Study Conducted to Further Understand the Elimination Pathways, Metabolite Profile and PK Profile of 14C-estetrol

Study Overview
=================
Brief Summary
-----------------
This study is being conducted to further understand the elimination pathways, metabolite profile and pharmacokinetic (PK) profile of carbon 14 labelled estetrol ([14C] estetrol).

Detailed Description
-----------------
This will be an open-label, non-randomised, single dose study in healthy female volunteers of non-child bearing potential. Subjects will be screened for eligibility to participate in the study up to 28 days before dosing. The study will be executed in a single group, 6 subjects will be enrolled and dosed with a single oral dose of carbon 14 labelled estetrol. Subjects will be admitted to the clinical unit on the morning prior to study drug administration (Day -1). Dosing will take place on the morning of Day 1 after an overnight fast (approximately 10 h). Subjects will be resident in the clinic up to 240 h after dosing during which plasma, blood, urine and faeces samples will be collected. It is planned that subjects will be released as a group when all subjects have achieved a mass balance cumulative recovery of >90% or if a mean of <1% of the dose administered has been collected in urine and faeces within 2 separate, consecutive 24 h periods. In this case, collection of all samples (blood, urine and faeces) will be stopped and the subjects will undergo discharge assessments. If this criterion has not been met by all subjects on Day 11, home collections of urine and faeces may be requested at the discretion of the investigator for individual subjects.

Official Title
-----------------
An Open-Label, Single Dose Study Designed to Assess the Mass Balance Recovery, Metabolite Profiles and Metabolite Identification of [14C]-Estetrol in Healthy Female Volunteers

Conditions
-----------------
Contraception, Menopause

Intervention / Treatment
-----------------
* Drug: Estetrol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy females of non-child bearing potential, i.e. surgically sterilised or post menopausal subjects. Postmenopausal status will be defined by an absence of menses for a minimum of 12 months and confirmed by a FSH result ≥30 IU/ml Negative pregnancy test at screening and Day -1 30 to 65 years of age inclusive Body mass index between ≥18.0 and ≤30.0 kg/m2 Must be willing and able to communicate and participate in the whole study Must provide written informed consent Must have regular bowel movements (i.e. average stool production of ≥1 and ≤3 stools per day)Must agree to use an adequate method of contraception Exclusion Criteria: Participation in a clinical research study within the previous 3 months Subjects who are study site employees, or immediate family members of a study site or sponsor employee Subjects who have previously been enrolled in this study History of any drug or alcohol abuse in the past 2 years Regular alcohol consumption i.e. >14 units per week (1 unit = ½ pint beer, 25 ml of 40% spirit or a 125 ml glass of wine) Current smokers and those who have smoked within the last 12 months. A breath carbon monoxide reading of greater than 10 ppm at screening Females who are pregnant or lactating Radiation exposure, including that from the present study, excluding background radiation but including diagnostic x-rays and other medical exposures, exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years. No occupationally exposed worker, as defined in the Ionising Radiation Regulations 1999, shall participate in the study Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed at screening Clinically significant abnormal biochemistry, haematology or urinalysis as judged by the investigator Positive drugs of abuse test result Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results History or presence of clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease as judged by the investigator Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hayfever is allowed unless it is active Donation or loss of greater than 400 ml of blood within the previous 3 months Subjects who are taking, or have taken, any prescribed medications in the 28 days before IMP administration (exceptions may apply on a case by case basis provided they are considered not to interfere with the objectives of the study as agreed by the PI or delegate and sponsor's medical monitor), or over-the-counter drug or herbal remedies in the 14 days before IMP administration. If needed (i.e. an incidental and limited need) ibuprofen is acceptable as analgesic treatment, but must be documented in the (Case Report Form) CRF. Use of paracetamol is forbidden during the entire study Subjects who are not in euthyroid condition (thyroid-stimulating hormone [TSH] and free thyroxine [fT4] within the normal reference range) Any history of suspected malignancy with the exception of basal cell (excluded if within the prior 2 years) or squamous cell (excluded if within the prior one year) carcinoma of the skin History or presence of prolonged QT interval corrected by Bazett's formula or any other clinically significant ECG abnormalities as judged by the investigator based on 12-lead ECG readings at screening Subjects with abnormal supine blood pressure at screening: at least 2 readings of systolic blood pressure greater than 140 mmHg or lower than 90 mmHg, and/or diastolic blood pressure of more than 90 mmHg or lower than 50 mmHg after minimum intervals of 5 min Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in case of participation in the study. The investigator should make this determination in consideration of the subject's medical history and/or clinical or laboratory evidence of any of the following: History or symptoms of inflammatory bowel disease, gastritis, ulcers, gastrointestinal or rectal bleeding, History of major gastrointestinal tract surgery (subjects who have had an appendectomy are acceptable for inclusion), History or presence of pancreatic injury or pancreatitis, History or presence of impaired hepatic function, History or presence of liver disease or liver injury as indicated by abnormal liver function tests such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), or total serum bilirubin. Any single parameter elevated ≥1.5 fold upper limit of normal should be re-checked once prior to enrolment/randomisation (subject who have had a cholecystectomy are acceptable for inclusion if all liver/gallbladder parameters are in the normal range), History or presence of impaired renal function if considered as clinically significant, Abnormal urinary constituents (e.g. albumin if considered as clinically significant). Suspected or current history of gynaecological or breast pathology, including any abnormal Pap smear within the 3 previous years (ASCUS , ASC-H , LGSIL or worse) or history of abnormal mammogram within the 2 previous years Failure to satisfy the investigator of fitness to participate for any other reason

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Estetrol<br>A single oral dose of 15 mg carbon 14 labelled estetrol ([14C]-estetrol), containing approximately 2.8 MBq (76 µCi) 14C | Drug: Estetrol<br>* 15 mg [14C]-estetrol containing approximately 2.8 MBq (76 μCi) 14C<br>* Other names: E4;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mass Balance of Total Radioactivity in Urine | Amount excreted in urine (Ae[urine]) | From Day -1 prior study treatment intake to 312 hours post-dose | 
| Mass Balance of Total Radioactivity in Faeces: | Amount excreted in faeces (Ae[faeces]) | From Day -1 prior study treatment intake to 312 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Concentration (Cmax) of Total Radioactivity in Plasma |  | Predose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-dose | 
| Time to Maximum Concentration (Tmax) of Total Radioactivity in Plasma |  | Predose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-dose | 
| Area Under the Curve From 0 Time to Last Measurable Concentration [AUC(0-last)] of Total Radioactivity in Plasma |  | Predose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-dose | 
| The Elapsed Time (Tlag) of Total Radioactivity in Plasma |  | Predose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-dose | 
| Cmax of Estetrol in Plasma |  | Predose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-dose | 
| Tmax of Estetrol in Plasma |  | Predose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-dose | 
| AUC(0-last) of Estetrol in Plasma |  | Predose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-dose | 
| AUC(0-infinity) of Estetrol in Plasma |  | Predose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-dose | 
| Tlag of Estetrol in Plasma |  | Predose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-dose | 
| Half-life (t1/2) of Estetrol in Plasma |  | Predose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-dose | 
| The Mean Residence Time (MRT) of Estetrol in Plasma |  | Predose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-dose | 
| Cmax of Total Radioactivity in Whole Blood |  | Predose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-dose | 
| The Terminal Elimination Rate Constant (Lambda-z) of Estetrol in Plasma |  | Predose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-dose | 
| AUC(0-last) of Total Radioactivity in Whole Blood |  | Predose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-dose | 
| Renal Clearance (CLr) for Estetrol |  | From Day-1 prior study treatment intake to 240 hours post-dose | 
| Renal Clearance (CLr) for Total Radioactivity |  | From Day-1 prior study treatment intake to 240 hours post-dose | 
| Number of Subjects With Adverse Events as a Measure of Safety and Tolerability |  | From maximum 28 days prior study treatment intake to 240 hours post-dose |