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A Dose-ranging Study of the Efficacy of ESN364 in Postmenopausal Women Suffering Vasomotor Symptoms (Hot Flashes)

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ClinicalTrials.gov Identifier: NCT03192176
Recruitment Status : Completed
First Posted : June 19, 2017
Last Update Posted : September 11, 2019
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Brief Summary:
This study is to determine the effects of different doses and dosing regimens of ESN364 on the frequency and severity of hot flashes. The treatment will be administered for 12 weeks to postmenopausal women, ages 40 to 65, suffering at least 50 moderate to severe hot flashes per week.

Condition or disease Intervention/treatment Phase
Menopause Hot Flashes Drug: fezolinetant Drug: Placebo Phase 2

Detailed Description:

This is a 12-week randomized, double-blind, placebo-controlled, dose-ranging, parallel-group, multicenter study to assess the efficacy of ESN364 in postmenopausal women suffering from vasomotor symptoms (hot flashes).

This study will consist of a screening period (Days -35 to -1, including the screening visit [Visit 1] and a minimum 7-day collection of baseline vasomotor symptom frequency and severity assessments), a 12 week treatment period (Day 1 [Visit 2] to Week 12 [Visit 5]), and a follow up visit (Week 15 [Visit 6]) 3 weeks after the last dose of study drug.

The study will be performed on an ambulatory basis. The screening visit (Visit 1) will occur up to 35 days prior to randomization. Eligibility will be assessed via physical examination, clinical laboratory testing, vital signs, ECG, Pap smear, mammography, and endometrial biopsy. Subjects will receive an electronic diary in which to record daily vasomotor symptoms during the duration of the screening period. Subjects must have ≥7 consecutive days of vasomotor symptom recordings to participate in the study. Subjects are encouraged to continue recording for the duration of the whole screening period. The electronic diary will be reviewed by study site staff on Day 1 (Visit 2) to confirm study eligibility. Subjects may be rescreened 1 time upon approval of the medical monitor.

During the treatment period, subjects will return to the study site every 4 weeks for assessments.

The follow-up visit will occur approximately 3 weeks following the last dose of study drug.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 356 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Placebo-Controlled, Double-Blind, Dose-Ranging, Phase 2b Study to Investigate the Efficacy of ESN364 in Postmenopausal Women Suffering From Vasomotor Symptoms (Hot Flashes)
Actual Study Start Date : July 19, 2017
Actual Primary Completion Date : September 19, 2018
Actual Study Completion Date : September 19, 2018

Arm Intervention/treatment
Experimental: Lowest dose ESN364
ESN364 lowest dose twice daily (BID), oral, 12 weeks
Drug: fezolinetant
The dose of ESN364 varies across 7 treatment groups, with groups receiving once a day or twice a day blinded study drug. Doses range from 30 mg to 180 mg total daily dosing for 12 weeks.
Other Name: ESN364

Placebo Comparator: Placebo
Placebo BID, oral, 12 weeks
Drug: Placebo
Placebo administered BID for 12 weeks

Experimental: Low dose ESN364
ESN364 low dose BID, oral, 12 weeks
Drug: fezolinetant
The dose of ESN364 varies across 7 treatment groups, with groups receiving once a day or twice a day blinded study drug. Doses range from 30 mg to 180 mg total daily dosing for 12 weeks.
Other Name: ESN364

Experimental: Medium dose ESN364
ESN364 medium dose BID, oral, 12 weeks
Drug: fezolinetant
The dose of ESN364 varies across 7 treatment groups, with groups receiving once a day or twice a day blinded study drug. Doses range from 30 mg to 180 mg total daily dosing for 12 weeks.
Other Name: ESN364

Experimental: High dose ESN364
ESN364 high dose BID, oral, 12 weeks
Drug: fezolinetant
The dose of ESN364 varies across 7 treatment groups, with groups receiving once a day or twice a day blinded study drug. Doses range from 30 mg to 180 mg total daily dosing for 12 weeks.
Other Name: ESN364

Experimental: Low dose ESN364 + Placebo
ESN364 low dose once daily (QD) + placebo QD, oral, 12 weeks
Drug: fezolinetant
The dose of ESN364 varies across 7 treatment groups, with groups receiving once a day or twice a day blinded study drug. Doses range from 30 mg to 180 mg total daily dosing for 12 weeks.
Other Name: ESN364

Drug: Placebo
Placebo administered QD for 12 weeks

Experimental: Medium dose ESN364 + Placebo
ESN364 medium dose QD + placebo QD, oral, 12 weeks
Drug: fezolinetant
The dose of ESN364 varies across 7 treatment groups, with groups receiving once a day or twice a day blinded study drug. Doses range from 30 mg to 180 mg total daily dosing for 12 weeks.
Other Name: ESN364

Drug: Placebo
Placebo administered QD for 12 weeks

Experimental: Highest dose ESN364 + Placebo
ESN364 highest dose QD + placebo QD, oral, 12 weeks
Drug: fezolinetant
The dose of ESN364 varies across 7 treatment groups, with groups receiving once a day or twice a day blinded study drug. Doses range from 30 mg to 180 mg total daily dosing for 12 weeks.
Other Name: ESN364

Drug: Placebo
Placebo administered QD for 12 weeks




Primary Outcome Measures :
  1. Mean change in the frequency of moderate to severe vasomotor symptoms (VMS) from baseline to week 4 [ Time Frame: baseline to week 4 ]
    Frequency of moderate or severe VMS events will be calculated as the sum of moderate and severe VMS events per day.

  2. Mean change in the frequency of moderate to severe VMS from baseline to week 12 [ Time Frame: baseline to week 12 ]
    Frequency of moderate or severe VMS events will be calculated as the sum of moderate and severe VMS events per day.

  3. Mean change in the severity of moderate to severe VMS from baseline to week 4 [ Time Frame: baseline to week 4 ]
    The severity of moderate or severe VMS events will be calculated using a weighted average of VMS events.

  4. Mean change in the severity of moderate to severe VMS from baseline to week 12 [ Time Frame: baseline to week 12 ]
    The severity of moderate or severe VMS events will be calculated using a weighted average of VMS events.


Secondary Outcome Measures :
  1. Mean change in the frequency of mild, moderate, and severe VMS from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    Frequency of mild, moderate or severe VMS events will be calculated as the sum of mild, moderate, and severe VMS events per day.

  2. Mean change in the frequency of moderate and severe VMS per 24 hours from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    Frequency of moderate or severe VMS events will be calculated as the sum of moderate and severe VMS events per 24 hours.

  3. Mean change in the severity of mild, moderate, and severe VMS from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The severity of mild, moderate or severe VMS events will be calculated using a weighted average of VMS events.

  4. Mean change in the severity of moderate and severe VMS from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The severity of moderate or severe VMS events will be calculated using a weighted average of VMS events.

  5. Mean change in the hot flash score of mild, moderate, and severe VMS from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The hot flash score of mild, moderate or severe VMS events will be calculated using a weighted sum of VMS events.

  6. Mean change in the hot flash score of moderate and severe VMS from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The hot flash score of moderate or severe VMS events will be calculated using a weighted sum of VMS events.

  7. Mean percent reduction of mild, moderate, and severe VMS from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The sum of mild, moderate or severe VMS events per day will be calculated. Mean percent change will be reported.

  8. Mean percent reduction of moderate and severe VMS from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The sum of moderate or severe VMS events per day will be calculated. Mean percent change will be reported.

  9. Mean percent reduction of 50% of mild, moderate, and severe VMS from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The sum of mild, moderate or severe VMS events per day will be calculated. Percent reduction of 50% will be reported.

  10. Mean percent reduction of 70% of mild, moderate, and severe VMS from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The sum of mild, moderate or severe VMS events per day will be calculated. Percent reduction of 70% will be reported.

  11. Mean percent reduction of 90% of mild, moderate, and severe VMS from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The sum of mild, moderate or severe VMS events per day will be calculated. Percent reduction of 90% will be reported.

  12. Mean percent reduction of 100% of mild, moderate, and severe VMS from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The sum of mild, moderate or severe VMS events per day will be calculated. Percent reduction of 100% will be reported.

  13. Mean percent reduction of 50% of moderate and severe VMS from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The sum of moderate or severe VMS events per day will be calculated. Percent reduction of 50% will be reported.

  14. Mean percent reduction of 70% of moderate and severe VMS from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The sum of moderate or severe VMS events per day will be calculated. Percent reduction of 70% will be reported.

  15. Mean percent reduction of 90% of moderate and severe VMS from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The sum of moderate or severe VMS events per day will be calculated. Percent reduction of 90% will be reported.

  16. Mean percent reduction of 100% of moderate and severe VMS from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The sum of moderate or severe VMS events per day will be calculated. Percent reduction of 100% will be reported.

  17. Absolute reduction of 2 in mean number of mild, moderate, and severe VMS per 24 hours from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The sum of mild, moderate or severe VMS events per 24 hours will be calculated. Absolute reduction of 2 VMS events will be reported.

  18. Absolute reduction of 3 in mean number of mild, moderate, and severe VMS per 24 hours from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The sum of mild, moderate or severe VMS events per 24 hours will be calculated. Absolute reduction of 3 VMS events will be reported.

  19. Absolute reduction of 4 in mean number of mild, moderate, and severe VMS per 24 hours from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The sum of mild, moderate or severe VMS events per 24 hours will be calculated. Absolute reduction of 4 VMS events will be reported.

  20. Absolute reduction of 5 in mean number of mild, moderate, and severe VMS per 24 hours from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The sum of mild, moderate or severe VMS events per 24 hours will be calculated. Absolute reduction of 5 VMS events will be reported.

  21. Absolute reduction of 2 in mean number of moderate and severe VMS per 24 hours from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The sum of moderate or severe VMS events per 24 hours will be calculated. Absolute reduction of 2 VMS events will be reported.

  22. Absolute reduction of 3 in mean number of moderate and severe VMS per 24 hours from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The sum of moderate or severe VMS events per 24 hours will be calculated. Absolute reduction of 3 VMS events will be reported.

  23. Absolute reduction of 4 in mean number of moderate and severe VMS per 24 hours from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The sum of moderate or severe VMS events per 24 hours will be calculated. Absolute reduction of 4 VMS events will be reported.

  24. Absolute reduction of 5 in mean number of moderate and severe VMS per 24 hours from baseline to each study week [ Time Frame: baseline and up to week 15 ]
    The sum of moderate or severe VMS events per 24 hours will be calculated. Absolute reduction of 5 VMS events will be reported.

  25. Change from baseline in the Hot Flash Related Daily Interference Scale (HFRDIS) [ Time Frame: baseline and up to week 15 ]
    The HFRDIS is a 10-item scale that measures a woman's perceptions of the degree to which VMS interfere with 9 daily life activities (work, social activities, leisure, sleep, mood, concentration, relations with others, sexuality, and enjoying life); the 10th item measures interference with overall quality of life. This scale is modeled after items on the Brief Pain Inventory and Brief Fatigue Inventory, which assess the extent to which pain or fatigue interfere with daily life. Participants will be asked to rate the extent to which VMS have interfered with each item during the previous 4-week time interval using a 0 (do not interfere) to 10 (completely interfere) scale, the overall mean score (sum of items/10) will be calculated. Change from baseline will be reported.

  26. Change from baseline in Leeds Sleep Evaluation Questionnaire (LSEQ) [ Time Frame: baseline and up to week 15 ]
    The LSEQ is a 10-item self-rated questionnaire that assesses a patient's aspects of sleep and early morning behavior. The questions are grouped into 4 chronological areas: ease of getting to sleep, perceived quality of sleep, ease of awaking from sleep, and integrity of early morning behavior following wakefulness. The LSEQ is a visual analog scale that requires respondents to place marks on a group of 10 cm lines. Lines extend between extremes like "more difficult than usual" and "easier than usual." Responses are measured using a 100 mm scale and are averaged to a score for each domain. Change from baseline will be reported.

  27. Change from baseline in Greene Climacteric Scale (GCS) [ Time Frame: baseline and up to week 15 ]
    The GSC is a 21-item scale that provides a brief but comprehensive and valid measure of climacteric symptomatology. Each item is rated by the patient according to its severity using a 4-point rating scale from 0 (none) to 3 (severe). The first 20 items of the scale combine into 3 main independent symptom measures by summing up the individual item scores: psychological symptoms (items 1 to 11; score 0 to 33), physical symptoms (items 12 to 18; score 0 to 21), and VMS (items 19 to 20; score 0 to 6). Item 21 is a probe for sexual dysfunction. The total score can range from 0 to 63. Higher scores indicate worse symptoms. Change from baseline will be reported.

  28. Change from baseline in Menopause-Specific Quality of Life (MENQoL) questionnaire [ Time Frame: baseline and up to week 15 ]
    The MENQoL is self-administered and consists of a total of 29 items in a Likert-scale format. Each item assesses the impact of 1 of 4 domains of menopausal symptoms, as experienced over the last month: vasomotor (items 1 to 3), psychosocial (items 4 to 10), physical (items 11 to 26), and sexual (items 27 to 29). Items pertaining to a specific symptom are rated as present or not present, and if present, how bothersome on a 0 (not bothersome) to 6 (extremely bothersome) scale.. Means are computed for each subscale by dividing the sum of the domain's items by the number of items within that domain. Non-endorsement of an item is scored a "1" and endorsement a "2," plus the number of the particular rating, so that the possible score on any item ranges from 1 to 8. Change from baseline will be reported.

  29. Change from baseline to week 12 in plasma concentrations of luteinizing hormone (LH) [ Time Frame: baseline to week 12 ]
    To assess the pharmacodynamics (PD) of fezolinetant. Change from baseline will be reported.

  30. Change from baseline to week 12 in plasma concentrations of follicle-stimulating hormone (FSH) [ Time Frame: baseline to week 12 ]
    To assess the PD of fezolinetant. Change from baseline will be reported.

  31. Change from baseline to week 12 in plasma concentrations of estradiol (E2) [ Time Frame: baseline to week 12 ]
    To assess the PD of fezolinetant. Change from baseline will be reported.

  32. Change from baseline to week 12 in plasma concentrations of sex hormone-binding globulin (SHBG) [ Time Frame: baseline to week 12 ]
    To assess the PD of fezolinetant. Change from baseline will be reported.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   40 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Women >40 years and ≤65 years of age at the screening visit;
  • A body mass index between 18 kg/sqm to 38 kg/sqm (extremes included);
  • Spontaneous amenorrhea for ≥12 consecutive months; or spontaneous amenorrhea for ≥6 months with biochemical criteria of menopause (follicle-stimulating hormone [FSH] >40 IU/L); or having had bilateral oophorectomy ≥6 weeks prior to the screening visit (with or without hysterectomy);
  • At least 50 moderate to severe vasomotor symptoms per week (ie, 7 consecutive days), as recorded in the daily diary during the screening period;
  • In good general health as determined on the basis of medical history and general physical examination, including a bimanual clinical pelvic examination and clinical breast examination devoid of relevant clinical findings, performed at the screening visit; hematology and biochemistry parameters, pulse rate and/or blood pressure, and ECG within the reference range for the population studied, or showing no clinically relevant deviations, as judged by the Investigator;
  • Women >40 years of age who have documentation of a normal/negative or no clinically significant findings mammogram (obtained at Screening or within the prior 9 months of trial enrollment.) Appropriate documentation includes a written report or an electronic report indicating normal/negative or no clinically significant mammographic findings;
  • Willing to undergo a transvaginal ultrasound to assess endometrial thickness at Screening and at Week 12 (end-of-treatment, - and subjects) who are withdrawn from the study prior to completion, at the Early Termination (ET) Visit. This is not required for subjects who have had a partial (supracervical) or full hysterectomy;
  • Willing to undergo an endometrial biopsy at Screening (in the event that the subject's transvaginal ultrasound shows endometrial thickness ≥4 mm) and at Week 12 (end--of--treatment) - all subjects), for subjects with uterine bleeding, and for subjects who are withdrawn from the study prior to completion, at the ET Visit if study drug exposure is ≥10 weeks. This is not required for subjects who have had a partial (supracervical) or full hysterectomy;
  • Negative alcohol breath test and negative urine test for selected drugs of abuse (amphetamines, tricyclic antidepressants, cocaine, or opiates) at the screening visit;
  • Negative urine pregnancy test;
  • Negative serology panel (including hepatitis B surface antigen, hepatitis C virus antibody, and human immunodeficiency virus antibody screens);
  • Informed Consent Form signed voluntarily before any study-related procedure is performed, indicating that the subject understands the purpose of and procedures required for the study and is willing to participate in the study; and
  • Documentation of a normal Pap smear (or equivalent cervical cytology) or of no clinical significance in the opinion of the Investigator within the previous 9 months or at Screening.

Exclusion Criteria:

  • Use of a prohibited therapy (hormone therapy, hormonal contraceptive, or vasomotor symptom medication [prescription, over the counter, or herbal]) or not willing to wash out drugs
  • History (in the past year) or presence of drug or alcohol abuse;
  • Previous or current history of a malignant tumor, except for basal cell carcinoma;
  • Uncontrolled hypertension and a systolic blood pressure ≥140 mmHg and/or a diastolic blood pressure ≥90 mmHg;
  • Judged by the Investigator to be unsuited to participate in the study based on findings observed during physical examination, vital sign assessment, or 12-lead electrocardiogram (ECG);
  • History of severe allergy, hypersensitivity, or intolerance to drugs in general, including the study drug and any of its excipients;
  • Exclusion criterion 7 has been removed in Amendment 1;
  • An unacceptable result from endometrial biopsy (performed when endometrial thickness is ≥ 4mm measured by transvaginal ultrasound) of endometrial hyperplasia, endometrial cancer, or inadequate specimen at Screening (1 repeat biopsy permitted if technically possible);
  • History of endometrial hyperplasia or uterine/endometrial cancer;
  • History of unexplained uterine bleeding;
  • History of seizures or other convulsive disorders;
  • Medical condition or chronic disease (including history of neurological [including cognitive], hepatic, renal, cardiovascular, gastrointestinal, pulmonary [eg, moderate asthma], endocrine, or gynecological disease) or malignancy that could confound interpretation of the study outcome;
  • Presence or sequelae of gastrointestinal, liver, kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion (ADME) mechanisms of drugs as judged by the Investigator;
  • Active liver disease or jaundice, or values of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >1.5 x the upper limit of normal (ULN); or total bilirubin >1.5 x ULN; or creatinine >1.5 x ULN; or estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula ≤59 mL/min/1.73 sqm at the screening visit;
  • Concurrent participation in another interventional study (or participation within 3 months prior to screening in this study);
  • Suicide attempt in the past 3 years;
  • Unable or unwilling to complete the study procedures; or
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03192176


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Sponsors and Collaborators
Astellas Pharma Global Development, Inc.
Investigators
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Study Director: Medical Director Astellas Pharma Global Development, Inc.

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Responsible Party: Astellas Pharma Global Development, Inc.
ClinicalTrials.gov Identifier: NCT03192176     History of Changes
Other Study ID Numbers: ESN364_HF_205
First Posted: June 19, 2017    Key Record Dates
Last Update Posted: September 11, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
URL: https://www.clinicalstudydatarequest.com/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):
Vasomotor symptoms
Menopause
Hot flashes
Perimenopause
Additional relevant MeSH terms:
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Hot Flashes
Signs and Symptoms