Multicentre, Open-Label Trial to Assess the Safety and Tolerability of LF111 (Drospirenone 4.0 mg) Over 6 Cycles in Female Adolescents, With a 7-Cycle Extension Phase

Drospirenone (DRSP) is a fourth generation progestogen, which is derived from
spironolactone. DRSP has a pharmacological profile similar to natural
progesterone and possesses anti-mineralocorticoid and anti-androgenic activity.

In combination with ethinyl estradiol (EE) and 17B-estradiol (E2), DRSP has
been extensively studied in the preclinical and clinical setting. DRSP 3 mg in
combination with EE 30 microgram or 20 microgram, from 21 days to 24 days, is
registered for use in the prevention of pregnancy as an oral contraceptive,
(e.g. Yasmin®, Yasminelle®, YAZ®). In addition, DRSP is registered for use in
combination with E2 1 mg as Angeliq®[3] (in Europe at 2 mg and in the USA at
0.5 mg) as hormone replacement therapy for estrogen deficiency symptoms in
postmenopausal women and the prevention of postmenopausal osteoporosis in women
who are intolerant to or contraindicated for other medicinal products approved
for the prevention of osteoporosis.

Leon Farma has developed a new formulation with 4.0 mg of DRSP (LF111). This
formulation has been tested in a pharmacokinetic (PK) study in comparison with
a drospirenone-containing COCP on the market. PK study CF111/103A confirmed
that absorption after a single dose is higher with the 4.0 mg drospirenone
compared to standard products on the market containing 3.0 mg drospirenone
(YAZ). However, after multiple-dose administration in study CF111/103A, the
relative bioavailability was found to be only 76.51% for LF111 compared to YAZ,
indicating that there is an influence of ethinyl estradiol on the PK of
drospirenone. Ovulation inhibition with LF111 was confirmed and maintained
despite delaying two pills for 24 hours.

The dosing regimen of the POPs currently on the market is to take verum tablets
continuously with no placebo tablets or gaps between packs. Unscheduled
bleeding is a major reason for discontinuing these POPs. Mechanisms relevant to
uterine bleeding are complex and novel strategies to manage these significant
problems are needed. LF111 is a new POP formulation with a new regimen of 24
verum tablets followed by 4 placebo tablets, designed to try to reduce
unscheduled bleeding.

Overall, 1527 healthy volunteers have been enrolled into the LF111 clinical
programme, of which approximately 1332 subjects have received LF111. In total,
116 subjects participated in the phase I programme, 146 subjects were enrolled
into the phase II and 1265 subjects have been enrolled into the phase III
studies. There is no indication that the safety profile of DRSP would be
altered when given alone without EE or E2. In the pivotal trial CF111-301 the
contraceptive efficacy of LF111 was demonstrated with an overall Pearl Index
[95% CI] of 0.5106 [0.1053; 1.4922]

It is expected that LF111 will offer benefits to adults in the form of efficacy
similar to COCPs, absence of estrogen-related risks, reduced tendency to weight
gain and extended dosing window. It is likely that adolescents will share these
benefits. However, LF111 has no particular features that would make it
particularly appropriate in this age group, as the risks associated with the
estrogen component of COCPs are generally perceived as very low in this age
group and it is these products that are routinely prescribed to teenage girls
seeking contraception.

As agreed on with the EMA, the current study intends to evaluate the safety and
tolerability, including bleeding pattern, of LF111 (4.0 mg DRSP) in
approximately 100 adolescents

Multicentre, open-label, phase-III safety trial in female adolescents aged
12-17 years. (In some countries the lower age limit may be higher due to
national legislation.) After six treatment cycles the subjects may continue
with the seven-cycle extension phase.

The trial will consist of a screening visit (V1a), an IMP dispensing visit
(V1b), six 28-day treatment cycles with five on-site visits (V2, V3, V4, V5 and
V6/EDV) and a follow-up visit V FU, 10-14 days after last IMP intake. For
subjects participating in the extension phase and continuing IMP intake during
treatment cycles 7-13, two additional visits will be performed before V FU:
telephone visit V7 and on-site visit V8/EDV

The study will start with a screening visit. During the screening visit
standard medical assessments including safety laboratory tests (blood draw,
urine collection, pregnancy test), a physical examination, a gynaecological
examination (If the hymen is intact, no vaginoscopy and no intravaginal
ultrasound will be performed) and a vital signs measurement will be performed.

If the subject is considered eligible, the subject will be enrolled in the study

During study the subjects will visit the unit 6 times (day of treatment
allocation,14 days after, start cycle 2, start cycle 3, start cycle 5 and end
of cycle 6) . Subjects will also complete a bleeding diary daily. If the
subject participates in the extension phase, the subject will have 1 follow-up
call start of cycle 10 and 1 visit end of cycle 13.

A final follow-up visit will be performed.

During the visits the subjects will be asked for possible side effects, a
pregnancy test will be perfomed and vital signs will be checked, at V6 and V8
(if applicable) blood will be drawn and urine collected for safety, a pregnancy
test will be perfomed and a physical and a gynaecological examination will be
conducted

LF111 is a new contraceptive formulation and there is a certain risk that it
might be not as effective as other oral contraceptives that are already on the
market. Therefore, there is a risk to get pregnant during the trial. As with
any other drugs, this trial medication has the potential to cause side effects.
Their influence on the subjects health can vary from symptoms that cause the
subject to have mild discomfort to more severe conditions that will require
treatment.

The side effect profile of DRSP (LF111) given alone is not fully elucidated.
When given in combination with ethinyl estradiol or estradiol the most common
events that have been reported in more than 1% of subjects in the pivotal
clinical studies include, which may or may not be drug-related: Upper
respiratory infection, headache, breast pain, vaginal yeast infection
(moniliasis), vaginal discharge (leukorrhea), diarrhea, nausea, vomiting,
vaginitis, abdominal pain, flu syndrome, painful menstruation (dysmenorrhea),
allergic reaction, urinary tract infection, accidental injury, bladder
infection (cystitis), tooth disorder, sore throat (pharyngitis), infection,
fever, surgery, sinusitis, back pain, emotional lability, migraine, Pap smear
(microscopic examination of cervical cells) suspicious, indigestion
(dyspepsia), rhinitis, acne, gastric flu (gastroenteritis), bronchitis,
inflammation of the throat (pharyngitis), skin disorder, intermenstrual
bleeding, libido decreased, weight gain, pain, depression, cough increased,
dizziness, menstrual disorder, pain in extremity, pelvic pain, and weakness
(asthenia).

The use of combination oral contraceptives is associated with increased risks
of several serious conditions including venous and arterial thrombotic and
thromboembolic events (such as myocardial infarction, thromboembolism, stroke),
liver tumor, gallbladder disease, and high blood pressure. The risk of serious
morbidity or mortality is very small in healthy women without underlying risk
factors. The risk of morbidity and mortality increases significantly in the
presence of other underlying risk factors such as high blood pressure, high
cholesterol levels, obesity, diabetes and smoking. The risk of venous
thromboembolic events with the use of DRSP alone is not yet known.

The subjects will be closely monitored. The subjects will be regularly
questioned for any side effects. The subjects will be asked to report, as soon
as possible, any changes in physical and/or mental well being