None listed
Conditions
Brief summary
Malaria volunteer infection studies, particularly the IBSM model, play a key role in accelerating antimalarial drug development. We recently manufactured a new, in vitro expanded malaria cell bank, P. falciparum 3D7-MBE008, and conducted a small pilot study (ACTRN12619001079134) that showed that the 3D7-MBE008 parasites were safe and infective in healthy participants. The next step is to evaluate the ability of the 3D7-MBE008 parasites to be transmitted from humans to mosquitoes. This is a randomised study that will use the IBSM model to evaluate the transmission of P. falciparum 3D7-MBE008 parasites from participants to mosquitoes. The study will be conducted in four participants. This study will be essential for determining whether this new parasite bank can be used in future studies testing novel transmission blocking antimalarial drugs.
Interventions
This is a randomised study that will use the induced blood stage malaria (IBSM) model to evaluate the transmission of P. falciparum 3D7-MBE008 parasites from volunteers to mosquitoes. The study will be conducted in four participants.
Eligible participants will be inoculated intravenously on Day 0 with approximately 2,800 viable P. falciparum 3D7-MBE008 infected red blood cells in a volume of 2 mL. Volunteers will be followed up daily via phone call or text message on Days 1 to 3 post-inoculatio
This is a randomised study that will use the induced blood stage malaria (IBSM) model to evaluate the transmission of P. falciparum 3D7-MBE008 parasites from volunteers to mosquitoes. The study will be conducted in four participants. Eligible participants will be inoculated intravenously on Day 0 with approximately 2,800 viable P. falciparum 3D7-MBE008 infected red blood cells in a volume of 2 mL. Volunteers will be followed up daily via phone call or text message on Days 1 to 3 post-inoculation to solicit any adverse events. On Days 4 to 7 volunteers will attend the clinical unit once daily (or twice daily if required) for clinical evaluation and blood sampling to monitor the progression of parasitaemia. Malaria parasitaemia will be quantified using quantitative polymerase chain reaction (qPCR) targeting the gene encoding 18S rRNA. On Day 8 when parasitaemia for the majority of volunteers is expected to be above 10,000 parasites/mL, participants will be administered a dose of 480 mg piperaquine as oral tablets. Participants will return to the clinic on Days 9 and 10 to ensure adequate clinical and parasitological response to piperaquine dosing. An additional dose of piperaquine (960 mg as oral tablets) will be administered on Day 10. Between Day 11 and Day 24, regular outpatient visits will occur to monitor parasitaemia and perform safety assessments. On Day 25, transmission of gametocytes to Anopheles mosquitoes will be assessed with an enriched membrane-feeding assay using blood samples taken from the participants (blood sampling done at clinic as per other blood samples taken for this study). Volunteers will be randomised to receive either an oral tablet dose of approximately 0.25 mg/kg primaquine (Primacinactive control group) or no transmission blocking intervention (no drug control group) in a 1:1 ratio. No blinding will be performed. Additional enriched membrane-feeding assays will be performed on Days 26, 27, 29, 32, and 39 to determine if parasites remain transmissible over this period in the no drug control group, and to determine the effect of primaquine on transmission (active control group). All participants will begin antimalarial rescue treatment with a standard course of artemether-lumefantrine on Day 39 (Riamet; six doses of four tablets totaling 480 mg artemether and 2880 mg lumefantrine administered orally twice daily over three consecutive days), or earlier in the event that piperaquine treatment fails to clear asexual parasitaemia or prevent recrudescence. Each tablet contains 20 mg artemether and 120 mg lumefantrine. If gametocytes are present at or after the time of treatment with artemether-lumefantrine, 45 mg primaquine as oral tablets may be administered at the Investigator’s discretion. The end of study visit will occur on Day 42 plus or minus 2 days. Strategies to monitor adherence to the intervention include The Investigator or delegate administering the malaria challenge agent intravenously at the clinical trial unit. Piperaquine and primaquine will be administered at the clinical trial unit under direct observation by staff. The first dose of artemether-lumefantrine will be administered at the clinical trial unit under direct observation by staff. The subsequent five doses of artemether-lumefantrine may be taken at home. Participants will receive a phone call or text message from the clinical trial unit staff to ensure compliance.
Sponsors
QIMR Berghofer Medical Research Institute
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male or female (non-pregnant, non-lactating) aged 18 to 55 years inclusive who will be contactable and available for the duration of the trial and up to two weeks following the End of Study visit. 2. Total body weight greater than or equal to 50 kg, and a body mass index within the range of 18 to 32 kg/m2 (inclusive). 3. Certified as healthy by a comprehensive clinical assessment (detailed medical history and full physical examination). 4. At least normal G6PD enzyme activity levels as defined by the parameters of the specific quantitative G6PD test employed. 5. Fully vaccinated (meaning first, second and booster dose) against COVID-19 at least 7 days prior to inoculation with the malaria challenge agent. 6. Vital signs at screening and pre-inoculation (measured after 5 min in the supine position): • Systolic blood pressure (SBP) - 90–140 mmHg, • Diastolic blood pressure (DBP) - 40–90 mmHg, • Heart rate (HR) 40–100 bpm.
Exclusion criteria
1. Any history of malaria or participation in a previous malaria challenge study or malaria vaccine study. 2. Must not have travelled to or lived (greater than 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. Must not have lived for greater than 1 year in a malaria-endemic region in the past 10 years. Must not have ever lived in a malaria-endemic region for more than 10 years inclusive. 3. Has evidence of increased cardiovascular disease risk. 4. Known hypersensitivity to artesunate or any of its excipients, artemether or other artemisinin derivatives, proguanil/atovaquone, primaquine, or 4-aminoquinolines. 5. Haematology, clinical chemistry or urinalysis results at screening or at the eligibility visit that are outside of Sponsor-approved clinically acceptable laboratory ranges and are considered clinically significant by the Investigator. 6. Participation in any investigational product trial within the 12 weeks preceding inoculation. 7. Symptomatic postural hypotension at screening (confirmed on two consecutive readings). 8. History or presence of diagnosed (by an allergist/immunologist) or treated (by a physician) food or known drug allergies (including but not limited to allergy to any of the antimalarial rescue medications), or any history of anaphylaxis or other severe allergic reactions including face, mouth, or throat swelling or any difficulty breathing. 9. History of convulsion (including drug or vaccine-induced episodes). 10. Presence of current or suspected serious chronic diseases. 11. Individuals with history of schizophrenia bi-polar disease, psychoses, disorders requiring lithium, attempted or planned suicide, or any other severe (disabling) chronic psychiatric diagnosis. 12. Presence of clinically significant infectious disease or fever (e.g., sublingual temperature greater than or equal to 38.5 Degrees Celsius) within the five days prior to inoculation. 13. Blood product donation to any blood bank during the 12 weeks (whole blood) or 4 weeks (plasma and platelets) prior to malaria challenge agent administration. 14. Cardiac/QT risk.
Outcome results
None listed