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Trial registered on ANZCTR


Registration number
ACTRN12622001097730
Ethics application status
Approved
Date submitted
5/07/2022
Date registered
8/08/2022
Date last updated
24/10/2022
Date data sharing statement initially provided
8/08/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Assessing transmission of Plasmodium falciparum 3D7-MBE008 parasites from healthy participants to mosquitoes
Scientific title
A pilot volunteer infection study to determine the utility of the Plasmodium falciparum 3D7-MBE008 master cell bank in assessing malaria transmission blocking interventions
Secondary ID [1] 307484 0
P3821/CTM2005
Universal Trial Number (UTN)
n/a
Trial acronym
n/a
Linked study record
ACTRN12619001079134 is parent study

Health condition
Health condition(s) or problem(s) studied:
Malaria 326894 0
Condition category
Condition code
Infection 324096 324096 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 323954 0
Treatment: Drugs
Comparator / control treatment
Participants randomised to the no transmission blocking intervention (no drug control group; n=2) on Day 25 will not receive any treatment.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 331910 0
Transmissibility of Plasmodium falciparum 3D7-MBE008 parasites from humans to mosquitoes assessed by proportion of participants who transmit to mosquitoes. The primary outcome will be calculated from transmission data obtained from enriched membrane feeding assays performed for all participants on Day 25 (prior to primaquine administration for those participants randomised to the active control group). The enriched membrane feeding assays use freshly drawn blood from the participants. A mosquito is defined as infected if the presence of oocysts are detected in midgut dissections by 18S qPCR.
Timepoint [1] 331910 0
25 Days after inoculation.
Secondary outcome [1] 411567 0
The intensity of mosquito infection of P. falciparum 3D7-MBE008 parasites when transmitted from humans to mosquitoes. The value of intensity of mosquito infection will be calculated as the proportion of infected mosquitoes per individual. A mosquito is defined as infected if the presence of oocysts are detected in midgut dissections by 18S qPCR. The median (range) intensity of mosquito infection intensity will be reported. A separate analysis of mosquito infectivity at the sporozoite level may be performed. In this case, a mosquito is defined as infected if the presence of sporozoites are detected in head/thorax dissections by 18S qPCR. The results of the sporozoite analysis (if performed) will be supportive to the results of the oocyst results.
Timepoint [1] 411567 0
25 days after inoculation
Secondary outcome [2] 411568 0
Transmission blocking activity of primaquine and transmission in the no drug control assessed by the within-person percentage change in mosquito infection intensity. The intensity of mosquito infection will be calculated as the proportion of infected mosquitoes per individual per time-point. The percent change from baseline (Day 25) at each post-treatment time point will be reported for each participant. A mosquito is defined as infected if the presence of oocysts are detected in midgut dissections by 18S qPCR. A separate analysis of mosquito infectivity at the sporozoite level may be performed. In this case, a mosquito is defined as infected if the presence of sporozoites are detected in head/thorax dissections by 18S qPCR. The results of the sporozoite analysis (if performed) will be supportive to the results of the oocyst results.
Timepoint [2] 411568 0
26, 27, 29, 32, and 39 days after inoculation compared to 25 days after inoculation
Secondary outcome [3] 411569 0
Gametocytocidal activity of primaquine and gametocytaemia in compared to the no drug control assessed by the within-person percentage change in gametocyte density. Gametocyte density (based on 18S qPCR results from participant blood samples) will be calculated per individual per time-point. The percent reduction change from baseline (Day 25) at each post-treatment time point will be reported for each participant.
Timepoint [3] 411569 0
26, 27, 29, 32, and 39 days after inoculation compared to 25 days after inoculation
Secondary outcome [4] 412573 0
Safety and tolerability of the P. falciparum 3D7-MBE008 malaria challenge agent assessed by the incidence, severity and relationship of adverse events. Adverse events consistent with the symptoms of early malaria infection include headache, fever, fatigue, malaise, myalgia, arthralgia, and gastrointestinal upset. Safety assessments including physical examination, clinical laboratory analysis (biochemistry, haematology, and urinalysis), malaria clinical score recording, and electrocardiographs will be used for assessment.
Timepoint [4] 412573 0
Adverse event recording at all clinic visits and by phone contact from parasite inoculation (Day 0) to end of study. There will be clinic visits on Day 0, daily visits between Days 4 and 10, visits 3 times a week between Days 11 and 24, and visits on Days 25, 26, 27, 29, 32, 39, and 42. There will be phone contact on Days 1 to 3

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
55 Years
Sex
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 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
This is a pilot study to investigate the transmissibility of the P. falciparum 3D7-MBE008 parasites from humans to mosquitoes. The sample size selected is not based on formal statistical calculations. A sample of four participants is considered sufficient to address the study objectives.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
8/09/2022
Actual
Date of last participant enrolment
Anticipated
8/07/2023
Actual
Date of last data collection
Anticipated
27/10/2023
Actual
Sample size
Target
4
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment postcode(s) [1] 37984 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 311763 0
Charities/Societies/Foundations
Name [1] 311763 0
QIMR Berghofer Medical Research Institute
Country [1] 311763 0
Australia
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] 313224 0
None
Name [1] 313224 0
Address [1] 313224 0
Country [1] 313224 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311205 0
QIMR Berghofer Medical Research Institute Human Research Ethics Committee (QIMR Berghofer HREC; EC00278)
Ethics committee address [1] 311205 0
Locked Bag 2000, Royal Brisbane and Women’s Hospital, Brisbane QLD 4029
Ethics committee country [1] 311205 0
Australia
Date submitted for ethics approval [1] 311205 0
07/06/2022
Approval date [1] 311205 0
01/09/2022
Ethics approval number [1] 311205 0
P3821

Summary
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.
Trial website
Trial related presentations / publications
Public notes
Participants will be excluded if they test Positive on a COVID-19 rapid antigen test on Day 0 prior to scheduled malaria challenge agent administration.

Contacts
Principal investigator
Name 120322 0
A/Prof Bridget Barber
Address 120322 0
USC Clinical Trials Centre and QIMR Berghofer Medical Research Institute
Level 5, 300C Herston Road,
Herston QLD 4006
Country 120322 0
Australia
Phone 120322 0
+61733620498
Fax 120322 0
Email 120322 0
[email protected]
Contact person for public queries
Name 120323 0
Bridget Barber
Address 120323 0
USC Clinical Trials Centre and QIMR Berghofer Medical Research Institute
Level 5, 300C Herston Road,
Herston QLD 4006
Country 120323 0
Australia
Phone 120323 0
+61733620498
Fax 120323 0
Email 120323 0
[email protected]
Contact person for scientific queries
Name 120324 0
Bridget Barber
Address 120324 0
USC Clinical Trials Centre and QIMR Berghofer Medical Research Institute
Level 5, 300C Herston Road,
Herston QLD 4006
Country 120324 0
Australia
Phone 120324 0
+61733620498
Fax 120324 0
Email 120324 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Pilot data will not be shared


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.