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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03542149




Registration number
NCT03542149
Ethics application status
Date submitted
11/05/2018
Date registered
30/05/2018
Date last updated
30/05/2018

Titles & IDs
Public title
Safety, Tolerability and Antimalarial Activity of Single Doses of OZ439 and PQP
Scientific title
Phase 1b to Assess Safety, Tolerability, Pharmacokinetic Profile, and Antimalarial Activity of Single Doses of Co-administered OZ439and PQP Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Adult Volunteers
Secondary ID [1] 0 0
QP17C19
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - OZ439 + a-tocopherol polyethylene glycol 1000 succinate

Experimental: A - 200mg of OZ439 and 480 mgPQP.
(OZ439 + a-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral suspension).
The data will be used to determine the relationship between OZ439 and PQP concentrations and parasitaemia levels.

Experimental: B - 200mg of OZ439 and 640 mg PQP.
(OZ439 + a-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral suspension).
The data will be used to determine the relationship between OZ439 and PQP concentrations and parasitaemia levels.

Experimental: C - 400mg of OZ439 and 480 mg PQP.
(OZ439 + a-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral suspension).
The data will be used to determine the relationship between OZ439 and PQP concentrations and parasitaemia levels.

Experimental: D - 400mg of OZ439 and 640 mg PQP.
(OZ439 + a-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral suspension).
The data will be used to determine the relationship between OZ439 and PQP concentrations and parasitaemia levels.


Treatment: Drugs: OZ439 + a-tocopherol polyethylene glycol 1000 succinate
Artefenomel (OZ439), is a novel trioxolane Piperaquine is a bis 4-aminoquinoline and was used mainly in China from the 1960's to the 1980's as an antimalarial monotherapy.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
To characterise the PK/PD relationship between OZ439 and PQP plasma concentrations and blood stage asexual parasitaemia in healthy subjects following P. falciparum IBSM infection. - OZ439 and PQP plasma concentrations (ng/mL), blood stage asexual parasitaemia (parasites/µL)
Timepoint [1] 0 0
PD data up to Day 35 and PK data up to Day 28 post-dose
Secondary outcome [1] 0 0
To describe the area under the plasma concentration-time curve of PK of OZ439 and PQP when co-administered as single doses in healthy volunteers under fasted conditions. - Area under the plasma concentration versus time curve (AUC) 168h,last,time zero to infinity
Timepoint [1] 0 0
over 35 days after co-administration of single doses
Secondary outcome [2] 0 0
To describe the maximum concentration of OZ439 and PQP when co-administered as single doses in healthy volunteers under fasted conditions. - Maximum concentration (Cmax)
Timepoint [2] 0 0
over 35 days after co-administration of single doses
Secondary outcome [3] 0 0
To describe the terminal elimination half-life of OZ439 and PQP when co-administered as single doses in healthy volunteers under fasted conditions. - t1/2,
Timepoint [3] 0 0
over 35 days after co-administration of single doses
Secondary outcome [4] 0 0
To describe the time to reach maximum plasma concentration of OZ439 and PQP when co-administered as single doses in healthy volunteers under fasted conditions. - t max
Timepoint [4] 0 0
over 35 days after co-administration of single doses
Secondary outcome [5] 0 0
To describe the peak plasma concentration PK of OZ439 and PQP when co-administered as single doses in healthy volunteers under fasted conditions after 168 hrs. - C168h
Timepoint [5] 0 0
over 35 days after co-administration of single doses
Secondary outcome [6] 0 0
To describe the apparent systemic plasma clearance of OZ439 and PQP when co-administered as single doses in healthy volunteers under fasted conditions. - CL/F
Timepoint [6] 0 0
over 35 days after co-administration of single doses
Secondary outcome [7] 0 0
To describe the PD Parasite Reduction Ratio of OZ439 and PQP when co-administered as single doses in healthy volunteers under fasted conditions.
Timepoint [7] 0 0
over 35 days after co-administration of single doses
Secondary outcome [8] 0 0
To describe the PD Parasite Clearance Half-life (t t/2of OZ439 and PQP when co-administered as single doses in healthy volunteers under fasted conditions.
Timepoint [8] 0 0
over 35 days after co-administration of single doses

Eligibility
Key inclusion criteria
1. Adult (male and female) subjects between 18 and 55 years of age inclusive, who do not
live alone (from inoculation day until at least the end of the Riamet® treatment) and
will be contactable and available for the duration of the trial and contactable up to
2 weeks following the End of Study visit (approximately 8.5 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,
complete physical examination and special investigations).

4. Vital signs after 5 minutes resting in supine position:

- 90 mmHg = systolic blood pressure (SBP) = 140 mmHg,

- 40 mmHg = diastolic blood pressure (DBP) = 90 mmHg,

- 40 bpm = heart rate (HR) = 100 bpm.

5. Must have QTcF =450 ms, QTcB =450 ms for male subjects, QTcF =470 ms, QTcB =470 ms for
female subjects and PR interval =210 ms at screening and at pre-inoculation on
inoculation day.

6. Heterosexual women of childbearing potential should be surgically sterile or using an
insertable, injectable, transdermal or combination oral contraceptive approved by the
TGA combined with a barrier contraceptive for the duration of the study, and have
negative results on a urine pregnancy test done before inoculation. Abstinent,
heterosexual female subjects must agree to start a double method if they start a
sexual relationship during the study. Adequate contraception does not apply to
subjects of childbearing potential with same sex partners (abstinence from
penile-vaginal intercourse), when this is their preferred and usual lifestyle. Female
subjects with same sex partners must not be planning in vitro fertilisation within the
required contraception period.

Women of non-childbearing potential who will not require contraception during the
study are defined as: post-menopausal (spontaneous amenorrhoea for = 12 months, or
spontaneous amenorrhoea for 6-12 months and follicle-stimulating hormone (FSH) = 40
IU/mL; either should be together with the absence of oral contraceptive use for > 12
months).

Male subjects participating must agree to use a double-barrier method of contraception
including condom plus diaphragm or condom plus intrauterine device or condom plus
stable oral/transdermal/injectable hormonal contraceptive by the female partner from
the time of informed consent through to 90 days after the last dose of OZ439 and PQP.
Abstinent male subjects must agree to start a double-barrier method if they begin
sexual relationships during the study and up to 90 days after the last dose of study
drug.

Male subjects with female partners that are surgically sterile, or male subjects who
have undergone sterilisation and have had testing to confirm the success of the
sterilisation may also be included.

7. Having given written informed consent prior to undertaking any study-related
procedure.

8. Must be willing and able to communicate and participate in the whole study. -
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Haematology, clinical chemistry, coagulation or urinalysis results at screening or on
admission prior to Inoculation or IMP administration that are outside of
Sponsor-approved clinically acceptable laboratory ranges documented in the laboratory
manual or are considered clinically relevant.

2. Any history of malaria or participation in a previous malaria challenge study.

3. 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 (for endemic regions see https://map.ox.ac.uk/country-profiles/#!/). Bali is not
considered a malaria-endemic region.

4. Participation in any investigational product study within the 12 weeks preceding IMP
administration.

5. 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.

6. Symptomatic postural hypotension at screening 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 minutes when
changing from supine to standing position.

7. History of splenectomy.

8. History or presence of diagnosed (by an allergist/immunologist) or treated (by a
physician) food or known drug allergies (including but not limited to allergy to any
of the antimalarial rescue medications to be used in the study), or history of
anaphylaxis or other severe allergic reactions. Note. Subjects with seasonal
allergies/hay fever, house dust mite or allergy to animals that are untreated and
asymptomatic at the time of dosing can be enrolled in the study

9. History of convulsion (including intravenous drug or vaccine-induced episodes) Note. A
medical history of a single febrile convulsion during childhood is not an exclusion
criterion.

10. Presence of current or suspected serious chronic diseases such as cardiac or
autoimmune disease (HIV or other immuno-deficiencies), insulin-dependent and
non-insulin dependent diabetes (excluding glucose intolerance if exclusion criterion 4
is met), progressive neurological disease, severe malnutrition, acute or progressive
hepatic disease, acute or progressive renal disease, porphyria, psoriasis, rheumatoid
arthritis, asthma, epilepsy, or obsessive-compulsive disorder.

11. 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 5 years of
screening, regardless of whether there is evidence of local recurrence or metastases.

12. Subjects with history of schizophrenia, bi-polar disease, or other severe (disabling)
chronic psychiatric diagnosis including depression or receiving psychiatric drugs or
who has been hospitalised within the past 5 years prior to enrolment for psychiatric
illness, history of suicide attempt, or confinement for danger to self or others.

13. History of serious psychiatric condition that may affect participation in the study or
preclude compliance with the protocol, including but not limited to past or present
psychoses, disorders requiring lithium, a history of attempted or planned suicide,
more than one previous episode of major depression, any previous single episode of
major depression lasting for or requiring treatment for more than 6 months, or any
episode of major depression during the 5 years preceding screening.The Beck Depression
Inventory (Appendix 4) will be used as an objective tool for the assessment of
depression at screening. In addition to the conditions listed above, subjects with a
score of 20 or more on the Beck Depression Inventory 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 subjects will be referred to a general practitioner or medical
specialist as appropriate. Subjects with a Beck 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 this criterion and their mental state is not considered to
pose additional risk to the health of the subject or to the execution of the study and
interpretation of the data gathered.

14. History of recurrent headache (e.g. tension-type, cluster or migraine) with a
frequency of =2 episodes per month on average and/or severe enough to require medical
therapy.

15. Presence of acute infectious disease or fever (e.g. sublingual temperature =38.5°C)
within the 5 days prior to inoculation with malaria parasites.

16. Evidence of acute illness within the 4 weeks prior to screening that the Investigator
deems may compromise subject safety.

17. Significant inter-current disease of any type, in particular liver, renal, cardiac,
pulmonary, neurologic, rheumatologic, or autoimmune disease by history, physical
examination, and/or laboratory studies including urinalysis.

18. Subject has a clinically significant disease or any condition or disease that might
affect drug absorption, distribution or excretion (e.g. gastrectomy, diarrhoea).

19. 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 Australian Red Cross Blood Service (Blood Service) or other blood bank
during the 8 weeks prior to the treatment drug dose in the study.

20. Subject unwilling to defer blood donations to the Blood Service for at least 6 months.

21. Medical requirement for intravenous immunoglobulin or blood transfusions.

22. Subject who has ever received a blood transfusion.

23. History or presence of alcohol abuse (alcohol consumption more than 40 g per day) or
drug habituation, or any prior intravenous usage of an illicit substance.

24. Tobacco use of more than 5 cigarettes or equivalent per day, and unable to stop
smoking for the duration of the clinical unit confinement.

25. Female subject who is breastfeeding.

26. Any vaccination within the last 28 days.

27. Any corticosteroids, anti-inflammatory drugs, immunomodulators or anticoagulants. Any
subject currently receiving or having previously received immunosuppressive therapy
(including systemic steroids, adrenocorticotrophic hormone or inhaled steroids) at a
dose or duration associated with hypothalamic-pituitary-adrenal axis suppression (e.g.
1 mg/kg/day prednisone, chronic use of inhaled high potency corticosteroids such as
budesonide 800 µg/day or fluticasone 750 µg, or equivalent).

28. Any recent (<6 weeks) or current systemic therapy with an antibiotic or drug with
potential antimalarial activity (e.g. chloroquine, piperaquine phosphate,
benzodiazepine, flunarizine, fluoxetine, tetracycline, azithromycin, clindamycin,
doxycycline etc.).

29. Ingestion of any poppy seeds within the 24 hours prior to the screening blood test
(subjects will be advised by phone not to consume any poppy seeds in this time
period).

30. Excessive consumption of beverages or food containing xanthine bases including Red
Bull, chocolate, coffee etc. (more than 400 mg caffeine per day, equivalent to more
than 4 cups of coffee per day).

31. Unwillingness to abstain from consumption of grapefruit or Seville oranges from
inoculation day until end of Riamet® treatment.

32. Unwillingness to abstain from consumption of quinine containing foods/beverages such
as tonic water and lemon bitter, from inoculation day until end of Riamet® treatment.

33. Use of prescription drugs or non-prescription drugs or herbal supplements (such as St
John's Wort), within 14 days or 5 half-lives (whichever is longer) prior to the
malaria inoculation. As an exception, ibuprofen (preferred) may be used at doses of up
to 1.2 g/day or paracetamol at doses of up to 4 g/day after discussion with the
Investigator. 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 on a case-by-case basis following approval by the Sponsor in
consultation with the Investigator. Subjects are requested to refrain from taking
non-approved concomitant medications from recruitment until the conclusion of the
study.

34. Any subject who, in the judgment of the Investigator, is likely to be non-compliant
during the study, or is unable to cooperate because of a language problem or poor
mental development.

35. Any subject in the exclusion period of a previous study according to applicable
regulations.

36. Any subject who is the Principal Investigator or any sub-Investigator, research
assistant, pharmacist, study coordinator, or other staff thereof, directly involved in
conducting the study.

37. Any subject without a good peripheral venous access. Biological status

38. 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).

39. Positive urine drug test. Any drug listed in Section 7.2.1 in the urine drug screen
unless there is an explanation acceptable to the Investigator (e.g., 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 may still be eligible for study participation, at the
Investigator's discretion.

40. Positive alcohol breath test.

41. 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.

- Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia, or
hypomagnesaemia.

- ECG abnormalities in the standard 12-lead ECG (at screening or at pre-inoculation
on inoculation day) which in the opinion of the Investigator is clinically
relevant or will interfere with the ECG analyses.

42. Known hypersensitivity to artesunate or any of its excipients, artemether or other
artemisinin derivatives, piperaquine phosphate, proguanil/atovaquone, primaquine, or
4-aminoquinolines.

Study design
Purpose of the study
Other
Allocation to intervention
Randomised controlled 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
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
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] 0 0
Q-Pharm - Herston
Recruitment postcode(s) [1] 0 0
4006 - Herston

Funding & Sponsors
Primary sponsor type
Other
Name
Medicines for Malaria Venture
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
QIMR Berghofer Medical Research Institute
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/Industry
Name [2] 0 0
Clinical Network Services (CNS) Pty Ltd
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Commercial sector/Industry
Name [3] 0 0
Q-Pharm Pty Limited
Address [3] 0 0
Country [3] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
A single-centre Phase 1b study to assess the safety, tolerability, pharmacokinetic profile,
and antimalarial activity of single doses of coadministered artefenomel (OZ439) and
piperaquine phosphate (PQP) against early Plasmodium falciparum blood stage infection in
healthy adult volunteers.
Trial website
https://clinicaltrials.gov/show/NCT03542149
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Rebecca Webster, Dr
Address 0 0
QIMR Berghofer Medical Research Institute
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Heike Huegel Koerpert, MBA
Address 0 0
Country 0 0
Phone 0 0
0041 789 48 18 58
Fax 0 0
Email 0 0
huegelh-consultants@mmv.org
Contact person for scientific queries

No data has been provided for results reporting
Summary results
Not applicable