Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multi-centre, Randomised, Double-blind, Double Dummy Study Comparing the Efficacy and Safety of Chlorproguanil-dapsone-artesunate Versus Artemether-lumefantrine in the Treatment of Acute Uncomplicated Plasmodium Falciparum Malaria in Children and Adolescents in Africa.
Brief Summary: Chlorproguanil-dapsone has been approved for the treatment of uncomplicated Plasmodium falciparum malaria in a number of countries across sub-Sahara Africa, and by the UK's Medicines and Healthcare products Regulatory Agency.

CDA is a combination of chlorproguanil, dapsone and artesunate, being developed in a public-private partnership with the Medicines for Malaria Venture (MMV), World Health Organisation (WHO-TDR) and academic partners from the London School of Hygiene and Tropical Medicine, University of Liverpool and the Liverpool School of Tropical Medicine as a treatment for acute uncomplicated P. falciparum malaria.

The combination of chlorproguanil-dapsone-artesunate (CDA) is being developed to supersede chlorproguanil-dapsone for the same indication, but the addition of an artemisinin derivative, artesunate, should provide additional population benefits over chlorproguanil-dapsone alone. The artemisinins have been demonstrated to rapidly reduce parasite load and have activity against the sexual stages of the P.falciparum lifecycle. The addition of a second agent to the chlorproguanil-dapsone combination should also protect against the selection of resistant strains of P.falciparum.

Artemether-lumefantrine is the only available fixed-dose Artemisinin-based Combination Therapy actually available and is considered as the gold standard for the treatment of P. falciparum malaria. This study will therefore aim to demonstrate the non-inferiority of the combination of CDA to artemether-lumefantrine in terms of efficacy at 28-days. The key secondary objectives will compare the Parasite Clearance Times (PCT) and the Fever Clearance Times (FCT) between CDA and artemether-lumefantrine.


Options:
A: Inclusion criteria:

* Acute, uncomplicated P.falciparum malaria, microscopically confirmed
* Temperature at screening of 37.5oC or or more or confirmed history of fever within previous 24 hours
* Weigh 7.5kg or over
* Screening haemoglobin (Hb) of 7g/dl or over, or haematocrit of 25% or more(If Hb not available at screening)
* Willingness to comply with the study visits and procedures, as outlined in the informed consent form
* Written or oral witnessed consent has been obtained from parent or guardian
* Assent is given by a child aged 12 years or over, in addition to the consent of their parent or guardian

Exclusion criteria:

* Features of severe/complicated falciparum malaria
* Hypersensitivity to active substances (chlorproguanil, dapsone, artesunate, artemether, lumefantrine)
* Known allergy to biguanides, sulphones, sulphonamides, artemisinin derived products or aminoalcohol drugs
* Known history of G6PD deficiency
* Infants with a history of hyperbilirubinaemia during the neonatal period
* Use of concomitant medications that may induce haemolysis or haemolytic anaemia from the WHO (World Health Organization) list of essential drugs
* Evidence of any concomitant infection at the time of presentation (including P. vivax, P. ovale and P. malariae)
* Any other underlying disease that may compromise the diagnosis and the evaluation of the response to the study medication (including clinical symptoms of immunosuppression, tuberculosis, bacterial infection; cardiac or pulmonary disease)
* Malnutrition, defined as a child whose weight-for-height is below -3 standard deviations or less than 70% of the median of the NCHS/WHO normalised reference values
* Treatment within the past three months with mefloquine or mefloquine-sulphadoxine-pyrimethamine; twenty-eight days with sulphadoxine/pyrimethamine, sulfalene/pyrimethamine, lumefantrine or artemether/lumefantrine, amodiaquine, atovaquone or atovoquone/proguanil, halofantrine; 14-days with chlorproguanil/dapsone, or 7-days with quinine (full course), proguanil, artemisinins, tetracycline doxycycline or clindamycin
* Positive sulphadoxine/pyrimethamine urine screen for 'unknown' antimalarial drug use in prior 28-days
* Use of an investigational drug within 30 days or 5 half-lives whichever is the longer
* Previous participation in this study
* Female subjects of child-bearing age, who have had a positive pregnancy test at screening, or do not give their consent to take a pregnancy test
* Female subjects who will be breast-feeding an infant for the duration of the study
B: Inclusion criteria:

* Acute, uncomplicated P.falciparum malaria, microscopically confirmed infection.
* Temperature at screening of 37.5oC or over or confirmed history of fever within previous 24-hours.
* Weight 7.5kg or over , no upper weight limit.
* Screening haemoglobin (Hb) of 7g/dl, or more or haematocrit of 25% or over(if Hb not available at screening).
* Willingness to comply with the study visits and procedures, as outlined in the informed consent form.
* Written or oral witnessed consent obtained from subject, parent or guardian.
* Assent is given by a child aged 12 to \<18years, in addition to the consent of their parent or guardian.

Exclusion criteria:

* Features of severe/complicated falciparum malaria.
* Hypersensitivity to active substances (chlorproguanil, dapsone, artesunate), or excipients of the investigational products.
* Known allergy to biguanides, sulphones, sulphonamides or artemisinin derived products.
* Known history of G6PD deficiency.
* Infants with a history of hyperbilirubinaemia during the neonatal period.
* Evidence of any concomitant infection at the time of presentation (including P. vivax, P. ovale and P. malariae).
* Use of concomitant medications that may induce haemolysis or haemolytic anaemia from the WHO (World Health Organization) list of essential drugs.
* Any other underlying disease that may compromise the diagnosis and the evaluation of the response to the study medication (including clinical symptoms of immunosuppression, tuberculosis, bacterial infection; cardiac or pulmonary disease).
* Malnutrition, defined as a child whose weight-for-height is below -3 standard deviations or less than 70% of the median of the NCHS/WHO normalised reference values
* Treatment within the past three months with mefloquine or mefloquine-sulphadoxine-pyrimethamine; twenty-eight days with sulphadoxine/pyrimethamine, sulfalene/pyrimethamine, lumefantrine or artemether/lumefantrine, amodiaquine, atovaquone or atovaquone/proguanil, halofantrine; 14-days with chlorproguanil/dapsone, or 7-days with quinine (full course), proguanil, artemisinin, tetracycline doxycycline or clindamycin.
* Positive sulphadoxine/pyrimethamine urine screen for 'unknown' antimalarial drug use in prior 28-days.
* Use of an investigational drug within 30 days or 5 half-lives whichever is the longer.
* Previous participation in this study.
* Female subjects of child-bearing potential who have had a positive pregnancy test at enrolment, or do not give their consent to take a pregnancy test.
* Female subjects who will be breast-feeding an infant for the duration of the study.
C: Inclusion Criteria:

Age ≥1 year

* Weight \>10 Kg
* P. falciparum mono-infection, density of at least 20 parasites/μL
* Axillary temperature \< 37.5ºC
* Resident in the study area and willingness to reside for the duration of the study
* Written informed consent (plus an assent in children \>12years of age)

Exclusion Criteria:

* G6PD Deficiency Haemoglobin \<8g/dl

  * Known allergy to any of the study medications
  * Known Pregnancy or breastfeeding
  * Clear/documented history of anti-malarial treatment 2 weeks before contact with study team
  * History of blood transfusion in the previous 3 months
  * Any chronic or acute conditions that might interfere with the study as judged by the research clinician
  * History of sickle cell anaemia
D: Inclusion criteria

* Age over 6 months and
* Weight ≥ 5 kg, and
* Slide-confirmed infection with Plasmodium falciparum (including mixed infections), and
* Asexual parasite density between 500 and 200,000/µl of blood, and
* Informed consent from a parent or guardian aged at least 18 years.

Exclusion criteria

* General danger signs according to the WHO definition or
* Signs of severe/complicated malaria according to the WHO definition or
* Severe anaemia (haemoglobin \< 5 g/dL), or
* Known history of hypersensitivity to any of the study drugs, or
* Severe malnutrition (as defined by a weight-for-height below 70% of median and/or symmetrical oedemas involving at least the feet), or
* Concomitant febrile illness due to causes other than malaria with the potential to confound study outcome (measles, acute lower tract respiratory infection, otitis media, tonsillitis, abscesses, severe diarrhoea with dehydration, etc.; mild flu should not lead to exclusion) or
* History of psychiatric diseases, or
* Having received a full course treatment including MQ in the preceding 9 weeks or
* Having received any other antimalarials in the previous 48 hours.

Answer: A