Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001326684p
Ethics application status
Submitted, not yet approved
Date submitted
15/11/2023
Date registered
18/12/2023
Date last updated
18/12/2023
Date data sharing statement initially provided
18/12/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A pilot study to characterize the safety and infectivity of a Plasmodium knowlesi parasite bank in healthy volunteers
Scientific title
A pilot study to characterise the in vivo safety and infectivity of an in vitro expanded Plasmodium knowlesi YH1-HS master cell bank in healthy participants
Secondary ID [1] 311105 0
NIL
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 331994 0
Condition category
Condition code
Infection 328734 328734 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Challenge Agent
The malaria challenge agent, containing the relevant number of viable Plasmodium knowlesi YH1-HS parasite-infected erythrocytes in a volume of 2 mL, will be administrated intravenously on Day 0. The first cohort will receive approximately 2,800 viable parasites. Subsequent cohorts may receive a higher dose of approximately 28,000 viable parasites or 280,000 viable parasites in accordance with the dose escalation criteria. The actual number of parasites inoculated will take into account the loss of viability resulting from cryopreservation, storage and thawing. If a dose increase is required between cohort 1 and cohort 2, the dose will increase from 2800 parasites in cohort 1 to 28,000 parasites in cohort 2. If a further dose increase is required, the dose will increase from 28,000 parasites to 280,000 parasites in the subsequent cohort. The maximum dose will be 280,000 parasites.

Participants will report to the clinical unit on inoculation day after fasting for greater than or equal to 8 hours and undergo intravenous cannulation. The inoculum will be injected, and the cannula flushed with clinical grade saline. The cannula will then be removed. An extra syringe will be prepared to quantify the parasite count of the challenge agent by Polymerase Chain Reaction (PCR). The duration of the inoculation is less than 1 minute.

Definitive antimalarial medications
Compulsory definitive antimalarial treatment for all participants will be initiated when parasitaemia is greater than or equal to 10,000 parasites/mL, or on Day 21 (whichever occurs first). Earlier treatment will be initiated if a participant experiences a serious adverse event (SAE), or at the Investigator’s discretion in the interest of participant safety.

Riamet® tablets will be administered as six oral doses of four tablets (total course of 24 tablets equivalent to 480 mg artemether and 2.88 g lumefantrine). The second dose of four tablets will be administered 8±1 h after the first dose. The remaining doses will be administered twice daily (morning and evening).

Malarone® will be utilised as a backup medication to Riamet® in the event of allergy or contraindication to Riamet®. A treatment course consists of four tablets administered daily for three days (total course of 12 tablets equivalent to 3 g atovaquone and 1.2 g proguanil hydrochloride). Malarone is adminstered daily for 3 days. The 2nd and 3rd doses will be taken approximately 24 and 48 hours after the first dose.

The first dose of Riamet and Malarone will be supervised. The subsequent doses may be taken at home. Participants will receive a phone call or text message from the clinical trial unit staff to ensure compliance.

Intravenous artesunate may be administered in the event a participant vomits or cannot tolerate oral drugs. In this case, the participant will be admitted to hospital for treatment. Artesunate will be administered as 2.4 mg/kg IV bolus on admission, with repeat dosing at 12 hours and 24 hours, then once daily until oral therapy is possible.
Intervention code [1] 327360 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 336545 0
To evaluate the safety of the P. knowlesi YH1-HS malaria challenge agent.
Timepoint [1] 336545 0
Adverse event recording: at all clinic visits from parasite inoculation (Day 0) until the end of study (day 24 +/- 3). Adverse events will be recorded at all clinic visits from parasite inoculation (Day 0) until the end of study (day 24 +/- 3). Adverse events will also be measured 4, 8 and 12 hours post administration of antimalarial treatment.
Secondary outcome [1] 428750 0
The presence of parasites in blood samples after inoculation as detected by qPCR.
Timepoint [1] 428750 0
The day following inoculation (day 1) until day 21. The parasite reduction ratio over a 48-hour period (PRR48) will be measured at 48 hours. Day of treatment is the day on which the antimalarial treatment is administered. Parasitemia by PCR will be measured every hour for 12 hours following antimalarial treatment.


Day of treatment
The parasite reduction ratio over a 48-hour period (PRR48) and the corresponding parasite clearance half-life following administration of artemether/lumefantrine.

48 hours post treatment.
Secondary outcome [2] 428817 0
The parasite multiplication ratio (PMR) from inoculation until initiation of artemether/lumefantrine treatment.
Timepoint [2] 428817 0
Day of treatment (the day on which antimalarial treatment is administered)
Secondary outcome [3] 428818 0
The parasite reduction ratio over a 48-hour period (PRR48) and the corresponding parasite clearance half-life following administration of artemether/lumefantrine.
Timepoint [3] 428818 0
48 hours post treatment

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 EOS visit.
2. Total body weight greater than or equal to 50 kg, and a body mass index (BMI) 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. Vital signs at screening (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.
5. At screening, and pre-inoculation: QTcF less than or equal to 450 msec (male volunteers); QTcF less than or equal to 470 msec (female volunteers); PR interval less than or equal to 210 msec for both males and females.
6. Women of childbearing potential (WOCBP) who anticipate being sexually active with a male during the trial must agree to use a highly effective method of birth control combined with a barrier contraceptive from the screening visit until 30 days after the end of study (covering a full menstrual cycle) and have a negative urine pregnancy test result prior to inoculation with the malaria challenge agent on Day 0.

Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Known hypersensitivity to artesunate or other artemisinin derivatives, lumefantrine, proguanil/atovaquone, primaquine, or 4-aminoquinolines.
2. Any history of anaphylaxis or other severe allergic reactions, or other food or drug allergy that the Investigator considers may impact on participant safety.
3. History of convulsion (including drug or vaccine-induced episodes). A medical history of febrile convulsion during childhood (less than 5 years) is not an exclusion criterion.
4. Presence of current or suspected uncontrolled chronic diseases that may impact participant safety or interpretation of clinical trial results, such as (but not limited to) cardiac or autoimmune disease, diabetes, progressive neurological disease, severe malnutrition, hepatic or renal disease, epilepsy, or asthma.
5. History of malignancy of any organ system (other than localised basal or squamous cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within five years of screening, regardless of whether there is no evidence of local recurrence or metastases.
6. Individuals with history of schizophrenia, bipolar disorder psychoses, attempted or planned suicide, or any other severe (disabling) chronic psychiatric diagnosis including generalised anxiety disorder.
7. History of an episode of depression lasting more than 6 months that required pharmacological therapy and/or psychotherapy within the last 2 years.
8. A score of 20 or more on the Beck Depression Inventory-II (BDI-II) and/or a response of 1, 2 or 3 for item 9 of this inventory (related to suicidal ideation).
• The BDI-II will be used as a validated tool for the assessment of depression at screening. Participants that meet criterion 8 will be referred to a general practitioner or medical specialist as appropriate. Participants with a BDI-II score of 17 to 19 may be enrolled at the discretion of the Investigator if they do not have a history of the psychiatric conditions mentioned in criterion 6 and their mental state is not considered to pose additional risk to the health of the participant during the trial or to the execution of the trial and interpretation of the data gathered.
9. History of splenectomy.
10. Symptomatic postural hypotension at screening (confirmed on two consecutive readings), irrespective of the decrease in blood pressure, or asymptomatic postural hypotension defined as a decrease of SBP of greater than or equal to 20 mmHg after 3 min standing and/or a decrease of DBP of greater than or equal to 10 mmHg after 3 min standing. This 3 min standing period will commence after the volunteer has rested for 5 min in the supine position.
11. Cardiac/QT risk:
• Family history of sudden death or of congenital prolongation of the QTc interval or known congenital prolongation of the QTc interval or any clinical condition known to prolong the QTc interval.
• History of symptomatic cardiac arrhythmias or of clinically relevant bradycardia.
12. Evidence of increased cardiovascular disease risk (defined as greater than 10%, 5 year risk for those greater than 35 years of age, as determined by the Australian Absolute Cardiovascular Disease Risk Calculator [http://www.cvdcheck.org.au/]). Risk factors include sex, age, systolic blood pressure (mm/Hg), smoking status, total and HDL cholesterol (mmol/L), and reported diabetes status.
13. Presence of clinically significant infectious disease or fever (e.g., sublingual temperature greater than or equal to 38°C) within the five days prior to inoculation.
Prior medications and treatments
1. Any vaccination within 28 days of malaria challenge, and any vaccination planned during the study.
2. Use of prescription drugs (excluding contraceptives), investigational medical products, or non-prescription drugs or herbal supplements, that in the opinion of the investigator may potentially interfere with study interventions, within 14 days or five half-lives (whichever is longer) prior to malaria challenge. Requirements for concomitant medication use (from inoculation until the end of study).
3. Individual who has ever received a blood transfusion.

Malaria exposure:
4. Any history of malaria or participation in a previous malaria challenge trial or malaria vaccine trial.
5. Must not have had malaria exposure that is considered by the Principal Investigator or their delegate to be significant. This includes but is not limited to: history of having 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 trial; history of having lived for greater than 1 year in a malaria-endemic region in the past 10 years; history of having ever lived in a malaria-endemic region for more than 10 years inclusive. Bali is not considered a malaria-endemic region.

Alcohol use and smoking
6. History or presence of alcohol abuse (regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = half a pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 units = 125 mL glass of wine, depending on type), or drug habituation, or any prior intravenous usage of an illicit substance.
7. Any individual who currently smokes cigarettes on a daily basis (including e-cigarettes, vaping, and other nicotine use).
Blood donation:
8. Blood product donation to any blood bank during the 8 weeks (whole blood) or 4 weeks (plasma and platelets) prior to malaria challenge.
9. Individual unwilling to defer blood donations for at least twelve months after the EOS visit.
Laboratory results
10. Haematology, biochemistry or urinalysis results at screening or at the eligibility visit (Day -1 to Day -3) that are outside of the standard clinically acceptable laboratory ranges or are considered clinically significant by the Principal Investigator.
11. Positive result for: hepatitis B surface antigen (HBs Ag), anti-hepatitis B core antibodies (anti-HBc Ab), anti-hepatitis C virus (anti-HCV) antibodies, anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2 Ab), COVID-19 by rapid test on Day 0, red blood cell alloantibodies.
12. Positive urine drug test. Any drug listed in the urine drug screen unless there is an explanation acceptable to the Investigator (e.g., the participant has stated in advance that they consumed a prescription or over-the-counter product that contained the detected drug) and the participant has a negative urine drug screen on retest by the pathology laboratory.
13. Positive alcohol breath test.
14. Positive serum pregnancy test at screening visit, positive urine pregnancy test on Day 0.

Other
15. Individual who, in the judgement of the Investigator, is likely to be non-compliant during the trial
16. Individual who is an Investigator, research assistant, pharmacist, trial coordinator, or other staff thereof, directly involved in conducting the trial.
17. Individual without good peripheral venous access.
18. Individual who is breastfeeding or lactating.

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
Other
Other design features
All participants will be inoculated with the P. knowlesi challenge agent. However, doses may differ between cohorts, and will be determined by the Safety Data Review Team based on data from the preceding cohort.
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. knowlesi YH1-HS malaria challenge agent. Growth and clearance of parasitaemia will be compared to data from existing induced blood stage malaria trials using other Plasmodium species. A sample size of up to four participants is considered sufficient to meet the study objectives and is consistent with previous similar pilot studies.

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, are enrolled in the study and inoculated with the P. knowlesi YH1-HS challenge agent.
Analysis of the primary endpoint: The primary endpoint is the incidence, severity and relationship to the P. knowlesi YH1-HS malaria challenge agent of adverse events as determined by self-reported symptoms, clinical laboratory analysis, vital signs, physical examinations and ECG assessments. Additionally, the severity of the induced malaria infection in each participant graded by the malaria clinical score.

Secondary endpoints: The parasite multiplication rate (PMR) will be calculated by applying a log-linear or sine-wave growth model to the summarised replicate parasitaemia data from patency to before treatment. Mixed-effects models will be used to obtain parameter estimates for each treatment group. The growth rate parameter from the model will be transformed into the PMR for reporting. The parasite clearance kinetics following dosing with artemether/lumefantrine will be determined by calculating the parasite reduction ratio over a 48 hour period (PRR48) and corresponding parasite clearance half-life (PCt1/2).
This is a pilot study to investigate the safety and infectivity of the P. knowlesi YH1-HS malaria challenge agent. Growth and clearance of parasitaemia will be compared to data from existing induced blood stage malaria trials using other Plasmodium species. A sample size of up to four participants is considered sufficient to meet the study objectives and is consistent with previous similar pilot studies.

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, are enrolled in the study and inoculated with the P. knowlesi YH1-HS challenge agent.
Analysis of the primary endpoint: The primary endpoint is the incidence, severity and relationship to the P. knowlesi YH1-HS malaria challenge agent of adverse events as determined by self-reported symptoms, clinical laboratory analysis, vital signs, physical examinations and ECG assessments. Additionally, the severity of the induced malaria infection in each participant graded by the malaria clinical score.

Secondary endpoints: The parasite multiplication rate (PMR) will be calculated by applying a log-linear or sine-wave growth model to the summarised replicate parasitaemia data from patency to before treatment. Mixed-effects models will be used to obtain parameter estimates for each treatment group. The growth rate parameter from the model will be transformed into the PMR for reporting. The parasite clearance kinetics following dosing with artemether/lumefantrine will be determined by calculating the parasite reduction ratio over a 48 hour period (PRR48) and corresponding parasite clearance half-life (PCt1/2).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
10/01/2024
Actual
Date of last participant enrolment
Anticipated
1/03/2024
Actual
Date of last data collection
Anticipated
29/03/2024
Actual
Sample size
Target
4
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 25910 0
University of the Sunshine Coast Clinical Trials Centre - South Bank - South Brisbane
Recruitment postcode(s) [1] 41664 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 315190 0
Government body
Name [1] 315190 0
National Health and Medical Research Council, Australia
Country [1] 315190 0
Australia
Primary sponsor type
Government body
Name
QIMR Berghofer Medical Research Institute
Address
300 Herston Road, Herston QLD 4066
Country
Australia
Secondary sponsor category [1] 317217 0
None
Name [1] 317217 0
Address [1] 317217 0
Country [1] 317217 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 314121 0
Queensland Institute of Medical Research Berghofer Human Research Ethics Committee (EC00278)
Ethics committee address [1] 314121 0
300 Herston Road, Herston, QLD 4006
Ethics committee country [1] 314121 0
Australia
Date submitted for ethics approval [1] 314121 0
31/10/2023
Approval date [1] 314121 0
Ethics approval number [1] 314121 0

Summary
Brief summary
This is an open-label, non-randomised pilot study to evaluate the safety and infectivity of a Plasmodium knowlesi parasite bank. Up to 4 participants will be enrolled in cohorts of 1 participant each.

The monkey parasite Plasmodium knowlesi is an important cause of human malaria in South East Asia. This parasite now accounts for all cases of locally-acquired malaria in Malaysia, and has prevented Malaysia from being able to eliminate malaria. Malaria volunteer infection studies (VIS) have provided key insights into the biology of other causes of human malaria, including P. falciparum, P. vivax and P. malariae, and have provided a model for evaluating antimalarial therapeutics against these species. However, a VIS for P. knowlesi has not been established. Using similar methods utilized for other Plasmodium parasites, we have recently developed a P. knowlesi parasite bank. In this pilot study, we will now evaluate the safety and infectivity of this new P. knowlesi parasite bank in up to 4 healthy human volunteers. This study will provide valuable information on P. knowlesi replication rates, host response to disease, and pharmacodynamic response to artemether-lumefantrine, in addition to establishing a model to evaluate novel antimalarials and vaccines against this emerging parasite.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 130482 0
Dr Bridget Barber
Address 130482 0
QIMR Berghofer, 300 Herston Rd, Herston QLD 4006
Country 130482 0
Australia
Phone 130482 0
+61 7 3362 0498
Fax 130482 0
Email 130482 0
Bridget.barber@qimrberghofer.edu.au
Contact person for public queries
Name 130483 0
Dr Bridget Barber
Address 130483 0
QIMR Berghofer, 300 Herston Rd, Herston QLD 4006
Country 130483 0
Australia
Phone 130483 0
+61 7 3362 0498
Fax 130483 0
Email 130483 0
Bridget.barber@qimrberghofer.edu.au
Contact person for scientific queries
Name 130484 0
Dr Bridget Barber
Address 130484 0
QIMR Berghofer, 300 Herston Rd, Herston QLD 4006
Country 130484 0
Australia
Phone 130484 0
+61 7 3362 0498
Fax 130484 0
Email 130484 0
Bridget.barber@qimrberghofer.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 Supporting Document Provided



Results publications and other study-related documents

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

Documents added automatically
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