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Trial registered on ANZCTR


Registration number
ACTRN12617001502325
Ethics application status
Approved
Date submitted
19/10/2017
Date registered
25/10/2017
Date last updated
7/02/2020
Date data sharing statement initially provided
7/02/2020
Date results information initially provided
7/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Apheresis of healthy subjects with induced blood stage Plasmodium vivax
Scientific title
Apheresis of healthy subjects with induced blood stage Plasmodium vivax
Secondary ID [1] 293123 0
none
Universal Trial Number (UTN)
none
Trial acronym
none
Linked study record

Health condition
Health condition(s) or problem(s) studied:
malaria infection 305084 0
Condition category
Condition code
Infection 304399 304399 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a Phase 1 study designed to determine the safety and feasibility of using apheresis as a method for extracting all lifecycle stages of malaria parasites from the blood of healthy subjects experimentally infected with blood stage Plasmodium vivax. This study will be conducted in up to 8 subjects (8 cohorts of 1 subject each).

The apheresis procedure will involve the insertion of 2 large intravenous needles into large veins located in both antecubital fossae (elbow crease). Blood will be removed from the cannula in one arm and passed through the apheresis machine and then returned to the participant through the cannula in the other arm. The Spectra Optia Apheresis System acts by separating blood into its various components by density. At the same time as the blood is removed, an anticoagulant (citrate) will be infused into your other arm meaning the total blood volume will remain the same. The whole apheresis procedure will take approximately 2-4 hours.

Subjects will be inoculated intravenously on Day 0 with approximately 1100 viable P. vivax HMPBS02-Pv parasite-infected erythrocytes. On an outpatient basis, subjects will be monitored daily via phone and then will attend the clinical unit daily from 4 days post-inoculation for blood sampling to measure parasitaemia via quantitative polymerase chain reaction (qPCR) targeting the P. vivax 18S rRNA gene (referred to as malaria 18S qPCR), to monitor symptoms and signs of malaria, and to record adverse events. The threshold for the commencement of apheresis and subsequent antimalarial rescue treatment with artemether/lumefantrine will occur when parasitaemia is greater than 20,000 parasites/mL or the Malaria Clinical Score is greater than 6 (within 24 hours of notification) or at the Investigator’s discretion. On the day that this threshold is reached (expected to occur on Day 10), the subject will be admitted to the clinical unit for initial safety assessments before undergoing apheresis whilst being supervised by the apheresis specialist nurse. The subject will then be administered the first dose of artemether/lumefantrine and will remain confined within the clinical unit for 72 hours to monitor for safety and tolerability of apheresis and rescue therapy, and to ensure adequate clinical and parasitological response to treatment. A course of artemether/lumefantrine treatment consists of 20 mg artemether/120 mg lumefantrine oral tablets with 6 doses of 4 tablets administered over a period of 60 hours.

In the unlikely event that artemether/lumefantrine fails to clear parasitaemia, subjects will be treated with chloroquine phosphate. Chloroquine phosphate 250 mg oral tablets will be administered as an initial dose of 4 tablets, followed by a dose of 2 tablets each at 6, 24 and 48 hours (i.e. a total dose of 2.5 g chloroquine phosphate). If oral administration of either artemether/lumefantrine or chloroquine phosphate is not possible (e.g. the subject is vomiting), the subject will receive intravenous treatment with artesunate. This would be done at the recommended dose regime of 2.4 mg/kg at approximately 0, 12, 24, 48 hours and then daily for up to 7 days or until able to take oral drugs. After discharge from the clinical unit, subjects will be followed up on an out-patient basis for monitoring of safety and parasite clearance. 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 7(End of Study).

Intervention code [1] 299369 0
Treatment: Drugs
Intervention code [2] 299446 0
Treatment: Other
Comparator / control treatment
No Control Group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 303716 0
Primary outcome
The primary objectives will be assessed by adverse events (AE) recording, safety laboratory parameters, vital signs recording, electrocardiograms (ECGs), physical examination findings and
Malaria Clinical Score recording.
Timepoint [1] 303716 0
Time-point 1
Adverse event recording: at all clinic visits from parasite inoculation to Day 90 plus or minus 7 (End of Study).

Safety laboratory parameters (biochemistry, haematology, urinalysis):
biochemistry and haematology testing done at screening, Day -3 to Day -1 eligibility confirmation visit (if required), Day 9, on clinic admission prior to apheresis, post-apheresis pre-artemether/lumefantrine treatment, prior to exit of confinement, prior to chloroquine phosphate treatment (if required), post-chloroquine phosphate treatment, during out-patient monitoring at the Investigator’s discretion, and Day 28 plus or minus 3. Urinalysis will be done at screening, Day -3 to Day -1 eligibility confirmation visit (if required), on clinic admission prior to apheresis, during out-patient monitoring at the Investigator’s discretion, and Day 28 plus or minus 3.

Vital signs recording: screening and at all clinic visits from parasite inoculation to Day 90 plus or minus 7.

ECGs: screening, prior to parasite inoculation on Day 0, post-apheresis pre-artemether/lumefantrine treatment, prior to exit of confinement, and Day 28 plus or minus 3.

Malaria Clinical Score recording: Day 0, Day 4 until artemether/lumefantrine treatment, on clinic admission prior to apheresis, during confinement, and during out-patient monitoring at the Investigator’s discretion.
Secondary outcome [1] 339954 0
The feasibility of apheresis as a method of extracting and concentrating all stages of malaria parasites will be determined by qPCR, qRT-PCR, microscopy, and flow cytometry on blood products extracted using apheresis, and expressed as a percentage of baseline parasitaemia (pre-apheresis).
Timepoint [1] 339954 0
Pre-apheresis, apheresis samples, post-apheresis pre-artemether/lumefantrine treatment.
Secondary outcome [2] 339955 0
The success of cryopreservation of gametocytes will be determined by measuring their infectivity to mosquitoes using a membrane feeding assay, reported as prevalence of infection (percentage of oocyst positive mosquitoes). The success of cryopreservation of asexual parasites will be determined based on their viability tested using in vitro reinvasion
assay.
Timepoint [2] 339955 0
Apheresis samples before and after cryopreservation.

Eligibility
Key inclusion criteria
1. Adult (male and non-pregnant, non-lactating female) subjects 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 up to 2 weeks following end of study visit.
2. Body mass index between 18.0 and 32.0 kg/m2, inclusive and a minimum body weight of 50 kg.
3. Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination).
4. Normal standard 12-lead electrocardiogram (ECG) after 5 minutes resting in supine position.
5. Laboratory parameters within the normal range, unless the Investigator considers an abnormality to be clinically irrelevant for healthy subjects enrolled in this study.
6. As there is the risk of adverse effects with artemether/lumefantrine and chloroquine in pregnancy, it is important that any subjects involved in this study do not get pregnant.
7. All subjects must be Duffy Blood group positive and have blood type O. Female subjects of childbearing potential should be blood group Rh positive.
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Any history of malaria or participation in a previous malaria challenge 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.
3. Has evidence of increased cardiovascular disease risk.
4. History of splenectomy.
5. Presence or history of drug hypersensitivity, or allergic disease diagnosed by an allergist/immunologist and/or treated by a physician for allergy or history of a severe allergic reaction, anaphylaxis or convulsions following any vaccination or infusion.
6. Presence of current or suspected serious chronic diseases such as cardiac or autoimmune disease (HIV or other immuno-deficiencies), insulin-dependent and non-insulin dependent diabetes, progressive neurological disease, severe malnutrition, acute or progressive hepatic disease, acute or progressive renal disease, porphyria, psoriasis, rheumatoid arthritis, asthma, epilepsy, or obsessive compulsive disorder.
7. Frequent headaches and/or migraines, recurrent nausea, and/or vomiting (more than twice a month).
8. Presence of acute infectious disease or fever (e.g., sub-lingual temperature greater than or equal to 38.5 Degrees Celcius) within the 5 days prior to inoculation with malaria parasites.
9. Evidence of acute illness within the 4 weeks prior to screening that the Investigator deems may compromise participant safety.
10. Participant has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion (e.g. gastrectomy, diarrhoea).
11. Participation in any investigational product study within the 12 weeks preceding the study.
12. 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 the Australian Red Cross Blood Service (Blood Service) or other blood bank during the 8 weeks preceding the treatment drug dose in the study.
13. Participant who has ever received a blood transfusion.
14. Any vaccination within the last 28 days.
15. 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, doxycycline etc.).
16. Cardiac/QT risk.
17. Known hypersensitivity to artemether/lumefantrine or chloroquine or any of thier excipients, or 4-aminoquinolines, artemether or other artemisinin derivatives, lumefantrine, piperaquine.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
This study is a exploratory study to investigate the safety and plausibility of apheresis as a method for extracting and concentrating parasites from healthy subjects experimentally infected with blood stage P. vivax. Therefore, statistical considerations regarding sample size do not apply. We estimate that a total of up to 8 subjects inoculated in a sequential manner will be sufficient to meet the objectives of this study. Approximately 4 weeks after the inoculation of each subject an assessment of all data collected will be performed. If it is deemed by the Principal Investigator that there is no need to proceed further as all objectives of the study have been met, the study may be considered complete with fewer than 8 subjects enrolled.

No formal statistical analysis plan will be generated. Continuous data will be summarised using descriptive statistics (mean and standard deviation, or median and interquartile range). Categorical data will be presented using N and percentage (using the number of subjects without missing data in the calculation).

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 9213 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 17868 0
4007 - Herston

Funding & Sponsors
Funding source category [1] 297749 0
Charities/Societies/Foundations
Name [1] 297749 0
QIMR Berghofer Medical Research Institute
Address [1] 297749 0
300 Herston Road, Herston, Queensland 4006
Country [1] 297749 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
QIMR Berghofer Medical Research Institute
Address
300 Herston Road, Herston, Queensland 4006
Country
Australia
Secondary sponsor category [1] 296843 0
None
Name [1] 296843 0
Address [1] 296843 0
Country [1] 296843 0
Other collaborator category [1] 279776 0
Hospital
Name [1] 279776 0
Associate Professor Glen Kennedy Royal Brisbane and Women’s Hospital, Brisbane
Address [1] 279776 0
Metro North HHS
Herston QLD 4029
Country [1] 279776 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298812 0
QIMR Berghofer Human Research Ethics Committee
Ethics committee address [1] 298812 0
300 Herston Road, Herston, QLD 4006
Ethics committee country [1] 298812 0
Australia
Date submitted for ethics approval [1] 298812 0
Approval date [1] 298812 0
22/09/2017
Ethics approval number [1] 298812 0

Summary
Brief summary
This study will investigate the safety of carrying out an apheresis procedure on healthy participants infected with Plasmodium vivax malaria parasites. Apheresis is the name of a process, which involves the removal of all or, as is the case in this study, part of one of the components that makes up a person’s blood. We want to see whether apheresis can be used as a way of collecting all the stages of the P. vivax parasite found in the blood. We hypothesise that the apheresis procedure is safe in healthy participants infected with P. vivax and that apheresis can be used to extract and concentrate all stages of P. vivax parasites at numbers greater than can be attained by simple blood draws. It is hoped that information gained from this study may lead to the development of interventions that effectively treat and prevent malaria and its spread in areas of the world where this parasite continues to cause significant sickness and death.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 78306 0
Prof James McCarthy
Address 78306 0
Q-Pharm Pty Limited
Level 5, Clive Berghofer Cancer Research Centre (CBCRC)
300C Herston Rd
Herston QLD 4006
Country 78306 0
Australia
Phone 78306 0
+61 7 3845 3636
Fax 78306 0
+61 7 3845 3637
Email 78306 0
j.mccarthy@uq.edu.au
Contact person for public queries
Name 78307 0
Prof James McCarthy
Address 78307 0
Q-Pharm Pty Limited
Level 5, Clive Berghofer Cancer Research Centre (CBCRC)
300C Herston Rd
Herston QLD 4006
Country 78307 0
Australia
Phone 78307 0
+61 7 3845 3636
Fax 78307 0
+61 7 3845 3637
Email 78307 0
j.mccarthy@uq.edu.au
Contact person for scientific queries
Name 78308 0
Prof James McCarthy
Address 78308 0
Q-Pharm Pty Limited
Level 5, Clive Berghofer Cancer Research Centre (CBCRC)
300C Herston Rd
Herston QLD 4006

Country 78308 0
Australia
Phone 78308 0
+61 7 3845 3636
Fax 78308 0
+61 7 3845 3637
Email 78308 0
j.mccarthy@uq.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary