Clinical trial NCT02718378: Evaluation of Safety and Efficacy of Estetrol in Healthy Men
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Prostatic Neoplasms
Keywords: safety
pharmacokinetics
pharmacodynamics
randomized
Lead sponsor: Pantarhei Oncology B.V.
Sponsor class: OTHER
First posted: 2016-03-24
Enrollment: 45
Sex: MALE
Minimum age (years): 40
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Number of participants with Adverse Events (AEs)
timeFrame: 28 days
measure: Change from baseline in hormone levels
timeFrame: 28 days
Secondary outcomes:
measure: Change from baseline in haemostasis parameters
timeFrame: 28 days
measure: Change from baseline in lipid parameters
timeFrame: 28 days
measure: Change from baseline in glucose levels
timeFrame: 28 days
measure: Change from baseline in bone turnover markers
timeFrame: 28 days
measure: Change from baseline in sex-hormone binding globulin (SHBG) levels
timeFrame: 28 days
measure: Pharmacokinetic effect of estetrol
timeFrame: 28 days
measure: Pharmacokinetic effect of estetrol
timeFrame: 28 days
measure: Pharmacokinetic effect of estetrol
timeFrame: 28 days
measure: Pharmacokinetic effect of estetrol
timeFrame: 28 days
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: QPS Netherlands BV
Study officials:
affiliation: QPS Netherlands BV
name: Tjeert Mensinga, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.