Evaluation of Safety and Efficacy of Estetrol in Healthy Men

Study Overview
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Brief Summary
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The current study is designed as a phase Ib multiple dose study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of E4 in healthy men after daily oral administration for 28 days.

Official Title
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A Phase I, Double-blind, Randomised, Placebo-controlled, Multiple Dose Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Multiple Dosages of Estetrol in Healthy Men

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Drug: estetrol
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male, age between 40 and 70 years (both inclusive); Good physical and mental health as judged by the Investigator determined by medical history, physical examination (including prostate palpation), clinical laboratory, vital signs and ECG recording; Body mass index between ≥ 18.5 and ≤ 30.0 kg/m2; Normal prostate-specific antigen (PSA) value (< 3.0 ng/mL); Non-vasectomized men must agree to use a condom with spermicide or abstain from sexual intercourse during the study until 90 days beyond the last dose of study medication. Men who have been vasectomized less than 4 months prior to study start must follow the same restrictions as non-vasectomized men; Men must agree not to donate sperm from the first dose until 90 days after the last dose; Ability to communicate well with the Investigator and to comply with the requirements of the entire study; Willing to give informed consent in writing. Exclusion Criteria: Any clinically significant abnormality following review of medical history, laboratory results, physical examination and ECG at screening as judged by the Investigator; Conditions or disorders that might affect the absorption, distribution, metabolism or excretion of any of the study drugs; Previous use of steroids within: 8 weeks for oral preparations 4 weeks for transdermal preparations Any time for injections; Contraindications for steroids or estetrol; Prostate hyperplasia or micturition problems that suggest the presence of prostate hyperplasia; Presence of an active acute or chronic infection, including syphilis, HIV or viral hepatitis B and/or C (or previously treated); Treatment for any major psychiatric disorder in the previous 12 months or use of antidepressant medication before screening; Hypersensitivity to the active substances or to any of the excipients of the investigational product or placebo therapy; Use of probiotics (as present in dairy products, fortified foods etc.) during the 3 months before screening and during the clinical study; Use of one or more of the following medications: Antihypertensive drugs Present use or use within 30 days before the start of the study drug of the following drugs: aprepitant, bosentan, armodafinil, phenytoin, barbiturates, primidone, carbamazepine, oxcarbazepine, glucocorticoids, topiramate, felbamate, rifampicin, clobazamechinacea; vemurafenib, non-nucleoside reverse transcriptase inhibitors, griseofulvin, ketoconazole, and herbal remedies containing Hypericum perforatum Any medication (including over-the-counter products) within 14 days before first dosing except for occasional non-steroidal anti-inflammatory drugs (NSAIDs; e.g. ibuprofen); paracetamol is not permitted Use of antibiotics; Administration of any other investigational drug within 3 months before first dosing; Loss of more than 400 mL blood during the 3 months before screening, e.g. as a blood donor, or intention to donate blood in the 3 months after completing the study; Subjects with a history of (within 12 months) alcohol or drug abuse or with a positive result at screening, for tests of: alcohol intake drug abuse; Currently smoking or smoked within the last 6 months before screening.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: No added active<br>placebo without estetrol | Drug: placebo<br> <br> |
| Active Comparator: estetrol dose level 1<br>estetrol given in dose level 1 | Drug: estetrol<br> <br> |
| Active Comparator: estetrol dose level 2<br>estetrol given in dose level 2 | Drug: estetrol<br> <br> |
| Active Comparator: estetrol dose level 3<br>estetrol given in dose level 3 | Drug: estetrol<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Adverse Events (AEs) | Changes from baseline measurements considered clinically significant by the Investigator will be reported as AEs. | 28 days | 
| Change from baseline in hormone levels | The serum concentrations of Follicle Stimulating Hormone (FSH), Luteinising Hormone (LH), Estradiol (E2), total testosterone and free testosterone levels (actual values as well as percentage change from pre-dose concentration) will be listed and summarized descriptively by treatment group. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in haemostasis parameters | The relative change in Activated Protein C (APC)-resistance, prothrombin factor 1 + 2, D-dimer, free Tissue Factor Pathway Inhibitor (TFPI), antothrombin activity, protein S activity and angiotensinogen levels and the actual change from baseline will be calculated by treatment group. | 28 days | 
| Change from baseline in lipid parameters | The relative change in total cholesterol, triglycerides, High Density Lipoprotein (HDL) cholesterol, Low Density Lipoprotein (LDL) cholesterol, Lipoprotein A (Lp(A)) levels and the actual change from baseline will be calculated by treatment group. | 28 days | 
| Change from baseline in glucose levels | The relative change in glucose levels and the actual change from baseline will be calculated by treatment group. | 28 days | 
| Change from baseline in bone turnover markers | The relative change in osteocalcin, type I collagen telopeptide (CTX-1) and parathyroid hormone (PTH) and the actual change from baseline will be calculated by treatment group. | 28 days | 
| Change from baseline in sex-hormone binding globulin (SHBG) levels | The relative change in SHBG levels and the actual change from baseline will be calculated by treatment group. | 28 days | 
| Pharmacokinetic effect of estetrol | Area under the plasma concentration versus time curve (AUC) | 28 days | 
| Pharmacokinetic effect of estetrol | Terminal elimination half-life (t1/2) | 28 days | 
| Pharmacokinetic effect of estetrol | Time to reach Cmax (tmax) | 28 days | 
| Pharmacokinetic effect of estetrol | Peak plasma concentration (Cmax) | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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safety, pharmacokinetics, pharmacodynamics, randomized