A phase II, randomized, double-blind, placebo-controlled trial investigating the efficacy and safety of Org 3236 tablets in men with Lower Urinary Tract Symptoms (LUTS) suggestive of Benign Prostatic Hyperplasia (BPH)

Benign prostatic hyperplasia (BPH) is a common disorder in the elderly male
population that is characterized by a progressive enlargement of prostatic
tissue,
resulting in obstruction of the proximal urethra and causing urinary flow
disturbances.
Currently, pharmacological treatment of Lower Urinary Tract Symptoms suggestive
of
Benign Prostatic Hyperplasia (LUTS/BPH) mainly consists of α-adrenergic
inhibitors
or 5α-reductase inhibitors, but also the combination of these inhibitors has
been
investigated.
The α-adrenergic inhibitors relieve the obstructed urinary flow and consequently
symptoms by relaxing the smooth muscle in the prostate (act on the dynamic
component). Because α-blockers have a good symptom relief with a fast time to
onset (within days), these are often the first choice of treatment,
particularly in men
with smaller prostates. However, these blockers delay but do not reduce the
longterm
risk of acute urinary retention (AUR) and the need for invasive surgery.
5α-Reductase inhibitors block the 5α-reduction of testosterone to the more
potent
dihydrotestosterone (DHT), and by this pathway prostate volume is reduced and
symptoms relieved. 5α-Reductase inhibitors are mainly prescribed in patients
with
larger prostates (>40 mL). Compared to α-blockers, time to onset of action
is longer and symptom relieve is less, however, long term risk of acute urinary
retention and need for invasive surgery are smaller.
Combination therapy of α-blockers and 5α-reductase inhibitors has been shown to
be
effective in improving symptom scores and preventing clinical progression of
BPH. One single compound with fast onset of action (faster than 5α-reductase
inhibitors)
and prevention of clinical progression would be an improvement to currently
available BPH therapies. Intermittent therapy with Gonadotropin Releasing
Hormone (GnRH) antagonists might provide such improvement.

Suppression of testosterone to the low normal range can also be achieved by
progestins as has been shown in the broad male contraception experience. In
addition, progestins are well tolerated in men.

Allylestrenol is a progestin that has been approved for the indication BPH in
Japan.
Etonogestrel (ENG, Org 3236) is the active metabolite of desogestrel (DSG), and
has
been used in female contraceptives since 1981. Both ENG and DSG in combination
with testosterone pellets or injections have been studied in males as a
potential male
hormonal contraceptive. Also some data are available on DSG and
Org 3236 alone in males
In conclusion, both 150 and 300 µg DSG or Org 3236 provide testosterone
suppression to a level that has been proven to be effective and safe for
intermittent
treatment of LUTS/BPH, as shown by the two GnRH antagonists and allylestrenol.
In the current protocol an explorative clinical trial is described to test this
concept of
Org 3236 (ENG) for LUTS/BPH.

The objectives are to evaluate:
- The effect of Org 3236 on prostate volume compared to placebo;
- The effect of Org 3236 on LUTS compared to placebo;
- The effect of Org 3236 on urinary flow and postvoid residual volume compared
to
placebo;
- The effect on progression of LUTS;
- The effect of Org 3236 on sexual function, well-being and LUTS-
Life compared to placebo;
- The safety of Org 3236;
- The pharmacokinetic (Org 3236) and pharmacodynamic (T, DHT,
SHBG) properties.

The effects will be evaluated during treatment and post-treatment.

This is a randomized, double-blind, placebo-controlled, comparative,
multiple dose trial in 240 subjects with LUTS/BPH. Subjects will be randomly
to one of the following regimens (60 subjects per treatment group):
Group 1: 150 µg Org 3236 per two days
Group 2: 150 µg Org 3236 per day
Group 3: 300 µg Org 3236 per day
Group 4: placebo

Treatment duration is eight weeks with a follow up period of 16 weeks.

RISKS AND DISCOMFORTS
Because of the anticipated reduction of testosterone concentration in the blood,
effects related to too low testosterone concentrations may occur during the
treatment
period. These include libido decrease, reduced production of sperm, mood effects
(like short temper, emotional lability, depression, and tiredness), increased
sweating,
hot flushes, slight breast enlargement, and mild anemia. These effects are
expected
to recover soon after treatment cessation. Moreover, possible effects related to
Etonogestrel may occur, like weight gain and a transient decrease of a subtype
of
cholesterol, i.e. High Density Lipoprotein (HDL) Cholesterol which is also
called the
*good cholesterol*.
Possible side effects from blood drawing include faintness, swelling of the
vein, pain,
bruising or bleeding at the site of puncture. There is also a slight
possibility of
infection at the site where blood was drawn.
The assessment of the prostate volume for which a small probe is placed into the
rectum (transrectal ultrasound) may be experienced as unpleasant. In addition,
if a
prostate biopsy is needed to exclude prostate cancer, this may also cause
discomfort.

POTENTIAL BENEFITS
The urinary complaints may improve and the prostate volume may reduce as a
result of
the treatment. Participation in the trial may provide useful information that
will help
individuals having a similar medical condition.