 100,000 asexual parasite count/μl of blood.
* Written informed consent, in accordance with local practice, provided by patient and/or parent/guardian/spouse.
* Ability to swallow oral medication.

Exclusion Criteria:

* Patients with signs and symptoms of severe/complicated malaria requiring parenteral treatment according to the World Health Organization Criteria 2000.
* Mixed Plasmodium infection.
* Severe vomiting or severe diarrhoea.
* Known history or evidence of clinically significant disorders.
* Presence of significant anaemia, as defined by Hb \<8 g/dL.
* Presence of febrile conditions caused by diseases other than malaria.
* Known history of hypersensitivity, allergic or adverse reactions to pyronaridine, lumefantrine or artesunate or other artemisinins.
* Patients with known disturbances of electrolytes balance, e.g., hypokalaemia or hypomagnesaemia.
* Use of any other antimalarial agent within 2 weeks prior to start of the study as evidenced by a positive urine test.
* Female patients of child-bearing potential must be neither pregnant (as demonstrated by a negative pregnancy test) nor lactating, and must be willing to take measures to not become pregnant during the study period.
* Patients taking any drug which is metabolised by the cytochrome enzyme CYP2D6 (flecainide, metoprol, imipramine, amitriptyline, clomipramine).
* Received an investigational drug within the past 4 weeks.
* Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen. (HBsAg) or Hepatitis C antibody (HCV Ab).
* Known seropositive HIV antibody.
* Liver function tests \[ASAT/ALAT levels\] \>2.5 times the upper limit of normal range.
* Known significant renal impairment as indicated by serum creatinine \>1.4 mg/dL.
C: Inclusion Criteria:

* Children between 6 months and 12 years old, with a body weight of ≥5 kg;
* Living in the catchment area of the study (within a radius of \~10 km from St. Jude's Clinic, Mbita, Kenya);
* Having microscopically confirmed P. falciparum mono-infection (asexual parasite density 1,000-200,000 µL-1).

Exclusion Criteria:

* Signs and symptoms of severe malaria (according to WHO criteria for severe malaria, (WHO 2012)) or any other severe illness necessitating parenteral treatment;
* Mixed Plasmodium infection;
* Clinically suspected (oedema, jaundice and/or ascites) or reported hepatic and/or renal impairment (any cause, as reported by parents/guardians and/or evident from medical history);
* Having anaemia with an Hb \<6 g/dL;
* Evidence of severe malnutrition (severe wasting: z-score weight for age \<-3 and severe stunting: z-score height for age \<-3 (WHO 2009b));
* Having received anti-malarial therapy in the previous two weeks;
* Known history of hypersensitivity, allergic or adverse reactions to artesunate, artemether-lumefantrine or other artemisinins;
* Participating in other anti-malarial drug intervention studies;
* Previous participation in the PAAL study, e.g. in the previous transmission season (each individual child can only take part in this study once);
* Not being available for follow-up.
D: Inclusion Criteria:

* Uncomplicated malaria (Plasmodia of any species) diagnosed as per national policies and in line with WHO recommendations:

  * Fever or history of fever in the previous 24 h and/or the presence of anaemia, for which pallor of the palms appears to be the most reliable sign in young children.
  * Confirmation of malaria by a parasitological diagnosis (RDT or Microscopy (thick blood smear). analysis).
* Weight ≥5 kg - \< 20 kg (granules); ≥20 kg (tablets).
* Ability to take an oral medication.
* Ability and willingness to participate based on signed informed consent (a parent or a guardian has to sign for children below 18 years old) and on signed assent form for minors that could be required per national regulations in each participating country.
* The patient has to comply with all scheduled follow-up visits.

Exclusion Criteria:

* Patients with clinical signs or symptoms of hepatic injury (such as nausea, abdominal pain associated with jaundice) or known severe liver disease (i.e. decompensated cirrhosis, Child-Pugh stage 3 or 4).
* Known allergy to artemisinin and/or to pyronaridine.
* Known pregnancy.
* Lactating women should be excluded if other anti-malarial treatments are available.
* Complicated malaria as per WHO definition (Annex 2)
* Patients that the investigator considers would be at particular risk if receiving an anti-malarial or if participating in the study.
* Patients having been treated with Pyramax in the previous 28 days.

Answer: A