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Trial registered on ANZCTR


Registration number
ACTRN12617000244303
Ethics application status
Approved
Date submitted
14/02/2017
Date registered
17/02/2017
Date last updated
14/05/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety of Plasmodium falciparum K13 isolate in healthy participants.
Scientific title
An experimental study to characterise the in vivo safety and infectivity of a Plasmodium falciparum Cam3.II^R539T (K13) artemisinin-resistant isolate in healthy participants.
Secondary ID [1] 291175 0
NIl
Universal Trial Number (UTN)
Nil
Trial acronym
SOK13
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria infection 302049 0
Condition category
Condition code
Infection 301682 301682 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a single-centre, open-label study using the induced blood stage malaria (IBSM) model to characterise the safety and infectivity of an in vitro expanded P. falciparum Cam3.II^R539T (K13) artemisinin-resistant isolate in healthy malaria-naive participants. The study will be conducted in 2 participants.

Each participant will be inoculated on Day 0 with approximately 2,800 viable P. falciparum K13-infected human erythrocytes administered intravenously. On an outpatient basis, participants will be monitored daily via phone call and then will attend the clinic daily (AM) from Day 4 until quantitative polymerase chain reaction (qPCR) positive for presence of malaria parasites. Once qPCR positive they will be monitored twice daily, morning (AM) and evening (PM), until artesunate antimalarial treatment, for adverse events and the unexpected early onset of symptoms, signs or parasitological evidence of malaria. On the day designated for commencement of antimalarial treatment, as determined by qPCR results (parasitaemia greater than or equal to 5,000 parasites/mL) or a malaria clinical symptom score greater than 6, participants will be admitted to the study unit and confined for safety monitoring and a single dose of artesunate tablets of approximately 2 mg/kg according to a dosing table prepared by a pharmacist as outlined in the study protocol.

Following artesunate treatment, participants will be followed up as in-patients for 72 hours to ensure treatment tolerance and adequate clinical response. Once clinically well, participants will be followed up on an out-patient basis for monitoring of safety and clearance of malaria parasites via qPCR. If parasite clearance does not occur, participants will be administered piperaquine, which is known to be active against this isolate (as a single oral dose of Eurartesim ‘Registered Trademark’ piperaquine tetraphosphate/dihydroartemisinin tablets).

The antimalarial Malarone ‘Registered Trademark’ (atovaquone/proguanil hydrochloride) will be administered to all participants as a rescue treatment. It will commence as close as possible to Day 26, within the Day 26 plus or minus 3 window, at the Investigator’s discretion. A treatment course consists of 4 tablets of proguanil hydrochloride 100 mg/atovaquone 250 mg once daily, orally for 3 days. Participants will be treated with a single oral dose of 45 mg primaquine as primaquine phosphate at the time of atovaquone/proguanil hydrochloride treatment if gametocytes are determined to be present based on reverse transcriptase qPCR, to ensure complete clearance of gametocytes. 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 -14 (End of Study). The overall period of participation will therefore be around 13 weeks from the time malaria infection.

The parasite inoculum, artesunate, Eurartesim ‘Registered Trademark’, and Primacin ‘Trademark’ will be administered in the presence of clinic staff. Malarone ‘Registered Trademark’ will be administered at the clinic for initial dosing followed by monitoring, either in the clinic, or by telephone for 3 days to ensure adherence to the therapy.

Intervention code [1] 297172 0
Treatment: Drugs
Comparator / control treatment
'No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 301086 0
Primary outcome 1
Safety of the P. falciparum K13 isolate as determined by monitoring of adverse events and serious adverse events including severity and causality. Safety parameters that will be monitored include physical examination, electrocardiograms, haematology, clinical biochemistry, urinalysis, and red cell alloantibodies.

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 v4.0 published May 28, 2009.
Timepoint [1] 301086 0
Physical examinations: complete physical examinations at screening and Day 28+/-3; abbreviated physical examinations at Day 0 prior to parasite inoculum, on clinic admission prior to artesunate treatment, prior to exit of confinement, and Day 90+/-14; abbreviated physical examination will also be performed when signs or symptoms of malaria are identified if clinically indicated. Electrocardiogram: screening, Day 0 prior to parasite inoculum, on clinic admission prior to artesunate treatment, prior to Eurartesim ‘Registered Trademark’ treatment, at the next scheduled visit after Eurartesim ‘Registered Trademark’ treatment, and Day 28+/-3. Haematology and biochemistry: 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 Eurartesim ‘Registered Trademark’ treatment (if required), 3 days post-Eurartesim ‘Registered Trademark’ 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. Red cell alloantibody testing: screening, Day 28+/-3, and Day 90+/-14.
Primary outcome [2] 301087 0
Primary outcome 2:
P. falciparum K13 isolate infectivity will be determined by presence of parasites in participants after inoculation as measured by qPCR.
Timepoint [2] 301087 0
Primary timepoint 2:
qPCR: Day 0 prior to parasite inoculum, daily from Day 4 (morning) until qPCR positive, and when qPCR positive twice daily (morning and evening) until dosing with artesunate.
Secondary outcome [1] 331697 0
Secondary outcome 1
To characterise the parasite clearance profile, the parasite reduction ratio after artesunate treatment will be determined using qPCR.
Timepoint [1] 331697 0
Secondary timepoint 1
qPCR: prior to artesunate treatment, at approximately 4, 8, 12, 16, 24, 30, 36, and 48 after artesunate treatment.

Eligibility
Key inclusion criteria
1. Adult (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 antimalarial treatment) and will be contactable and available for the duration of the trial and follow-up period (maximum 15 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 participants enrolled in this clinical investigation.
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 or urine pregnancy test done before administration of malaria inoculum.
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 (>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., sub-lingual 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 participant safety.
7. Participant 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. Participant who has ever received a blood transfusion.
11. 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.)
12. Male participant with a female partner who is pregnant or lactating from the time of administration of study medication.
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 citrus (grapefruit, Seville orange.) from inoculation (Day 0) until end of antimalarial treatment.

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
In 5 previous pilot safety and infectivity studies the number of participants necessary to gain sufficient data was 2 participants, thus informing the group size for this study.

This is a pilot study and no formal statistical analysis is planned. All measured variables and derived values will be listed, including data from all participants who meet the eligibility criteria and are enrolled in the study.

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] 7482 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 15305 0
4007 - Herston

Funding & Sponsors
Funding source category [1] 295617 0
Charities/Societies/Foundations
Name [1] 295617 0
Medicines for Malaria Venture (MMV)
Address [1] 295617 0
Route de Pre-Bois 20, 1215 Geneva

Country [1] 295617 0
Switzerland
Primary sponsor type
Other
Name
QIMR Berghofer Medical Research Institute
Address
300 Herston Road, Herston, Queensland 4006
Country
Australia
Secondary sponsor category [1] 294455 0
None
Name [1] 294455 0
Address [1] 294455 0
Country [1] 294455 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296936 0
QIMR Berghofer Human Research Ethics Committee
Ethics committee address [1] 296936 0
300 Herston Road, Herston, QLD 4006
Ethics committee country [1] 296936 0
Australia
Date submitted for ethics approval [1] 296936 0
11/01/2017
Approval date [1] 296936 0
28/02/2017
Ethics approval number [1] 296936 0

Summary
Brief summary
This study will evaluate the safety and infectivity of a P. falciparum K13 artemisinin-resistant malaria parasite in healthy participants using the IBSM model. P. falciparum K13 was isolated from a person with malaria infection and is resistant to the antimalarial drug artemisinin and related drugs such as artesunate. We expect that artesunate treatment will kill the K13 parasites, although at a slower rate compared to drug sensitive isolates. In addition, the P. falciparum K13 isolate retains sensitivity to other antimalarial drugs including piperaquine and atovaquone. Participants will be treated with artesunate to characterise the parasite clearance profile of P. falciparum K13 in response to artesunate .If artesunate does not clear parasitaemia participants will be administered piperaquine, which is known to be active against P. falciparum K13 (as a single oral dose of Eurartesim ‘Registered Trademark’ piperaquine tetraphosphate/dihydroartemisinin tablets) The availability of a P. falciparum artemisinin-resistant isolate in the IBSM model will allow investigation of the efficacy of novel antimalarial drug candidates in clearance of artemisinin-resistant P. falciparum, which is a growing problem in South-East Asia and threatens to spread across the world.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 72486 0
Prof James McCarthy
Address 72486 0
Level 5, Clive Berghofer Cancer Research Centre (CBCRC)
300C Herston Rd
Herston QLD 4006
Country 72486 0
Australia
Phone 72486 0
+61 7 3845 3636
Fax 72486 0
+61 7 3845 3637
Email 72486 0
j.mccarthy@uq.edu.au
Contact person for public queries
Name 72487 0
Dr Silvana Sekuloski
Address 72487 0
QIMR Berghofer Medical Research Institute
300 Herston Rd
Herston QLD 4006
Country 72487 0
Australia
Phone 72487 0
+61 7 3845 3856
Fax 72487 0
+61 7 3845 3507
Email 72487 0
Silvana.Sekuloski@qimrberghofer.edu.au
Contact person for scientific queries
Name 72488 0
Prof James McCarthy
Address 72488 0
Q-Pharm Pty Limited
Level 5, Clive Berghofer Cancer Research Centre (CBCRC)
300C Herston Rd
Herston QLD 4006
Country 72488 0
Australia
Phone 72488 0
+61 7 3845 3636
Fax 72488 0
+61 7 3845 3637
Email 72488 0
j.mccarthy@uq.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary