A Combined Escalating Single Oral Dose and Multiple Oral Dose Trial investigating Safety, Tolerance, Pharmacokinetics and Pharmacodynamics of SCH 900479 in Healthy Postmenopausal Female Subjects

The drug to be given, is a new, investigational compound that may eventually be
used for the treatment of menopausal symptoms. Hot flashes are the most common
symptom related to menopause. A hot flash, or flush, is the spontaneous
sensation of warmth, often associated with perspiration, palpitations, and
anxiety, resulting from a dilatation of the blood vessel diameter to release
the warmth as quick as possible.
Oestrogen (a hormone involved in the regulation of the menstrual cycle and
pregnancy) has been used as a hormone supplement for nearly 60 years to treat
postmenopausal symptoms. However, it has the potential to induce growth of the
endometrium ((inner cell layer of the uterus) which may lead to malignant
tumors of the endometrium. This risk can be reduced by concurrent
administration of progestogen (a hormone involved in the regulation of the
menstrual cycle and pregnancy). In combination with oestrogen treatment,
progestogen treatment commonly causes regular and/or irregular vaginal
bleeding, which is unacceptable for many postmenopausal women. A major drawback
of this combined therapy is that it may lead to an increased risk of breast
cancer.
It is expected that the compound will be effective for the treatment of
menopausal symptoms, whilst not inducing the growth of the endometrium and
thereby not increasing the risk of malignant tumors of the endometrium.

Primary:
To investigate the safety and tolerability of single oral administration of
study medication in healthy postmenopausal females (Part I)
To investigate the general safety and tolerability of the study medication in
healthy postmenopausal females following once daily oral administration of
escalating doses for 10 days (Part II)

Secondary:
To investigate the single dose pharmacokinetics (PK) of the study medication
and its active metabolite following single oral administration (Part I)
To investigate the steady state PK of the study medication and its active
metabolite following once daily oral administration for 10 days (Part II)
To investigate the LH effects of the study medication following single oral
administration (Part I)
To investigate the LH effects of the study medication following once daily oral
administration for 10 days (Part II)

Exploratory :
To explore effects of the study medication on FSH following single oral dose
administration, and following once daily oral administration for 10 days
To explore effects of the study medication on SHBG following daily oral
administration for 10 days
To explore and, if possible, identify the major metabolites of the study
medication in plasma and urine
To explore if Provera® induces a withdrawal bleeding after completion of the
study medication treatment for 10 days as biomarker for uterine safety

Optional:
To explore the effects of the study medication on NTx following daily oral
administration for 10 days
To compare the pharmacodynamic effects (LH, FSH, SHBG and Provera® challenge )
of a full ER-*/ER-* agonist of 2 mg oral 17*-estradiol (E2) for 10 days and the
partial ER-* / ER- * agonist of the study medication for 10 days

Design:
Part I:
A randomized, third party blind (within dose level), placebo-controlled,
cross-over single rising dose study with two groups of eight healthy
postmenopausal females each receiving a single oral dose of the study
medication or placebo (six verum and two placebo) in four periods; a washout of
at least seven days between dosing

Part II:
A randomized, third-party blind (within dose level), placebo-controlled,
multiple rising dose study with four or five groups of eight healthy
postmenopausal females each receiving an oral dose of the study medication or
placebo (six verum and two placebo) once daily on Days 1-10 and an oral dose of
Provera® on Days 15-24 (at home) and one control group of eight healthy
postmenopausal females receiving an oral dose of 17-* estradiol once daily on
Days 1-10 and an oral dose of Provera® on Days 15-24 (at home)

Procedures and assessments:
Screening and follow-up:
Clinical laboratory, vital signs physical examination, gynaecological
examination, 12-lead ECG, pregnancy test; at eligibility screening: medical
history, height, weight, elbow breadth measurement, mammography/cervical smear,
TVU endometrium (Part II only), drug screen, PT, aPTT, FSH, HBsAg, anti HCV,
anti-HIV 1/2; physical exam, drug screen, clinical laboratory, PT and aPTT
(Part II only) and pregnancy test to be repeated upon (each) admission

Part I (SAD) :
Observation period:
4 periods, each period in clinic from -17 h up to 48 h after drug
administration and ambulatory visits on Days 4 and 5

Blood sampling:
For pharmacokinetics of the study medication and its active metabolite:
pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72 and 96 h
post-dose
for pharmacodynamics of FSH/LH in serum: pre-dose and 1, 2, 3, 4, 5, 6, 8, 12,
24 and 48 h post-dose
for genotyping: pre-dose (Period 1 only)

Safety assessments:
Adverse events: throughout the study; clinical laboratory: once on Day 2;
12-lead ECG pre-dose and 1, 3, 8 and 24 h post-dose; vital signs pre-dose and
1, 3, 8 , 24, 48 and 72 h post-dose

Part II (MAD):
Observation period:
2 periods, first period in clinic from -17 h before drug administration on Day
1 up to 24 h after drug administration on Day 2 and ambulatory visits on Days
3-8, second period in clinic from -17 h up to 48 h after drug administration on
Day 10 (up to 24 h after drug administration for Group 8) and ambulatory visits
on Days 12 (Group 8 only), 13 and 14

Blood sampling:
For pharmacokinetics of the study medication and its active metabolite (Groups
3-6 only): pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 and 24 h
post-dose on Day 1, pre-dose on Days 4, 7 and 9 and pre-dose and 0.5, 1, 1.5,
2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72 and 96 h post-dose on Day 10 and
additionally 3 post-dose samples on Day 7 at around tmax (projected tmax=3 h)
will be collected for interim analysis
For pharmacodynamics of FSH/LH in serum: pre-dose and 1, 2, 3, 4, 5, 6, 8, 12,
24 and 48 h post-dose on Days 1 and 10 and pre-dose on Days 4, 7 and 9
For pharmacodynamics of SHBG: pre-dose on Days 1, 7, 9, 10 and once at follow-up
For metabolic profiling (Groups 3-6 only): pre-dose and 1, 2, 3, 5, 8, 12 and
24 h post-dose on Days 1 and 10
For genotyping: pre-dose on Day 1

Urine sampling:
For metabolic profiling (Groups 3-6 only): 12 h pre-dose on Day 1 and intervals
0-12 and 12-24 h post-dose on Days 1 and 10
for NTx and creatinine: second morning void on Days -1 and 1

Provera® challenge:
Record vaginal bleeding in diary from Day 14 to follow-up

Safety assessments:
Adverse events: throughout the study; physical examination: once on Days -1, 5
and 11; PT and aPTT: once on Day 10; clinical laboratory: pre-dose on Days 1, 4
and 7 and 24 h post-dose on Day 10; 12-lead ECG: pre-dose and 1, 3, 8 and 24 h
post-dose on Days 1 and 10 and pre-dose and 3 h post-dose on Days 4 and 7;
vital signs (supine and standing; including oral temperature): pre-dose and 1,
3, 8 and 24 h post-dose on Days 1 and 10, pre-dose and 3 h post-dose on Days 4
and 7 and once on Day 12

Bioanalysis:
Analysis of plasma the study medication and its active metabolite using a
validated method by Sponsor
analysis of serum FSH/LH samples using a validated method by Sponsor
analysis of SHBG samples using a validated method by Sponsor
metabolic profiling in plasma and urine by Sponsor
analysis of urine NTx and creatinine samples using a validated method by
Sponsor
genotyping by Sponsor

Active substance: SCH 900479,17-* estradiol, Provera®

Procedures: pain, light bleeding, heamatoma, possibly an infection.