Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase II, Open-label, Multicentre, Pharmacokinetic, Pharmacodynamics and Safety Study of a New Paediatric Eurartesim Dispersible Formulation and Crushed Film Coated Eurartesim Tablet, in Infant Patients With P. Falciparum Malaria
Brief Summary: There is a need for paediatric formulations that permit accurate dosing and enhance patient compliance. However, for the treatment of malaria, scarce paediatric-friendly formulations are available on the market. Thus, a new water dispersible formulation of eurartesim has been developed for oral administration.

Aim of this study is to provide data on pharmacokinetic profile, safety and efficacy of this new paediatric formulation and compare it with the crushed film coated tablet in infant patients (6 to ≤12 months of age) suffering from uncomplicated Plasmodium falciparum malaria.

Furthermore, a Pharmacokinetic/Pharmacodynamic(PK/PD) modelling will be built up to establish PK/PD relationship in adult and paediatric populations.


Options:
A: Inclusion Criteria:

* Patient is a child between 6 to 59 months
* Visiting health facility for treatment of fever
* Do not have signs of severe disease
* Are not being referred to another health facility
* Living within a defined distance from the health facility (\<8 km/ 5 miles)
* Have not taken part in the study already or are not part of a household that has already taken part in the study
* Responsible caretakers/parents provide additional informed consent

Exclusion Criteria:

-
B: Inclusion Criteria:

* Male and Female infants aged from 6 months to ≤ 12 months included.
* Ability to swallow oral suspension.
* Body weight \>5 kg.
* Uncomplicated malaria, with microscopically confirmed mono-infection by P. falciparum (parasitaemia ≥1000/microL and \<200000/microL).
* History of fever anytime during the preceding 48 hours or presence of fever (axillary temperature ≥37.5 °C or ≥38.0 °C rectally).
* Ability of parents or guardians to understand the nature of the trial and providing signed informed consent.
* Stable residence in the study area during the two months after recruitment and willingness to comply with the study protocol and the study visit schedule.

Exclusion Criteria:

* Antimalarial treatment with amodiaquine, chloroquine, quinine or lumefantrine-based compounds within the previous 6 weeks, with piperaquine-based compound, or mefloquine, or sulphadoxine pyrimethamine within the previous 3 months and with halofantrine within the 30 days prior to screening.
* Any other antimalarial treatment or antibiotics with antimalarial activity (including cotrimoxazol) and any herbal products, within the 7 days prior to screening.
* Severe malnutrition (defined as weight for height \<70% of the median National Center for Health Statistics(NCHS)/WHO reference).
* Severe vomiting or dehydration.
* Presence of jaundice.
* Known hypersensitivity to the artemisinin-based therapy or piperaquine.
* History of relevant clinical allergic reaction of any origin.
* Clinical and/or laboratory features of severe malaria.
* Known moderate/ severe renal or liver insufficiency.
* Evidence of clinically relevant haematological, pulmonary, metabolic-endocrine, neurological, urogenital diseases as judged by the investigator.
* Already diagnosed HIV infection, hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
* Previous admission for, or evidence of symptomatic cardiac arrhythmias or with clinically relevant bradycardia at screening (bpm \< 90).
* Family history of sudden death, or known congenital prolongation of the QT interval, or any clinical condition known to prolong the QT interval.
* ECG abnormality that requires urgent management.
* Any treatment which can induce a lengthening of QT interval.
* Gastrointestinal dysfunction that could alter absorption or motility (i.e. malabsorption syndromes, intestinal sub-occlusion or previous major gastrointestinal surgery).
* Any contraindication to blood sampling.
* Moderate and severe anaemia (Hb \< 7 g/dL).
* Patients who have used any drugs or substances known to be strong inhibitors of Cytochrome P enzymes (formerly known as cytochrome P450 enzymes) within 10 days prior to screening.
* Patients who have used any drugs or substances known to be strong inducers of CYP enzymes (formerly known as cytochrome P450 enzymes)within 28 days prior to screening.
* Children lactated by HIV positive women who are undergoing treatment with antiretroviral drugs.
* Participation in any investigational drug study during the 30 days prior to screening or previously randomised in the present trial.
C: 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.
D: Inclusion Criteria:

* Children aged between 6 and 59 months
* Minimum body weight of 5kg
* Presence of fever (Temp \>/= 37.5°C) or a history of fever in the last 24 hours
* Presence of asexual P. falciparum monoinfection
* Initial parasite density of between 2,000 and 200,000 asexual parasites/µl of blood
* Not suffering from severe and complicated forms of malaria
* Able to take drugs under study by the oral route
* Parent or guardian gives informed written consent to participate in study

Exclusion Criteria:

* Severe and/or complicated malaria (WHO, 2000 classification), including severe anaemia (Hb =/\<5 g/dl), two or more seizures in last 24 hrs and hyper-parasitaemia (\>200,000 µl)
* Patients treated with mefloquine, halofantrine within the 7 days before Day 0 or with quinine salts and artemisinin derivatives within 3 days before Day 0, or artemether-lumefantrine 30 days before Day 0
* Patients who require intensive care for malaria or another severe concomitant illness capable of interfering with the clinical evolution of malaria
* Patients with vomiting and/or diarrhoea
* Signs of severe malnutrition (defined as follows: children with weight/height ratio below 3 standard deviations or below 70% of the median of the WHO standardized reference values, or still with symmetrical oedema affecting both feet)
* Presence of general danger signs in children below 5 years or other signs of serious and complex Plasmodium falciparum, as stated in the present WHO definitions
* Patients with known history of heart disease or arrhythmia
* History of allergy to artemether/lumefantrine or quinine

Answer: B