Evaluation of Safety and Efficacy of Estetrol in Healthy Men

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

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.

Study Overview

• Status: Completed
• Conditions: Prostatic Neoplasms
• Intervention / Treatment: Drug: placebo; Drug: estetrol

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands, 9713 AG
    • QPS Netherlands BV

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: No added active; placebo without estetrol	Drug: placebo
ACTIVE_COMPARATOR: estetrol dose level 1; estetrol given in dose level 1	Drug: estetrol
ACTIVE_COMPARATOR: estetrol dose level 2; estetrol given in dose level 2	Drug: estetrol
ACTIVE_COMPARATOR: estetrol dose level 3; estetrol given in dose level 3	Drug: estetrol

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Pantarhei Oncology B.V.
• Investigators: Principal Investigator: Tjeert Mensinga, MD, PhD, QPS Netherlands BV

Publications and helpful links

General Publications

• Phillips I, Shah SI, Duong T, Abel P, Langley RE. Androgen Deprivation Therapy and the Re-emergence of Parenteral Estrogen in Prostate Cancer. Oncol Hematol Rev. 2014 Spring;10(1):42-47. doi: 10.17925/ohr.2014.10.1.42.
• Coelingh Bennink HJ, Holinka CF, Diczfalusy E. Estetrol review: profile and potential clinical applications. Climacteric. 2008;11 Suppl 1:47-58. doi: 10.1080/13697130802073425.
• Coelingh Bennink HJT, Zimmerman Y, Verhoeven C, Dutman AE, Mensinga T, Kluft C, Reisman Y, Debruyne FMJ. A Dose-Escalating Study With the Fetal Estrogen Estetrol in Healthy Men. J Clin Endocrinol Metab. 2018 Sep 1;103(9):3239-3249. doi: 10.1210/jc.2018-00147.

Study record dates

Study Major Dates

• Study Start: March 1, 2016
• Primary Completion (ACTUAL): February 1, 2017
• Study Completion (ACTUAL): February 1, 2017

Study Registration Dates

• First Submitted: February 18, 2016
• First Submitted That Met QC Criteria: March 18, 2016
• First Posted (ESTIMATE): March 24, 2016

Study Record Updates

• Last Update Posted (ESTIMATE): February 9, 2017
• Last Update Submitted That Met QC Criteria: February 8, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: safety; pharmacokinetics; pharmacodynamics; randomized
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms
• Other Study ID Numbers: PR3107