The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12619001085167
Ethics application status
Approved
Date submitted
19/07/2019
Date registered
6/08/2019
Date last updated
26/02/2020
Date data sharing statement initially provided
6/08/2019
Date results information initially provided
26/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A pilot study to characterise the in vivo safety and infectivity of a Plasmodium falciparum 3D7-GL master cell bank in healthy subjects
Scientific title
A pilot study to characterise the in vivo safety and infectivity of a Plasmodium falciparum 3D7-GL master cell bank in healthy subjects
Secondary ID [1] 298726 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 313646 0
Condition category
Condition code
Infection 312070 312070 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will evaluate the in vivo safety and infectivity of a Plasmodium falciparum 3D7-GL master cell bank (MCB) in healthy subjects using the induced blood stage malaria (IBSM) model. The study will be conducted in up to 2 subjects. The safety data review team (SDRT) will review the parasitaemia and safety data obtained from the first subject up until the end of Riamet® treatment before the second subject is inoculated with the malaria challenge agent.

Subjects will undergo a whole body PET/MRI scan and dedicated brain MRI before inoculation. Prior to administration of 18F FDG, subjects are to fast for roughly 6 hours and avoid strenuous exercise and adhere to a low carbohydrate diet for 24 hours. An estimated dose of 4.5MBq per kg (based on screening weight) 18F FDG is to be administered once by intravenous infusion (minimum dose 90MBq, maximum dose 400MBq) by the radiology technologist. PET/MRI scanning and dedicated brain MRI will be performed.
The malaria challenge agent, containing an estimated ~2,800 viable P. falciparum 3D7 parasite-infected RBCs in a volume of 2 mL, will be administered once intravenously on Day 0. The subject will undergo intravenous cannulation with an appropriate gauge cannula. The challenge agent will be injected immediately by an infectious disease physician, and the cannula again flushed with 5-10 mL of clinical grade saline. The cannula will then be removed, and haemostasis ensured by use of an appropriate dressing. The subject will be observed for a minimum of 60 minutes after inoculation.

Subjects will be monitored daily via phone call or text message on Days 1 to 3 to solicit any adverse events (AEs). Subjects will then come to the clinical unit twice daily from Day 4, separated by approximately 12 hours, for safety assessments and to monitor the progression of parasitaemia by collecting blood samples and performing qPCR targeting the gene encoding P. falciparum 18S rRNA.

A day prior to confinement, subjects will undergo a second whole body PET/MRI scan and dedicated brain MRI.

Antimalarial treatment with artemether/lumefantrine (Riamet®) will be initiated when parasitaemia reaches =10,000 parasites/mL. Subjects will be admitted to the clinical unit for earlier treatment if:
• they have a malaria clinical score greater than or equal to 6,
• or if they experience an SAE,
• or if they have a CTCAE grade 3 AE deemed possibly related to malaria and not self-resolved or relieved with concomitant medications,
• or if the Principal Investigator (PI) or Co-Investigator (Co-I), both of whom are infectious diseases physicians, considers it necessary for subject safety. In this situation, the PI or Co-I will consult with the independent medical monitor; however, antimalarial medication may be administered prior to receiving approval if immediate treatment is deemed necessary for subject safety.
Following initiation of treatment, subjects will be followed up as inpatients for at least 24 hours to ensure tolerance of the first three doses of Riamet® and adequate clinical response. Follow-up will then continue on an out-patient basis at 36, 48 and 72 hours post-treatment initiation for continued Riamet® dosing, safety monitoring, and to ensure clearance of parasitaemia. Additional visits may occur at the PI or Co-I’s discretion based on results of safety and parasitaemia assessments. Follow-up safety assessments will occur on Day 30±2 (phone call only), Day 60±2 (phone call only) and Day 90±2 (EOS).
Primacin® (primaquine) may also be administered as a single oral dose if gametocytes are detected using qRT-PCR. The decision to administer primaquine will be made by the PI or Co-I in consultation with the independent medical monitor.
Intervention code [1] 315057 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 320788 0
Adverse events including their severity, seriousness, and causality. Safety assessments including physical examination, clinical laboratory analysis (biochemistry, haematology, and urinalysis), malaria clinical score recording, and electrocardiographs.
Timepoint [1] 320788 0
Adverse event recording: at all clinic visits from parasite inoculation to Day 90+/-2.
Physical examinations: complete physical examinations at screening and Day 11; abbreviated physical examinations prior to parasite inoculum, on clinic admission prior to Riamet® treatment; symptom directed physical examination will also be performed when signs or symptoms of malaria are identified if clinically indicated.
Vital signs: screening, parasite inoculation, and from Day 4 to Day 11.
Biochemistry and haematology (including iron studies): screening, Day -3 to Day -1 safety visit (if required), on clinic admission prior to Riamet® treatment, prior to exit of confinement, Day 11 and Day 90+/-2 (iron studies only)
Urinalysis: screening, Day -3 to Day -1 safety visit (if required), on clinic admission prior to Riamet® treatment and Day 11.
Secondary outcome [1] 372845 0
The presence of parasites in blood samples after inoculation. This will be assessed using malaria 18S qPCR
Timepoint [1] 372845 0
qPCR: prior to Riamet® treatment and at approximately 2, 4, 8, 12, 16, 20, 24, 36, 48 and 72 hours after Riamet®treatment.
Secondary outcome [2] 372846 0
The growth rate of parasites in subjects after inoculation until Riamet® treatment. This will be assessed using malaria 18S qPCR
Timepoint [2] 372846 0
qPCR: following inoculation and prior to Riamet® treatment. Assessments - qPCR Day 4 to 7 (twice daily AM & PM) and Day 8 (prior to Riamet Treatment).
Secondary outcome [3] 372847 0
The parasite reduction ratio (PRR) and the corresponding parasite clearance half-life. This is a composite secondary outcome. This will be assessed using malaria 18S qPCR.
Timepoint [3] 372847 0
qPCR: prior to Riamet® treatment and at approximately 2, 4, 8, 12, 16, 20, 24, 36, 48 and 72 hours after Riamet®treatment.
Secondary outcome [4] 372848 0
18F FDG uptake values from specific regions of interest, including spleen, bone marrow (lumbar spine and/or pelvis), and brain as assessed by PET/MRI imaging. This is a composite outcome.
Timepoint [4] 372848 0
PET/MRI Imaging – 1-2 days before inoculation with the challenge agent and approximately 1-2 days prior to confinement at the clinical site.

Eligibility
Key inclusion criteria
1. Adult male subjects between 18 and 55 years of age inclusive, who do not live alone (from inoculation day until the end of the antimalarial treatment) and will be contactable and available for the duration of the trial and up to 2 weeks following the End of Study visit.
2. Body weight minimum 50 kg, body mass index between 18 and 32 kg/m2, inclusive.
3. Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination).
4. Normal standard 12-lead 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. Must be able to lie supine and still for the duration of the PET/MRI image acquisition.
Minimum age
18 Years
Maximum age
55 Years
Gender
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Subject with Rh (D) Negative Blood Group
2. Any history of malaria or participation in a previous malaria challenge study.
3. 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.
4. Has evidence of increased cardiovascular disease risk.
5. History of splenectomy.
6. Presence of acute infectious disease or fever (e.g., sublingual temperature greater than or equal to 38.5 degrees C) within the 5 days prior to inoculation with malaria parasites.
7. Evidence of acute illness within the 4 weeks prior to screening that the Investigator deems may compromise subject safety.
8. Subject has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion, e.g. gastrectomy, diarrhoea.
9. Participation in any investigational product study within the 12 weeks preceding the study.
10. 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.
11. Subject who has ever received a blood transfusion.
12. Any vaccination within the last 28 days.
13. 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.)
14. Cardiac/QT risk
15. Known hypersensitivity to artesunate or any of its excipients, artemether or other artemisinin derivatives, piperaquine, atovaquone/proguanil hydrochloride, primaquine, or 4-aminoquinolines.
16. Unwillingness to abstain from consumption of grapefruit or Seville oranges from inoculation day until end of antimalarial treatment.
17. Significant previous radiation exposure

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 is a pilot study, to investigate the safety and infectivity of the P. falciparum 3D7-GL malaria challenge agent. A sample of two subjects is considered sufficient to meet the study objectives.
The safety of the P. falciparum 3D7-GL malaria challenge agent will be assessed by monitoring of AEs and SAEs including severity and causality. Safety assessments will include physical examination, clinical laboratory analysis, vital signs, electrocardiographs, and malaria clinical score recording.

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] 14295 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 27290 0
4007 - Herston

Funding & Sponsors
Funding source category [1] 303277 0
Charities/Societies/Foundations
Name [1] 303277 0
Medicines for Malaria Venture
Address [1] 303277 0
Route de Pre-Bois 20, 1215 Geneva
Country [1] 303277 0
Switzerland
Primary sponsor type
Charities/Societies/Foundations
Name
QIMR Berghofer Medical Research Institute
Address
300 Herston Road, Herston QLD 4006
Country
Australia
Secondary sponsor category [1] 303293 0
None
Name [1] 303293 0
Address [1] 303293 0
Country [1] 303293 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303815 0
QIMR Berghofer Human Research Ethics Committee
Ethics committee address [1] 303815 0
300 Herston Road, Herston QLD 4006
Ethics committee country [1] 303815 0
Australia
Date submitted for ethics approval [1] 303815 0
Approval date [1] 303815 0
17/07/2019
Ethics approval number [1] 303815 0

Summary
Brief summary
The induced blood stage malaria (IBSM) model provides an attractive tool to test the efficacy of vaccines and drugs for non-immune subjects in a rapid and cost effective manner. The purpose of this pilot clinical trial is to characterise the P. falciparum 3D7-GL MCB as a malaria challenge agent for use in future IBSM studies.
Another aim of this study is to investigate advanced imaging techniques in malaria infection. Nuclear medicine imaging techniques, particular hybrid PET/CT and PET/MRI have a central role primarily in oncology for assessing the biodistribution and activity of malignancy. The ability of these techniques to detect and locate biological and biochemical changes have more recently been applied to other medical fields including Infectious Diseases, though there are no studies in malaria.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 94906 0
A/Prof Bridget Barber
Address 94906 0
QIMR Berghofer Medical Research Institute
300 Herston Rd, Herston QLD 4006
Country 94906 0
Australia
Phone 94906 0
+61 7 3362 0498
Fax 94906 0
Email 94906 0
Bridget.Barber@qimrberghofer.edu.au
Contact person for public queries
Name 94907 0
Prof James McCarthy
Address 94907 0
QIMR Berghofer Medical Research Institute
300 Herston Rd, Herston QLD 4006
Country 94907 0
Australia
Phone 94907 0
+61 7 3845 3636
Fax 94907 0
Email 94907 0
j.mccarthy@uq.edu.au
Contact person for scientific queries
Name 94908 0
Prof James McCarthy
Address 94908 0
QIMR Berghofer Medical Research Institute
300 Herston Rd, Herston QLD 4006
Country 94908 0
Australia
Phone 94908 0
+61 7 3845 3636
Fax 94908 0
Email 94908 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
All information obtained during the study, including clinic and hospital records, personal information and research data, will be kept confidential.
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?
No
Results – basic reporting
Results – plain English summary