Please select the eligibility criteria that correspond to the clinical trial below.
Title: Monitoring and Evaluation of the Therapeutic Efficacy and Safety of Pyronaridine-artesunate for the Treatment of Uncomplicated Falciparum Malaria in Western Cambodia, an Area of Artemisinin-resistant Falciparum Malaria
Brief Summary: This study is a prospective, single arm, open-labelled clinical trial. The total number subjects will be 145 patients to receive Pyronaridine-artesunate once daily for 3 days. Dosing will be according to the body weight.

All patients will have a blood smear examined daily during the first week by microscopy until parasite clearance (2 consecutive negative slides on two consecutive days; both asexual and sexual stages). A negative blood slide will be defined as parasite count negative per 1000 WBC in two consecutive days. The sample on day 3 will be taken as close as possible to 72h after the initial blood smear.

Participant will follow up for 42 days to assess the drug efficacy and safety (Day 7, 14, 21, 28, 35 and 42).


Options:
A: 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.
B: 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.
C: 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
D: 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.

Answer: D