Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619000961145
Ethics application status
Approved
Date submitted
1/07/2019
Date registered
8/07/2019
Date last updated
13/11/2019
Date data sharing statement initially provided
8/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase I, Randomised, Double-Blinded, Placebo Controlled, Safety and Pharmacokinetic Study of (Z)-Endoxifen in Healthy Female Volunteers
Scientific title
A Phase I, Randomised, Double-Blinded, Placebo Controlled, Safety and Pharmacokinetic Study of (Z)-Endoxifen in Healthy Female Volunteers
Secondary ID [1] 297555 0
Nil known
Universal Trial Number (UTN)
U1111-1236-2048
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Estrogen Receptor Positive (ER+) breast cancer 311776 0
Condition category
Condition code
Cancer 310389 310389 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
n=24healthy female subjects will be divided evenly into 2 groups, Group 1 (n = 12) receiving Z-endoxifen 4mg capsules or matching placebo and Group 2 (n = 12) receiving Z-endoxifen 4mg tablets or placebo.

Subjects will all complete screening procedures from day -28 to day -2 prior to dosing. subjects will then check into the clinical facility on Day -1. Following confirmation of eligibility on Day 1 each subject will be receive 1 dose of study drug in the clinic. Subjects will remain in-house until Day 2, when they will check out of the facility.
On Days 4, 6 and 15 subjects will return to the clinical facility to attend out-patient visits including safety tests and pharmacokinetics (PK).
A Safety and PK Review Committee will review safety and PK data for all patients (Group 1 and Group 2) up to and including up to Day 6 samples. The Committee we determine if the study can safely move to the Multiple Administration Dosing (MAD) and whether Group 1 and Group 2 or Group 2 alone will be dosed in MAD. If the SAD PK results show equivalence for capsule and tablet, only the tablet group will be dosed in the MAD.
On Day 26 subjects will attend an out-patient visit for safety and PK and will then be administered one dose of allocated study drug. The subject will continue to take 1 daily dose of study drug at home (or in clinic on out-patient days) for 14 days. Participants will complete a daily (paper) diary to record when study drug is dosed; adverse events and concomitant medications can also be recorded in the diary. Subjects will be reminded to return the study drug bottle, even if empty, at their clinic visit for the site to perform accountability and, together with the diary, to assess participant study drug compliance.
Subjects will return to the clinic for safety assessments and PK on Day 32.
Subjects will check in to the clinical facility on Day 38 and on Day 39 and undergo study assessments including blood draws for safety and PK before taking the final dose of study medication (Day 39). Subjects will remain at the clinical facility until Day 40 when they will be discharged.
Subjects will then attend out-patient visits on Days 42, 44 and 46 for safety assessments.
All study visits (out patient and in-house) will consist of PK and safety assessments.
Intervention code [1] 313785 0
Treatment: Drugs
Comparator / control treatment
A matching placebo will be the control for each intervention.

The matching placebo capsule contains the requisite amount of microcrystalline cellulose, an inert common capsule and tablet excipient.

The matching placebo tablet consists of the same ingredients s the active tablet, without the (Z)-endoxifen with added excipients to yield the same weight and size.
Control group
Placebo

Outcomes
Primary outcome [1] 319270 0
Determine the pharmacokinetics of a single and multiple oral doses of a previously studied oral (Z)-endoxifen capsule with a (Z)-endoxifen tablet in healthy female volunteers.

Mean and individual (Z)-Endoxifen concentration-time curves will be tabulated for each treatment, and presented graphically with concentration displayed on a linear and logarithmic scale.
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 to calculate pharmacokinetic parameters for each participant.
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, geometric means and geometric CV will be calculated for AUC and Cmax.
Mean and 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 pharmacokinetic parameters using validated statistical software.
Timepoint [1] 319270 0
PK blood sampling will occur at the following timepoints:
Day 1: predose (-10min), Post dose: 0.5hrs, 1, 2, 3, 4, 6, 8, 10, 12hrs
Day 2: 24hrs (post Day 1 dose), Day 4: 72hrs Day 6: 120hrs Day 15, Day 26: pre-dose, Day 22 pre-dose, Day 32: pre-dose, Day 39: pre-dose, 0.5hrs, 1, 2, 3, 4, 6, 8, 10, 12hrs, Day 40: 24hrs (post day 39 dose), Day 42: 72 hrs (post day 39 dose), Day 44: 120hrs (post day 39 dose), Day 46: 168hrs (post day 39 dose).
Secondary outcome [1] 367530 0
Determine the safety and tolerability of each of the study drugs.
Timepoint [1] 367530 0
Vital signs will performed at the following timepoints:
Screening, Day -1, Day 1 pre dose, 1 hr, 2hr, 4 hr, 8hr and 12hr, Day 2 24hr (post Day 1 dose), Day 4, Day 6, Day 15, Day 26, Day 32, Day 39: pre-dose, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr (post Day 39 dose), Day 40: 24 hr (post Day 39 dose), Day 42, 44, 46.

ECGs will performed at the following timepoints:
Screening, Day -1, Day 1 Predose, 4hrs (post dose), Day 2 24hrs (post dose), Day 26 (60 mins prior to dose), Day 40, Day 46.

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

Safety Blood and urine Sampling will performed at the following timepoints:
Haematology, Coagulation, Serum Chemistry and Urinalysis on Day -1, Day 8, Day 21, Day 22 and Day 28.
Virology at Screening only.
Serum Pregnancy testing (hCG) at screening, Urine pregnancy testing Day -1 and Day 28.

Physicals will performed at the following timepoints:
Full physical at Screening and Day 28
Abbreviated Physical at Day -1, Day 2, Day 8, Day 11, Day 14, Day 21,

Secondary outcome [2] 367531 0
To assess and compare the side effects associated with Z-endoxifen capsule and tablet using a Questionnaire.

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] 367531 0
A questionnaire will be completed by subjects at the following timepoints: Day -1, Day 32, Day 39 and Day 46.

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 to 32 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)
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. Sterilization (vasectomy) of male partner prior to commencement of the volunteer’s last normal menstrual
9. Have no air travel commitments during the study and for four weeks following completion of the
study treatment;
10. Have suitable venous access for blood sampling;
11. 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. 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. A family history (first degree relative) of venous thrombosis that was NOT due to a transient major risk factor, i.e., hip surgery, knee replacement.
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 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, that according to 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 randomised off-site by PCI/PPP prior to shipment to site. The randomisation codes provided to PCI/PPP 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 Single Administration Dose (SAD) will be reviewed and submitted to the ethics committee for authorisation of progression of study to Multiple Administration Dose (MAD) part of the study. The outcome of the data review between SAD and MAD will also determine if Group 1 (capsules) and Group 2 (tablets) are dosed in the MAD part of the study or only Group 2 (tablets).
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
This study is a 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.
Screening data will be tabulated by and summaries per treatment group. Safety endpoints will be summarised by treatment group. Treatment -emergent adverse events (AEs) will be coded using the latest version of MedDRA. Incidence and frequency of AEs and serious adverse events (SAEs) will be summarised by treatment group according to SOC and Preferred Terms. Summaries of Treatment-Emergent Adverse Events (TEAE) will be presented by severity and relationship.
The duration of AEs will be determined and included in listings.
Cardiac (12-lead ECG), vitial signs and safety laboratory parameters will be summaried by treatment group and each time point using descriptive statistics.
Pharmacokinetic (PK) data:
The mean and individual Z-endoxifen concentration-time curves will be tabulated for each treatment. Concentrations of Z-endoxifen colelcted at specified time points post-dose after Dat 1 dose (SAD) and after 14 days of once-daily dosing will be used to calculate PK parameter for each participant.
PK parameters will be determined using non-compartmental analysis methods and summarised per treatment group.
Mean and Analysis will be perfromed to assess time dependence and accumulation (multiple dose), and attainment of steady state (multiple;e dose).
Statistical analysis will be performed on the PK parameters using validated statistical software.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
9/07/2019
Actual
9/07/2019
Date of last participant enrolment
Anticipated
Actual
11/07/2019
Date of last data collection
Anticipated
Actual
30/09/2019
Sample size
Target
24
Accrual to date
Final
25
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 14125 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 26930 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 302108 0
Commercial sector/Industry
Name [1] 302108 0
Atossa Genetics, Inc
Country [1] 302108 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] 301938 0
Commercial sector/Industry
Name [1] 301938 0
Atossa Genetics Inc
Address [1] 301938 0
107 Spring St
Seattle
Washington, 98104
USA
Country [1] 301938 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302787 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 302787 0
Ethics committee country [1] 302787 0
Australia
Date submitted for ethics approval [1] 302787 0
06/03/2019
Approval date [1] 302787 0
28/05/2019
Ethics approval number [1] 302787 0
2019-03-187

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

Contacts
Principal investigator
Name 91402 0
Dr Dr Nicholas Farinola
Address 91402 0
CMAX Clinical Research Pty Ltd
Level 5, 18a North Terrace
Adelaide, SA, 5000
Australia
Country 91402 0
Australia
Phone 91402 0
+61421570586
Fax 91402 0
Email 91402 0
Nicholas.Farinola@sa.gov.au
Contact person for public queries
Name 91403 0
Janet R Rea
Address 91403 0
C/O Atossa Genetics Inc.
107 Spring St
Seattle, WA 9 8104
Country 91403 0
United States of America
Phone 91403 0
+1.206.799.7186
Fax 91403 0
Email 91403 0
janet.rea@atossagenetics.com
Contact person for scientific queries
Name 91404 0
Janet R Rea
Address 91404 0
C/O Atossa Genetics Inc.
107 Spring St
Seattle, WA 9 8104
Country 91404 0
United States of America
Phone 91404 0
+1.206.799.7186
Fax 91404 0
Email 91404 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 fillings 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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