Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomised, Multi-Centre, Phase II, Dose-ranging Clinical Study to Assess the Safety and Efficacy of Fixed Dose, Orally Administered Pyronaridine and Artesunate (3:1) in Adult Patients With Acute Uncomplicated Plasmodium Falciparum Malaria
Brief Summary: The primary trial objective is to determine the clinically effective dose of orally administered pyronaridine/artesunate (Pyramax®, PA) with a 3:1 ratio to treat adults with acute, symptomatic, uncomplicated P. falciparum malaria in South East Asia and Africa. Secondary trial objectives are to determine the safety of once-daily dosing for 3 days of PA and to explore possible ethnic differences in safety or efficacy.


Options:
A: Inclusion Criteria:

1. Male or female patients between the age of 15 and 60 years of age inclusive
2. Written informed consent, in accordance with local practice, provided by patient and/or parent/guardian/spouse. If the patient is unable to write, witnessed consent is permitted according to local ethical considerations
3. Absence of severe malnutrition (defined as the weight-for-height being below -3 standard deviations or \<70% of the median of the NCHS/WHO normalized reference values)
4. Weight of between 35 kg and 75 kg inclusive
5. 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 history of fever within the previous 24 hours or a measured temperature of ≥37.5°C (depending on method of measurement):

   * the acceptable range is between 1,000 and 100,000 asexual parasite count/μl of blood and
   * axillary/tympanic temperature of ≥ 37.5°C or oral/rectal temperature of ≥ 38.0°C
6. Ability to swallow oral medication
7. Ability to comply with study visit schedule: patients will be hospitalised for at least 4 days and will be required to remain in the vicinity of the trial site for a minimum of 7 days or until clearance of fever and parasite for at least 24 hours, whichever is the later. The patient is to return to the study site or to make themselves available for all scheduled follow up visits, until discharge at Day 42.
8. Females must not be pregnant or lactating and be willing to take measures to not become pregnant during the study period
9. Willingness and ability to comply with the study protocol for the duration of the study

Exclusion Criteria:

1. Patients with signs and symptoms of severe/complicated malaria requiring parenteral treatment according to the World Health Organization Criteria 2000
2. Mixed Plasmodium infection
3. Severe vomiting, defined as \>3 times in the 24 hours prior to inclusion in the trial or inability to tolerate oral treatment
4. Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia), respiratory (including active tuberculosis), hepatic, renal, gastrointestinal, immunological (including active HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric or other clinically important abnormality (including head trauma).
5. Presence of febrile conditions caused by diseases other than malaria
6. Known history of hypersensitivity, allergic or adverse reactions to pyronaridine or artesunate or other artemisinins
7. Evidence of use of any other antimalarial agent within 2 weeks prior to the start of the study confirmed by a negative urine test or using Eggelte dipsticks
8. Positive urine pregnancy test or lactating
9. Received an investigational drug within the past 4 weeks
10. Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab)
11. Known seropositive HIV antibody
12. Liver function tests \[ASAT/ALAT levels\] \>2.5 times upper limit of normal values
13. Known significant renal impairment as indicated by a serum creatinine of ≥ 1.4 mg/dl
14. Previous participation in this clinical trial
B: 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.
C: Inclusion Criteria:

* Adults and children ≥ 20 kg
* Symptomatic of malaria infection, i.e. history of fever within 24 hours and/or presence of fever \>37.5°c.
* Microscopic confirmation of asexual stages of P. falciparum (P. falciparum and mixed infection in Pailin only)
* Capability of taking an oral medication
* Written informed consent given to participate in the trial
* Willingness and ability to adhere to follow-up visit schedule

Exclusion Criteria:

* Pregnancy or lactation (urine test for β HCG to be performed on any woman of child bearing age, that is 18 to 45 y/o)
* Female aged 12-18y
* Parasitemia \> 150 000/µL).
* Signs or symptoms indicative of severe malaria:

  * Impaired consciousness (Blantyre Coma Score \<5)
  * Severe anaemia (Hct\<15%)
  * Bleeding disorder -evidenced by epistaxis, bleeding gums, frank haematuria, bleeding from venepuncture sites
  * Respiratory distress
  * Severe jaundice
* Known hypersensitivity to artemisinins - defined as history of erythroderma/other severe cutaneous reaction, angioedema or to pyronaridine
* History of splenectomy
* Known history or evidence of clinically significant disorders, such as:

  * Known active Hepatitis A, e.g. by detection of anti HAV-IgM.
  * Known hepatitis B surface antigen (HBsAg) carrier.
  * Known hepatitis C antibody (HCV Ab).
  * Liver function tests (AST/ALT levels) more than 2.5 times the upper limit of normal range.
D: 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

Answer: A