Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619000127101
Ethics application status
Approved
Date submitted
18/01/2019
Date registered
29/01/2019
Date last updated
10/05/2021
Date data sharing statement initially provided
29/01/2019
Date results information initially provided
10/05/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety and tolerability of increasing doses of ZY-19489 compared to placebo in healthy volunteers.
Scientific title
Randomised, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics (PK) following a single-dose oral administration of ZY-19489 in healthy adult volunteers
Secondary ID [1] 296985 0
QP18C07
Secondary ID [2] 296998 0
ZRC-3278
Secondary ID [3] 296999 0
P3433
Universal Trial Number (UTN)
U1111-1226-6868
Trial acronym
Linked study record
NA

Health condition
Health condition(s) or problem(s) studied:
Malaria 310969 0
Condition category
Condition code
Infection 309632 309632 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
ZY-19489: Capsules for oral administration. Single dose administration.

Initial dose escalation plan:
-Cohort 1 :25mg
-Cohort 2 :75mg
-Cohort 3 :150mg
-Cohort 4 :450mg
-Cohort 5 :900mg
-Cohort 6/7: Max 1500mg

At the conclusion of Cohort 6, the SDRT reviewed safety and PK Data and determined that no further cohorts would be enrolled.
Intervention code [1] 313273 0
Treatment: Drugs
Comparator / control treatment
Placebo: Capsules for oral administration. Capsules are matched to ZY-19489 with respect to size and appearance.
Control group
Placebo

Outcomes
Primary outcome [1] 318588 0
To evaluate the safety and tolerability of ZY-19489 administered to healthy subjects.
Timepoint [1] 318588 0
- Physical examination (Screening),
- Abbreviated physical examination (Day -1),
- 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, EOS (Day 49))
- Urine analysis (Screening, Day -1. Day 14, EOS (Day 49)),
- Haematology & Biochemistry (Screening, Day -1, Day 1, Day 2, Day 3, Day 7. Day 14, Day 21, EOS (Day 49))
Secondary outcome [1] 365446 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
Drug will be quantified through plasma assay and pharmacokinetic analysis will be performed through phoenix winnolin software as per protocol.
Timepoint [1] 365446 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 (504 hr)
EOS Day 28 (672 hr)
Secondary outcome [2] 366121 0
Estimation of Y-20486 pharmacokinetic parameters using non-compartmental methods: AUC0-t, AUC0-8, Cmax, tmax, t1/2, CL/F, Vd/F and gamma. Drug will be quantified through plasma assay and pharmacokinetic analysis will be performed through phoenix winnolin software as per protocol.
Timepoint [2] 366121 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 (504 hr)
EOS Day 28 (672 hr)

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
Sex
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.

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)
The clinical unit pharmacist will allocate a randomisation number (generated using SAS® software by the Sponsor) to each subject as per the randomisation schedule. Pharmacist will have unblinded envelopes and there will be code break envelopes for emergency use only (with sponsor approval).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The clinical unit pharmacist will allocate a randomisation number (generated using SAS® software by the Sponsor) to each subject as per the randomisation schedule immediately before the administration of ZY-19489 or placebo. Block randomisation will be generated to divide the subjects in each cohort.

Part 1, Single Ascending Dose:
All subjects who satisfy the inclusion and exclusion criteria will be randomized to either ZY-19489 or Placebo in a 6:2 ratio within a cohort. The first two patients in each cohort will be randomized in a 1:1 ratio to ZY-19489 or Placebo and the remaining patients in the cohort will be randomized in a 5:1 ratio to ZY-19489 or Placebo.

Cohort 6 enrollment: Due to COVID-19, recruitment paused after randomisation of the two sentinel participants. When recruitment restarted, the remainder of the 6 participants were divided into 2 (of 3 participants each) sub-cohorts for safety reasons. The M:F ratio was still maintained for Cohort 6.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
The safety analysis dataset will include all subjects who receive at least one dose of ZY-19489.
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
Completed
Date of first participant enrolment
Anticipated
11/02/2019
Actual
11/02/2019
Date of last participant enrolment
Anticipated
20/03/2020
Actual
17/07/2020
Date of last data collection
Anticipated
1/05/2020
Actual
24/08/2020
Sample size
Target
88
Accrual to date
Final
48
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 12837 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 25307 0
4007 - Herston

Funding & Sponsors
Funding source category [1] 301558 0
Commercial sector/Industry
Name [1] 301558 0
Cadila Healthcare Limited
Country [1] 301558 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] 301255 0
Commercial sector/Industry
Name [1] 301255 0
George Clinical Pty Limited
Address [1] 301255 0
Level 5, 1 King Street,
Newtown NSW 2042
Australia
Country [1] 301255 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302289 0
Queensland Institute of Medical Research Berghofer Human Research Ethics Committee
Ethics committee address [1] 302289 0
Locked Bag 2000, Royal Brisbane and Women’s Hospital,
Brisbane QLD 4029, Australia
Ethics committee country [1] 302289 0
Australia
Date submitted for ethics approval [1] 302289 0
01/11/2018
Approval date [1] 302289 0
05/12/2018
Ethics approval number [1] 302289 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 1. Part 1 will be a single ascending dose) study which will provide information on the safety, tolerability and pharmacokinetic profile of different single oral doses of ZY-19489 administered to fasted subjects. It will be conducted in up to 7 cohorts of 8 subjects each. Each cohort will be enrolled within a 28 day screening period to ensure subjects meet all the inclusion criteria and none of the exclusion criteria. Subjects will be randomised within each cohort to receive a single oral dose of ZY-19489 or placebo on Day 0 after an overnight fast of at least 10 hours in a ratio of 6:2. A sentinel dosing strategy will be employed for each dose cohort. Two sentinel subjects (one subject randomised to ZY-19489 and the other subject randomised to placebo) will be dosed and a review of the blinded safety data obtained up to 48 hours post-dosing will be conducted by the Investigator. If no safety concerns are identified, the remaining 6 subjects of the cohort will be dosed (5 subjects randomised to ZY-19489 and 1 subject randomised to placebo).
Adverse events and concomitant medications will be followed throughout the study.
The study will be over-sighted 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 89710 0
Dr Bridget Barber
Address 89710 0
Q-Pharm Pty Ltd (visiting Medical Officer) and
QIMR Berghofer Medical Research Institute
Level 5, 300C Herston Rd
Herston QLD 4006, Australia
Country 89710 0
Australia
Phone 89710 0
+61 7 3362 0498
Fax 89710 0
Email 89710 0
[email protected]
Contact person for public queries
Name 89711 0
Dr Bridget Barber
Address 89711 0
Q-Pharm Pty Ltd (visiting Medical Officer) and
QIMR Berghofer Medical Research Institute
Level 5, 300C Herston Rd
Herston QLD 4006, Australia
Country 89711 0
Australia
Phone 89711 0
+61 7 3362 0498
Fax 89711 0
Email 89711 0
[email protected]
Contact person for scientific queries
Name 89712 0
Dr Bridget Barber
Address 89712 0
Q-Pharm Pty Ltd (visiting Medical Officer) and
QIMR Berghofer Medical Research Institute
Level 5, 300C Herston Rd
Herston QLD 4006, Australia
Country 89712 0
Australia
Phone 89712 0
+61 7 3362 0498
Fax 89712 0
Email 89712 0
[email protected]

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 Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseSafety, pharmacokinetics, and antimalarial activity of the novel triaminopyrimidine ZY-19489: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study, pilot food-effect study, and volunteer infection study.2022https://dx.doi.org/10.1016/S1473-3099%2821%2900679-4
EmbaseSimultaneous estimation of ZY-19489 and its active metabolite ZY-20486 in human plasma using LC-MS/MS, a novel antimalarial compound.2021https://dx.doi.org/10.4155/bio-2021-0194
N.B. These documents automatically identified may not have been verified by the study sponsor.