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

Study Overview
=================
Brief Summary
-----------------
The primary purpose of this study was to evaluate the effect of ESN364 on the severity and frequency of hot flashes in early postmenopausal women suffering from hot flashes, in terms of changes in weekly Hot Flash Score from baseline to Week 12. This study also evaluated the effect of ESN364 on the severity and frequency of hot flashes at additional timepoints; hot flash interference on daily life, in terms of changes from baseline over time in Hot Flash Related Daily Interference Scale (HFRDIS); the effect of ESN364 on climacteric symptoms, in terms of changes from baseline over time in Leeds Sleep Evaluation Questionnaire (LSEQ), Greene Climacteric Scale (GCS), and Sheehan Disability Scale (SDS); pharmacodynamic (PD) effect; and safety and tolerability.

Official Title
-----------------
Pilot/Phase IIa Trial to Investigate the Effect of ESN364 in Early Postmenopausal Women Suffering From Hot Flashes

Conditions
-----------------
Hot Flashes

Intervention / Treatment
-----------------
* Drug: Fezolinetant
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Spontaneous amenorrhea for at least 12 consecutive months; or spontaneous amenorrhea for at least 6 months with biochemical criteria of menopause (FSH >40 IU/L); or spontaneous amenorrhea for at least 3 months with biochemical/physical criteria of menopause (FSH >40 IU/L and E2 <0.21 nmol/); or having had bilateral oophorectomy at least 6 weeks prior to screening (with or without hysterectomy); At least 49 moderate or severe hot flashes or night sweats over a period of 7 consecutive days, as recorded in the daily diary during the screening period, with at least 4 of those days with 7 or more moderate or severe hot flashes per day; In good general health as determined on the basis of medical history and general physical examination performed at screening; hematology and chemistry parameters, pulse rate and/or blood pressure, and ECG within the reference range for the population studied, or showing no clinically relevant deviations; Negative urine test for selected drugs of abuse (amphetamines, tricyclic antidepressants, cannabinoids, cocaine, tetrahydrocannabinol, or opiates) at screening; Negative serology panel (including hepatitis B surface antigen [HBsAg], antihepatitis C virus [HCV] and human immunodeficiency virus (HIV) antibody screens); Negative urine pregnancy test at screening; Exclusion Criteria: Use of a prohibited therapy or not willing to wash-out drugs considered prohibited therapies; History (in the past year) or presence of drug or alcohol abuse; Suicide attempt in the past 3 years; Previous or current history of a malignant tumor (except basal cell carcinoma); Active liver disease or jaundice, or out-of-range values of alanine aminotransferase (ALT) and aspartate aminotransferase (AST); or total bilirubin >1.3 times the upper limit of normal (ULN); or creatinine >1.5 times the ULN; or estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) formula <60 mL/min/1.73 m2 at screening; Medical condition or chronic disease (including history of neurological [including cognitive], hepatic, renal, cardiovascular, gastrointestinal, pulmonary [e.g., moderate asthma], or endocrine disease) or malignancy that could confound interpretation of the study outcome; Any psychological disorder according to the criteria indicated in the Diagnostics and Statistical Manual of Mental Disorders (DSM, 4th edition) within one year prior to screening. Such disorders include but are not limited to current major depression, alcohol (more than 3 glasses of wine, beer, or equivalent/day) or substance abuse/dependence; Unsuited to participate in the study, based on findings observed during physical examination, vital sign assessment, or 12-lead ECG; History of severe allergy, hypersensitivity, or intolerance to drugs in general, including the study drug and any of its excipients; Presence or sequellae of gastrointestinal, liver, kidney or other conditions known to interfere with the absorption, distribution, metabolism, or excretion (ADME) mechanisms of drugs; Concurrent participation in another interventional study (or participation within 3 months prior to screening in this study); History of poor compliance in clinical studies; Unable or unwilling to complete the study procedures; Subject is the Investigator or any sub-investigator, research assistant, pharmacist, study coordinator, or other staff or relative thereof who is directly involved in the conduct of the study.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fezolinetant<br>Participants received 90 milligrams (mg) fezolinetant capsules orally, twice daily (BID) for a period of 12 weeks | Drug: Fezolinetant<br>* Oral Capsule<br>* Other names: ASP2693;|
| Placebo Comparator: Placebo<br>Participants received fezolinetant matching placebo capsules orally, BID for a period of 12 weeks. | Drug: Placebo<br>* Oral Capsule<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 12 in The Weekly General Hot Flash Score | 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. | Baseline and week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in The Weekly Hot Flash Severity Score at Weeks 4, 8 and 12 (Method 1) | 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. | Baseline and weeks 4, 8 and 12 | 
| Change From Baseline in The Weekly Hot Flash Severity Score at Weeks 4, 8 and 12 (Method 2) | 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. | Baseline and weeks 4, 8 and 12 | 
| Change From Baseline in The Weekly Mild, Moderate and Severe Hot Flash Frequency at Weeks 4, 8 and 12 | 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. | Baseline and weeks 4, 8 and 12 | 
| Percentage of Participants With >=70% Reduction in the Weekly Hot Flash Score From Baseline to Weeks 4, 8 and 12 | 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. | Baseline and weeks 4, 8 and 12 | 
| Percentage of Participants With >=80% Reduction in the Weekly Hot Flash Score From Baseline to Weeks 4, 8 and 12 | 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. | Baseline and weeks 4, 8 and 12 | 
| Percentage of Participants With >=90% Reduction in the Weekly Hot Flash Score From Baseline to Weeks 4, 8 and 12 | 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. | Baseline and weeks 4, 8 and 12 | 
| Percentage of Participants With >=50% Reduction in the Weekly Frequency of Moderate and Severe HF From Baseline to Weeks 4, 8 and 12 | 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. | Baseline and weeks 4, 8 and 12 | 
| Percentage of Participants With >=70% Reduction in the Weekly Frequency of Moderate and Severe HF From Baseline to Weeks 4, 8 and 12 | 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. | Baseline and weeks 4, 8 and 12 | 
| Percentage of Participants With >=90% Reduction in the Weekly Frequency of Moderate and Severe HF From Baseline to Weeks 4, 8 and 12 | 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. | Baseline and weeks 4, 8 and 12 | 
| Change From Baseline in Hot Flash Related Daily Interference Scale (HFRDIS) Score at Weeks 4, 8 and 12 | 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. | Baseline and weeks 4, 8 and 12 | 
| Change From Baseline in Leeds Sleep Evaluation Questionnaire (LSEQ) at Weeks 4, 8 and 12 | 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. | Baseline and weeks 4, 8 and 12 | 
| Change From Baseline in Greene Climacteric Scale (GCS) at Weeks 4, 8 and 12 | 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. | Baseline and weeks 4, 8 and 12 | 
| Change From Baseline in Sheehan Disability Scale (SDS) at Weeks 4, 8 and 12 | 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. | Baseline and weeks 4, 8 and 12 | 
| Change From Baseline in Sheehan Disability Scale (SDS) at Weeks 4, 8 and 12 (Days Lost and Days Unproductive) | 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? | Baseline and weeks 4, 8 and 12 | 
| Change From Baseline in Plasma Concentration of Luteinizing Hormone (LH) | Change From baseline in plasma concentration of LH was reported. | Baseline and week 4: pre-dose, week 8:pre-dose, week 12:pre-dose, week 12: 3h, follow-up (week 15) | 
| Change From Baseline in Plasma Concentration of Follicle-Stimulating Hormone (FSH) | Change From baseline in plasma concentration of FSH was reported. | Baseline and week 4: pre-dose, week 8:pre-dose, week 12:pre-dose, week 12:3h, follow-up (week 15) | 
| Change From Baseline in Plasma Concentration of Estradiol (E2) | Change From baseline in plasma concentration of E2 was reported. | Baseline and week 4: pre-dose, week 8:pre-dose, week 12:pre-dose, week 12:3h, follow-up (week 15) | 
| Change From Baseline in Plasma Concentration of Sex Hormone-Binding Globulin (SHBG) | Change From baseline in plasma concentration of SHBG was reported. | Baseline and week 4: pre-dose, week 8:pre-dose, week 12:pre-dose, week 12:3h, follow-up (week 15) | 
| Change From Baseline in Plasma Concentration of Leptin | Change From baseline in plasma concentration of leptin was reported. | Baseline and week 4: pre-dose, week 8:pre-dose, week 12:pre-dose, week 12:3h, follow-up (week 15) | 
| Change From Baseline in Plasma Concentration of Insulin | Change From baseline in plasma concentration of insulin was reported. | Baseline and week 4: pre-dose, week 8:pre-dose, week 12:pre-dose, week 12:3h, follow-up (week 15) | 
| Change From Baseline in Plasma Concentration of C-peptide | Change From baseline in plasma concentration of C-peptide was reported. | Baseline and week 4: pre-dose, week 8:pre-dose, week 12:pre-dose, week 12:3h, follow-up (week 15) | 
| Change From Baseline in Plasma Concentration of Glycated Hemoglobin (HBA1c) | Change From baseline in plasma concentration of HBA1C was reported. | Baseline and week 12 | 
| Number of Participants With Adverse Events (AE's) | 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. | From first dose of study drug until end of the study (Up to week 15) | 
| Change From Baseline in Plasma Concentration of Bone Alkaline Phosphatase (BALP) at Week 12 | Change from baseline in plasma concentration of BALP was reported. | Baseline and week 12 | 
| Change From Baseline in Plasma Concentration of Carboxy-terminal Telopeptide of Type I Collagen (CTX) at Week 12 | Change from baseline in plasma concentration of CTX was reported. | Baseline and week 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hot flashes, ESN364, ASP2693, fezolinetant, menopause, postmenopausal