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Trial registered on ANZCTR


Registration number
ACTRN12619001466134
Ethics application status
Approved
Date submitted
18/10/2019
Date registered
23/10/2019
Date last updated
23/10/2019
Date data sharing statement initially provided
23/10/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of high-fat meal followed by a single-dose oral administration of ZY-19489 in healthy adult volunteers
Scientific title
Open label, 2-period cross-over, randomised, pilot food effect study to provide preliminary information on the effect of a high-fat meal on the pharmacokinetics (PK) of a single-dose oral administration of ZY-19489 in health volunteers
Secondary ID [1] 299589 0
QP18C07
Secondary ID [2] 299590 0
ZRC-3278
Universal Trial Number (UTN)
U1111-1226-6868
Trial acronym
Linked study record
This is a follow on study from ACTRN12619000127101 and this is the 2nd of a 3 part study

Health condition
Health condition(s) or problem(s) studied:
Malaria 314870 0
Condition category
Condition code
Infection 313214 313214 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
As per the randomisation schedule, subjects will be in the fasted condition (10 hours fast) or fed condition (high fat meal after an overnight fast of 10 hours) in a 1:1 ratio. Participants will cross over following a 28 days washout period.
Fasted condition: Subjects will be administered a single oral dose of 300mg ZY-19489 after an overnight fast of at least 10 hours.
Fed condition: Subjects will consume a high-fat meal after an overnight fast of at least
10 hours. 300mg oral capsule ZY-19489 will be administered 30 minutes after the start of
the test meal; subjects will be required to consume the whole meal prior to dosing.
High fat meal (based on FDA guidance): A high-fat (approximately 50 percent of total caloric content of the meal) and high-calorie (approximately 800 to 1000 calories) meal is recommended as a test meal for food-effect BA and fed BE studies. This test meal should derive approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively

Intervention code [1] 315844 0
Treatment: Drugs
Comparator / control treatment
Participants will be randomised in 1: 1 ratio (n=8) therefore 4 fed: 4 fasted will cross over to 4 fasted: 4 fed as the two conditions are being compared in a crossover design.
Control group
Active

Outcomes
Primary outcome [1] 321716 0
To evaluate the safety and tolerability of ZY-19489 administered to healthy subjects
Timepoint [1] 321716 0
- Physical examination (Screening),
- Abbreviated physical examination (Day 0 pre-dose),
- Symptom directed physical examination (Throughout as directed)
- Vitals (Screening, Days -1, 0, 1, 2, 3, 5, 7, 10, 14, 20, 21, 22, 23, 24, 26, 28, 31, 35, 42, EOS (Day 49))
- Triplicate ECG (Screening, Day -1, Day 0, Day 1, Day 2, Day 3, Day 7. Day 14, Day 21, 22, 23, 24, 28, 35, 42 and EOS (Day 49))
- Urine analysis (Screening, Day -1. Day 20, Day 35 and EOS (Day 49)),
- Haematology & Biochemistry (Screening, Day -1, Day 1, Day 2, Day 3, Day 7. Day 14, Day 2-, Day 21, Day 22, Day 23, Day 24, Day 28, Day 35, EOS (Day 49))
Secondary outcome [1] 375996 0
Estimation of ZY-19489 PK parameters using non-compartmental methods: AUC0-t, AUC0-8, Cmax, tmax, t1/2, CL/F, Vd/F and gamma.
Timepoint [1] 375996 0
Pharmacokinetic time points:
Day 0 (Pre-dose, 0.5hr, 1hr, 2hr, 3hr, 4hr, 4.5hr, 5hr, 5.5hr, 6hr, 6.5hr, 7hr, 7.5hr, 8hr, 8.5hr, 9hr, 10hr, 12hr,)
Day 1 (16hr, 24hr, 36hr)
Day 2 (48hr)
Day 3 (72 hr)
Day 5 (120 hr)
Day 7 (168hr)
Day 10 (240hr)
Day 14 (336hr)
Day 21 (day of dosing following washout (pre-dose, 0.5hr, 1hr, 2hr, 3hr, 4hr, 4.5hr, 5hr, 5.5hr, 6hr, 6.5hr, 7hr, 7.5hr, 8hr, 8.5hr, 9hr, 10hr, 12hr)
Day 22 (16hr, 24hr, 36hr)
Day 23 (48 hours)
Day 24 (72 hours)
Day 26 (120 hours)
Day 28 (168 hours)
Day 31 (240 hours)
Day 35 (336 hours)
Day 42 (504 hours)
Day 49 EOS (672 hours)
Secondary outcome [2] 375997 0
ZY-20486 pharmacokinetics (including AUC0-t, AUC0-8, Cmax, tmax, t1/2, CL/F, Vd/F and gamma) assessed using plasma assay
Timepoint [2] 375997 0
Pharmacokinetic time points:
Day 0 (Pre-dose, 0.5hr, 1hr, 2hr, 3hr, 4hr, 4.5hr, 5hr, 5.5hr, 6hr, 6.5hr, 7hr, 7.5hr, 8hr, 8.5hr, 9hr, 10hr, 12hr,)
Day 1 (16hr, 24hr, 36hr)
Day 2 (48hr)
Day 3 (72 hr)
Day 5 (120 hr)
Day 7 (168hr)
Day 10 (240hr)
Day 14 (336hr)
Day 21 (day of dosing following washout (pre-dose, 0.5hr, 1hr, 2hr, 3hr, 4hr, 4.5hr, 5hr, 5.5hr, 6hr, 6.5hr, 7hr, 7.5hr, 8hr, 8.5hr, 9hr, 10hr, 12hr)
Day 22 (16hr, 24hr, 36hr)
Day 23 (48 hours)
Day 24 (72 hours)
Day 26 (120 hours)
Day 28 (168 hours)
Day 31 (240 hours)
Day 35 (336 hours)
Day 42 (504 hours)
Day 49 EOS (672 hours)

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. Any subject who, in the opinion of the Investigator, would be unwilling or unable to
consume the pre-dose test meal during the fed arm.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled 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)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
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
Not yet 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] 15004 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 28289 0
4007 - Herston

Funding & Sponsors
Funding source category [1] 304071 0
Commercial sector/Industry
Name [1] 304071 0
Cadila Healthcare Limited
Address [1] 304071 0
Survey No. 396/403, Opp. Sarvotam Hotel, Nr. Nova
Petrochemicals, Sarkhej-Bavla N.H. No. 8A, Moraiya,
Ahmedabad-382213 Gujarat, India
Country [1] 304071 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] 304267 0
Commercial sector/Industry
Name [1] 304267 0
George Clinical Pty Limited
Address [1] 304267 0
Level 5, 1 King Street,
Newtown NSW 2042
Australia
Country [1] 304267 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304562 0
Queensland Institute of Medical Research Berghofer Human Research Ethics Committee
Ethics committee address [1] 304562 0
Locked Bag 2000, Royal Brisbane and Women’s Hospital,
Brisbane QLD 4029, Australia
Ethics committee country [1] 304562 0
Australia
Date submitted for ethics approval [1] 304562 0
01/11/2018
Approval date [1] 304562 0
05/12/2018
Ethics approval number [1] 304562 0
P3433

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 2.

Part 2 is an open label, 2-period cross-over, randomised, pilot food effect study to provide preliminary information on the effect of a high-fat meal on the pharmacokinetics of a single-dose oral administration of ZY-19489 to healthy male and female subjects aged between 18-55 years old. Part 2 will consist of a single cohort of 8 subjects. For safety, the cohort will be split into 2 groups of 4 subjects each (Cohorts 1A and 1B).

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 97394 0
Prof James McCarthy
Address 97394 0
Q-Pharm Pty Ltd (visiting Medical Officer) and
QIMR Berghofer Medical Research Institute
Level 5, 300C Herston Rd
Herston QLD 4006, Australia
Country 97394 0
Australia
Phone 97394 0
+61 7 3845 3647
Fax 97394 0
Email 97394 0
j.mccarthy@uq.edu.au
Contact person for public queries
Name 97395 0
Prof James McCarthy
Address 97395 0
Q-Pharm Pty Ltd (visiting Medical Officer) and
QIMR Berghofer Medical Research Institute
Level 5, 300C Herston Rd
Herston QLD 4006, Australia
Country 97395 0
Australia
Phone 97395 0
+61 7 3845 3647
Fax 97395 0
Email 97395 0
j.mccarthy@uq.edu.au
Contact person for scientific queries
Name 97396 0
Prof James McCarthy
Address 97396 0
Q-Pharm Pty Ltd (visiting Medical Officer) and
QIMR Berghofer Medical Research Institute
Level 5, 300C Herston Rd
Herston QLD 4006, Australia
Country 97396 0
Australia
Phone 97396 0
+61 7 3845 3647
Fax 97396 0
Email 97396 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