Background: The World Health Organization has recommended addition of a 0.25 mg/kg
single-dose primaquine (PQ) to standard artemisinin-based combination therapy (ACT) for
elimination of malaria in low transmission-settings and for containment in areas threatened
by artemisinin resistance. However, PQ metabolism is dependent on a highly polymorphic
cytochrome P450 (CYP) 2D6 isoenzyme which probably compromises the drugs' safety and
efficacy, particularly in individuals with reduced isoenzyme activity. This trial therefore,
aims to assess the safety and efficacy of 0.25 mg/kg single-dose PQ when added to standard
artemether-lumefantrine regimen for clearance and sterilization of Plasmodium falciparum
gametocytes in patients with CYP450 2D6 reduced/null activity as compared to those with
normal/increased enzyme activity.
Methods: On hundred and fifty-five children aged between 1 and 10 years and with
uncomplicated P. falciparum malaria will be enrolled, treated with standard
artemether-lumefantrine regimen plus a 0.25 mg/kg single-dose of PQ and then followed up on
days 0, 1, 2, 3, 7, 14, 21 and 28 for clinical and laboratory assessment. Primaquine will be
administered together with the first dose of artemether-lumefantrine. Safety assessment will
be performed using the Primaquine Roll Out Monitoring Pharmacovigilance Tool (PROMPT).
Gametocytes will be detected and quantified by microscopy and Pfs25 mRNA quantitative nucleic
acid sequence based amplification (QT-NASBA) on days 0 and 7. For a subset of 100
participants, post-treatment infectiousness will be assessed by mosquito feeding assays on
day 7. The CYP2D6 status will be determined using a polymerase chain reaction (PCR) followed
by a restriction fragment length polymorphism (RFLP). The primary outcome will be the safety
of single low-dose primaquine in patients with CYP2D6 reduced/null compared to those with
normal/increased activity.
Expected outcomes: The findings will provide the much-needed information on the safety and
efficacy of single low-dose primaquine for clearance and sterilization of P. falciparum
gametocytes in individuals with reduced/null compared to those with normal/increased CYP450
2D6 isoenzyme activity prior to the implementation of the treatment policy particularly in
Africa.
Phase:
Phase 4
Details
Lead Sponsor:
Tropical Pesticides Research Institute, Tanzania
Collaborator:
European and Developing Countries Clinical Trials Partnership (EDCTP)