Patient case: 19-year-old female with long QT syndrome; genetic feature: KCNH2

Clinical trial: A Trial to Compare the Efficacy, Safety and Tolerability of Combinations of 3 Anti-malarial Drugs Against Combinations of 2 Anti-malarial Drugs (Asia)

Summary: A randomised controlled non-inferiority trial of the Triple ACTs artemether-lumefantrine + amodiaquine (AL+AQ) and artesunate-piperaquine + mefloquine (AS-PPQ+MQ) with the ACTs artemether-lumefantrine + placebo (AL+PBO) and artesunate-piperaquine + placebo (AS-PPQ+PBO) OR artesunate-mefloquine (AS-MQ) for the treatment of uncomplicated Plasmodium falciparum malaria to assess and compare their efficacy, safety, tolerability.

Detailed description: In each site subjects will be randomized between four arms: artemether-lumefantrine + amodiaquine, artemether-lumefantrine + placebo, artesunate-piperaquine + mefloquine and artesunate-piperaquine + placebo.
  In Cambodia the comparator will be artesunate-mefloquine due to the current well-documented low treatment efficacy of DHA-piperaquine.
  In the control arms, the ACT will be blister-packed with a matched (in appearance) placebo.
  In lower transmission settings (Annual Parasite Incidence <50 per 1000 population per year) the treatment will include a single 0.25 mg/kg gametocytocidal dose of primaquine as recommended by the WHO for children ≥10 kg. All drug administrations will be observed.
  Subjects will be treated in an in-patient unit for 3 days and followed up weekly up to D63. Microscopy to detect and quantify malaria parasitaemia will be performed daily (more frequently in patients with parasite density of >5000/µL at inclusion) during hospitalization, at all weekly and unscheduled visits. A physical examination and measurements of vital signs along with a symptom questionnaire for tolerability will be performed and recorded through a standardized method at baseline, daily during admission and weekly during follow up through D42 and at all unscheduled visits. Physical exam, vital sign measurements and assessments of symptoms will be performed on D49, D56, and D63 only for patients who are parasitaemic or those who report fever or other symptoms. Electrocardiographs will be performed during admission (H0, H4, H52, or H64) and day 42 of follow up to assess and compare the effect of ACTs and TACTs antimalarials on QTc-intervals.
  Safety assessments will be performed by measuring markers of renal and hepatic toxicity, haemoglobin, , platelet counts, absolute and differential white blood cell counts and ECGs. Pharmacokinetic profiles in a subset of subjects will be linked to measures of efficacy and toxicity. To avoid extensive blood sampling, especially in children, a population pharmacokinetic approach will be followed, requiring sparse blood sampling reducing the burden of sampling for the patient [21].
  Blood samples for parasite genotyping as well as genomic, transcriptomic and immunology studies will be collected at baseline and at selected time-points on follow-up and also on the day of a recurrent infection.
  In patients with parasite densities >5000 per µL at screening, parasite clearance rates will be assessed by repeated assessments of the parasite counts after the start of the antimalarial treatments. At each visit a capillary blood sample will be taken for parasite count and haematocrit.
  If a patient presents with a new uncomplicated falciparum malaria infection after 3 months or longer after the initial enrolment, the patient or relative (in case of a child) will be asked to re-enter the patient in the trial.
  In selected study sites, P. falciparum parasites will be cryopreserved for in vitro antimalarial drug sensitivity testing. Where possible, ex vivo or in vitro assessments of parasite susceptibility to artemisinins and partner drugs will be assessed.
  The in vivo and ex vivo data on artemisinin and partner drug sensitivity will potentially be used to identify new genetic or transcriptomic markers/patterns of artemisinin or partner drug resistance.
  The pharmacogenetics of antimalarial agents are poorly known despite the fact that application of pharmacogenetics might be critical in optimizing treatment of malaria in individuals but also populations at large. Blood samples (dried blood blots) for human genotyping will be obtained and stored from all subjects recruited with subject's consent.
  Subjects or their guardians will be asked a short set of questions on their place of residence, place of work and their history of travel in the last 2 months. In addition, basic questions on use of mobile phones will be asked. These questions will help in understanding the use of mobile phones in each country in subjects prone to malaria infections which can inform future malaria studies or interventions.

Eligibility: Inclusion Criteria:
  -  Male or female, aged 6 months and above
  -  Ability to take oral medication
  -  Acute uncomplicated P. falciparum (or mixed with other plasmodium species)
  -  Asexual P. falciparum parasitaemia: 96 to 200,000/µL, determined on a thin or thick peripheral blood film
  -  Fever defined as > 37.5°C tympanic temperature or a history of fever within the last 24 hours
  -  Written informed consent by the subject or parent/guardian in case of children lower than the age of consent and assent if required (per local regulations)
  -  Willingness and ability of the subjects or parents/guardians to comply with the study protocol for the duration of the study
  Exclusion Criteria:
  -  Signs of severe malaria
  -  Patients not fulfilling criteria for severe malaria but with another indication for parenteral antimalarial treatment at the discretion of the treating physician
  -  Haematocrit < 20%
  -  Subjects who have received artemisinin or a derivative or an ACT within the previous 7 days
  -  Treatment with mefloquine in the previous 1 month
  -  Acute illness other than malaria requiring systemic treatment
  -  Severe acute malnutrition with complications requiring inpatient nutritional treatment
  -  Known HIV infection
  -  Known tuberculosis infection
  -  For females: pregnant, trying to get pregnant or are lactating
  -  History of allergy or known contraindication to any of the study drugs, including neuropsychiatric disorders and epilepsy
  -  Previous splenectomy
  -  Enrolment in DeTACT in the previous 3 months
  -  Participation in another interventional study in the previous 3 months
  Criteria for severe malaria
  -  Impaired consciousness (Glasgow Coma Scale, Blantyre Coma Scale)
  -  Prostration
  -  Respiratory distress (defined as maximal respiratory rate, by age)
  -  ≥2 convulsions in the past 24 hours
  -  Circulatory collapse
  -  Pulmonary edema
  -  Abnormal bleeding
  -  Visible jaundice
  -  Haemoglobinuria (blackwater)
  -  Hyperparasitaemia (>10%)

Relevance to patient case: not relevant