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Trial registered on ANZCTR


Registration number
ACTRN12618001509257
Ethics application status
Approved
Date submitted
7/07/2018
Date registered
7/09/2018
Date last updated
30/08/2019
Date data sharing statement initially provided
13/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Study of Safety, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Oral Doses of VE-01902 in Healthy Volunteers
Scientific title
A multi-center, double-blinded, randomized, placebo-controlled, single ascending dose study with food effect crossover and multiple ascending dose study to investigate the safety, tolerability, pharmacokinetic, pharmacodynamic, and hemostatic profile of VE-01902
Secondary ID [1] 295395 0
None
Universal Trial Number (UTN)
Trial acronym
VE-01902-REPLACE-Ia-001
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Atrial Fibrillation 309108 0
Condition category
Condition code
Cardiovascular 307476 307476 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Healthy volunteer study with single dose and multiple ascending doses:

For the SAD, VE-01902 will be administered to fasted patients as an enterically coated oral tablet or as an oral suspension starting at 45mg/kg/day for 1 day of dosing. There will be 6 cohorts, with an option to add a 7th if a certain PD threshold has not been met, and there were no serious safety signals. The second cohort will be used to investigate the differences between the different tablet strengths. Dosing levels will be adaptively decided after each dosing of a cohort via reviewing the PD and safety data by the safety review committee (SRC). There will be a maximum increase of 3x. Once a cohort hits a certain biologically relevant dose, a portion of subjects from a single cohort will be brought back for the same dose of drug, after a 9 day washout period. This dose will be administered after a high-fat breakfast to assess the effect of food on the drug. The ensuing SAD cohorts will be dosed in a fasted or fed state, depending on these results. The maximum dose will be decided by reviewing PD and safety data, passed down from the SRC.

For the MAD, VE-01902 will be administered, to either fasted or fed patients depending on the food effect cohort, as an enterically coated oral tablet or as an oral suspension starting at a dose level decided from the SAD's available data, for 7 consecutive days of once-a-day dosing in the first MAD cohort. After the first cohort, the dose will be administered for 5 consecutive days of once-a-day dosing. There will be 4 cohorts, with an option to add a 5th if a certain PD threshold has not been met, and there were no serious safety signals. The maximum dose will be decided by reviewing PD and safety data, passed down from the safety review committee.

Adherence will be monitored through visual confirmation of dosing.
Intervention code [1] 301641 0
Treatment: Drugs
Comparator / control treatment
Placebo, an enterically coated oral tablet composed of microcrystalline cellulose and mannitol, will be administered in both the SAD and MAD phases of the study. For participants in both the SAD and MAD in cohort sizes of six, two participants will be allocated to placebo and four participants will be allocated to active. For participants in both the SAD and MAD in cohort sizes of twelve, three participants will be allocated to placebo and ten participants will be allocated to active. If the participants are in an oral suspension cohort, the placebo will be crushed placebo tablets suspended in water.
Control group
Placebo

Outcomes
Primary outcome [1] 306588 0
Assess the safety and tolerability to VE-01902
Timepoint [1] 306588 0
Look for AEs (especially Clinically Evident Bleeding) 7 days post dose for patients receiving a single dose, 14 days post dose for patients receiving 7 days of dosing, or 11 days post dose for patients receiving 5 days of dosing
Primary outcome [2] 306589 0
Assess composite hemostatic activity of VE-01902 via hematology (platelet count) and coagulation screens (PT, aPTT, INR).
Timepoint [2] 306589 0
Screen patient blood on hematology and coagulation screens SAD (pre-dose, day 2, day 4, day 7) MAD 1 (pre-dose, day 1, day 2, day 3, day 5, day 7, day 10, and day 13) MAD 2-5 ((pre-dose, day 2, day 3, day 8, and day 11)
Secondary outcome [1] 348954 0
Assess effect on pharmacodynamics of VE-01902
Timepoint [1] 348954 0
Analysis of blood (at pre-dose 1h, 2h, 3h, 4h, 6h, 8h, and 24h) via the Thrombin Generation Assay, Analysis of blood (at pre-dose, 2h, 3h) via the Direct Thrombin Inhibition Analysis of blood (at predose, 2h, 3h, 4h, and 6h) via the P-selectin flow cytometry for platelet biomarkers
Secondary outcome [2] 349056 0
Assess pharmacokinetic profile of VE-01902, parameters: AUC, Cmax, Tmax, dose proportionality, accumulation, time dependence, steady state, food effect.
Timepoint [2] 349056 0
Bioanalysis of blood (pre-dose, and at 30m, 1h, 2h, 3h, 4h, 6h, 8h, 12h, and 24h post-dose) via liquid chromatography mass spec system. For the MAD 1 this analysis will occur on day 7 as well as day 1, for SAD just on day 1. For MAD 2-5 this analysis will occur on day 5 as well as day 1,

Eligibility
Key inclusion criteria
1. Male or female aged 18 to 55 years, inclusive;
2. Body mass index (BMI) between 19 and 33 kg/m2 inclusive, with a minimum weight of 50 kg;
3. Healthy as determined by pre-study medical history, physical examination, vital signs,
complete neurological examination and 12-lead electrocardiogram (ECG) confirming normal sinus rhythm;
4. Negative tests for Hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (anti-HCV)
and human immunodeficiency virus (HIV)-1and HIV-2 antibody at screening;
5. Routine laboratory screening tests as specified below should be within normal limits or any abnormalities should be not clinically significant, as determined by the investigator at screening and day -1; however, results of the coagulation panel, platelet count and hemoglobin should be within normal limits, and liver function tests (specifically, total bilirubin, ALT and AST) should not exceed 1.5x the upper limit of normal;
6. Negative screen for alcohol and drugs of abuse at screening and admission;
7. Non-smokers or casual smoker who uses no more than 10 cigarettes (or equivalent quantity of any other nicotine containing products e.g. cigars, chewing tobacco, snuff, vaping, e-cigarettes, and etc.) per week. Subject must abstain from smoking 5 days prior to admission and throughout the entire study period, and test negative on Day -1 for urine cotinine test. ;
Female participants:
8. Must be of non-child-bearing potential by surgical sterilization or postmenopausal (no menses for the previous 12 months without alternative medical cause and confirmed by FSH testing),
OR
9. Must not be pregnant, breast feeding, or planning to become pregnant AND must be practicing both a highly effective method of birth control for at least 30 days after the last dose of study drug and a barrier method (such as condom use). Highly-effective methods of birth control include: hormonal contraception (e.g. birth control pill, injection, implant, transdermal patch or vaginal ring), an intrauterine device, tubal ligation or a sole partner with a vasectomy. Progestin-based contraception that suppresses ovulation (e.g. Depo-Provera) is allowed. Estrogen-containing contraceptives that provide suppression of ovulation may be allowed. However, high-dose estrogen (greater than 35 microgram ethinyloestradiol)-containing contraceptives are not allowed in this study. Gonadotropin-releasing hormone agonist contraceptives are not allowed in this study. Abstinence from penile-vaginal intercourse for the above duration is acceptable, if it is consistent with the usual and preferred lifestyle of the participant;
10. Negative serum pregnancy test at screening and negative urine pregnancy test on admission of each treatment period (women of childbearing potential only);
Male participants:
11. Must be practicing a highly effective method of birth control with female partners of
childbearing potential from screening throughout the study and for at least 90 days after the last investigational drug administration. Highly effective birth control methods are as described above and include vasectomy, or condom use in combination with partner’s use of highly effective contraception
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
If any of the following exclusion criteria apply, the volunteer must not enter/continue in the study:
1. Aspirin or Non-steroidal anti-inflammatory drug (with the exception of acetaminophen) use in the preceding 2 weeks.
2. Have used any anticoagulants independent of participating in a clinical trial, or if anticoagulant use was due to participation in a clinical trial then washout period should be maximum of the longer period of either 5x PK t1/2 or PD t1/2
3. Have any significant hematologic past medical history of hypercoagulable or bleeding disorders, unexplained bleeding, bruising, hemorrhage, blood clots, or thromboembolism as determined by the PI;
4. Have a clinically relevant history or presence of respiratory, gastrointestinal, renal, hepatic, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, endocrine, connective tissue diseases or disorders;
5. Have a clinically relevant surgical history (surgery within the last 2 months, planned surgery within the following month);
6. Have a history of hyperemesis, Crohn’s, Inflammatory Bowel Disease, Irritable Bowel Syndrome, hematuria, melena, hematochezia;
7. Have a history of severe drug allergy or hypersensitivity or food allergy, including anaphylaxis;
8. Have a history of alcoholism or drug abuse;
9. Consume more than 14 units of alcohol a week (1 unit of EtOH = 1 glass (25 cl) of beer with 3% of alcohol = 7.5 g, or 1 glass (25 cl) of beer with 6% of alcohol = 15 g, or 1 glass (12.5 cl) of wine with 10% of alcohol = 12 g, or 1 glass (4cl) of aperitif with 42% of alcohol = 17 g] on history, or exhibit detectable alcohol levels by breathalyzer;
10. Have a significant infection or known inflammatory process on screening or admission (ie. infection, autoimmune disease, immunosuppression regimen);
11. Have acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea, heartburn) at the time of screening or admission;
12. Have used any prescription medicines, over the counter medicines, or herbal supplements, within two weeks of admission, with the exception of acetaminophen or approved method of hormonal contraception;
13. Have used any investigational drug or participated in any clinical trial within 90 days prior (or if longer, 5 times the half life of the investigational product) to screening;
14. Have participated in more than 1 clinical trial within the 3 months prior to screening;
15. Have donated or received any blood or blood products within the 3 months prior to screening;
16. Have medical dietary restrictions that cannot be accommodated by the clinical unit;
17. Are an employee of the sponsor or research site personnel directly affiliated with this study or their immediate family members defined as a spouse, parent, sibling, or child, whether biological or legally adopted.
18. Cannot communicate reliably with the investigator;
19. Are unlikely to co-operate with the requirements, including duration of admission to the study and expected follow up visit;
20. Are unwilling or unable to give written informed consent.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

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)
SA,VIC

Funding & Sponsors
Funding source category [1] 299987 0
Commercial sector/Industry
Name [1] 299987 0
Verseon Corp.
Address [1] 299987 0
47071 Bayside Parkway, Fremont, CA 94538
Country [1] 299987 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
VCR1
Address
58 Gipps Street, Collingwood VIC 3066,
Country
Australia
Secondary sponsor category [1] 299368 0
None
Name [1] 299368 0
Address [1] 299368 0
Country [1] 299368 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300771 0
Bellberry Committee B
Ethics committee address [1] 300771 0
129 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [1] 300771 0
Australia
Date submitted for ethics approval [1] 300771 0
18/07/2018
Approval date [1] 300771 0
06/09/2018
Ethics approval number [1] 300771 0

Summary
Brief summary
A multi-center, double-blinded, randomized, placebo-controlled, single ascending dose study and multiple ascending dose study to investigate the safety, tolerability, pharmacokinetic, pharmacodynamic, and hemostatic profile of VE-01902. The single ascending dose phase will encompass a single bridging cohort across tablet strengths, and a food effect cohort.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 84762 0
Dr Jason Lickliter // Nicholas Farinola
Address 84762 0
Nucleus Network Pty Ltd 5th Floor, Burnet Tower, AMREP Precinct 89 Commercial Road Melbourne, Victoria, 3004
//
CMAX Clinical Research Pty Ltd.
Level 5
18a North Terrace
Adelaide, South Australia, 5000
Country 84762 0
Australia
Phone 84762 0
+ 613 8593 9800 for Dr. Lickliter // +618 7088 7900 for Dr. Farinola
Fax 84762 0
+ 613 9076 8911
Email 84762 0
J.Lickliter@nucleusnetwork.com.au // Nicholas.Farinola@sa.gov.au
Contact person for public queries
Name 84763 0
Mr Taylor Kilfoil
Address 84763 0
InClin PTY LTD
25 Berry St
North Sydney, NSW 2060
Country 84763 0
Australia
Phone 84763 0
+ 61 408 880 403
Fax 84763 0
Email 84763 0
taylor.kilfoil@vcr1.com.au
Contact person for scientific queries
Name 84764 0
Dr Anirban Datta
Address 84764 0
47071 Bayside Parkway
Fremont, California 94538
Country 84764 0
United States of America
Phone 84764 0
+1 (510) 225 9013
Fax 84764 0
Email 84764 0
adatta@verseon.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results