Chloroquine effects on Plasmodium vivax isolate HMPBS02-Pv
A Phase IB Experimental Study to Assess the in vivo Safety and Response to Chloroquine of Plasmodium vivax isolate HMPBS02-Pv in Healthy Participants with Induced Blood Stage Malaria Infection
QIMR Berghofer Medical Research Institute
24 participants
Feb 19, 2016
Interventional
Conditions
Summary
This is a single-centre study using naturally acquired Plasmodium vivax (P. vivax) HMPBS02-Pv challenge inoculum to infect healthy participants in order to characterize the infectivity of the parasite isolate P. vivax HMPBS02-Pv in vivo. The goal is to determine the safety of the P. vivax blood stage malaria model following inoculation of healthy participants with P. vivax HMPBS02-Pv and the registered Chloroquine anti-malarial drug treatment. This study will be conducted in consenting and eligible male or female participants. Each participant will be inoculated on Day 0 with around 1,100 viable P. vivax-infected human erythrocytes administered intravenously. On an outpatient basis, the participants will be monitored for presence of parasites by qPCR following the challenge and then during and after the treatment, until free of parasites. During this time, participants will also be monitored for the unexpected early onset of malaria symptoms, signs or parasitological evidence of malaria. On the day designated for commencement of treatment, as determined by PCR results and/or onset of clinical symptoms of malaria infection, participants will be admitted to the study unit and confined for safety monitoring and registered Chloroquine anti-malarial treatment. Based on previous studies, it is anticipated that treatment will occur on approximately Day 8 to Day 10. Following treatment, the participants will be followed up as in-patients for 72 hours to ensure tolerance of therapy and clinical response. Once clinically well, the participants will be followed up on an out-patient basis for continued assessment of anti-malarial drug levels, and monitoring of safety, in particular liver function tests, and clearance of malaria parasites via qPCR. Follow up visits for safety assessments will be performed at specific time points until Day 28 after the malaria infection and the participants are required to be contactable and available up to 2 weeks following this end of study visit. The overall period of participation will therefore be around 4 weeks from the time malaria infection.
Eligibility
Inclusion Criteria9
- Adults (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 anti-malarial drug treatment) and will be contactable and available for the duration of the trial and follow up period (maximum of 6 weeks).
- Body mass index between 18.0 and 32.0 kg/m2, inclusive.
- Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination).
- Normal vital signs after 5 minutes resting in supine position
- Normal standard 12-lead electrocardiogram (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.
- As there is the risk of adverse effects of the study treatment drug (chloroquine), in pregnancy, it is important that any participants involved in this study do not get pregnant
- All participants must be Duffy Blood group positive. Female participants of childbearing potential should be blood group Rh positive.
- Female participants of childbearing potential and all male participants must also have adequate contraception in place for the duration of the study
Exclusion Criteria16
- Any history of malaria or participation to a previous malaria challenge study
- Any history of retinal abnormalities, disease of the retina or macula of the eye, visual field defects, hearing disorders (e.g. reduced hearing, tinnitus).
- 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°C) within the 5 days prior to inoculation with malaria parasites.
- Evidence of acute illness within the 4 weeks before trial 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, 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 Red Cross (or other) blood bank during the 8 weeks preceding the reference 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 anti-malarial activity (i.e. chloroquine, piperaquine, benzodiazepine, flunarizine, fluoxetine, tetracycline, azithromycin, clindamycin etc.)
- Cardiac/QT risk
- Known hypersensitivity to chloroquine, or any of its excipients or 4-aminoquinolines, artemether or other artemisinin derivatives, lumefantrine, or other arylaminoalcohols.
- Known severe reaction to mosquito bites other than local itching and redness.
- Unwillingness to abstain from consumption of citrus (grapefruit, Seville orange, etc.) for greater than or equal to 21 days prior to initiation of the study (inoculation, Day 0) and for the study duration
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Interventions
Description of intervention(s) / exposure: This is a single-centre, open label study using induced blood stage malaria (IBSM) infection to characterize in healthy malaria-naive participants inoculated with Plasmodium vivax (P. vivax) isolate HMPBS02-Pv the safety and the effectiveness of chloroquine in reducing parasitaemia. 8 participants in a single cohort will be inoculated on Day 0 with around 1,100 viable P. vivax-infected human erythrocytes administered intravenously. On the day designated for commencement of treatment as determined by symptom onset (approximately study Day 8), participants will be admitted to the study confinement unit and monitored. The threshold for commencement of treatment, as determined by the Investigator, will be onset of symptoms of malaria infection with parasitaemia anticipated to be at around 20,000 parasites/mL at this time. The first dose of chloroquine will be administered with food in the morning after an overnight fasting period of greater than 8 hours. Participants will be treated with chloroquine phosphate administered orally over 3 days. For adults greater than or equal to 60 kg in weight, chloroquine will be administered as 4 tablets (1 g) as an initial dose, followed by 2 tablets (500 mg) at 6, 24, and 48 hours for a total dose of 2.5 g over 3 days. For adults less than 60 kg in weight, chloroquine will be administered as 10 mg/kg as an initial dose, followed by 5 mg/kg at 6, 24, and 48 hours for a total dose of 25 mg/kg over 3 days. Each participant’s mouth will be checked following administration to ensure the medication was swallowed. Participants will be subsequently discharged from the study unit. Follow-up visits for safety assessments will be performed until day 28 after malaria infection. Paracetamol and ibuprofen are allowed as non-prescription drugs to be used by the participants in this study for relieve of any minor discomforts that might occur due to the malaria infection or the treatment with the anti-malarial drug. The dosing of these analgesics will be in accordance with the directions on the labels. Cohort 1: All participants are allowed to take ibuprofen orally up to 1.2 g/day or paracetamol orally up to 4 g/day for as long as clinically required. Cohort 2: All participants are allowed to use paracetamol only up to 4 g per day orally (500 mg-1 g every 4-6 hours up to a maximum of 4 g daily) for as long as clinically required. Cohort 3: All participants are allowed to use ibuprofen only up to 1.2 g/day orally (200 to 400 mg orally every 4 to 6 hours up to a maximum of 1.2 g/day) for as long as clinically required. Transmission studies will also be undertaken by direct skin feeding and indirect membrane feeding of mosquitoes. The experimental infection of mosquitoes by direct skin feeding on participants will be performed up to a maximum of 2 time-points and membrane feeding assays performed up to a maximum of 3 time-points prior to antimalarial treatment.
Locations(1)
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ACTRN12616000174482