Patient case: 36-year-old female with Brugada syndrome; genetic feature: SCN5A

Clinical trial: A Study by the Development of Triple Artemisinin Combination Therapies (DeTACT) Collaboration (Africa)

Summary: A randomised 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) 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 the control arms, the ACT will be blister-packed with a matched (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. 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 parasitaemia 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, haematocrit, 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.
  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 in approximately 270 patients. 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.
  All the organisations in this collaboration will work closely with local counterparts including the National Malaria Control Programmes (NMCPs), non-governmental and other relevant organisations. Training is an integral part of this collaborative working relationship, and the building of local research capacity is an essential component of all research plans.
  All research-related activities, from study design, planning, implementation through to analysis and writing of reports will be performed jointly with local counterparts. Both on-the-job training and formal training will be provided when needed, in particular for Good Clinical Practice (GCP) skills.
  The close interaction between WHO and its regional offices will ensure that new knowledge is disseminated efficiently and effectively throughout the region. The Worldwide Antimalarial Resistance Network website (www.wwarn.org) will be also used as a medium to disseminate information.

Eligibility: Inclusion Criteria:
  -  Male or female, aged 6 months to 12 years (For Gambia site only: >6 months)
  -  Ability to take oral medication
  -  Acute uncomplicated P. falciparum (or mixed with other plasmodium species)
  -  Asexual P. falciparum parasitaemia: 1,000/µL to ≤10% parasitaemia, determined on a peripheral blood film (For Gambia site only: 1000/µL to 200,000/µL)
  -  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 by 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 <15% at screening (For Gambia site only: For subjects >12 years - Haematocrit <20% at screening)
  -  Subjects who have received artemisinin or a derivative or an ACT within the previous 7 days
  -  In applicable countries: use of seasonal malaria chemoprophylaxis (SMC) within the last 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: post-menarche (For Gambia site only: Female who are pregnant, trying to get pregnant or 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

Relevance to patient case: not relevant