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Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women (E4Comfort Study I)

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ClinicalTrials.gov Identifier: NCT04209543
Recruitment Status : Recruiting
First Posted : December 24, 2019
Last Update Posted : January 28, 2020
Sponsor:
Collaborator:
ICON Clinical Research
Information provided by (Responsible Party):
Estetra

Brief Summary:
This is a two-part study designed to evaluate the effect of Estetrol (E4) 15 or 20 mg, or placebo on the severity and frequency of vasomotor symptoms (VMS) (Efficacy Study Part) and the safety of E4 20 mg (Endometrial and General Safety Study Part)

Condition or disease Intervention/treatment Phase
Vasomotor Symptoms Menopausal Symptoms Drug: Estetrol oral tablet Drug: Placebo oral tablet Drug: Progesterone oral tablet Phase 3

Detailed Description:

This is a two-part study:

  • The Efficacy Study Part is designed to evaluate the frequency and severity of vasomotor symptoms [VMS] in both hysterectomized and non-hysterectomized postmenopausal participants after treatment with E4 15 mg or 20 mg or placebo for up to 13 consecutive weeks. For endometrial protection, all non-hysterectomized participants will be treated with 200 mg progesterone (P4) once daily for 14 consecutive days, after completion of the E4/placebo treatment.
  • The Endometrial and General Safety Study Part (Safety Part) is designed to evaluate the general safety, endometrial safety, secondary efficacy (lipid, glucose metabolism, health-related quality of life [HRQoL] and treatment satisfaction of E4 in non-hysterectomized participants. All participants will receive E4 20 mg in combination with 100 mg P4 continuously for up to 53 weeks.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: There are 3 blinded arms in the Efficacy part and 1 open-labeled arm in the Safety part
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized Double-blind Placebo Controlled Phase 3 Trial to Evaluate the Efficacy and Safety of Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women (E4Comfort Study I)
Actual Study Start Date : December 30, 2019
Estimated Primary Completion Date : August 2021
Estimated Study Completion Date : August 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Estetrol 15 mg -Efficacy Part
Estetrol (E4) 15 mg will be administered orally once daily for up to 13 consecutive weeks
Drug: Estetrol oral tablet
Estetrol oral tablet will be administered orally once daily

Experimental: Estetrol 20 mg -Efficacy Part
Estetrol (E4) 20 mg will be administered orally once daily for up to 13 consecutive weeks
Drug: Estetrol oral tablet
Estetrol oral tablet will be administered orally once daily

Placebo Comparator: Placebo - Efficacy Part
Placebo will be administered orally once daily for up to 13 consecutive weeks
Drug: Placebo oral tablet
Placebo oral tablet will be administered orally once daily

Experimental: Estetrol 20 mg + P4 100 mg - Safety Part
Estetrol (E4) 20 mg and Progesterone (P4) 100 mg will be administered once daily for up to 53 weeks
Drug: Estetrol oral tablet
Estetrol oral tablet will be administered orally once daily

Drug: Progesterone oral tablet
Progesterone oral tablet will be administered orally once daily




Primary Outcome Measures :
  1. Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 4 (Efficacy Study Part) [ Time Frame: Baseline and Week 4 ]

    The weekly frequency of moderate to severe VMS at Baseline and Week 4 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 4.

    Mean change = mean weekly frequency at Week 4 - mean weekly frequency at Baseline


  2. Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 12 (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]

    The weekly frequency of moderate to severe VMS at Baseline and Week 12 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 12.

    Mean change = mean weekly frequency at Week 12 - mean weekly frequency at Baseline


  3. Mean change in severity of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 4 (Efficacy Study Part) [ Time Frame: Baseline and Week 4 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 4 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 4.

    Baseline and Week 4 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS).

    Mean change = mean severity score at Week 4 - mean severity score at Baseline


  4. Mean change in severity of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 12 (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 12 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 12.

    Baseline and Week 12 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS).

    Mean change = mean severity score at Week 12 - mean severity score at Baseline


  5. Change from Baseline to each measured time point in endometrial thickness (Endometrial and General Safety Study Part) [ Time Frame: Screening, Baseline, Weeks 13, 29, and 53 ]
    Endometrial thickness will be assessed by transvaginal ultrasound (TVUS).

  6. Endometrial biopsy histology at Screening and Week 53 (Endometrial and General Safety Study Part) [ Time Frame: Screening and Week 53 ]
    Endometrial biopsies will be centrally evaluated by three independent expert pathologists from different institutions, blinded to treatment group and to each other's readings. The concurrence of two of the three pathologists will be accepted as the final diagnosis. If there is no agreement among the three pathologists, the most severe pathologic diagnosis, i.e., atypical hyperplasia >complex hyperplasia >simple hyperplasia >benign endometrium, will be used as the final diagnosis.


Secondary Outcome Measures :
  1. Mean change from Baseline to Week 1 in the weekly frequency of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 1 ]

    The weekly frequency of moderate to severe VMS at Baseline and Week 1 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 1.

    Mean change = mean weekly frequency at Week 1 - mean weekly frequency at Baseline


  2. Mean change from Baseline to Week 2 in the weekly frequency of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 2 ]

    The weekly frequency of moderate to severe VMS at Baseline and Week 2 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 2.

    Mean change = mean weekly frequency at Week 2 - mean weekly frequency at Baseline


  3. Mean change from Baseline to Week 3 in the weekly frequency of moderate to severe vasomotor symptoms (VMS) ((Efficacy Study Part) [ Time Frame: Baseline and Week 3 ]

    The weekly frequency of moderate to severe VMS at Baseline and Week 3 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 3.

    Mean change = mean weekly frequency at Week 3 - mean weekly frequency at Baseline


  4. Mean change from Baseline to Week 4 in the weekly frequency of moderate to severe vasomotor symptoms (VMS) (Efficacy part) [ Time Frame: Baseline and Week 4 ]

    The weekly frequency of moderate to severe VMS at Baseline and Week 4 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 4.

    Mean change = mean weekly frequency at Week 4 - mean weekly frequency at Baseline


  5. Mean change from Baseline to Week 5 in the weekly frequency of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 5 ]

    The weekly frequency of moderate to severe VMS at Baseline and Week 5 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 5.

    Mean change = mean weekly frequency at Week 5 - mean weekly frequency at Baseline


  6. Mean change from Baseline to Week 6 in the weekly frequency of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 6 ]

    The weekly frequency of moderate to severe VMS at Baseline and Week 6 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 6.

    Mean change = mean weekly frequency at Week 6 - mean weekly frequency at Baseline


  7. Mean change from Baseline to Week 7 in the weekly frequency of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 7 ]

    The weekly frequency of moderate to severe VMS at Baseline and Week 7 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 7.

    Mean change = mean weekly frequency at Week 7 - mean weekly frequency at Baseline


  8. Mean change from Baseline to Week 8 in the weekly frequency of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 8 ]

    The weekly frequency of moderate to severe VMS at Baseline and Week 8 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 8.

    Mean change = mean weekly frequency at Week 8 - mean weekly frequency at Baseline


  9. Mean change from Baseline to Week 9 in the weekly frequency of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 9 ]

    The weekly frequency of moderate to severe VMS at Baseline and Week 9 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 9.

    Mean change = mean weekly frequency at Week 9 - mean weekly frequency at Baseline


  10. Mean change from Baseline to Week 10 in the weekly frequency of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 10 ]

    The weekly frequency of moderate to severe VMS at Baseline and Week 10 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 10.

    Mean change = mean weekly frequency at Week 10 - mean weekly frequency at Baseline


  11. Mean change from Baseline to Week 11 in the weekly frequency of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 11 ]

    The weekly frequency of moderate to severe VMS at Baseline and Week 11 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 11.

    Mean change = mean weekly frequency at Week 11 - mean weekly frequency at Baseline


  12. Mean change from Baseline to Week 12 in the weekly frequency of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]

    The weekly frequency of moderate to severe VMS at Baseline and Week 12 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization for Baseline and at Week 12.

    Mean change = mean weekly frequency at Week 12 - mean weekly frequency at Baseline


  13. Mean change from Baseline to Week 1 in the severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 1 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 1 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 1.

    Baseline and Week 1 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS).

    Mean change = mean severity score at Week 1 - mean severity score at Baseline


  14. Mean change from Baseline to Week 2 in the severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 2 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 2 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 2.

    Baseline and Week 2 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS).

    Mean change = mean severity score at Week 2 - mean severity score at Baseline


  15. Mean change from Baseline to Week 3 in the severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 3 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 3 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 3.

    Baseline and Week 3 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS).

    Mean change = mean severity score at Week 3 - mean severity score at Baseline


  16. Mean change from Baseline to Week 4 in the severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 4 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 4 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 4.

    Baseline and Week 4 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS).

    Mean change = mean severity score at Week 4 - mean severity score at Baseline


  17. Mean change from Baseline to Week 5 in the severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 5 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 5 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 5.

    Baseline and Week 5 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS).

    Mean change = mean severity score at Week 5 - mean severity score at Baseline


  18. Mean change from Baseline to Week 6 in the severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 6 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 6 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 6.

    Baseline and Week 6 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS).

    Mean change = mean severity score at Week 6 - mean severity score at Baseline


  19. Mean change from Baseline to Week 7 in the severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 7 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 7 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 7.

    Baseline and Week 7 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS).

    Mean change = mean severity score at Week 7 - mean severity score at Baseline


  20. Mean change from Baseline to Week 8 in the severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 8 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 8 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 8.

    Baseline and Week 8 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS).

    Mean change = mean severity score at Week 8 - mean severity score at Baseline


  21. Mean change from Baseline to Week 9 in the severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 9 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 9 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 9.

    Baseline and Week 9 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS).

    Mean change = mean severity score at Week 9 - mean severity score at Baseline


  22. Mean change from Baseline to Week 10 in the severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 10 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 10 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 10.

    Baseline and Week 10 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS).

    Mean change = mean severity score at Week 10 - mean severity score at Baseline


  23. Mean change from Baseline to Week 11 in the severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 11 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 11 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 11.

    Baseline and Week 11 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS).

    Mean change = mean severity score at Week 11 - mean severity score at Baseline


  24. Mean change from Baseline to Week 12 in the severity of moderate to severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 12 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of moderate and severe VMS observed at Week 12.

    Baseline and Week 12 severity score = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS).

    Mean change = mean severity score at Week 12 - mean severity score at Baseline


  25. Mean change from Baseline to Week 1 in the severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 1 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 1 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 1.

    Baseline and Week 1 severity score = [(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of mild + moderate + severe VMS).

    Mean change = mean severity score at Week 1 - mean severity score at Baseline


  26. Mean change from Baseline to Week 2 in the severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 2 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 2 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 2.

    Baseline and Week 2 severity score = [(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of mild + moderate + severe VMS).

    Mean change = mean severity score at Week 2 - mean severity score at Baseline


  27. Mean change from Baseline to Week 3 in the severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 3 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 3 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 3.

    Baseline and Week 3 severity score = [(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of mild + moderate + severe VMS).

    Mean change = mean severity score at Week 3 - mean severity score at Baseline


  28. Mean change from Baseline to Week 4 in the severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 4 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 4 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 4.

    Baseline and Week 4 severity score = [(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of mild + moderate + severe VMS).

    Mean change = mean severity score at Week 4 - mean severity score at Baseline


  29. Mean change from Baseline to Week 5 in the severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 5 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 5 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 5.

    Baseline and Week 5 severity score = [(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of mild + moderate + severe VMS).

    Mean change = mean severity score at Week 5 - mean severity score at Baseline


  30. Mean change from Baseline to Week 6 in the severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 6 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 6 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 6.

    Baseline and Week 6 severity score = [(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of mild + moderate + severe VMS).

    Mean change = mean severity score at Week 6 - mean severity score at Baseline


  31. Mean change from Baseline to Week 7 in the severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 7 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 7 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 7.

    Baseline and Week 7 severity score = [(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of mild + moderate + severe VMS).

    Mean change = mean severity score at Week 7 - mean severity score at Baseline


  32. Mean change from Baseline to Week 8 in the severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 8 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 8 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 8.

    Baseline and Week 8 severity score = [(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of mild + moderate + severe VMS).

    Mean change = mean severity score at Week 8 - mean severity score at Baseline


  33. Mean change from Baseline to Week 9 in the severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 9 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 9 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 9.

    Baseline and Week 9 severity score = [(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of mild + moderate + severe VMS).

    Mean change = mean severity score at Week 9 - mean severity score at Baseline


  34. Mean change from Baseline to Week 10 in the severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 10 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 10 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 10.

    Baseline and Week 10 severity score = [(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of mild + moderate + severe VMS).

    Mean change = mean severity score at Week 10 - mean severity score at Baseline


  35. Mean change from Baseline to Week 11 in the severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 11 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 11 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 11.

    Baseline and Week 11 severity score = [(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of mild + moderate + severe VMS).

    Mean change = mean severity score at Week 11 - mean severity score at Baseline


  36. Mean change from Baseline to Week 12 in the severity of mild, moderate and severe vasomotor symptoms (VMS) (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]

    The severity score is derived as follows: mild = 1, moderate = 2, and severe = 3.

    The mean severity score of VMS at Baseline and Week 12 is defined as the arithmetic mean of the daily severity score values of mild, moderate and severe VMS observed from the last 7 days prior randomization for Baseline and of mild, moderate and severe VMS observed at Week 12.

    Baseline and Week 12 severity score = [(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of mild + moderate + severe VMS).

    Mean change = mean severity score at Week 12 - mean severity score at Baseline


  37. Percentage of participants with 50% reduction from Baseline in the weekly frequency of moderate to severe vasomotor symptoms (VMS) at Week 4 (Efficacy Study Part) [ Time Frame: Baseline and Week 4 ]
    The weekly frequency of moderate to severe VMS at Baseline and Week 4 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization (Baseline) and days 22 to 28 (Week 4).

  38. Percentage of participants with 50% reduction from Baseline in the weekly frequency of moderate to severe vasomotor symptoms (VMS) at Week 12 (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]
    The weekly frequency of moderate to severe VMS at Baseline and Week 12 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization (Baseline) and days 78 to 84 (Week 12).

  39. Percentage of participants with 75% reduction from Baseline in the weekly frequency of moderate to severe VMS at Week 4 (Efficacy Study Part) [ Time Frame: Baseline and Week 4 ]
    The weekly frequency of moderate to severe VMS at Baseline and Week 4 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization (Baseline) and days 22 to 28 (Week 4).

  40. Percentage of participants with 75% reduction from Baseline in the weekly frequency of moderate to severe VMS at Week 12 (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]
    The weekly frequency of moderate to severe VMS at Baseline and Week 12 is defined as the total number (sum) of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization (Baseline) and days 78 to 84 (Week 12).

  41. Percentage of participants with a clinically important difference (CID) compared to Baseline in the weekly frequency of moderate to severe VMS at Week 4 using the Clinical Global Impression (CGI) questionnaire (Efficacy Study Part) [ Time Frame: Week 4 ]
    The CGI score is a seven point scale in which subjects will be asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse.

  42. Percentage of participants with a clinically important difference (CID) compared to baseline in the weekly frequency of moderate to severe VMS at Week 12 using the Clinical Global Impression (CGI) questionnaire (Efficacy Study Part) [ Time Frame: Week 12 ]
    The CGI score is a seven point scale in which subjects will be asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse.

  43. Change from Baseline to Week 12 in vulvovaginal atrophy (VVA) symptoms (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]

    Genitourinary syndrome of menopause (GSM) will be assessed by the subjects using the vulvovaginal atrophy (VVA) self assessment questionnaire. The following GSM symptoms will be assessed:

    • Vaginal dryness
    • Vaginal and/or vulvar irritation/itching
    • Dysuria
    • Vaginal pain associated with sexual activity
    • Vaginal bleeding associated with sexual activity

    All GSM symptoms except vaginal bleeding associated with sexual activity will be graded by the participants using the following scale: [0] none, [1] mild, [2] moderate, or [3] severe. Vaginal bleeding associated with sexual activity is documented using 2 categories: [0] absent or [1] present. A negative change from baseline score indicates improvement in symptoms.


  44. Change from Baseline to Week 12 in the vulvovaginal atrophy (VVA) symptom that is initially identified by the participant as being the most bothersome using the VVA questionnaire at baseline (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]

    Genitourinary syndrome of menopause (GSM) will be assessed by the subjects using the vulvovaginal atrophy (VVA) self assessment questionnaire. The following GSM symptoms will be assessed:

    • Vaginal dryness
    • Vaginal and/or vulvar irritation/itching
    • Dysuria
    • Vaginal pain associated with sexual activity
    • Vaginal bleeding associated with sexual activity

    All GSM symptoms except vaginal bleeding associated with sexual activity were graded by the participants using the following scale: [0] none, [1] mild, [2] moderate, or [3] severe. Vaginal bleeding associated with sexual activity was documented using 2 categories: [0] absent or [1] present. A negative change from baseline score indicates improvement in symptoms.

    At baseline the participant will be asked which of the above mentioned symptoms she identifies as being the most bothersome.


  45. Change from Baseline to Week 12 in plasma concentration of triglycerides (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]
  46. Change from Baseline to Week 12 in plasma concentration of low-density lipoprotein (LDL)-cholesterol (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]
  47. Change from Baseline to Week 12 in plasma concentration of total cholesterol (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]
  48. Change from Baseline to Week 12 in the total cholesterol/high density cholesterol (HDL) cholesterol ratio (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]
  49. Change from Baseline to Week 12 in the HDL-cholesterol ratio (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]
  50. Change from Baseline to Week 12 in plasma concentration of lipoprotein (a) (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]
  51. Change from Baseline to Week 12 in fasting glycaemia (Efficacy Study part) [ Time Frame: Baseline and Week 12 ]
  52. Change from Baseline to Week 12 in plasma concentration of insulin (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]
  53. Change from Baseline to Week 12 in plasma concentration of glycated hemoglobin (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]
  54. Change from Baseline to Week 12 in Homeostasis model-assessment-estimated insulin resistance (HOMA-IR) (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]
  55. Change from baseline to Week 12 in health-related quality of life assessment (HRQoL) using the menopause-specific Quality of Life (MENQOL) (Efficacy Study Part) [ Time Frame: Baseline and Week 12 ]
    The MENQOL is self-administered questionnaire which will ssess changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores will be converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Vasomotor domain score is mean of = Q1,Q2, Q3, with 1 being "not at all bothered" and 8 being "extremely bothered".

  56. Total score in treatment satisfaction using the Clinical Global Impression (CGI) questionnaire (Efficacy Study Part) [ Time Frame: Weeks 4 and 12 ]
    The CGI score is a seven point scale in which subjects will be asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse.

  57. Number of participants with treatment-emergent adverse events (TEAEs) (Efficacy Study Part) [ Time Frame: From baseline to Follow-up visit (up to Week 16) ]
    TEAEs are those adverse events occurring from time point of first ingestion of the study until last visit or any event already present that worsens in either intensity or frequency following exposure to the treatment.

  58. Number of participants with changes in physical and gynecological examination results (Efficacy Study Part) [ Time Frame: Baseline and Week 13 ]

    Physical examination will include an examination of general appearance, head, eyes, ears, nose, throat, skin neck, lungs, breast, lymph nodes, abdomen, and the cardiovascular musculoskeletal and neurological systems.

    Gynecological examination will include a manual pelvic examination.


  59. Number of participants with changes in vital sign results (Efficacy Study Part) [ Time Frame: From screening to Week 13 ]
    Vital signs will include height, body weight, body mass index, sitting systolic and diastolic blood pressures, and heart rate.

  60. Number of participants with changes in electrocardiogram (ECG) results (Efficacy Study Part) [ Time Frame: Screening and Week 13 ]
    The ECG interpretation scheme will include the analysis of the morphology, rhythm, conduction, ST segment, PR, QRS, QT and corrected QT (QTc) intervals, T waves, U waves and the presence or absence of any pathological changes.

  61. Number of participants with changes in breast examination results (Efficacy Study Part) [ Time Frame: Screening and Week 13 ]
  62. Number of participants with changes in routine clinical laboratory test results (Efficacy Study Part) [ Time Frame: Screening, Baseline and Week 13 ]
    Routine laboratory tests include hematology and chemistry.

  63. Change from baseline to each measured time point in endometrial thickness (Efficacy Study Part) [ Time Frame: Screening, Baseline, Week 13, Week 16 ]
    Endometrial thickness will be assessed by transvaginal ultrasound (TVUS).

  64. Endometrial biopsy histology at Screening and Week 13 (Efficacy Study Part) [ Time Frame: Screening and Week 13 ]
    Endometrial biopsies will be centrally evaluated by three independent expert pathologists from different institutions, blinded to treatment group and to each other's readings. The concurrence of two of the three pathologists will be accepted as the final diagnosis. If there is no agreement among the three pathologists, the most severe pathologic diagnosis, i.e., atypical hyperplasia >complex hyperplasia >simple hyperplasia >benign endometrium, will be used as the final diagnosis.

  65. Number of participants with vaginal bleeding and/or spotting during each 28-day cycle of treatment with E4 (Efficacy Study Part) [ Time Frame: From Baseline up to Follow-up (Week 16) ]
    Vaginal bleeding will be daily recorded by the participant on the diary. Absence or occurrence of vaginal bleeding/ spotting will be assessed using the scale below: 0 = Absence of vaginal bleeding or spotting; 1 = Spotting: evidence of minimal blood loss requiring none or at most one pad, tampon or panty liner per day; 2 = Bleeding: evidence of blood loss requiring more than one pad, tampon or panty liner per day.

  66. Number of participants with amenorrhea (absence of any bleeding or spotting) during each 28-day cycle of treatment with E4 (Efficacy Study Part) [ Time Frame: From Baseline up to Follow-up (Week 16) ]
    Vaginal bleeding will be daily recorded by the participant on the diary. Absence or occurrence of vaginal bleeding/ spotting will be assessed using the scale below: 0 = Absence of vaginal bleeding or spotting; 1 = Spotting: evidence of minimal blood loss requiring none or at most one pad, tampon or panty liner per day; 2 = Bleeding: evidence of blood loss requiring more than one pad, tampon or panty liner per day.

  67. Number of participants with treatment-emergent adverse events (TEAEs) (Endometrial and General Safety Part) [ Time Frame: From baseline to Week 53 ]
    TEAEs are those adverse events occurring from time point of first ingestion of the study until last visit or any event already present that worsens in either intensity or frequency following exposure to the treatment.

  68. Number of participants with changes in physical and gynecological examination results (Endometrial and General Safety Part) [ Time Frame: Baseline and Week 53 ]

    Physical examination will include an examination of general appearance, head, eyes, ears, nose, throat, skin neck, lungs, breast, lymph nodes, abdomen, and the cardiovascular musculoskeletal and neurological systems.

    Gynecological examination will include a manual pelvic examination.


  69. Number of participants with changes in vital sign results (Endometrial and General Safety Part) [ Time Frame: From screening to Week 53 ]
    Vital signs will include height, body weight, body mass index, sitting systolic and diastolic blood pressures, and heart rate.

  70. Number of participants with changes in breast examination results (Endometrial and General Safety Part) [ Time Frame: From screening to Week 53 ]
    Vital signs will include height, body weight, body mass index, sitting systolic and diastolic blood pressures, and heart rate.

  71. Number of participants with changes in electrocardiogram (ECG) results (Endometrial and General Safety Part) [ Time Frame: Screening and Week 53 ]
    The ECG interpretation scheme will include the analysis of the morphology, rhythm, conduction, ST segment, PR, QRS, QT and corrected QT (QTc) intervals, T waves, U waves and the presence or absence of any pathological changes.

  72. Number of participants with changes in mammography results (Endometrial and General Safety Part) [ Time Frame: Screening and Week 53 ]
  73. Number of participants with changes in routine clinical laboratory test results (Endometrial and General Safety Part) [ Time Frame: Screening, Baseline and Week 13 ]
    Routine laboratory tests include hematology and chemistry.

  74. Number of women with vaginal bleeding and/or spotting during each 28-day cycle of treatment with E4 (Endometrial and General Safety Part) [ Time Frame: From Baseline to Week 53 ]
    Vaginal bleeding will be daily recorded by the participant on the diary. Absence or occurrence of vaginal bleeding/spotting will be assessed using the scale below: 0 = Absence of vaginal bleeding or spotting; 1 = Spotting: evidence of minimal blood loss requiring none or at most one pad, tampon or panty liner per day; 2 = Bleeding: evidence of blood loss requiring more than one pad, tampon or panty liner per day.

  75. Number of participants with amenorrhea (absence of any bleeding or spotting) during each 28-day cycle of treatment with E4 (Endometrial and General Safety Part) [ Time Frame: From Baseline to Week 53 ]
    Vaginal bleeding will be daily recorded by the participant on the diary. Absence or occurrence of vaginal bleeding/spotting will be assessed using the scale below: 0 = Absence of vaginal bleeding or spotting; 1 = Spotting: evidence of minimal blood loss requiring none or at most one pad, tampon or panty liner per day; 2 = Bleeding: evidence of blood loss requiring more than one pad, tampon or panty liner per day.

  76. Change from Baseline to Weeks 12 and 52 in health-related quality of life assessment (HRQoL) using the menopause-specific Quality of Life (MENQOL) (Endometrial and General Safety Part) [ Time Frame: Baseline and Weeks 12 and 52 ]
    The MENQOL is self-administered questionnaire which will assess changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Vasomotor domain score is mean of = Q1,Q2, Q3, with 1 being "not at all bothered" and 8 being "extremely bothered".

  77. Total score in treatment satisfaction assessed after 4, 12 and 52 weeks of treatment using the Clinical Global Impression (CGI) questionnaire (Endometrial and General Safety Part) [ Time Frame: Weeks 4, 12, and 52 ]
    The CGI score is a seven point scale in which subjects will be asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse.

  78. Change from Baseline to Weeks 12 and 52 in plasma concentration of triglycerides (Endometrial and General Safety Part) [ Time Frame: Baseline and Weeks 12 and 52 ]
  79. Change from Baseline to Weeks 12 and 52 in plasma concentration of high-density lipoprotein (HDL)-cholesterol (Endometrial and General Safety Part) [ Time Frame: Baseline and Weeks 12 and 52 ]
  80. Change from Baseline to Weeks 12 and 52 in plasma concentration of low-density lipoprotein (LDL)-cholesterol (Endometrial and General Safety Part) [ Time Frame: Baseline and Weeks 12 and 52 ]
  81. Change from Baseline to Weeks 12 and 52 in plasma concentration of total cholesterol (Endometrial and General Safety Part) [ Time Frame: Baseline and Weeks 12 and 52 ]
  82. Change from Baseline to Weeks 12 and 52 in the total cholesterol/high density cholesterol (HDL) cholesterol ratio (Endometrial and General Safety Part) [ Time Frame: Baseline and Weeks 12 and 52 ]
  83. Change from Baseline to Weeks 12 and 52 in the high density cholesterol (HDL) cholesterol (Endometrial and General Safety Part) [ Time Frame: Baseline and Weeks 12 and 52 ]
  84. Change from Baseline to Weeks 12 and 52 in plasma concentration of lipoprotein (a) (Endometrial and General Safety Part) [ Time Frame: Baseline and Weeks 12 and 52 ]
  85. Change from Baseline to Weeks 12 and 52 in fasting glycaemia (Endometrial and General Safety Part) [ Time Frame: Baseline and Weeks 12 and 52 ]
  86. Change from Baseline to Weeks 12 and 52 in plasma concentration of insulin (Endometrial and General Safety Part) [ Time Frame: Baseline and Weeks 12 and 52 ]
  87. Change from Baseline to Weeks 12 and 52 in plasma concentration of glycated hemoglobin (Endometrial and General Safety Part) [ Time Frame: Baseline and Weeks 12 and 52 ]
  88. Change from Baseline to Weeks 12 and 52 in Homeostasis model-assessment-estimated insulin resistance (HOMA-IR) (Endometrial and General Safety Part) [ Time Frame: Baseline and Weeks 12 and 52 ]


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:   Yes
Criteria

Inclusion Criteria:

  • Signed and dated written informed consent form and any required privacy authorization prior to the initiation of any trial procedure, after the nature of the trial has been explained according to local regulatory requirements;
  • Females, ≥ 40 up to ≤ 65 years of age at randomization;
  • For hysterectomized subjects: documented hysterectomy must have occurred at least 6 weeks prior to the start of screening. Hysterectomy can be total or subtotal (i.e., cervix was not removed).
  • For non-hysterectomized subjects: an evaluable endometrial biopsy taken during screening that reveals no abnormal results, i.e., presence of hyperplasia (simple or complex, with or without atypia), presence of carcinoma, and presence of disordered proliferative findings. The screening biopsy should have sufficient endometrial tissue for diagnosis;
  • Seeking treatment for relief of VMS associated with menopause;

    1. For the Efficacy Study part: at least 7 moderate to severe bothersome VMS per day or at least 50 moderate to severe bothersome VMS per week in the last 7 consecutive days during the Screening period;
    2. For the Endometrial and General Safety Study part: at least 1 moderate to severe VMS per week;
  • Body mass index ≥ 18.0 kg/m^2 to ≤ 38.0 kg/m^2;
  • A mammogram that shows no sign of significant disease performed during screening or within 9 months prior to the start of screening ;
  • Post-menopausal status defined as any of the following:
  • For non-hysterectomized subjects:

    1. at least 12 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) >40 milli-International unit (mIU)/mL (value obtained after washout of estrogen/progestin containing drugs, see exclusion criteria 18 and 20);
    2. or at least 6 months of spontaneous amenorrhea with serum FSH >40 mIU/mL and E2 <20 pg/mL (value obtained after washout of estrogen/progestin containing drugs, see exclusion criteria 18 and 20);
    3. or at least 6 weeks postsurgical bilateral oophorectomy;
  • For hysterectomized subjects:

    1. serum FSH >40 mIU/mL and E2 <20 pg/mL (values obtained after washout of estrogen/progestin containing drug see exclusion criteria 18 and 20);
    2. or at least 6 weeks post-surgical bilateral oophorectomy.

Exclusion Criteria:

  • History of malignancy with the exception of basal cell or squamous cell carcinoma of the skin if diagnosed more than 1 year prior to the Screening visit;
  • Any clinically significant findings found by the Investigator at the breast examination and/or on mammography suspicious of breast malignancy that would require additional clinical testing to rule out breast cancer (however, simple cysts confirmed by ultrasound are allowed);
  • Papanicolaou (PAP) test with atypical squamous cells undetermined significance (ASC-US) or higher (low-grade intraepithelial lesion [LSIL], atypical squamous cells- cannot exclude high-grade intraepithelial lesion [HSIL] [ASC-H], HSIL, dysplastic or malignant cells) in sub-totally hysterectomized and non-hysterectomized subjects . Note: ASC-US is allowed if a reflex human papilloma virus (HPV) testing is performed and is negative for high risk oncogene HPV;
  • For non-hysterectomized subjects:

    1. History or presence of uterine cancer, endometrial hyperplasia, disordered proliferative findings;
    2. Presence of endometrial polyps;
    3. Undiagnosed vaginal bleeding or undiagnosed abnormal uterine bleeding;
    4. Endometrial ablation;
    5. Enlarged uterus with myoma;
  • Systolic blood pressure (BP) higher than 130 mmHg, diastolic BP higher than 80 mmHg during screening;
  • History of venous or arterial thromboembolic disease (e.g., superficial or deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, angina pectoris, etc.), or first degree family history of venous thromboembolism (VTE);
  • History of known acquired or congenital coagulopathy or abnormal coagulation factors, including known thrombophilia's;
  • Diabetes mellitus with poor glycemic control in the last 6 months assessed by laboratory values of fasting glucose outside the normal ranges and glycated hemoglobin above 7%;
  • Dyslipoproteinaemia (LDL >190 mg/dL and triglycerides >300 mg/dL);
  • Smoking:

    • Efficacy Study part: subjects smoking >5 cigarettes per day or >2 packs per week;
    • Endometrial and General Safety Study part: subjects smoking >15 cigarettes per day or >6 packs per week;
  • Presence or history of gallbladder disease, unless cholecystectomy has been performed;
  • Systemic lupus erythematosus;
  • Any malabsorption disorders including gastric by-pass surgery;
  • History of acute liver disease in the preceding 12 months before the start of screening or presence or history of chronic or severe liver disease [alanine transaminase (ALT) or aspartate transaminase (AST) >2x upper limit of normal (ULN), bilirubin >1.5 ULN]; or liver tumors;
  • Chronic or current acute renal impairment (estimated glomerular filtration rate <60 ml/min);
  • Porphyria;
  • Diagnosis or treatment of major psychiatric disorder (e.g., schizophrenia, bipolar disorder, etc.), in the judgement of the Investigator;
  • Use of estrogen/progestin containing drug(s) up to:

    1. 1 week before screening start for vaginal non systemic hormonal products (rings, creams, gels);
    2. 4 weeks before screening start for vaginal or transdermal estrogen or estrogen/progestin products;
    3. 8 weeks before screening start for oral estrogen and/or progestin products and/or selective estrogen receptor modulator therapy;
    4. 8 weeks before screening start for intrauterine progestin therapy;
    5. 3 months before screening start for progestin implants or estrogen alone injectable drug therapy;
    6. 6 months before screening start for estrogen pellet therapy or progestin injectable drug therapy;
  • Use of androgen/dehydroepiandrosterone (DHEA) containing drugs:

    1. 8 weeks before screening start for oral, topical, vaginal or transdermal androgen;
    2. 6 months before screening start for implantable or injectable androgen therapy;
  • Use of phytoestrogens or black cohosh for the treatment of VMS up to 2 weeks before the start of screening;
  • For the women participating in the Efficacy Study part: use of prescription or over-the-counter products used for the treatment of VMS, e.g., anti-depressants: paroxetine, escitalopram, methyldopa, opioid and clonidine up to 4 weeks before the start of screening, and venlafaxine and desvenlafaxine up to 3 months before the start of screening , and not willing to stop these during their participation in the trial;
  • Not willing to stop any hormonal products as described in exclusion criteria 18, 19 and 20, during their participation in the trial;
  • Inadequately treated hyperthyroidism at screening;
  • History or presence of allergy/intolerance to the investigational product or drugs of this class or any component of it, or history of drug or other allergy that, in the opinion of the Investigator contraindicates subject participation;
  • History of alcohol or substance abuse (including marijuana, even if legally allowed) or dependence in the previous 12 months before the start of screening as determined by the Investigator, based on reported observations;
  • Sponsor or contract research organization (CRO) employees or employees under the direct supervision of the Investigator and/or involved directly in the trial;
  • Subjects with known or suspected history of a clinically significant systemic disease, unstable medical disorders, life-threatening disease or current malignancies that would pose a risk to the subject in the opinion of the Investigator;
  • Participation in another investigational drug clinical trial within 1 month (30 days) or having received an investigational drug within the last month (30 days) before the start of screening;
  • Is judged by the Investigator to be unsuitable for any reason.

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): NCT04209543


Contacts
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Contact: Estetra 003243492822 clinical.trials@mithra.com
Contact: Estetra

Locations
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Lithuania
Saules Family Medicine Centre Recruiting
Kaunas, Lithuania, LT-50425
Contact: Audrone Urboniene, Prof       mailto:a.urboniene@ssmc.lt   
Sponsors and Collaborators
Estetra
ICON Clinical Research
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Responsible Party: Estetra
ClinicalTrials.gov Identifier: NCT04209543    
Other Study ID Numbers: MIT-Do001-C301
First Posted: December 24, 2019    Key Record Dates
Last Update Posted: January 28, 2020
Last Verified: December 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Estetra:
Estetrol
Hot Flushes
Vasomotor Symptoms
Additional relevant MeSH terms:
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Progesterone
Progestins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs