Please select the eligibility criteria that correspond to the clinical trial below.
Title: Phase III Comparative, Open-labelled, Randomised, Clinical Study to Assess a Fixed Dose of Oral Pyronaridine Artesunate Granule Formulation vs. Coartem® Crushed Tablets in Infants With Acute Uncomplicated Plasmodium Falciparum Malaria
Brief Summary: The primary objective of this Phase III clinical study is to demonstrate the efficacy of the fixed combination of pyronaridine artesunate (PA) granule formulation (60:20 mg; pediatric PYRAMAX®) by showing a PCR-corrected adequate clinical and parasitological cure rate (ACPR) of more than 90%.

Secondary objectives of this clinical study are to compare the efficacy (non-inferiority) and safety of the PA granule formulation compared to Coartem® (ie, the combination of artemether/lumefantrine \[AL\]) crushed tablets in a paediatric population and to assess the safety of the PA granule formulation.


Options:
A: Inclusion Criteria:

Patients presenting with symptoms of acute uncomplicated falciparum malaria with the following inclusion criteria:

* Male or female children, being between 2 and 14 years of age inclusive
* Weight between 10 and 40 kg inclusive
* Written informed consent, in accordance to local practice, provided by parent/guardian. If the parent/guardian is unable to write, witnessed consent is permitted according to local ethical considerations. Where possible, parent assent will be sought
* Absence of severe malnutrition (defined as mid upper arm circumference \<110mm)
* Presence of acute symptomatic uncomplicated P. falciparum malaria with a diagnosis confirmed by a positive blood smear with asexual forms of P. falciparum only (i.e. no mixed infection) plus measured temperature of ≥37.5°C (depending on method of measurement as below) or history of fever within the past 24 hours :
* the acceptable range is between 1,000 and 200,000 asexual parasite count/μl of blood and
* axillary/tympanic temperature of ≥37.5°C or oral/rectal temperature of ≥38.0°C
* Females of childbearing potential are not allowed to be pregnant or lactating and must be willing to use adequate measures of contraception during the study period
* Ability to comply with the study visit schedule and the study protocol for the duration of the study

Exclusion Criteria:

* Patients with signs and symptoms of severe/complicated malaria requiring parenteral antimalarial treatment according to the WHO Criteria 2000
* Mixed Plasmodium infection
* Severe vomiting, defined as \>3 times in the 24 hours prior to inclusion in the study or inability to tolerate oral treatment, or severe diarrhoea defined as \>3 watery stools per day
* Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia, acute QTc interval greater or equal to 450 msec), respiratory (including active tuberculosis), hepatic, renal, gastrointestinal, immunological (including active HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric or other abnormality (including head trauma)
* Presence of febrile conditions caused by diseases other than malaria
* Known history of hypersensitivity, allergic or adverse reactions to pyronaridine or artesunate or other artemisinins
* Use of any other antimalarial treatment within 2 weeks prior to start of the study as confirmed by Lignin test and Saker Solomon urine test
* For females of childbearing potential, positive urine pregnancy test or lactating
* Use of an investigational drug within the past 8 weeks
* Known active Hep A immunoglobulin, Hep B surface antigen, or Hep C antibody
* Known seropositive HIV antibody
* Liver function tests (aspartate aminotransferase \[AST\] or alanine aminotransferase \[ALT\] levels) \>3 times the upper limit of normal
* Known significant renal impairment as indicated by a serum creatinine ≥2 mg/dL
* Previous participation in this clinical study
B: Inclusion Criteria:

1. Male or female patients ≤12 years of age.
2. Body weight ≥ 5 kg and \< 25 kg with no clinical evidence of severe malnutrition (defined as a child whose weight-for-height is below -3 standard deviations or \<70% of the median of the NCHS/WHO normalised reference values).
3. Presence of acute uncomplicated P. falciparum mono-infection confirmed by:

   1. Fever, as defined by axillary temperature ≥37.5°C or oral/tympanic/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 200,000 asexual parasite count/µl of blood.
4. Written informed consent, in accordance with local practice, provided by parent/guardian. If the parent/guardian is unable to write, witnessed consent is permitted according to local ethical considerations. Where possible, patient assent will be sought.
5. Ability to swallow whole volume of liquid in which medication is suspended.
6. 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.
7. Ability and willingness to participate based on information given to parent or guardian and access to health facility. The patient is to comply with all scheduled follow up visits until D42.

Exclusion Criteria:

1. Patients with signs and symptoms of severe/complicated malaria requiring parenteral treatment according to the World Health Organization Criteria 2000 \[Attachment 3\].
2. Mixed Plasmodium infection.
3. Severe vomiting, defined as \>3 times in the 24 hours prior to inclusion in the study or inability to tolerate oral treatment, or severe diarrhoea defined as ≥3 watery stools per day.
4. Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia, QTc interval ≥450 milliseconds), respiratory (including active tuberculosis), history of jaundice, hepatic, renal, gastrointestinal, immunological (including active HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric, history of convulsions or other abnormality (including recent head trauma).
5. Presence of significant anaemia, as defined by Hb \<8 g/dL.
6. Presence of febrile conditions caused by diseases other than malaria.
7. Known history of hypersensitivity, allergic or adverse reactions to pyronaridine, lumefantrine or artesunate or other artemisinins.
8. Patients with known disturbances of electrolytes balance, e.g. hypokalaemia or hypomagnesaemia.
9. Use of any other antimalarial agent within 2 weeks prior to start of the study as evidenced by reported patient history.
10. Pregnant or breastfeeding.
11. Patients taking any drug which is metabolised by the cytochrome enzyme CYP2D6 (flecainide, metoprol, imipramine, amitriptyline, clomipramine).
12. Received an investigational drug within the past 4 weeks.
13. Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab).
14. Known positive for HIV antibody.
15. Liver function tests \[ASAT/ALAT levels\] \>2.5 times upper limit of normal range.
16. Known significant renal impairment as indicated by serum creatinine of \>1.4 mg/dL.
17. Previous participation in any clinical study with pyronaridine artesunate.
C: Inclusion Criteria:

* Male or female patients between the ages 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 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, mefloquine or artesunate or other artemisinins.
* Use of any other antimalarial agent within 2 weeks prior to start of the study as evidenced by 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.
* Presence of significant renal or hepatic impairment.
* Receipt of an investigational drug within the past 4 weeks.
* Known active Hepatitis A IgM, Hepatitis B surface antigen or Hepatitis C antibody.
* Known seropositive HIV antibody.
* Previous participation in any clinical study with PA.
D: 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

Answer: B