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Trial registered on ANZCTR


Registration number
ACTRN12618000798268
Ethics application status
Approved
Date submitted
7/05/2018
Date registered
10/05/2018
Date last updated
25/02/2019
Date data sharing statement initially provided
25/02/2019
Date results information initially provided
25/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of HM30181A on the Pharmacokinetics of Digoxin
Scientific title
An Open-Label, Non-Randomized, Fixed-Sequence Study in Healthy Volunteers to Evaluate the Effect of HM30181A on the Pharmacokinetics of Digoxin
Secondary ID [1] 294807 0
KX-HM-002
Universal Trial Number (UTN)
U1111-1195-7884
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 307728 0
Condition category
Condition code
Cancer 306794 306794 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Digoxin is a substrate of P-gp and influences intestinal absorption, renal tubular secretion and biliary-intestinal secretion. Therefore, drugs that inhibit P-gp have the potential to alter digoxin pharmacokinetics. The primary objective of this study is to determine the effect of multiple once-daily doses of HM30181A on the single-dose PK of digoxin.
Eligible participants will receive a single oral tablet dose of digoxin 0.25mg and will provide blood samples for analysis for 6 days post-dosing (Treatment Period 1). After at least a 10 day washout, Treatment Period 2 will start. Participants will receive daily oral tablet doses of 15mg HM30181A for 3 days. One hour after the third dose (i.e. Day 3) they will receive another single oral tablet dose of digoxin 0.25mg. Blood samples will be collected for days 1-8, and at Day 17. Safety will be monitored regularly with laboratory tests, recording of AEs, ECGs and vital signs. Participants will be resident at the Zenith Clinical Site for dosing (all doses will be under the direct supervision of study site staff) and days when multiple blood samples are required.
Intervention code [1] 301119 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 305779 0
The primary objective of the study is to determine the effect of multiple once-daily doses of HM30181A on the single-dose pharmacokinetics of digoxin.
The primary endpoint will be the ratio of the AUC0-8 of digoxin in the plasma after digoxin administration on Day 3 after HM30181A in Treatment Period 2 vs digoxin administration alone in Treatment Period 1.
Timepoint [1] 305779 0
Blood samples for determination of plasma concentrations of digoxin will be collected on:
Treatment Period 1: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, 72, 96 and 120 hours, and Day 17 post-dose digoxin.
Treatment Period 2: Days 1, 2 and 3: predose HM30181A. Days 3-8: pre-dose digoxin and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, 72, 96 and 120 hours, and Day 17 post-dose Day 3 digoxin

During Treatment Period 2, blood samples collected on Days 3-8 will also be used for determination of plasma concentrations of HM30181 and its M1 metabolite.
Secondary outcome [1] 346521 0
To investigate the safety and tolerability of HM30181A and digoxin when administered sequentially by review of AEs/SAEs, laboratory values, vital signs, results of physical examinations and ECGs
Timepoint [1] 346521 0
Assessments will be conducted at the following time-points:
AEs/SAEs: at each study site visit - Screening; Treatment Period 1: Baseline, Days 1-6; Treatment Period 2: Baseline, Days 1-8 and Day 17.
Laboratory tests will be conducted at: Screening, Treatment Period 1 - Baseline and Day 6; Treatment Period 2 - Baseline, Days 5 and 17.
Vital signs will be conducted at: Screening, Treatment Period 1 - Baseline and Days 1- 3; Treatment Period 2 - Baseline, Days 1-5, and Day 17.
Physical examinations at Screening, Treatment Period 1 - Baseline; Treatment Period 2 - Baseline, Days 5 and 17.
ECGs at Screening; Treatment Period 1 - Days 1 and 2; Treatment Period 2 - Days 3, 4 and 17.
Secondary outcome [2] 346536 0
To determine the pharmacokinetics of HM30181 by determining its PK parameters including AUC0-24, Tmax, Cmax, Cmin, and T1/2.
Timepoint [2] 346536 0
Treatment Period 2 - Blood samples from:
Day 1 pre-dose HM30181;
Day 2: pre-dose HM 30181
Day 3: pre-dose digoxin and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 16 hours post-dose Day 3 digoxin
Day 4: 24 and 32 hours post-dose Day 3 digoxin
Day 5: 48 hours post-dose Day 3 digoxin
Day 6: 72 hours post-dose Day 3 digoxin
Day 7: 96 hours post-dose Day 3 digoxin
Day 8: 120 hours post-dose Day 3 digoxin
Day 17: 14 days post-dose Day 3 digoxin
Secondary outcome [3] 346669 0
To determine the pharmacokinetics of the M1 metabolite of HM30181 by determining its PK parameters including AUC0-24, Tmax, Cmax, Cmin, and T1/2.
Timepoint [3] 346669 0
reatment Period 2 - Blood samples from:
Day 1 pre-dose HM30181;
Day 2: pre-dose HM 30181
Day 3: pre-dose digoxin and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 16 hours post-dose Day 3 digoxin
Day 4: 24 and 32 hours post-dose Day 3 digoxin
Day 5: 48 hours post-dose Day 3 digoxin
Day 6: 72 hours post-dose Day 3 digoxin
Day 7: 96 hours post-dose Day 3 digoxin
Day 8: 120 hours post-dose Day 3 digoxin
Day 17: 14 days post-dose Day 3 digoxin

Eligibility
Key inclusion criteria
Males and females aged at least 18 years and up to 55 years on day of consent; Creatinine clearance >=80 mL/min; non-smoker; in good health; Body mass index (BMI) greater than or equal to 18.0 and <30.0 kg/m2 at Screening; willing to adhere to the alcohol and caffeine restrictions. Females must be postmenopausal or surgically sterile or must be using effective
contraception for at least 4 weeks prior to dosing and agree to continue use of
contraception for 30 days after their last dose.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
A history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases; an elevated prothrombin time (PT) or aPTT or platelet count below the lower limit of normal at Screening or Baseline; History of gastrointestinal bleeding, intracerebral bleeding or frequent nose-bleeds or active bleeding; prolonged QTc interval (QTc >450 ms), or PR interval >180ms or QRS interval >110ms on ECG at Screening; Heart rate <45bpm; Wolff-Parkinson-White syndrome; serum potassium or calcium concentration below the lower limit of normal; history of drug or alcohol abuse or dependence; taking any prescription drug or herbal medicine or supplement within 2 weeks or 5 half-lives prior to dosing, whichever is longer, or vitamin supplement within 1 week prior to dosing; clinically significant drug allergy.

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)
Allocation is not concealed
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
Single group
Other design features
Fixed sequence design
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Statistical analyses will be reported using summary tables, graphs, and data listings. Continuous variables will be summarized using the mean, standard deviation (SD), median, minimum, and maximum. Categorical variables will be summarized by counts and by percentage of subjects in corresponding categories.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
17/09/2018
Actual
18/10/2018
Date of last participant enrolment
Anticipated
22/10/2018
Actual
31/10/2018
Date of last data collection
Anticipated
21/12/2018
Actual
17/12/2018
Sample size
Target
14
Accrual to date
Final
14
Recruitment outside Australia
Country [1] 10379 0
New Zealand
State/province [1] 10379 0
Otago

Funding & Sponsors
Funding source category [1] 299404 0
Commercial sector/Industry
Name [1] 299404 0
Athenex Inc
Country [1] 299404 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Athenex Inc
Address
20 Commerce Drive
Cranford
New Jersey 07016
Country
United States of America
Secondary sponsor category [1] 298690 0
Commercial sector/Industry
Name [1] 298690 0
Zenith Technology Corporation
Address [1] 298690 0
156 Frederick Street
Dunedin 9016
Country [1] 298690 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300307 0
Northern A HDEC
Ethics committee address [1] 300307 0
C/- Ministry of Health
Freyberg Building
20 Aitken Street
PO Box 5013
Wellington 6011
Ethics committee country [1] 300307 0
New Zealand
Date submitted for ethics approval [1] 300307 0
02/05/2018
Approval date [1] 300307 0
30/07/2018
Ethics approval number [1] 300307 0

Summary
Brief summary
HM30181 methanesulfonate monohydrate is a novel orally administered P-glycoprotein (P-gp) inhibitor that was discovered and originally developed by Hanmi Pharmaceutical Co., Ltd., Seoul, South Korea. The compound is in clinical development and is orally administered in combination with chemotherapeutic agents (paclitaxel, irinotecan) to enhance the oral bioavailability of these agents.
Digoxin is a substrate of P-gp and influences intestinal absorption, renal tubular secretion and biliary-intestinal secretion. Therefore, drugs that inhibit P-gp have the potential to alter digoxin pharmacokinetics. HM30181A has low systemic bioavailability and is present in plasma at concentrations that are far below those calculated to inhibit systemic or renal P-gp. Thus, it is anticipated that any effect of HM30101A on the bioavailability of digoxin will be due to its effect on the gastrointestinal (GI) P-glycoprotein, and not upon renal clearance.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 83234 0
Dr Christopher Jackson
Address 83234 0
Dunedin Hospital
Southern District Health Board
201 Great King Street
Dunedin 9016
Country 83234 0
New Zealand
Phone 83234 0
+64 3 474 0999 ext 9698
Fax 83234 0
Email 83234 0
[email protected]
Contact person for public queries
Name 83235 0
Mrs Linda Folland
Address 83235 0
Zenith Technology Corporation, Ltd.
156 Frederick Street
Dunedin 9016
Country 83235 0
New Zealand
Phone 83235 0
+64 3 477 9669
Fax 83235 0
Email 83235 0
[email protected]
Contact person for scientific queries
Name 83236 0
Dr Wing-Kai Chan
Address 83236 0
Athenex Pharmaceuticals
19F., No.460, Sec. 4, Xinyi Rd., Xinyi Dist.
Taipei City 110
Country 83236 0
Taiwan, Province Of China
Phone 83236 0
+886 277039399
Fax 83236 0
Email 83236 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
Not planned to be available by the Sponsor at this stage


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
Dimensions AIOral paclitaxel with encequidar compared to intravenous paclitaxel in patients with advanced cancer: A randomised crossover pharmacokinetic study2021https://doi.org/10.1111/bcp.14886
N.B. These documents automatically identified may not have been verified by the study sponsor.