Trial to Investigate the Effect of ESN364 in Early Postmenopausal Women Suffering From Hot Flashes

The HF Severity Score by method 1 takes into account the number and severity of moderate and severe HF occurred during a given time period and was calculated as follows HF Severity score = [(number of moderate HF/day × 2) + (number of severe HF/day × 3)]/(number of moderate HF + number of severe HF)

The severity of HFs was clinically defined as follows:

• Moderate: Sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets.
• Severe: Sensation of intense heat with sweating, causing disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., removing layers of clothes, open the window, or get out of bed).

Higher scores indicate worse symptoms. There is no maximum score since the score was participant-dependent for both number and severity.

The HF Severity Score by method 2 takes into account moderate and severe HF during a given time period and was calculated as follows HF Severity score = [(number of moderate HF/day × 2) + (number of severe HF/day × 3)]

The severity of HFs was clinically defined as follows:

• Moderate: Sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets.
• Severe: Sensation of intense heat with sweating, causing disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., removing layers of clothes, open the window, or get out of bed).

Higher scores indicate worse symptoms. There is no maximum score since the score was participant-dependent for both number and severity.

The weekly HF frequency was calculated as number of mild, moderate and severe hot flashes over the week.

• Mild: sensation of heat without sweating/dampness. If at night, participant didn't wake up but later notices damp sheets or clothing.
• Moderate: Sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets.
• Severe: Sensation of intense heat with sweating, causing disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., removing layers of clothes, open the window, or get out of bed).

Higher number of hot flashes is worse.

The HF score (based on severity and frequency) was calculated as:

(number of mild HF/day × 1) + (number of moderate HF/day × 2) + (number of severe HF/day × 3)

The severity of HFs is clinically defined as follows:

• Mild: sensation of heat without sweating/dampness. If at night, participant didn't wake up but later notices damp sheets or clothing.
• Moderate: Sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets.
• Severe: Sensation of intense heat with sweating, causing disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., removing layers of clothes, open the window, or get out of bed).

Higher scores indicate worse symptoms. There is no maximum score since the score was participant-dependent for both number and severity.

The HF score (based on severity and frequency) was calculated as:

(number of mild HF/day × 1) + (number of moderate HF/day × 2) + (number of severe HF/day × 3)

The severity of HFs is clinically defined as follows:

• Mild: sensation of heat without sweating/dampness. If at night, participant didn't wake up but later notices damp sheets or clothing.
• Moderate: Sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets.
• Severe: Sensation of intense heat with sweating, causing disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., removing layers of clothes, open the window, or get out of bed).

Higher scores indicate worse symptoms. There is no maximum score since the score was participant-dependent for both number and severity.

The HF score (based on severity and frequency) was calculated as:

(number of mild HF/day × 1) + (number of moderate HF/day × 2) + (number of severe HF/day × 3)

The severity of HF is clinically defined as follows:

• Mild: sensation of heat without sweating/dampness. If at night, participant didn't wake up but later notices damp sheets or clothing.
• Moderate: Sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets.
• Severe: Sensation of intense heat with sweating, causing disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., removing layers of clothes, open the window, or get out of bed).

Higher scores indicate worse symptoms. There is no maximum score since the score was participant-dependent for both number and severity.

The weekly HF frequency of moderate and severe HF was calculated as number of moderate and severe HF over the week.

• Moderate: Sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets.
• Severe: Sensation of intense heat with sweating, causing disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., removing layers of clothes, open the window, or get out of bed).

Higher number of HF indicates worse symptoms.

The weekly HF frequency of moderate and severe HF was calculated as number of moderate and severe HF over the week.

• Moderate: Sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets.
• Severe: Sensation of intense heat with sweating, causing disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., removing layers of clothes, open the window, or get out of bed).

Higher number of HF indicates worse symptoms.

The weekly HF frequency of moderate and severe HF was calculated as number of moderate and severe HF over the week.

• Moderate: Sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets.
• Severe: Sensation of intense heat with sweating, causing disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., removing layers of clothes, open the window, or get out of bed).

Higher number of HF indicates worse symptoms.

The HFRDIS was a 10-item scale which measured a woman's perceptions of the degree to which HF interfere with 9 daily life activities (work, social activities, leisure, sleep, mood, concentration, relations with others, sexuality, enjoying life); the 10th item measures interference with overall quality of life. This scale was modeled after items on the Brief Pain Inventory and Brief Fatigue Inventory both of which assessed the extent to which pain or fatigue interfere with daily life. Participants were asked to rate the extent to which HF had interfered with each item during the previous 4-week time interval using a 0 (do not interfere) to 10 (completely interfere) scale. Overall mean score was calculated as sum of items/number of available items. Higher score indicate a higher interference.

The LSEQ was a 10-item self-rated questionnaire which assessed participants aspects of sleep and early morning behavior. The questions were grouped into 4 chronological areas: the ease of getting to sleep, the perceived quality of sleep, the ease of awaking from sleep, and the integrity of early morning behavior following wakefulness. The LSEQ was a visual analogue scale which requires respondents to place marks on a group of 10 cm lines. representing the changes they have experienced in a variety of symptoms since the beginning of treatment. Lines extends between extremes like "more difficult than usual" and "easier than usual". Responses are measured using a 100-mm scale and are averaged to provide a score for each domain.

The GCS was a 21-item scale which provides a brief but comprehensive and valid measure of climacteric symptomatology. Each item was rated by the participant according to its severity using a four-point rating scale from 0 (none) to 3 (severe). The first 20 items of the scale combine into three main independent symptom measures: psychological symptoms (items 1 to 11; score 0 to 33), physical symptoms (items 12 to 18; score 0 to 21), and vasomotor symptoms (items 19 to 20; score 0 to 6), by summing up the individual item scores. Item 21 is a probe for sexual dysfunction (Loss of interest in sex). The total score ranges from 0 to 63. Higher scores indicate worse symptoms.

The SDS was a composite of 3 self-rated items designed to measure the extent to which 3 major sectors in a participant's life are impaired by panic, anxiety, phobic, or depressive symptoms. The participant rates the extent to which his/her 1- work/school, 2- social life, and 3- family life are impaired by his/her symptoms on a 10-point visual analog scale. The 3 items could be summed into a single dimensional measure of global functional impairment that ranges from 0 (unimpaired) to 30 (highly impaired).Higher scores indicate significant functional impairment.

The SDS was a composite of 3 self-rated items designed to measure the extent to which 3 major sectors in a participant's life are impaired by panic, anxiety, phobic, or depressive symptoms. The participant rates the extent to which his/her 1- work/school, 2- social life, and 3- family life are impaired by his/her symptoms. In addition to the 3 items, the participants were asked two questions Days Lost: On how many days in the last week did your symptoms cause you to miss school or work or leave you unable to carry out your normal daily responsibilities? Day Unproductive: On how many days in the last week did you feel so impaired by your symptoms, that even though you went to school or work, your productivity was reduced?

Change From baseline in plasma concentration of LH was reported.

Change From baseline in plasma concentration of FSH was reported.

Change From baseline in plasma concentration of E2 was reported.

Change From baseline in plasma concentration of SHBG was reported.

Change From baseline in plasma concentration of leptin was reported.

Change From baseline in plasma concentration of insulin was reported.

Change From baseline in plasma concentration of C-peptide was reported.

Change From baseline in plasma concentration of HBA1C was reported.

An AE is any untoward medical occurrence in a participant administered a study drug, \& which does not necessarily have to have a causal relationship with treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with use of a medicinal product (mp) whether or not considered related to the mp. An AE is considered "serious" if it results in death, is life-threatening, results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, results in congenital anomaly or birth defect, requires inparticipant hospitalization or leads to prolongation of hospitalization, hospitalization for treatment/observation/examination caused by AE is to be considered as serious, discontinuation due to increases in liver enzymes, other medically important events. TEAE was defined as an AE observed from first dose date up to end of study.

Change from baseline in plasma concentration of BALP was reported.

Change from baseline in plasma concentration of CTX was reported.