Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617001394336
Ethics application status
Approved
Date submitted
12/09/2017
Date registered
3/10/2017
Date last updated
19/02/2021
Date data sharing statement initially provided
19/02/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Comparison of artesunate parasite clearance of Plasmodium falciparum K13 and 3D7 isolates in healthy subjects
Scientific title
A comparative study of the parasitological response to single dose artesunate therapy among healthy subjects experimentally infected with either the artemisinin-resistant Plasmodium falciparum isolate K13 or the artemisinin-sensitive isolate 3D7
Secondary ID [1] 292868 0
nil
Universal Trial Number (UTN)
nil
Trial acronym
K13 vs 3D7
Linked study record
nil

Health condition
Health condition(s) or problem(s) studied:
Malaria Infection 304714 0
Condition category
Condition code
Infection 304022 304022 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This single-centre, open-label study will compare the response of the Plasmodium falciparum isolates Cam3.II^R539T (referred to as K13, artemisinin-resistant) and 3D7 (artemisinin-sensitive) to a single dose of the antimalarial drug artesunate in healthy subjects using the induced blood stage malaria model. The study will be conducted in up to 9 subjects per cohort, with up to 3 cohorts. Within each cohort, subjects will be randomised to receive either the K13 or 3D7 challenge agent, in a 2:1 ratio.

Subjects randomised to receive the K13 challenge agent will be inoculated on Day 0 with approximately 2,800 viable P. falciparum K13 parasite-infected red blood cells (RBCs). Subjects randomised to receive the 3D7 challenge agent will be inoculated on Day 1 with approximately 2,800 viable P. falciparum 3D7 parasite-infected RBCs. On an outpatient basis, subjects will be monitored daily via phone and then will attend the clinical unit daily from 4 days post-inoculation – Day 4 for K13 subjects and Day 5 for 3D7 subjects – until positive for presence of malaria parasites by quantitative polymerase chain reaction (qPCR) targeting the 18S rRNA gene. Once qPCR positive, subjects will be monitored twice daily until artesunate treatment for parasitaemia, symptoms or signs of malaria, and adverse events. The threshold for commencement of artesunate treatment will be when all subjects reach a parasitaemia of greater than or equal to 5,000 parasites/mL. If the parasitaemia of any subject is greater than or equal to 5,000 parasites/mL, and is accompanied by a malaria clinical score greater than 6 before all subjects have reached the treatment threshold, then treatment of that subject will begin within a 24 hour period. Subjects may also receive artesunate treatment at any time based on parasitaemia and/or clinical symptoms at the Investigator’s discretion.

Subjects will be admitted to the clinical unit (approximately Day 9), administered a single dose of approximately 2 mg/kg artesunate (as oral tablets), and confined for 72 hours to monitor for tolerability of therapy and to ensure adequate clinical response. Once clinically well, subjects will be followed up on an out-patient basis for monitoring of safety and parasite clearance. If artesunate does not clear parasitaemia, subjects will be administered piperaquine phosphate as a single dose of 960 mg (as oral tablets). All subjects will receive compulsory rescue treatment with atovaquone/proguanil hydrochloride on Day 26+/-3 or earlier at the Investigator’s discretion. A treatment course consists of 4 tablets of atovaquone 250 mg/proguanil hydrochloride 100 mg once daily, orally for 3 days. Subjects may also be treated with a single dose of 45 mg primaquine (as oral tablets) at the time of atovaquone/proguanil hydrochloride treatment, if gametocytaemia is suspected from parasite lifecycle stage reverse transcriptase qPCR or by the presence of stable low level parasitaemia, or at the Investigator’s discretion, to ensure complete clearance of gametocytes. Follow-up for safety assessments will be performed on Day 28+/-3 (End of Study).
Intervention code [1] 299111 0
Treatment: Drugs
Comparator / control treatment
The 3D7 challenge agent will act as an active control group in order to compare the parasite clearance of the K13 and 3D7 challenge agents. The 3D7 challenge agent has been used extensively in previous induced blood stage malaria clinical trials. The 3D7 challenge agent will be given at the same dose as the K13 challenge agent i.e. approximately 2,800 viable P. falciparum parasite-infected red blood cells, given intravenously.
Control group
Active

Outcomes
Primary outcome [1] 303356 0
The parasite clearance profiles of P. falciparum K13 and 3D7 after administration of artesunate will be characterised by the parasite reduction ratio and parasite clearance half-life as determined using qPCR. A t-test will be used to compare the slope of the clearance curves for K13 and 3D7 isolates.
Timepoint [1] 303356 0
qPCR: prior to artesunate treatment and at approximately 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 48 hours after artesunate treatment.
Primary outcome [2] 303357 0
The safety and tolerability of P. falciparum K13 and 3D7 infection will be evaluated from adverse event and serious adverse event recording (including severity and causality), physical examinations, vital signs, biochemistry, haematology, and urinalysis.

Adverse events consistent with the symptoms of early malaria infection include headache, fever, fatigue, malaise, myalgia, arthralgia and gastrointestinal upset. The medical assessment of AE severity of the study will be recorded in accordance with the Common Terminology Criteria for Adverse Events v4.03 published 14 June 2010.
Timepoint [2] 303357 0
Adverse event recording: at all clinic visits from parasite inoculation to Day 28+/-3.

Physical examinations: complete physical examinations at screening and Day 28+/-3; abbreviated physical examinations prior to parasite inoculum, on clinic admission prior to artesunate treatment, and prior to exit of clinic confinement; abbreviated physical examination will also be performed when signs or symptoms of malaria are identified if clinically indicated.

Vital signs: screening, and at all clinic visits from parasite inoculation to Day 28+/-3.

Biochemistry and haematology: screening, Day -3 to Day -1 safety visit (if required), on clinic admission prior to artesunate treatment, prior to exit of confinement, Day 14+/-2, Day 18+/-2, prior to piperaquine phosphate treatment (if required), 3 days post-piperaquine phosphate treatment (or next scheduled visit), prior to atovaquone/proguanil hydrochloride treatment, after completion of atovaquone/proguanil hydrochloride treatment (or next scheduled visit), and Day 28+/-3.

Urinalysis: screening, Day -3 to Day -1 safety visit (if required), on clinic admission prior to artesunate treatment, Day 14+/-2, Day 18+/-2, and Day 28+/-3.
Secondary outcome [1] 338733 0
nil
Timepoint [1] 338733 0
nil

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 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 (approximately 6 weeks).
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. Female participants of childbearing potential should be surgically sterile or using an insertable, injectable, transdermal or combination oral contraceptive approved by the Therapeutic Goods Administration combined with a barrier contraceptive for the duration of the study, and have negative results on a serum pregnancy test done before malaria parasite inoculation.
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.
2. 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.
3. Has evidence of increased cardiovascular disease risk.
4. History of splenectomy.
5. 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.
6. Evidence of acute illness within the 4 weeks prior to screening that the Investigator deems may compromise subject safety.
7. Subject has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion, e.g. gastrectomy, diarrhoea.
8. Participation in any investigational product study within the 12 weeks preceding the study.
9. 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.
10. Subject who has ever received a blood transfusion.
11. Any vaccination within the last 28 days.
12. 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.)
13. Cardiac/QT risk
14. Known hypersensitivity to artesunate or any of its excipients, artemether or other artemisinin derivatives, piperaquine, atovaquone/proguanil hydrochloride, primaquine, or 4-aminoquinolines.
15. Unwillingness to abstain from consumption of grapefruit or Seville oranges from inoculation day until end of antimalarial treatment.

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
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
Statistical methods / analysis
The sample size required to complete the primary objective of comparing the artesunate parasite clearance profiles of K13 and 3D7 isolates was estimated. Background information used to estimate the required sample size for this study came from previous induced blood stage malaria studies with the 3D7 isolate and fast acting antimalarial drugs, as well as artesunate clearance data from artemisinin-resistant isolates. nQuery Adviser was used to calculate the sample size required. Satterthwaite t-test of equal means but unequal variances was used with a 2-sided a=0.05, an estimated 30% mean difference in decay rate between the K13 and 3D7 isolates, and a power of 80%. The estimated sample size using a 2:1 ratio of K13 to 3D7 was 18 to 9 subjects. To achieve this sample size, subjects will be challenged with K13 or 3D7 in a 2:1 ratio in up to 3 cohorts of n=9.

The study will use parallel group comparison. 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 percent sign (using the number of subjects without missing data in the calculation).

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
6/11/2017
Actual
26/10/2017
Date of last participant enrolment
Anticipated
3/12/2018
Actual
28/08/2018
Date of last data collection
Anticipated
7/01/2019
Actual
19/11/2018
Sample size
Target
27
Accrual to date
Final
25
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 8990 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 17491 0
4007 - Herston

Funding & Sponsors
Funding source category [1] 297497 0
Charities/Societies/Foundations
Name [1] 297497 0
Medicines for Malaria Venture (MMV)
Country [1] 297497 0
Switzerland
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] 296502 0
None
Name [1] 296502 0
Address [1] 296502 0
Country [1] 296502 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298597 0
QIMR Berghofer Human Research Ethics Committee
Ethics committee address [1] 298597 0
Ethics committee country [1] 298597 0
Australia
Date submitted for ethics approval [1] 298597 0
Approval date [1] 298597 0
25/08/2017
Ethics approval number [1] 298597 0
P2339

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77606 0
Prof James McCarthy
Address 77606 0
Q-Pharm Pty Limited
Level 5, Clive Berghofer Cancer Research Centre (CBCRC)
300C Herston Rd
Herston QLD 4006
Country 77606 0
Australia
Phone 77606 0
+61 7 3845 3636
Fax 77606 0
+61 7 3845 3637
Email 77606 0
[email protected]
Contact person for public queries
Name 77607 0
James McCarthy
Address 77607 0
Q-Pharm Pty Limited
Level 5, Clive Berghofer Cancer Research Centre (CBCRC)
300C Herston Rd
Herston QLD 4006
Country 77607 0
Australia
Phone 77607 0
+61 7 3845 3636
Fax 77607 0
+61 7 3845 3637
Email 77607 0
[email protected]
Contact person for scientific queries
Name 77608 0
James McCarthy
Address 77608 0
Q-Pharm Pty Limited
Level 5, Clive Berghofer Cancer Research Centre (CBCRC)
300C Herston Rd
Herston QLD 4006
Australia
Country 77608 0
Australia
Phone 77608 0
+61 7 3845 3636
Fax 77608 0
+61 7 3845 3637
Email 77608 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


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
SourceTitleYear of PublicationDOI
Dimensions AISafety and parasite clearance of artemisinin-resistant Plasmodium falciparum infection: A pilot and a randomised volunteer infection study in Australia2020https://doi.org/10.1371/journal.pmed.1003203
EmbaseParasite Viability as a Superior Measure of Antimalarial Drug Activity in Humans.2021https://dx.doi.org/10.1093/infdis/jiaa678
EmbaseParasite Viability as a Measure of in Vivo Drug Activity in Preclinical and Early Clinical Antimalarial Drug Assessment.2022https://dx.doi.org/10.1128/aac.00114-22
N.B. These documents automatically identified may not have been verified by the study sponsor.