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Trial registered on ANZCTR


Registration number
ACTRN12619001623189
Ethics application status
Approved
Date submitted
1/11/2019
Date registered
22/11/2019
Date last updated
19/03/2020
Date data sharing statement initially provided
22/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase I, Randomised, Double-Blinded, Placebo Controlled, Safety and Pharmacokinetic Study of (Z)-Endoxifen Tablets in Healthy Female Volunteers
Scientific title
A Phase I, Randomised, Double-Blinded, Placebo Controlled, Safety and Pharmacokinetic Study of (Z)-Endoxifen Tablets in Healthy Female Volunteers
Secondary ID [1] 299312 0
Nil Known
Universal Trial Number (UTN)
U1111-1243-4135
Trial acronym
Linked study record
This is a follow up study to ACTRN12619000961145 further evaluating the tablet formulation of (Z)-endoxifen..

Health condition
Health condition(s) or problem(s) studied:
Estrogen Receptor Positive (ER+) Breast Cancer 314449 0
Condition category
Condition code
Cancer 312784 312784 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a single and multiple dose study with participants receiving oral (Z)-endoxifen 4mg tablets or placebo tablets. Participants will be assigned to the same allocated study treatment ((Z)-endoxifen or placebo) through both Part A and Part B.
12 healthy female volunteers will be screened 28 days prior to commencement of dosing.
Participants will be admitted to the clinical facility on Day -1 for up to 3 days in Part A (single dose). Participants will also be admitted for a second confinement period in Part B (multiple dose) on Day 13 for up to 3 days.
Part A: Single Dose
The first dose of study drug (one 4mg (Z)-endoxifen tablet or placebo tablet) will be administered on Day 1. Following completion of all safety assessments and sampling for PK analyses, participants will be discharged from the clinical facility on Day 3.
On days 4, 6, 8 and 15 participants will return to the clinical facility to attend out-patient visits including safety tests and pharmacokinetics (PK)
Days 2 through 25 is a study drug-free period, or daily dosing wash out period (of a minimum 25 days). The minimum period between the completion of Part A (Day 15) and commencement of Part B will be 10 days.
A Safety Summary, (consisting of laboratory safety data obtained though Day 6) and
pharmacokinetic (PK) data (through Day 6) will be analysed (in blinded manner) for review by the Principal Investigator and Sponsor’s Representative prior to the initiation (dosing) of the multiple dosing part of the study.

Part B: Multiple Dose
Day 1 starts the multi-dose administration period. Participants will return to the clinic for a pre-dose blood draw and commence daily oral administration of the study drug (one 4mg (Z)-endoxifen tablet or placebo tablet daily) for 14 consecutive days (Part B Days 1 - 14). Participants will be supplied with study drug and instructed to self-administer each morning on an empty stomach (defined as a minimum of 8 hours fasting).
Prior to dose administration on Part B Day 7 participants will visit the clinical facility for PK blood draws and safety assessments.
Part B Day 14 is the last day of study drug administration. Each participant will return to the clinical facility and check-in on Day 13 prior to final dose administration on Day 14 and will be confined to the facility until Day 16 to allow for the collection of blood for PK and safety assessments. Participants will be discharged from the clinical facility on Day 16 and will return for blood collection for PK and safety assessments on study Days 17, 19, and 21.

All study visits (out patient and in-house) will consist of PK and safety assessments.
Intervention code [1] 315580 0
Treatment: Drugs
Comparator / control treatment
A matching Placebo will be the control.
The matching placebo compressed coated tablet is produced by the same process as the (Z)-endoxifen tablet and consists of the same ingredients without the (Z)- Endoxifen and with added excipients to yield the same weight and size.
Control group
Placebo

Outcomes
Primary outcome [1] 321404 0
To determine the pharmacokinetics for a single dose of an orally administered 4mg (Z) - endoxifen, and after a washout period, daily multiple administration for 14-consecutive days in healthy female volunteers.
Mean and individual (Z)-Endoxifen concentration-time curves will be tabulated for each treatment and presented graphically.
The pharmacokinetic parameters will be determined using non-compartmental analysis methods. Pharmacokinetic parameters will be summarised by treatment using descriptive statistics including mean, standard deviation (SD), and coefficient of variation (CV), minimum and maximum. In addition, the analysis will include the following pharmacokinetic parameters as appropriate calculated after Part A (single dose) and Part B (multiple dose): AUC, Cmax, Tmax, T1/2, elimination rate, clearance and accumulation.
Statistical analysis will be performed on the pharmacokinetic parameters using validated statistical software.
Timepoint [1] 321404 0
PK blood sampling will occur at the following time points in Part A :
Day 1: predose , Post dose: 0.5hrs, 1, 2, 3, 4, 6, 8, 12hrs
Day 2: 24hrs and 36hrs (post Day 1 dose)
Day 3: 48hrs (post Day 1 dose)
Days 4, 6, 8 and 15: Blood samples will be collected during the treatment free period.

PK blood sampling will occur at the following time points in Part B:
Day 1 and Day 7: predose,
Day 14: predose (-10min), Post dose: 0.5hrs, 1, 2, 3, 4, 6, 8, 12hrs
Day 15: 24hrs and 36hrs (post Day 1 dose)
Day 16 to Day 21: 48hrs (Day 16), 72 (Day 17), 120 (Day 19) and 168 (Day 21)hrs (post Day 1 dose)
Secondary outcome [1] 374890 0
To determine the safety and tolerability of 4 mg (Z)-Endoxifen tablets/dose).
Safety and tolerability will be assessed through the collection of adverse events, clinical laboratory parameters (serum chemistry, hematology, coagulation and urinalysis), vital signs, EGCs and physical examinations. Examples of possible side effect, based on tamoxifen and AG-1001 data include possible: hot flashes or flushes: a change in menstrual cycle, vaginal bleeding or spotting: abdominal bloating or pain; headache, nausea or fatigue, gastro-intestinal intolerance, light-headedness dizziness and fluid retention, dry mouth, constipation, depression, mood swings or respiratory infection.
Timepoint [1] 374890 0
Vital signs will be performed at the following timepoints:
Screening, Day -1,
Part A :Day 1 Pre dose, 1hr, 2hr,4hr,8hr and 12hr following dose administration.
Part A Day 2: at 24 and 36 hrs following first dose
Part A Day 3: 48hrs post first dose
Part A Day 4, 6, 8 and 15
Part B Day 1 prior to administration of study drug
Part B Day 14: 1, 2, 4, 8 and 12 hours following dose administration
Part B Day 15: 24 hrs following last dose administration
Part B Day 16: 48hr following the last dose administration
Part B Day 17 and 19 and 21

12-lead ECG will be performed at the following timepoints:
Screening, Part A Day -1, Day 1 (predose and 4hrs post dose), Day 3 (48hrs post dose)
Part B :Day 1 (predose), Day 16 and Day 21

AEs and concomitant medication information will be collected throughout the trial.

Safety Blood and Urine Sampling will be performed at the following time points:
Screening, Day -1, Part A Day 4, 6, 8 and 15
Part B Day 1, Day 7, Day 14, Day 15,Day 16, Day 17 and 19, Day 21

Serum Pregnancy Testing at Screening, Urine pregnancy testing Day -1 , Part B Day 1 and Day 21

Full Physical examination will be performed at the following timepoints: Screening, Day -1 , Part B Day 1 and Day 21
Secondary outcome [2] 374891 0
To assess tolerability parameters associated with 4 mg of Z-Endoxifen using a questionnaire designed specifically for the study.
Examples of possible side effect, based on tamoxifen and AG-1001 data include possible: hot flashes or flushes: a change in menstrual cycle, vaginal bleeding or spotting: abdominal bloating or pain; headache, nausea or fatigue, gastro-intestinal intolerance, light-headedness, dizziness and fluid retention, dry mouth, constipation, depression, mood swings or respiratory infection.
Timepoint [2] 374891 0
Questionnaires will be completed by participants at the following timepoints:
Day -1, Part B Day 7, Day 14 and Day 21.

Eligibility
Key inclusion criteria
1. Healthy adult females, 18 to 65 years of age (inclusive) at the time of screening;
2. Body Mass Index (BMI) within the range of 18.0 to 32.0 kg/m2 inclusive at screening;
3. Absence of significant diseases which, at the physician's discretion, could have an impact on the volunteer's participation in the trial, according to protocol requirements, and study evaluations;
4. Medically healthy without clinically significant abnormalities at the screening visit or Day -1, including:
a. Electrocardiogram (ECG),
b. Physical examination, vital signs including temperature, heart rate, respiratory rate and
blood pressure;
5. Screening laboratory tests that are deemed to be non-clinically significant by the investigator;
6. Negative cotinine, drug and alcohol tests at screening and check in;
7. Ability to understand the nature and objectives of the trial, including risks and adverse events; willingness to cooperate with the researcher and proceed according to all study requirements;
8. Participants of child-bearing potential (a woman is considered of child-bearing potential unless she is permanently sterilized or post-menopausal for at least 12 months with no menses and no alternative medical cause) must agree to use one of the following appropriate contraceptive methods (hormonal contraception is not permitted)
a. Complete abstinence from intercourse (with a male partner) for at least 14 days prior to
dosing with study drug through the End-of-Study and at least 60 days after the conclusion
of study drug administration, provided it is true abstinence consistent with the usual and ongoing lifestyle of the participant.
b. A double-barrier method, i.e., condom and IUD;
c. Vasectomy with confirmed azoospermia on laboratory testing 3 months prior to screening of volunteer and the male partner is the sole partner for that female volunteer;
9. Female participants of non-childbearing potential must meet one of the following criteria:
a. Sterilised, by bilateral tubal ligation or oophorectomy;
b. Hysterectomy,
c. Post-menopausal for at least 12 months with FSH >40 IU/L.
10. Have no air travel commitments during the study and for four weeks following completion of the study treatment;
11. Have suitable venous access for blood sampling;
12. Willing and able to comply with the requirements of the study protocol.
Minimum age
18 Years
Maximum age
65 Years
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Current or recent use of (within 3 months) of cigarettes or any other tobacco-containing product.
2. Unexplained vaginal bleeding
3. History or presence of:
a. A clinically significant disorder including but not limited to: cardiovascular, pulmonary
(with the exception of mild asthma – no prevention treatment within prior 6 months),
hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic or
neurological disease, including any acute illness or surgery within the past three months
determined by the PI to be clinically relevant;
b. History of deep vein thrombosis, pulmonary embolism or significant thrombosis in any
other vein
c. Endometrial cancer, premalignant condition of the endometrium or a strong family history of endometrial cancer;
d. Arterial thrombotic disease such as stroke, coronary artery disease or peripheral vascular
disease;
e. Cataracts or retinal vein occlusion;
f. Drug addiction, including alcohol, within 1 year;
4. Family history (first degree relative) of venous thrombosis that was NOT due to a transient major risk factor, i.e., hip surgery, knee replacement, etc;
5. Current or recent (within 3 months) use of alcohol that exceeds 3 standard drinks per day;
6. Have a hypersensitivity or allergy to the investigational compound/compound class being used in this study or any ingredients of this medication;
7. Treatment, within 3 months before the trial, with any drugs known to have a well-established toxic potential to major organs;
8. Have participated in any other investigational study within 30 days of screening;
9. Use of any medications or over the-counter products within 7 days or 5 half-lives (whichever is longer) prior to administration of study medication (including analgesics (paracetamol up to and including 2 g per day is permitted), herbal products or diet aids);
10. Have received hormonal treatment (including the use of hormonal contraceptives (oral
contraceptive pills or implant)) within 3 months prior to commencement of study treatment;
11. Pregnancy, labour or miscarriage within 12 weeks before commencement of study treatment;
12. Donation of blood or plasma within 30 days prior to randomization, or loss of whole blood of more than 500 mL within 30 days prior to randomization, or receipt of a blood transfusion within 1 year of study enrolment.
13. Any conditions, according to the investigator's best judgment, prevent participation in the trial.

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)
Numbered study drug containers dispensed sequentially
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Containers are provided to the clinical site blind labeled and randomised. The randomisation codes are generated by the bio-statistician using a block randomisation algorithm for the generation of a randomisation table by computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Safety and Pharmacokinetic results from Part A Single Dose will be reviewed and submitted to the ethics committee for authorisation of progression of study to Part B Multiple Dose of the study. The outcome of the PK data review following Part A will also determine if the multiple dose Part B of the study is warranted.
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
This study is an exploratory pharmacokinetic study with (Z)-Endoxifen and as such no formal sample size calculation was performed. Results from this study will be utilized for sample size calculations of subsequent studies.
Treatment-emergent AEs will be coded using the latest version of MedDRA to the appropriate SOC and Preferred Term, classified from verbatim terms. The incidence and frequency of treatment emergent AEs, and SAEs, will be summarized by treatment and overall, according to SOC and Preferred Terms. Summaries of treatment-emergentAE’s) will also be presented by severity and relationship.
The time to onset and duration of AEs will be determined and included in listings, along with the action taken and outcome.
Cardiac (12-Lead ECG), vital signs and safety laboratory parameter values and post-dose change from baseline values will be listed and summarized by treatment at each scheduled time point using descriptive statistics.
Pharmacokinetic (PK) data:
Concentrations of (Z)-Endoxifen collected at specified time points post-dose after Day 1 dose (single dose) and after 14 days of once-daily administration will be used for the calculation of the pharmacokinetic parameters after Part A (single dose) Day 1 dose and Part B (multiple dose) Day 14 dose, as appropriate, using non-compartmental analysis methods.
Analyses will be performed to assess time dependence and accumulation (multiple dose), and attainment of steady state (multiple dose).
Statistical Analysis will be performed on the PK parameters using validated statistical software.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
2/12/2019
Actual
2/12/2019
Date of last participant enrolment
Anticipated
7/12/2019
Actual
6/12/2019
Date of last data collection
Anticipated
27/01/2020
Actual
18/02/2020
Sample size
Target
12
Accrual to date
Final
12
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 14804 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 28053 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 303832 0
Commercial sector/Industry
Name [1] 303832 0
Atossa Genetics Inc
Country [1] 303832 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Atossa Genetics Aus Pty Ltd
Address
Level 16, Tower 2 Darling Park
201 Sussex Street
Sydney NSW 2000
Australia
Country
Australia
Secondary sponsor category [1] 303959 0
Commercial sector/Industry
Name [1] 303959 0
Atossa Genetics Inc
Address [1] 303959 0
107 Spring St
Seattle,
Washington, 98104
USA
Country [1] 303959 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304347 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 304347 0
Ethics committee country [1] 304347 0
Australia
Date submitted for ethics approval [1] 304347 0
04/09/2019
Approval date [1] 304347 0
06/11/2019
Ethics approval number [1] 304347 0
2019-09-769

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 96630 0
Dr Ana Liza Sun
Address 96630 0
Linear Cinical Research
1st Floor, B Block
1 Hospital Avenue
Nedlands, WA, 6009
Australia
Country 96630 0
Australia
Phone 96630 0
+61 8 6382 5100
Fax 96630 0
Email 96630 0
asun@linear.org.au
Contact person for public queries
Name 96631 0
Janet R Rea
Address 96631 0
C/O Atossa Genetics Inc.
107 Spring St
Seattle, WA 98104
USA
Country 96631 0
United States of America
Phone 96631 0
+1 206 799 7186
Fax 96631 0
Email 96631 0
janet.rea@atossagenetics.com
Contact person for scientific queries
Name 96632 0
Janet R Rea
Address 96632 0
C/O Atossa Genetics Inc.
107 Spring St
Seattle, WA 98104
USA
Country 96632 0
United States of America
Phone 96632 0
+1 206 799 7186
Fax 96632 0
Email 96632 0
janet.rea@atossagenetics.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The individual participant clinical trial data and metadata arising from this study are considered confidential, commercial trade secret information which is subject to subsequent product development and potential patent filings relating to the formulation of the investigational product.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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