Trial Outcomes & Findings for A Study of the Effect of Estrogen on Estrogen Receptor Biomarkers in Healthy Postmenopausal Women (0000-094)(COMPLETED) (NCT NCT00799708)

Last Updated: 2016-03-16

Results Overview

Subset of genes on the log ratio intensity scale from a microarray platform - signature was pre-specified from an internally conducted study in knock-out mice treated with estrogens- quantified as a ratio of up regulated versus down regulated genes

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

27 participants

Primary outcome timeframe

Baseline and Day 7

Results posted on

2016-03-16

Participant Flow

This was a randomized, double-blind, placebo-controlled parallel group study in healthy postmenopausal women. Enrollment occurred from May 2008 through October 2008 across two US Phase I clinical research centers.

Participant milestones

Participant milestones
Measure	17β-estradiol 2.0 Milligrams Estrace 2 mg tablets once daily for 7 days.	17β-estradiol 0.5 Milligrams Estrace 0.5 mg tablets once daily for 7 days.	Placebo Placebo capsule once daily for 7 days.
Overall Study STARTED	10	6	11
Overall Study COMPLETED	9	6	11
Overall Study NOT COMPLETED	1	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	17β-estradiol 2.0 Milligrams Estrace 2 mg tablets once daily for 7 days.	17β-estradiol 0.5 Milligrams Estrace 0.5 mg tablets once daily for 7 days.	Placebo Placebo capsule once daily for 7 days.
Overall Study non-compliance	1	0	0

Baseline Characteristics

A Study of the Effect of Estrogen on Estrogen Receptor Biomarkers in Healthy Postmenopausal Women (0000-094)(COMPLETED)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	17β-estradiol 2.0 Milligrams n=10 Participants Estrace 2 mg tablets once daily for 7 days.	17β-estradiol 0.5 Milligrams n=6 Participants Estrace 0.5 mg tablets once daily for 7 days.	Placebo n=11 Participants Placebo capsule once daily for 7 days.	Total n=27 Participants Total of all reporting groups
Age, Continuous	54.3 years STANDARD_DEVIATION 5.0 • n=99 Participants	53.8 years STANDARD_DEVIATION 4.4 • n=107 Participants	54.4 years STANDARD_DEVIATION 4.8 • n=206 Participants	54.2 years STANDARD_DEVIATION 4.6 • n=157 Participants
Sex: Female, Male Female	10 Participants n=99 Participants	6 Participants n=107 Participants	11 Participants n=206 Participants	27 Participants n=157 Participants
Sex: Female, Male Male	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=157 Participants
Body Mass Index (BMI)	29.1 kg/m^2 STANDARD_DEVIATION 6.1 • n=99 Participants	28.7 kg/m^2 STANDARD_DEVIATION 3.2 • n=107 Participants	29.2 kg/m^2 STANDARD_DEVIATION 4.8 • n=206 Participants	29.0 kg/m^2 STANDARD_DEVIATION 4.9 • n=157 Participants

PRIMARY outcome

Timeframe: Baseline and Day 7

Population: All subjects with salivary gland tissue with RNA of acceptable quality based on pre-specified QC criteria

Outcome measures

Outcome measures
Measure	17β-estradiol 2.0 Milligrams n=7 Participants Estrace 2 mg tablets once daily for 7 days.	17β-estradiol 0.5 Milligrams n=4 Participants Estrace 0.5 mg tablets once daily for 7 days.	Placebo n=7 Participants Placebo capsule once daily for 7 days.
Change From Baseline in Estrogen Receptor Beta (ERbeta) -Specific Gene Signature After Treatment With 2 mg, 0.5 mg, or no Estradiol (Placebo) at Day 7	0.028 Fold change Standard Error 0.036	-0.011 Fold change Standard Error 0.048	0.080 Fold change Standard Error 0.039

SECONDARY outcome

Timeframe: Baseline and Day 7

Population: All subjects with salivary flow rate measured at baseline and 7 days

Change from baseline in unstimulated labial gland saliva flow rate at Day 7

Outcome measures

Outcome measures
Measure	17β-estradiol 2.0 Milligrams n=9 Participants Estrace 2 mg tablets once daily for 7 days.	17β-estradiol 0.5 Milligrams n=11 Participants Estrace 0.5 mg tablets once daily for 7 days.	Placebo Placebo capsule once daily for 7 days.
Change From Baseline in Minor Gland Salivary Flow Rate After Treatment With 2 mg Estradiol vs Placebo at Day 7.	-0.26 μL/min Interval -0.65 to 0.13	-0.64 μL/min Interval -1.0 to -0.28	—

Adverse Events

17β-estradiol 2.0 Milligrams

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

17β-estradiol 0.5 Milligrams

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp

Phone: 1-800-672-6372

Results disclosure agreements

Principal investigator is a sponsor employee Merck agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Merck supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Other adverse events
Measure	17β-estradiol 2.0 Milligrams n=10 participants at risk Estrace 2 mg tablets once daily for 7 days.	17β-estradiol 0.5 Milligrams n=6 participants at risk Estrace 0.5 mg tablets once daily for 7 days.	Placebo n=11 participants at risk Placebo capsule once daily for 7 days.
Cardiac disorders Palpitations	0.00% 0/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	16.7% 1/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Gastrointestinal disorders Abdominal Pain Lower	0.00% 0/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	9.1% 1/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Gastrointestinal disorders Diarrhoea	10.0% 1/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Gastrointestinal disorders Haemorrhoids	0.00% 0/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	9.1% 1/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Gastrointestinal disorders Hypoaesthesia Oral	0.00% 0/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	9.1% 1/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Gastrointestinal disorders Lip Disorder	0.00% 0/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	9.1% 1/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Gastrointestinal disorders Lip Pain	20.0% 2/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	16.7% 1/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	27.3% 3/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Gastrointestinal disorders Lip Swelling	0.00% 0/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	18.2% 2/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Gastrointestinal disorders Saliva Altered	0.00% 0/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	9.1% 1/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Gastrointestinal disorders Stomach Discomfort	10.0% 1/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
General disorders Chest Discomfort	0.00% 0/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	16.7% 1/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
General disorders Oedema Peripheral	0.00% 0/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	9.1% 1/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
General disorders Pain	0.00% 0/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	9.1% 1/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Injury, poisoning and procedural complications Joint Injury	10.0% 1/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Injury, poisoning and procedural complications Procedural Site Reaction	10.0% 1/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Musculoskeletal and connective tissue disorders Pain In Extremity	0.00% 0/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	9.1% 1/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Nervous system disorders Burning Sensation	10.0% 1/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Nervous system disorders Headache	30.0% 3/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	16.7% 1/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	18.2% 2/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Nervous system disorders Paraesthesia	10.0% 1/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Nervous system disorders Tongue Biting	0.00% 0/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	16.7% 1/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Psychiatric disorders Insomnia	0.00% 0/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	9.1% 1/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Reproductive system and breast disorders Adnexa Uteri Pain	0.00% 0/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	9.1% 1/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Reproductive system and breast disorders Breast Pain	0.00% 0/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	9.1% 1/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Reproductive system and breast disorders Breast Tenderness	10.0% 1/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Reproductive system and breast disorders Vaginal Disorder	10.0% 1/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Reproductive system and breast disorders Vaginal Haemorrhage	10.0% 1/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Vascular disorders Hot Flush	0.00% 0/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	9.1% 1/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Vascular disorders Hypertension	0.00% 0/10 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/6 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	9.1% 1/11 • AEs were collected from the time the subject signed the consent form until 14 days following the last dose of study medication. AEs were assessed by clinical evaluation including vital signs, physical examination, medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.