| Eligibility |
Inclusion Criteria:
Demography
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). BMI is an estimate of body weight adjusted
for height. It is calculated by dividing the weight in kilograms by the square of the
height in metres.
Health status
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 with the malaria challenge agent: normal standard
mean of triplicate 12-lead electrocardiogram (ECG) parameters after 5 minutes resting
in supine position in the following ranges:
1. QTcF =450 msec (male participants); QTcF =470 msec (female participants);
2. QRS 50-120 msec
3. PR interval = 210 msec for both males and females, and
4. Normal ECG tracing unless the PI or delegate considers an ECG tracing abnormality
to be not clinically relevant.
6. Women of childbearing potential (WOCBP) who anticipate being sexually active with a
male during the trial must agree to the use of a highly effective method of birth
control (see below) combined with a barrier contraceptive from the screening visit
until 100 days after the last dose of pyronaridine (covering a full menstrual cycle of
30 days starting after 5 half-lives of last dose pyronaridine) and have a negative
result on urine pregnancy test performed before inoculation with the malaria challenge
agent.
Note:
a. Highly effective birth control methods include: combined (oestrogen and progestogen
containing) oral/intravaginal/transdermal/implantable hormonal contraception associated
with inhibition of ovulation, progestogen-only oral/injectable/implantable hormonal
contraception associated with inhibition of ovulation, intrauterine device, intrauterine
hormone-releasing system, bilateral tubal occlusion, vasectomised partner, or sexual
abstinence or same sex relationship.
b. Female participants who are abstinent (from penile-vaginal intercourse) must agree to
start a double method if they start a sexual relationship with a male during the study.
Female participants must not be planning in vitro fertilisation within the required
contraception period.
7. Women of non-childbearing potential (WONCBP) are defined as:
1. Natural (spontaneous) post-menopausal defined as being amenorrhoeic for at least 12
months without an alternative medical cause with a screening follicle stimulating
hormone level (FSH) >25 IU/L (or at the local laboratory levels for post-menopause)
2. Premenopausal with irreversible surgical sterilization by hysterectomy and/or
bilateral oophorectomy or salpingectomy at least 6 months before screening (as
determined by participant medical history) 8. Males who have, or may have, female
sexual partners of child bearing potential during the course of the study must agree
to use a double method of contraception including condom plus diaphragm, or condom
plus intrauterine device, or condom plus stable
oral/transdermal/injectable/implantable hormonal contraceptive by the female partner,
from the time of informed consent through to 70 days (covering a spermatogenesis
cycle) after pyronaridine administration. Abstinent males must agree to start a double
method if they begin sexual relationship with a female during the study and up to 70
days after the last dose of pyronaridine. Males with female partners of child-bearing
potential that are surgically sterile, or males who have undergone sterilisation and
have had testing to confirm the success of the sterilisation, may also be included and
will not be required to use above described methods of contraception.
Regulations 9. Completion of the written informed consent process prior to undertaking
any trial-related procedure.
10. Must be willing and able to communicate and participate in the whole trial. 11.
Agreement to adhere to Lifestyle Considerations (see Section 5.3) throughout trial
duration 12. Agreement to provide current contact details (two telephone numbers
including a mobile number and a responsible adult as an emergency contact) and a
relevant email address.
Exclusion Criteria:
- Individual who lives alone, OR, does not satisfy the following criteria:
Participants who live alone may be included on a case-by-case basis, following
discussion with the Principal Investigator. Participants who live alone must
identify and provide contact details of a support person who is aware of the
participant's participation in the study and is available to provide assistance
if required (for example with contacting the participant in the event that study
staff are unable to, or with transporting the participant to and from the study
site if required).
2. Known hypersensitivity to pyronaridine, artesunate or any of its derivatives,
artemether, lumefantrine or other artemisinin derivatives, proguanil/atovaquone,
primaquine, or 4-aminoquinolines.
3. Haematology, biochemistry or urinalysis results at screening or at the
eligibility visit that are outside of Sponsor-approved clinically acceptable
laboratory ranges (appendix) or are considered clinically significant by the PI
or their delegate.
4. Participation in any investigational product trial within the 12 weeks
preceding pyronaridine administration.
5. 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 in systolic blood pressure =20 mmHg
within 2-3 min when changing from supine to standing position.
6. Any history of anaphylaxis or other severe allergic reactions including face,
mouth, or throat swelling or any difficulty breathing, or other food or drug
allergy that the Investigator considers may impact on participant safety.
Participants with seasonal allergies/hay fever or allergy to animals or house
dust mite that are untreated and asymptomatic at the time of dosing can be
enrolled in the trial.
7. History of convulsion (including drug or vaccine-induced episodes). A medical
history of a single febrile convulsion during childhood (< 5 years) is not an
exclusion criterion.
8. Presence of current or suspected serious chronic diseases such as cardiac or
autoimmune disease, diabetes, progressive neurological disease, severe
malnutrition, hepatic or renal disease. Acute or progressive hepatic or renal
disease, porphyria, psoriasis, rheumatoid arthritis, asthma (excluding childhood
asthma, or mild asthma with preventative asthma medication required less than
monthly), or epilepsy.
9. History of malignancy of any organ system (other than localised basal cell
carcinoma of the skin or in situ cervical cancer), treated or untreated, within
five years of screening, regardless of whether there is evidence of local
recurrence or metastases.
10. Individuals with history of schizophrenia, bipolar disorder psychoses,
disorders requiring lithium, attempted or planned suicide, or any other severe
(disabling) chronic psychiatric diagnosis including generalised anxiety disorder.
11. Individuals who have been hospitalised within five years prior to enrolment
for either a psychiatric illness or due to danger to self or others.
History of an episode of mild/moderate depression lasting more than 6 months that
required pharmacological therapy and/or psychotherapy within the last 5 years; or any
episode of major depression.
The Beck Depression Inventory-II (BDI-II) will be used as a validated tool for the
assessment of depression at screening. In addition to the conditions listed above,
participants with a score of 20 or more on the BDI-II and/or a response of 1, 2 or 3
for item 9 of this inventory (related to suicidal ideation) will not be eligible for
participation. These participants 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 an Investigator if they do not have a history of the
psychiatric conditions mentioned in this criterion and their mental state is not
considered to pose additional risk to the health of the participant or to the
execution of the trial and interpretation of the data gathered.
13. History of recurrent headache (e.g. tension-type, cluster, or migraine) with a
frequency of =2 episodes per month on average and severe enough to require medical
therapy, during the 2 years preceding screening.
14. Presence of clinically significant infectious disease or fever (e.g., sublingual
temperature =38.5°C) within the five days prior to inoculation.
15. Blood product donation to any blood bank during the 8 weeks (whole blood) or 4
weeks (plasma and platelets) prior to admission in the clinical unit on Day 8.
16. History or presence of alcohol abuse (alcohol consumption more than 40 g/4 units/4
standard drinks per day), or drug habituation, or any prior intravenous usage of an
illicit substance.
17. Any individual who currently (within 14 days prior to inoculation) smokes >5
cigarettes/day.
18. Breastfeeding or lactating; positive serum pregnancy test at screening, positive
urine pregnancy test upon admission or at other time points as specified by schedule
of activities tables.
19. Any COVID-19 vaccine within 14 days of inoculation, any other vaccination within
28 days of IMP intake, and any vaccination (including COVID-19 initial or second dose)
planned up to the final follow-up visit.
20. Any corticosteroids, anti-inflammatory drugs (excluding commonly used
over-the-counter anti-inflammatory drugs such as ibuprofen, acetylsalicylic acid,
diclofenac), immunomodulators or anticoagulants within the past three months. Any
individual currently receiving or having previously received immunosuppressive therapy
(including systemic steroids, adrenocorticotrophic hormone or inhaled steroids) at a
dose or duration potentially associated with hypothalamic-pituitary-adrenal axis
suppression within the past year.
21. Use of prescription drugs (excluding contraceptives) or non-prescription drugs or
herbal supplements (such as St John's Wort), within 14 days or five half-lives
(whichever is longer) prior to inoculation. Limited use of other non-prescription
medications or dietary supplements, not believed to affect participant safety or the
overall results of the trial, may be permitted on a case-by-case basis following
approval by the Sponsor in consultation with the PI. Participants are requested to
refrain from taking non-approved concomitant medications from recruitment until the
conclusion of the trial.
22. 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 with clinically relevant bradycardia.
23. Any history of malaria or participation in a previous malaria challenge trial or
malaria vaccine trial.
24. Must not have had malaria exposure that is considered by the PI or their delegate
to be significant. This includes but is not limited to: history of having 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 trial; history of having
lived for >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. For endemic
regions see https://malariaatlas.org/explorer/#/, Bali is not considered a
malaria-endemic region.
25. Has evidence of increased cardiovascular disease risk (defined as >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.
26. History of splenectomy. 27. Individual unwilling to defer blood donations to the
Blood Service for at least twelve months after the EOS visit.
28. Individual who has ever received a blood transfusion. 29. Any recent (<6 weeks)
therapy with an antibiotic or drug with potential antimalarial activity (e.g.
chloroquine, piperaquine phosphate, benzodiazepine, flunarizine, fluoxetine,
tetracycline, azithromycin, clindamycin, doxycycline etc.).
General conditions 30. Any individual who, in the judgement of an Investigator, is
likely to be non-compliant during the trial, or is unable to cooperate because of a
language problem or poor mental development.
31. Any individual in the exclusion period of a previous trial according to applicable
regulations.
32. Any individual who is an Investigator, research assistant, pharmacist, trial
coordinator, or other staff thereof, directly involved in conducting the trial.
33. Any individual without good peripheral venous access. Biological status 34.
Positive result on any of the following tests: 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).
35. Positive urine drug test. Any drug listed in the urine drug screen unless there is
an explanation acceptable to an 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.
36. Severe G6PD deficiency. 37. Positive alcohol breath test. 38. Positive for
SARS-CoV-2 by PCR. NPA testing is to occur between Day -3 to Day -1 but only in the
event that there is community transmission in South East Queensland (see section
8.3.7) 39. Positive for red cell antibodies
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