Safety of Plasmodium falciparum K13 isolate in healthy participants.
An experimental study to characterise the in vivo safety and infectivity of a Plasmodium falciparum Cam3.II^R539T (K13) artemisinin-resistant isolate in healthy participants.
QIMR Berghofer Medical Research Institute
2 participants
May 24, 2017
Interventional
Conditions
Summary
This study will evaluate the safety and infectivity of a P. falciparum K13 artemisinin-resistant malaria parasite in healthy participants using the IBSM model. P. falciparum K13 was isolated from a person with malaria infection and is resistant to the antimalarial drug artemisinin and related drugs such as artesunate. We expect that artesunate treatment will kill the K13 parasites, although at a slower rate compared to drug sensitive isolates. In addition, the P. falciparum K13 isolate retains sensitivity to other antimalarial drugs including piperaquine and atovaquone. Participants will be treated with artesunate to characterise the parasite clearance profile of P. falciparum K13 in response to artesunate .If artesunate does not clear parasitaemia participants will be administered piperaquine, which is known to be active against P. falciparum K13 (as a single oral dose of Eurartesim ‘Registered Trademark’ piperaquine tetraphosphate/dihydroartemisinin tablets) The availability of a P. falciparum artemisinin-resistant isolate in the IBSM model will allow investigation of the efficacy of novel antimalarial drug candidates in clearance of artemisinin-resistant P. falciparum, which is a growing problem in South-East Asia and threatens to spread across the world.
Eligibility
Inclusion Criteria6
- Adult (male and non-pregnant, non-lactating female) participants between 18 and 55 years of age inclusive, who do not live alone (from Day 0 until at least the end of the antimalarial treatment) and will be contactable and available for the duration of the trial and follow-up period (maximum 15 weeks).
- Body weight minimum 50 kg, body mass index between 18 and 32 kg/m2, inclusive.
- Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination).
- Normal standard 12-lead ECG after 5 minutes resting in supine position.
- Laboratory parameters within the normal range, unless the Investigator considers an abnormality to be clinically irrelevant for healthy participants enrolled in this clinical investigation.
- Female participants of childbearing potential should be surgically sterile or using an insertable, injectable, transdermal or combination oral contraceptive approved by the Therapeutic Goods Administration combined with a barrier contraceptive for the duration of the study, and have negative results on a serum or urine pregnancy test done before administration of malaria inoculum.
Exclusion Criteria15
- Any history of malaria or participation in a previous malaria challenge study.
- Must not have travelled to or lived (>2 weeks) in a malaria-endemic region during the past 12 months or planned travel to a malaria-endemic region during the course of the study.
- Has evidence of increased cardiovascular disease risk.
- History of splenectomy.
- Presence of acute infectious disease or fever (e.g., sub-lingual temperature greater than or equal to 38.5 degrees C) within the 5 days prior to inoculation with malaria parasites.
- Evidence of acute illness within the 4 weeks prior to screening that the Investigator deems may compromise participant safety.
- Participant has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion, e.g. gastrectomy, diarrhoea.
- Participation in any investigational product study within the 12 weeks preceding the study.
- Blood donation of any volume within 1 month before inclusion, or participation in any research study involving blood sampling (more than 450 mL/unit of blood), or blood donation to a blood bank during the 8 weeks prior to the treatment drug dose in the study.
- Participant who has ever received a blood transfusion.
- Any recent (less than 6 weeks) or current systemic therapy with an antibiotic or drug with potential antimalarial activity (i.e. chloroquine, piperaquine, benzodiazepine, flunarizine, fluoxetine, tetracycline, azithromycin, clindamycin, doxycycline etc.)
- Male participant with a female partner who is pregnant or lactating from the time of administration of study medication.
- Cardiac/QT risk
- Known hypersensitivity to artesunate or any of its excipients, artemether or other artemisinin derivatives, piperaquine, atovaquone, proguanil hydrochloride, primaquine, or 4-aminoquinolines.
- Unwillingness to abstain from consumption of citrus (grapefruit, Seville orange.) from inoculation (Day 0) until end of antimalarial treatment.
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Interventions
This is a single-centre, open-label study using the induced blood stage malaria (IBSM) model to characterise the safety and infectivity of an in vitro expanded P. falciparum Cam3.II^R539T (K13) artemisinin-resistant isolate in healthy malaria-naive participants. The study will be conducted in 2 participants. Each participant will be inoculated on Day 0 with approximately 2,800 viable P. falciparum K13-infected human erythrocytes administered intravenously. On an outpatient basis, participants will be monitored daily via phone call and then will attend the clinic daily (AM) from Day 4 until quantitative polymerase chain reaction (qPCR) positive for presence of malaria parasites. Once qPCR positive they will be monitored twice daily, morning (AM) and evening (PM), until artesunate antimalarial treatment, for adverse events and the unexpected early onset of symptoms, signs or parasitological evidence of malaria. On the day designated for commencement of antimalarial treatment, as determined by qPCR results (parasitaemia greater than or equal to 5,000 parasites/mL) or a malaria clinical symptom score greater than 6, participants will be admitted to the study unit and confined for safety monitoring and a single dose of artesunate tablets of approximately 2 mg/kg according to a dosing table prepared by a pharmacist as outlined in the study protocol. Following artesunate treatment, participants will be followed up as in-patients for 72 hours to ensure treatment tolerance and adequate clinical response. Once clinically well, participants will be followed up on an out-patient basis for monitoring of safety and clearance of malaria parasites via qPCR. If parasite clearance does not occur, participants will be administered piperaquine, which is known to be active against this isolate (as a single oral dose of Eurartesim ‘Registered Trademark’ piperaquine tetraphosphate/dihydroartemisinin tablets). The antimalarial Malarone ‘Registered Trademark’ (atovaquone/proguanil hydrochloride) will be administered to all participants as a rescue treatment. It will commence as close as possible to Day 26, within the Day 26 plus or minus 3 window, at the Investigator’s discretion. A treatment course consists of 4 tablets of proguanil hydrochloride 100 mg/atovaquone 250 mg once daily, orally for 3 days. Participants will be treated with a single oral dose of 45 mg primaquine as primaquine phosphate at the time of atovaquone/proguanil hydrochloride treatment if gametocytes are determined to be present based on reverse transcriptase qPCR, to ensure complete clearance of gametocytes. Follow-up for safety assessments will be performed on Day 28 plus or minus -3, Day 56 plus or minus -7 (phone call only), and Day 90 plus or minus -14 (End of Study). The overall period of participation will therefore be around 13 weeks from the time malaria infection. The parasite inoculum, artesunate, Eurartesim ‘Registered Trademark’, and Primacin ‘Trademark’ will be administered in the presence of clinic staff. Malarone ‘Registered Trademark’ will be administered at the clinic for initial dosing followed by monitoring, either in the clinic, or by telephone for 3 days to ensure adherence to the therapy.
Locations(1)
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ACTRN12617000244303