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Trial registered on ANZCTR


Registration number
ACTRN12619001215112
Ethics application status
Approved
Date submitted
13/08/2019
Date registered
2/09/2019
Date last updated
21/10/2019
Date data sharing statement initially provided
2/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Anti-malarial activity of increasing doses of ZY-19489 in healthy volunteers
Scientific title
Open label study using the P. falciparum induced blood stage malaria (IBSM) model to determine the safety and tolerablity and to characterise the antimalarial activity of a single-dose oral administration of ZY-19489 in healthy adult volunteers
Secondary ID [1] 298965 0
QP18C07
Secondary ID [2] 298966 0
ZRC-3278
Secondary ID [3] 298967 0
P3433
Universal Trial Number (UTN)
U1111-1226-6868
Trial acronym
Linked study record
This is a follow on study from ACTRN12619000127101 and this is the 3rd of a 3 part study

Health condition
Health condition(s) or problem(s) studied:
Malaria 313957 0
Condition category
Condition code
Infection 312362 312362 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Malaria Challenge Agent
The malaria challenge agent: P. falciparum 3D7 inoculum is manufactured (onsite in GMP lab). The malaria challenge agent, containing an estimated ~2,800 viable P. falciparum 3D7 parasite-infected RBCs in a volume of 2 mL, will be administered once intravenously on Day 0 (post-eligibility confirmation) at the clinical trial unit. The subject will undergo intravenous cannulation with an appropriate gauge cannula. The challenge agent will be injected immediately by an infectious disease physician, and the cannula again flushed with 5-10 mL of clinical grade saline. The cannula will then be removed, and haemostasis ensured by use of an appropriate dressing. The subject will be observed for a minimum of 60 minutes after inoculation.

Investigation Product
300mg ZY-19489 capsules will be administered in as a single dose orally 8 days after administration of the malaria challenge agent (Day 8 of the study). ZY-19489 will be administered at the clinical unit under direct observation of clinical unit staff (nurse or medical officer). Subjects will be confined within the clinical unit for 72 hours for safety assessments and for blood sampling to monitor parasitaemia and PK.

Antimalarial rescue medications
- Riamet® tablets for oral administration. Each tablet contains 20 mg artemether and 120mg lumefantrine. All subjects will receive a standard course of therapy with artemether/lumefantrine (Riamet®) on Day 33±3 (unless given earlier).
Riamet® therapy may be initiated earlier in the event of failure of clearance, recrudescence of parasitaemia, or at the Investigator’s discretion based on subject safety. A course of treatment will comprise 6 doses of 4 tablets administered over a period of 60 hours (total course of 24 tablets). Subjects may be administered Riamet® on site for initial dosing and complete the remainder of dosing at home; monitoring will be conducted either in the clinic or by phone for 3 days to ensure adherence to Riamet® therapy.
- Primacin® tablets for oral administration (if required). Each tablet contains 7.5 mg primaquine. A course of treatment will comprise a single dose of 6 tablets (45 mg primaquine). Primaquine (Primacin®) will be administered as a single oral dose if gametocytes are present at the time of Riamet® treatment
- Artesunate (if required). Administered intravenously at dose of 2.4 mg/kg at approximately 0, 12, 24 hours, and then daily for up to 7 days (or until the subject is able to take oral drugs).

Primacin® and artesunate (if required) will be administered at the clinical unit in the presence of clinical unit staff.
Intervention code [1] 315237 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 320989 0
To evaluate the safety and tolerability of ZY-19489 administered to healthy subjects.
Timepoint [1] 320989 0
- Physical examination (Screening and EOS (Day 36+/-3)),
- Abbreviated physical examination (Day 0, Day 8),
- Symptom directed physical examination (Throughout as directed)
- Vitals (Screening, Day 0,4-25 (daily), EOS(Day 36+/-3) )
- Triplicate ECG (Screening, Day 0,8- 35 (daily) EOS (Day 36+/-3)
- Urine analysis (Screening, Eligibility confirmation (Day -3-1). EOS (Day 36+/-3)
- Haematology & Biochemistry (Screening, Eligibility confirmation (Day -3-1), Day 8. 11-24 (daily), EOS (Day 36+/-3)
- AEs & con- meds- Day 0 - throughout study
- Malaria clinical score - Day 0 - throughout study
Secondary outcome [1] 373639 0
Parasite reduction ratio (PRR) and corresponding parasite clearance half-life (Pt ½) following ZY-19489 administration. This will be assessed using qPCR targeting the gene encoding 18S rRNA from blood samples collected to monitor parasitaemia.
Timepoint [1] 373639 0
qPCR timepoints – Day 0, Day 4-7: twice daily (AM/PM), Pre-Treatment with ZY-19489 (Day 8), 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 42, 48, 60 and 72 hours post treatment
Out-patient monitoring:
Day 11 PM (84 hrs),
Day 12 (AM/PM) (96, 108)
Day 13 (AM/PM) (120, 132)
PCR may be done daily depending on drug efficacy or 3 times a week until Riamet® treatment.
Day 33±3 (prior to Riamet® treatment)
Day 36±3 EOS
Secondary outcome [2] 373640 0
Percentage of subjects with recrudescence of parasitaemia following ZY-19489 administration. This will be assessed using qPCR targeting the gene encoding 18S rRNA from blood samples collected to monitor parasitaemia
Timepoint [2] 373640 0
qPCR timepoints –
Pre-Treatment with ZY-19489 (Day 8)
2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 42, 48, 60 and 72 hours post treatment
Out-patient monitoring:
Day 11 PM (84 hrs),
Day 12 (AM/PM) (96, 108)
Day 13 (AM/PM) (120, 132)
PCR may be done daily depending on drug efficacy or 3 times a week until Riamet® treatment.
Day 33±3 (prior to Riamet® treatment)
Day 36±3 EOS
Secondary outcome [3] 374333 0
Estimation of the PK/PD parameters.
1 –The PK/PD modelling will characterise the dose-killing rate between ZY-19489 plasma concentrations and blood stage parasitaemia in healthy subjects following P. falciparum infection. PK parameters include AUC0-t, AUC0-8, Cmax, tmax, t1/2, CL/F, Vd/F and lambda. PD parameters include minimum inhibitory concentration (MIC), the minimal parasiticidal concentration (MPC90), and the parasite reduction rate in 48 h (PRR48).
2. This outcome will be assessed using information on the ZY-19489 doses, PK concentrations, parasitaemia levels and typical covariates such as, age, height, weight, sex and race
Timepoint [3] 374333 0
qPCR timepoints – Day 0, Day 4-7: twice daily (AM/PM), Pre-Treatment with ZY-19489 (Day 8), 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 42, 48, 60 and 72 hours post treatment
Out-patient monitoring:
Day 11 PM (84 hrs),
Day 12 (AM/PM) (96, 108)
Day 13 (AM/PM) (120, 132)
PCR may be done daily depending on drug efficacy or 3 times a week until Riamet® treatment .
Day 33±3 (prior to Riamet® treatment)
Day 36±3 EOS

And

PK analysis Timepoints: Day 8 Baseline (before treatment start),
In- patient observation:
approx. 0.5, 1, 2, 3, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 12, 16, 24, 36, 48, and 72 hours post treatment
Out-patient observation:
Days 13, Day 15, Day 22, Day 29 and Day 36 (EOS).

Eligibility
Key inclusion criteria
1. Male or female (non-pregnant, non-lactacting) aged 18 -55 years inclusive
2. Total body weight greater than or equal to 50kg and BMI between 18-32kg/m2 (inclusive)
3. Certified as healthy by a comprehensive clinical assessment
4. Screening vital signs (measured after 5 minutes in the supine position):
- 90 mmHg - greater than or equal to - systolic blood pressure (SBP) - greater than or equal to - 140 mmHg,
- 40 mmHg - greater than or equal to - diastolic blood pressure (DBP) - greater than or equal to - 90 mmHg,
- 40 bpm - greater than or equal to - heart rate (HR) - greater than or equal to - 100 bpm.
5. At screening and before dosing with investigational medicinal product (IMP): QTcF - greater than or equal to - 450 ms, QTcB - greater than or equal to 450 ms (male subjects); QTcF - greater than or equal to - 470 ms, QTcB - greater than or equal to - 470 ms (female subjects); PR interval - greater than or equal to - 210 ms.
6. Heterosexual female subjects of childbearing potential should be using an insertable, injectable, transdermal or combination oral contraceptive approved by the TGA combined with a barrier contraceptive
7. Completion of the written informed consent process 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 or urinalysis results at screening or on admission prior to IMP administration that are outside of Sponsor-approved clinically acceptable laboratory ranges and are considered clinically significant by the Investigator.
2. Participation in any investigational product study within the 12 weeks preceding IMP administration.
3. Symptomatic postural hypotension at screening irrespective of the decrease in blood pressure, or asymptomatic postural hypotension defined as a decrease in systolic blood pressure greater than or equal to 20 mmHg within 2-3 minutes when changing from supine to standing position.
4. 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. 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.
5. History of convulsion (including intravenous drug or vaccine-induced episodes).A medical history of a single febrile convulsion during childhood is not an exclusion criterion.
6. 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, progressive neurological disease, severe malnutrition, acute or progressive hepatic disease, acute or progressive renal disease, porphyria, psoriasis, rheumatoid arthritis, asthma (excluding childhood asthma, or mild asthma with preventative asthma medication required less than monthly), epilepsy, or obsessive-compulsive disorder.
7. 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.
8. Subjects with history of schizophrenia, bi-polar disease, psychoses, disorders requiring lithium, attempted or planned suicide, or any other severe (disabling) chronic psychiatric diagnosis.
9. Subjects who have received psychiatric medications within 1 year prior to enrolment, or who have been hospitalised within 5 years prior to enrolment for either a psychiatric illness or due to danger to self or others.
10. History of 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 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.
11. History of recurrent headache (e.g. tension-type, cluster or migraine) with a frequency of greater than or equal to 2 episodes per month on average and/or severe enough to require medical therapy, during the 5 years preceding screening.
12. Presence of clinically significant infectious disease or fever (e.g. sublingual temperature greater than or equal to 38.5°C) within the 5 days prior to IMP administration.
13. Evidence of acute illness within the 4 weeks prior to screening that the Investigator deems may compromise subject safety.
14. 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.
15. Subject has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion (e.g. gastrectomy, diarrhoea).
16. Blood donation of any volume within 1 month before IMP administration, 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 IMP administration.
17. Medical requirement for intravenous immunoglobulin or blood transfusions.
18. 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.
19. Tobacco use of more than 5 cigarettes or equivalent per day, and unable to stop smoking for the duration of the clinical unit confinement.
20. Female subject who is breastfeeding
21. Any vaccination within the last 28 days.
22. Any corticosteroids, anti-inflammatory drugs (excluding ibuprofen, acetylsalicylic acid, diclofenac), immunomodulators or anticoagulants within the past 3 months. Any subject 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.
23. Ingestion of any poppy seeds within the 24 hours prior to screening (subjects will be advised by phone not to consume any poppy seeds in this time period).
24. 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).
25. Unwillingness to abstain from consumption of grapefruit or Seville oranges from 5 days prior to IMP dose until the EOS.
26. Use of prescription drugs (excluding oral contraceptives) 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 IMP dosing.
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.
27. 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.
28. Any subject in the exclusion period of a previous study according to applicable regulations.
29. 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.
30. Any subject without a good peripheral venous access.
31. Positive result on any of the following tests: hepatitis B surface antigen (HBs Ag), antihepatitis
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).
32. Positive urine drug test. Any drug 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 and/or inoculation day may still be eligible for study participation, at the
Investigator’s discretion.
33. Positive alcohol breath test.
34. 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, prior to IMP
dosing,) which in the opinion of the Investigator is clinically relevant or will interfere with the ECG analyses.
35. Subject lives alone (at any stage from inoculation day until the end of the Riamet® treatment).
36. Any history of malaria or participation in a previous malaria challenge study or malaria
vaccine trial.
37. 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. Must not have lived for >1 year in a malaria-endemic region in the past 10 years.
Must not have ever lived in a malaria-endemic region for more than 10 years inclusive.
For endemic regions see https://map.ox.ac.uk/country-profiles/#!/. Bali is not considered
a malaria-endemic region.
38. 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.
39. History of splenectomy.
40. Subject unwilling to defer blood donations to the Blood Service for at least 6 months
after the End of Study visit.
41. Subject who has ever received a blood transfusion.
42. 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.).
43. Unwillingness to abstain from consumption of quinine containing foods/beverages such as tonic water and lemon bitter from inoculation day until the end of the Riamet®
treatment.
44. Known hypersensitivity to artesunate or any of its excipients, artemether or other
artemisinin derivatives, proguanil/atovaquone, primaquine, or 4-aminoquinolines

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)
open label
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
NA
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
The safety analysis dataset will include all subjects who are inoculated with the malaria challenge agent. The population(s) used for calculation of PK, PD and PK/PD parameters will be defined in the SAP. Continuous variables will be summarised with the number of observations, mean, standard deviation, median, quartiles, minimum and maximum. Categorical variables will be summarised with the number of observations and the numbers and percent from each category.

Recruitment
Recruitment status
Recruiting
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] 14475 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 27490 0
4007 - Herston

Funding & Sponsors
Funding source category [1] 303508 0
Commercial sector/Industry
Name [1] 303508 0
Cadila Healthcare Limited
Address [1] 303508 0
Survey No. 396/403, Opp. Sarvotam Hotel, Nr. Nova
Petrochemicals, Sarkhej-Bavla N.H. No. 8A, Moraiya,
Ahmedabad-382213 Gujarat, India
Country [1] 303508 0
India
Primary sponsor type
Commercial sector/Industry
Name
Cadila Healthcare Limited
Address
Survey No. 396/403, Opp. Sarvotam Hotel, Nr. Nova
Petrochemicals, Sarkhej-Bavla N.H. No. 8A, Moraiya,
Ahmedabad-382213 Gujarat, India
Country
India
Secondary sponsor category [1] 303561 0
Commercial sector/Industry
Name [1] 303561 0
George Clinical Pty Limited
Address [1] 303561 0
Level 5, 1 King Street,
Newtown NSW 2042
Australia
Country [1] 303561 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304032 0
Queensland Institute of Medical Research Berghofer Human Research Ethics Committee
Ethics committee address [1] 304032 0
Locked Bag 2000, Royal Brisbane and Women’s Hospital,
Brisbane QLD 4029, Australia
Ethics committee country [1] 304032 0
Australia
Date submitted for ethics approval [1] 304032 0
01/11/2018
Approval date [1] 304032 0
05/12/2018
Ethics approval number [1] 304032 0

Summary
Brief summary
This study represents a first-in-human clinical trial for ZY-19489 and aims to determine the safety, tolerability and pharmacokinetics activity of the drug when administered to healthy human subjects. The study will be conducted in three parts. This registration is for Part 3.

Part 3 is an open label study using the P. falciparum induced blood stage malaria (IBSM) model to characterise the antimalarial activity of a single-dose oral administration of ZY-19489 to healthy, malaria naïve, male and female subjects aged between 18-55 years old. Part 3 will be conducted in up to 3 cohorts of 8 subjects each, enrolled sequentially. Each subject will be intravenously inoculated with approximately 2,800 viable P. falciparum 3D7 parasite infected human red blood cells (RBCs) on Day 0.

Adverse events and concomitant medications will be followed throughout the study.
The study will be overseen by Principal Investigator, Dr James McCarthy, an Infectious Diseases physician experienced in the conduct of malaria challenge studies.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 95606 0
Prof James McCarthy
Address 95606 0
Q-Pharm Pty Ltd (visiting Medical Officer) and
QIMR Berghofer Medical Research Institute
Level 5, 300C Herston Rd
Herston QLD 4006, Australia
Country 95606 0
Australia
Phone 95606 0
+61 7 3845 3647
Fax 95606 0
Email 95606 0
j.mccarthy@uq.edu.au
Contact person for public queries
Name 95607 0
Prof James McCarthy
Address 95607 0
Q-Pharm Pty Ltd (visiting Medical Officer) and
QIMR Berghofer Medical Research Institute
Level 5, 300C Herston Rd
Herston QLD 4006, Australia
Country 95607 0
Australia
Phone 95607 0
+61 7 3845 3647
Fax 95607 0
Email 95607 0
j.mccarthy@uq.edu.au
Contact person for scientific queries
Name 95608 0
Prof James McCarthy
Address 95608 0
Q-Pharm Pty Ltd (visiting Medical Officer) and
QIMR Berghofer Medical Research Institute
Level 5, 300C Herston Rd
Herston QLD 4006, Australia
Country 95608 0
Australia
Phone 95608 0
+61 7 3845 3647
Fax 95608 0
Email 95608 0
j.mccarthy@uq.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
EC approval has not been obtained for IPD sharing
What supporting documents are/will be available?
No other documents available
Summary results
No Results