| Eligibility |
Inclusion Criteria:
- Capable of giving signed informed consent as described in Appendix 2, which includes
compliance with the requirements and restrictions listed in the informed consent form
(ICF) and in this protocol, prior to any study-specific procedures.
- Men and women aged 18 to 55 years (inclusive), with suitable veins for cannulation or
repeated venipuncture.
- Total body weight =50 kg, and a body mass index between 18 to 32 kg/m2, inclusive.
- Female subjects are eligible to participate if they have a negative pregnancy test at
the Screening Visit and on admission to the study center, not lactating
- Male subjects with female partners of childbearing potential must agree to use
contraception as detailed in Appendix 7 of this protocol from the time of informed
consent until at least 3 months after dosing with the investigational product. Male
subjects with female partners that are surgically sterile, or male subjects who have
undergone sterilization and have had testing to confirm the success of the
sterilization, may also be included.
- Male subjects must not donate sperm from the day of dosing until at least 3 months
after dosing with the investigational product.
- Medically healthy with clinically insignificant screening results based on a
comprehensive medical history and physical examination as judged by the Principal
Investigator.
- Has to agree to abstain from alcohol intake 48 hours before administration of the
study treatment and inoculation with P. falciparum, and during the confinement period
of the study.
- Able to be compliant with the protocol and attend all scheduled visits.
Exclusion Criteria:
- Previously treated with study treatment in the present study.
- History of any clinically important disease or disorder which, in the opinion of the
Investigator, may either put the subject at risk because of participation in the
study, or influence the results or the subject's ability to participate in the study.
- Any known active current or history of recurrent bacterial, viral, fungal,
mycobacterial or other infections.
- Any clinically important illness, medical/surgical procedure or trauma within 4 weeks
of the first administration of investigational product.
- History of splenectomy.
- Subjects with history of schizophrenia, bi-polar disease, psychoses, disorders
requiring lithium, attempted or planned suicide, or any other severe (disabling)
chronic psychiatric diagnosis.
- Subjects who have been hospitalized within 5 years prior to enrollment for either a
psychiatric illness or due to danger to self or others.
- History of an episode of minor depression that required at least 6 months of
pharmacological therapy and/or psychotherapy within the last 5 years; or any episode
of major depression.
- Presence of clinically significant infectious disease or fever (eg, sublingual
temperature =38.5°C) within 5 days prior to study treatment administration (Parts A
and C) or inoculation with the malaria challenge agent (Part B).
- Hematology, biochemistry, or urinalysis results at Screening or at Day -1 (Parts A and
C) or between Day -11 to -9 (Part B) that are outside of Sponsor-approved clinically
acceptable laboratory ranges (Appendix 4), or are considered clinically significant by
the Investigator. One repeat is permitted at Screening.
- Any positive result at Screening for hepatitis B surface antigen, anti-hepatitis B
core antibodies, rapid plasma reagin, anti-hepatitis C virus antibody, and anti-human
immunodeficiency virus 1 and 2 antibodies.
- Symptomatic postural hypotension at Screening (confirmed on 2 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 to 3 minutes when
changing from supine to standing position.
- Abnormal vital signs at Screening (supine and standing) and on Day 1 (Parts A and C)
or pre-inoculation on Day 8 (Part B) (supine), defined as any of the following:
1. Systolic blood pressure <90 or >140 mmHg.
2. Diastolic blood pressure <40 or >90 mmHg.
3. Pulse rate <40 or >100 bpm.
- 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.
- Any clinically important abnormalities in rhythm, conduction or morphology of the
resting ECG, and any clinically important abnormalities in the 12 lead ECG as
considered by the Investigator that may interfere with the interpretation of QTc
interval changes.
- Prolonged Fridericia QT correction formula (QTcF) (>450 msec for males and >470 msec
for females), prolonged Bazett's QT correction formula (QTcB) (>450 msec for males and
>470 msec for females), or PR interval >210 msec (both males and females), or
shortened QTcF <340 msec or family history of long QT syndrome at the Screening Visit
and on Day 1 (Parts A and C) or pre-inoculation on Day -8 (Part B).
- Plasma donation within 1 month of the Screening Visit or any blood donation/blood loss
>500 mL or blood transfusion during the 3 months prior to the Screening Visit. For
Parts B and C, subjects who have ever received a blood transfusion will be excluded.
- Current smokers (tobacco use of >5 cigarettes or equivalent per day), or those unable
to stop smoking during confinement.
- History of alcohol abuse or excessive intake of alcohol defined as an average weekly
intake of >14 drinks/week for men or >7 drinks/week for women. One drink is equivalent
to 12 g alcohol = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5
ounces (45 mL) of 80-proof distilled spirits.
- History of drug habituation, or any prior intravenous usage of an illicit substance.
- Positive urine drug and alcohol breath test at Screening or on admission to the study
center prior to the administration of investigational product (Day -1 for Parts A and
C and Day 1 for Part B)/inoculation with malaria challenge agent (Day -8 for Part B
and Day 3 for Part C). Positive for any drug listed in Appendix 4 in the urine drug
screen, unless there is an explanation acceptable to an Investigator (eg, the subject
has stated in advance that they consumed a prescription or over-the-counter product
which contained the detected drug) and/or the subject has a negative urine drug screen
on retest by the pathology laboratory. Any subject testing positive for acetaminophen
(paracetamol) at Screening and/or inoculation day may still be eligible for study
participation, at the Investigator's discretion.
- Excessive intake of caffeine-containing drinks or food, eg, coffee, tea, chocolate,
Red Bull, or cola (more than 400 mg of caffeine per day, equivalent to >4 cups of
coffee per day) for 48 hours before the start of dosing or inoculation with malaria
challenge agent.
- Ingestion of any poppy seeds within 24 hours prior to each Drug Abuse Screening
(Screening Visit [all Parts], Day 1 [Part A and Part C], Day -8 and Day 1 [Part B],
and Day 3 [Part C]). Subjects will be advised by phone not to consume any poppy seeds
in this time period.
- Any history or presence of diagnosed (by an allergist/immunologist) or treated (by a
physician) food or known drug allergies, or history of anaphylaxis or other severe
allergic reactions including face, mouth, or throat swelling or any difficulty
breathing. Subjects 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 study.
- Use of any prescribed or nonprescribed medication including antacids, analgesics,
herbal preparations, or vitamins (other than paracetamol/acetaminophen [<4 g per day],
ibuprofen [<1.2 g per day], or routine vitamins [megadose intake of 20 to 600 times
the recommended daily dose is prohibited]) within 2 weeks prior to the first
administration of investigational product or 5 times the medication's half life,
whichever is longer. Limited use of other non prescription medications or dietary
supplements, not believed to affect subject safety or the overall results of the
study, may be permitted a case-by-case basis following discussion with the
Investigator and approval of the Sponsor. Hormone replacement therapy is allowed.
- Any vaccination within the last 28 days.
- Any recent (<6 weeks) or current systemic therapy with an antibiotic or drug with
potential antimalarial activity (eg, chloroquine, piperaquine phosphate,
benzodiazepine, flunarizine, fluoxetine, tetracycline, azithromycin, clindamycin,
doxycycline etc.).
- Has received another new chemical entity (defined as a compound which has not been
approved for marketing) or has participated in any other clinical study that included
drug treatment within 3 months of the administration of investigational product in
this study. The period of exclusion begins 3 months after dosing (or greater than 5
times half life) or 1 month after the last visit, whichever is the longest. Note:
Subjects consented and screened, but not dosed in this study or a previous Phase I
study, are not excluded.
- Involvement in the planning and/or conduct of the study (applies to the Sponsor,
contract research organizations, and study center staff, etc.).
- Subjects who are unlikely to co operate with the requirements of the study.
- Judgment by the Investigator that the subject should not participate in the study if
they have any ongoing or recent (ie, during the screening period) minor medical
complaints that may interfere with the interpretation of study data or are considered
unlikely to comply with study procedures, restrictions and requirements.
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