A Phase I, double-blind, randomised, placebo-controlled, multiple dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of two dosages of estetrol in healthy men

Estetrol (E4) is a is a potential new drug for treatment opportunities in
prostate cancer.

Primary objectives:
* To investigate the safety of multiple dosages of E4;
* To investigate the efficacy of multiple dosages of E4 on hormone levels
related to prostate
function.

Secondary objectives:
* To investigate the pharmacodynamic effects of E4 on:
o Haemostasis
o Lipids
o Carbohydrate metabolism
o Bone turnover
* To investigate steady state pharmacokinetics of E4
* To investigate tolerability and acceptability of E4

The current study is designed to continue the investigation on the safety and
the effect of E4 on hormones related to prostate function in healthy men.

The study will start with a screening. At the screening a physical examination
will take place and a few other standard medical assessments will be performed
(ECG, vital signs) including prostate palpation. Furthermore a blood and urine
sample will be taken for laboratory tests and an alcohol breath test and drug
screen will be done.

Subjects must be willing to adhere to the following prohibitions and
restrictions during the course of the study:
1. Strenuous exercise (e.g., long distance running >5 km/day, weight
lifting, or any physical
activity to which the subject is not accustomed) has to be avoided
in the two days preceding
Day 28 and until completion of the PK blood draws scheduled between
Day 28 through Day
31.
2. Alcohol consumption is not allowed for 24 hours before screening,
and before each study
admission and during the period of confinement. Subjects are not
allowed to consume more
than 3 units of alcohol per day during the periods of off-site
(ambulant) participation in the
study. A unit of alcohol is equal to the following: (1) a small
glass (125 mL) of wine or (2) 25
mL of spirit or a small glass of fortified wine, such as sherry or
port, or (3) about 300 mL of
ordinary-strength lager, beer or cider.
3. Use of probiotics is not allowed from 3 months prior to screening
until follow-up (Day 56).
4. Methylxanthine containing products (e.g. coffee, cola, tea,
chocolate) and quinine-
containing products (e.g. tonic water) and poppy seed containing
products are not permitted
from 48 hours before screening, and before each study admission and
during the period of
confinement.
5. Grapefruit and grapefruit juice are not permitted from 7 days before
admission in the
study until follow-up (Day 56).

On Day 1 the subject will be randomised to one of the two treatments (i.e.
active or placebo treatment). On day 1,2,7,14 and 28,the subjects will receive
the study medication or placebo. On Day 21 a phone call will be done to ask
about well-being. On Day 27 untill 29 the subjects will stay in the clinic and
on Day 30 untill 31 the subjects will return to the site for ambulant visits.
during the stay in the clinic and on ambulant visits, safety will be monitored
and blood samples will be collected.

Finally, a follow-up visit will take place.

Smalls risks are related to blood sampling. Regular blood sampling can cause
minor aches and bruises at the puncture site.

The risks of the study are small. The medication will be given in a controlled
surrounding. Possible side effects are related to the side effects known for
estrogen therapy, including cardiovascular side effects. Based on earlier
studies, it appears that estetrol minimally impacts the liver function. In this
context, estetrol could have a more favorable safety profile than other
estrogens.