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Clinical Trial Results:
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)

Summary
EudraCT number	2019-001289-14
Trial protocol	PL GB SK HU LT CZ ES IT RO
Global end of trial date	08 Feb 2024

Results information
Results version number	v1(current)
This version publication date	23 Feb 2025
First version publication date	23 Feb 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

MIT-Do001-C301

ISRCTN number

US NCT number

NCT04209543

WHO universal trial number (UTN)

Sponsor organisation name

Estetra SRL

Sponsor organisation address

Rue Saint-Georges 5, Liege, Belgium, 4000

Public contact

Clinical Study Leader, Estetra SRL, clinical.trials@estetra.com

Scientific contact

Clinical Study Leader, Estetra SRL, clinical.trials@estetra.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

08 Feb 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 Feb 2024

Was the trial ended prematurely?

Main objective of the trial

Arms 1-3: Efficacy Study Part: measure the effect of treatment with estetrol (E4) 15 mg or E4 20 mg compared with placebo, regarding the frequency and severity of moderate to severe vasomotor symptoms (VMS) in postmenopausal women at 4 and 12 weeks. This part of the study included non-hysterectomized and hysterectomized women. Arm 4: Safety Study Part: assess the effect of treatment with E4 20 mg + Progesterone (P4) 100 mg on the endometrium. This part of the study included non-hysterectomized women only.

Protection of trial subjects

The study was conducted according to the clinical study protocol, according with the principles of the Declaration of Helsinki, and local regulations, as well as according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) notes for guidance on Good Clinical Practice (GCP) (ICH/CPMP/135/95). Adverse events (AEs) and vital signs were recorded at all visits (from screening onward). Based on the medical opinion of the investigator, all new clinically relevant abnormalities or significant changes at the study visits were reported as AEs in the electronic case report form (eCRF). All safety assessments were performed according to accepted methods. All non-hysterectomized subjects received treatment with P4 200 mg once daily for 14 consecutive days after completion of treatment with E4/Placebo. An independent data safety monitoring board (DSMB) was involved in overseeing general and endometrial safety data of the study at regular, pre-defined intervals. The DSMB made recommendations regarding continuation, modification, or termination of the study. The DSMB was supported by a Clinical Event Committee, that was responsible for adjudicating cardiovascular and thrombotic events.

Background therapy

None.

Evidence for comparator

Not applicable. DEFINITIONS USED IN THIS DATA RECORD: ITT (Intent-to-Treat Set): included all randomized subjects who received at least one dose of randomized study drug. Used as the primary analysis population for the efficacy analyses. All analyses on this set were based on randomized treatment. SAF (Safety Analysis Set): included all (randomized*) subjects who received at least one dose of (randomized*) study drug. Used for all analyses of safety, tolerability and background characteristics. All analyses on this set were based on treatment received. (*) Efficacy Study Part only. Endometrial Safety Analysis Set: included all subjects who received at least one dose of study drug and had an evaluable biopsy at Baseline and at Month 12 (defined by a Visit window as on or after Day 326) or had a diagnosis of endometrial hyperplasia prior to Month 12. Evaluable biopsies included all biopsies, except for biopsies with no tissue or insufficient tissue. This analysis set was defined only for the Safety Study Part. ABBREVIATIONS Hx, hysterectomized NH, non-hysterectomized

Actual start date of recruitment

17 Dec 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 168

Country: Number of subjects enrolled

Russian Federation: 47

Country: Number of subjects enrolled

Brazil: 290

Country: Number of subjects enrolled

Argentina: 44

Country: Number of subjects enrolled

Canada: 42

Country: Number of subjects enrolled

Poland: 495

Country: Number of subjects enrolled

Romania: 87

Country: Number of subjects enrolled

Slovakia: 3

Country: Number of subjects enrolled

Spain: 41

Country: Number of subjects enrolled

United Kingdom: 119

Country: Number of subjects enrolled

Czechia: 168

Country: Number of subjects enrolled

Hungary: 14

Country: Number of subjects enrolled

Italy: 21

Country: Number of subjects enrolled

Lithuania: 23

Worldwide total number of subjects

1562

EEA total number of subjects

852

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

1551

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Postmenopausal women aged 40-65 y seeking treatment for the relief of VMS associated with menopause (N=4502) were screened according to study inclusion and exclusion criteria: -Efficacy Study Part: >=7 moderate to severe VMS/day or >=50 moderate to severe VMS/week. -Safety Study Part: non hysterectomized; >=1 moderate to severe VMS/week.

Screening details

Screening visit was generally up to 4 weeks before the first administration of the study drug. Screening was done according to the study inclusion and exclusion criteria. Signed Informed Consent Form was obtained prior to any study-related procedures.

Period 1 title

Treatment (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

Efficacy Study Part (ESP, Arms 1, 2, 3): randomized, double blind; Safety Study Part (SSP, Arm 4): open-label.

Are arms mutually exclusive

Yes

E4 15 mg

Arm description

Efficacy Study Part: randomized, double-blind. Estetrol monohydrate 15 mg (E4 15 mg), equivalent to estetrol 14.2 mg. The study drug was to be taken once a day for up to 13 weeks, at approximately the same time each day.

Arm type

Experimental

Investigational medicinal product name

Estetrol monohydrate

Investigational medicinal product code

Other name

E4 15 mg

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

E4 20 mg

Arm description

Efficacy Study Part: randomized, double-blind. Estetrol monohydrate 20 mg (E4 20 mg), equivalent to estetrol 18.9 mg. The study drug was to be taken once a day for up to 13 weeks, at approximately the same time each day.

Arm type

Experimental

Investigational medicinal product name

Estetrol monohydrate

Investigational medicinal product code

Other name

E4 20 mg

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo

Arm description

Efficacy Study Part: randomized, double-blind. Placebo, film-coated tablet, with no active substance. The study drug was to be taken once a day for up to 13 weeks, at approximately the same time each day.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Efficacy Study Part: randomized, double-blind. Film coated tablet, with no active substance. The study drug was to be taken once a day for up to 13 weeks, at approximately the same time each day.

E4 20 mg + P4 100 mg

Arm description

Safety Study Part: open-label. All subjects received estetrol monohydrate 20 mg (E4 20 mg), equivalent to estetrol 18.9 mg, in combination with Progesterone 100 mg (P4 100 mg) continuously, once a day, for up to 53 weeks.

Arm type

Experimental

Investigational medicinal product name

Progesterone

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Safety Study part: open-label arm. All subjects received E4 20 mg, equivalent to estetrol 18.9 mg, in combination with Progesterone 100 mg (P4 100 mg). The study drugs were to be taken once a day for up to 53 weeks, at approximately the same time each day.

Investigational medicinal product name

Estetrol monohydrate

Investigational medicinal product code

Other name

E4 20 mg

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Safety Study Part: open-label arm. All subjects received E4 20 mg, equivalent to estetrol 18.9 mg, in combination with Progesterone 100 mg (P4 100 mg) continuously for up to 53 weeks. The study drugs were to be taken once a day for up to 53 weeks, at approximately the same time each day.

Number of subjects in period 1	E4 15 mg	E4 20 mg	Placebo	E4 20 mg + P4 100 mg
Started	213	213	214	922
Completed	166	164	174	402
Not completed	47	49	40	520
Consent withdrawn by subject	15	13	9	154
Physician decision	-	-	-	37
Adverse event, non-fatal	11	9	4	220
Other	3	4	5	21
Death - Covid-19	1	-	-	-
Endometrial Biopsy With Proliferative Disorder	5	2	-	-
Adverse events - Serious	-	3	1	18
Covid-19	-	-	3	7
Lost to follow-up	5	4	4	33
Sponsor decision	-	-	2	2
Lack of efficacy	4	3	6	6
Protocol deviation	3	11	6	22

Baseline characteristics

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Reporting group title

E4 15 mg

Reporting group description

Reporting group title

E4 20 mg

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group title

E4 20 mg + P4 100 mg

Reporting group description

Reporting group values	E4 15 mg	E4 20 mg	Placebo	E4 20 mg + P4 100 mg	Total
Number of subjects	213	213	214	922	1562
Age categorical
Units: Subjects
18-64 years	209	213	211	918	1551
65-84 years	4	0	3	4	11
Age continuous
Units: years
arithmetic mean (standard deviation)	53.6 ( 4.47 )	53.8 ( 4.83 )	54.4 ( 5.25 )	53.9 ( 4.76 )	-
Gender categorical
Units: Subjects
Female	213	213	214	922	1562
Male	0	0	0	0	0
Race
Units: Subjects
American Indian or Alaska Native	0	0	0	1	1
Asian	1	3	2	2	8
Black or African American	17	11	12	43	83
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
White	185	194	192	843	1414
Other	10	5	8	33	56
Ethnic Origin
Units: Subjects
Hispanic/Latino	68	61	44	198	371
Not Hispanic/Latino	145	152	170	722	1189
Missing	0	0	0	2	2
Smoking habit
Units: Subjects
Yes	26	20	25	135	206
No	179	187	180	786	1332
Missing	8	6	9	1	24
Hysterectomy status
Units: Subjects
Hysterectomized	110	110	110	0	330
Non Hysterectomized	103	103	104	922	1232
Subject had a Bilateral Oophorectomy
Units: Subjects
Yes	47	53	45	8	153
No	165	160	169	914	1408
Missing	1	0	0	0	1
Frequency of Moderate to Severe VMS
Weekly frequency of moderate to severe vasomotor symptoms (VMS) at baseline is defined as the sum of all recorded moderate to severe VMS experienced between Day -7 and Day -1 of the study. VMS severity rating scale: Mild = sensation of heat without sweating. Moderate = sensation of heat with sweating. Allows continuation of activity. Severe = sensation of heat with sweating. Causes cessation of activity. Number of subjects with data for this characteristic: Hx E4 15 mg N=106 NH E4 15 mg N=103 Hx E4 20 mg N=109 NH E4 20 mg N=103 Hx Placebo N=108 NH Placebo N=104 Arm 4 N=777
Units: Number of Moderate to Severe VMS
arithmetic mean (standard deviation)	78.94 ( 37.580 )	83.81 ( 51.183 )	75.49 ( 34.666 )	29.88 ( 29.545 )	-
Body mass index (BMI)
Units: kg/m^2
arithmetic mean (standard deviation)	27.32 ( 4.319 )	27.42 ( 4.194 )	27.71 ( 4.651 )	26.77 ( 4.183 )	-

End points

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Reporting group title

E4 15 mg

Reporting group description

Reporting group title

E4 20 mg

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group title

E4 20 mg + P4 100 mg

Reporting group description

Subject analysis set title

E4 15 mg Hysterectomized

Subject analysis set type

Safety analysis

Subject analysis set description

E4 15 mg Hysterectomized

Subject analysis set title

E4 15 mg Non-Hysterectomized

Subject analysis set type

Safety analysis

Subject analysis set description

Non-Hysterectomized E4 15 mg

Subject analysis set title

E4 20 mg Hysterectomized

Subject analysis set type

Safety analysis

Subject analysis set description

E4 20 mg Hysterectomized

Subject analysis set title

E4 20 mg Non-Hysterectomized

Subject analysis set type

Safety analysis

Subject analysis set description

E4 20 mg Non-Hysterectomized

Subject analysis set title

Placebo Hysterectomized

Subject analysis set type

Safety analysis

Subject analysis set description

Placebo Hysterectomized

Subject analysis set title

Placebo Non-Hysterectomized

Subject analysis set type

Safety analysis

Subject analysis set description

Placebo Non-Hysterectomized

Primary: 1_Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 4 -- Efficacy Study Part

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End point title

1_Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 4 -- Efficacy Study Part ^[1]

End point description

Efficacy Study Part The weekly frequency of moderate to severe VMS at baseline is defined as the sum of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization. The weekly frequency of moderate to severe VMS at Week 4 is defined as the sum of all recorded moderate to severe VMS experienced during Week 4. (VMS=vasomotor symptoms)

End point type

Primary

End point timeframe

Week 0 (Baseline), Week 4.

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint belongs to the Efficacy Study Part and statistics are presented for all arms of the Efficacy Study Part, i.e., Arms 1-3.

End point values	E4 15 mg	E4 20 mg	Placebo
Number of subjects analysed	193 ^[2]	195 ^[3]	200 ^[4]
Units: number of moderate to severe VMS
arithmetic mean (confidence interval 95%)	-40.65 (-46.44 to -34.86)	-51.75 (-58.46 to -45.04)	-30.42 (-35.23 to -25.60)

Notes
[2] - ITT
[3] - ITT
[4] - ITT

Week 4; E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

393

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.038

Method

Mixed Model for Repeated Measures

Parameter type

Least square mean difference

Point estimate

-9.63

Confidence interval

level

95%

sides

2-sided

lower limit

-18.81

upper limit

-0.45

Week 4; E4 20 mg vs Placebo

Comparison groups

E4 20 mg v Placebo

Number of subjects included in analysis

395

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0004

Method

Mixed Model for Repeated Measures

Parameter type

Least square mean difference

Point estimate

-14.94

Confidence interval

level

95%

sides

2-sided

lower limit

-23.85

upper limit

-6.04

Primary: 2_Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 12 -- Efficacy Study Part

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End point title

2_Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 12 -- Efficacy Study Part ^[5]

End point description

Efficacy Study Part The weekly frequency of moderate to severe VMS at baseline is defined as the sum of all recorded moderate to severe VMS experienced during the last 7 consecutive days prior randomization. The weekly frequency of moderate to severe VMS at Week 12 is defined as the sum of all recorded moderate to severe VMS experienced during Week 12. (VMS=vasomotor symptoms)

End point type

Primary

End point timeframe

Week 0 (Baseline), Week 12.

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint belongs to the Efficacy Study Part and statistics are presented for all arms of the Efficacy Study Part, i.e., Arms 1-3.

End point values	E4 15 mg	E4 20 mg	Placebo
Number of subjects analysed	166 ^[6]	161 ^[7]	167 ^[8]
Units: number of moderate to severe VMS
arithmetic mean (confidence interval 95%)	-55.96 (-62.08 to -49.84)	-70.71 (-79.24 to -62.18)	-42.17 (-48.11 to -36.23)

Notes
[6] - ITT
[7] - ITT
[8] - ITT

Week 12; E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

333

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0003

Method

Mixed Model for Repeated Measures

Parameter type

Least square mean difference

Point estimate

-16.41

Confidence interval

level

95%

sides

2-sided

lower limit

-25.95

upper limit

-6.87

Week 12; E4 20 mg vs Placebo

Comparison groups

E4 20 mg v Placebo

Number of subjects included in analysis

328

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Model for Repeated Measures

Parameter type

Least square mean difference

Point estimate

-22.49

Confidence interval

level

95%

sides

2-sided

lower limit

-31.79

upper limit

-13.19

Primary: 3_Mean change in severity of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 4 -- Efficacy Study Part

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End point title

3_Mean change in severity of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 4 -- Efficacy Study Part ^[9]

End point description

Efficacy Study Part The mean severity score of VMS at Baseline is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS experienced during the last 7 days prior randomization. The mean severity score of VMS at Week 4 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS experienced during Week 4. (VMS=vasomotor symptoms) Daily severity score of VMS = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS), if at least one moderate to severe VMS was recorded during the day. In case of documented absence of moderate to severe VMS during the day, the daily severity was set to zero. Severity score is derived as follows: mild = 1, moderate = 2, severe = 3. Results are shown as change in mean severity score.

End point type

Primary

End point timeframe

Week 0 (Baseline) and Week 4.

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint belongs to the Efficacy Study Part and statistics are presented for all arms of the Efficacy Study Part, i.e., Arms 1-3.

End point values	E4 15 mg	E4 20 mg	Placebo
Number of subjects analysed	193 ^[10]	195 ^[11]	200 ^[12]
Units: severity score
arithmetic mean (confidence interval 95%)	-0.61 (-0.73 to -0.49)	-0.65 (-0.78 to -0.52)	-0.32 (-0.42 to -0.23)

Notes
[10] - ITT
[11] - ITT
[12] - ITT

Week 4; E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

393

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0109

Method

Mixed Model for Repeated Measures

Parameter type

Least square mean difference

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-0.49

upper limit

-0.05

Week 4; E4 20 mg vs Placebo

Comparison groups

E4 20 mg v Placebo

Number of subjects included in analysis

395

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0051

Method

Mixed Model for Repeated Measures

Parameter type

Least square mean difference

Point estimate

-0.29

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

-0.08

Primary: 4_Mean change in severity of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 12 -- Efficacy Study Part

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End point title

4_Mean change in severity of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 12 -- Efficacy Study Part ^[13]

End point description

Efficacy Study Part The mean severity score of VMS at Baseline is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS experienced during the last 7 days prior randomization. The mean severity score of VMS at Week 12 is defined as the arithmetic mean of the daily severity score values of moderate and severe VMS experienced during Week 12. (VMS=vasomotor symptoms) Daily severity score of VMS = [(2 x number of moderate VMS) + (3 x number of severe VMS)]/ (total number of moderate + severe VMS), if at least one moderate to severe VMS was recorded during the day. In case of documented absence of moderate to severe VMS during the day, the daily severity was set to zero. Severity score is derived as follows: mild = 1, moderate = 2, severe = 3. Results are shown as change in mean severity score.

End point type

Primary

End point timeframe

Week 0 (Baseline) and Week 12.

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint belongs to the Efficacy Study Part and statistics are presented for all arms of the Efficacy Study Part, i.e., Arms 1-3.

End point values	E4 15 mg	E4 20 mg	Placebo
Number of subjects analysed	166 ^[14]	161 ^[15]	167 ^[16]
Units: severity score
arithmetic mean (confidence interval 95%)	-1.20 (-1.36 to -1.03)	-1.34 (-1.50 to -1.18)	-0.65 (-0.80 to -0.51)

Notes
[14] - ITT
[15] - ITT
[16] - ITT

Week 12; E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

333

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Model for Repeated Measures

Parameter type

Least square mean difference

Point estimate

-0.54

Confidence interval

level

95%

sides

2-sided

lower limit

-0.77

upper limit

-0.31

Week 12; E4 20 mg vs Placebo

Comparison groups

E4 20 mg v Placebo

Number of subjects included in analysis

328

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed Model for Repeated Measures

Parameter type

Least square mean difference

Point estimate

-0.66

Confidence interval

level

95%

sides

2-sided

lower limit

-0.66

upper limit

-0.43

Primary: 5_Incidence (number) of endometrial hyperplasia with up to 12 months of treatment based on endometrial biopsies -- Safety Study Part

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End point title

5_Incidence (number) of endometrial hyperplasia with up to 12 months of treatment based on endometrial biopsies -- Safety Study Part ^[17] ^[18]

End point description

Safety Study Part A summary of the Final/Consensus diagnosis of endometrial biopsies across all post-baseline visits is provided. An endometrial biopsy was obtained during the Screening period and at the EOT/Early Discontinuation visit. An additional unscheduled biopsy could have been taken if a subject presented with endometrial thickness >10 mm on TVUS, or persistent and/or recurrent bleeding. Biopsies were read by a panel of 3 independent expert pathologists as per regulatory requirements. The Final/Consensus diagnosis was defined as the concurrence of at least 2 diagnoses from the 3 pathologists, and if there was no agreement among at least 2 pathologists, the most severe pathologic diagnosis was used. The WHO classification which separates endometrial diagnoses into 6 categories (benign endometrium, simple hyperplasia, complex hyperplasia, simple atypical hyperplasia, complex atypical hyperplasia, carcinoma) was applied for the assessment of the Final/Consensus diagnosis.

End point type

Primary

End point timeframe

Week 0 (Baseline) and Week 55 (Follow-Up).

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The Safety Study Part is single arm.
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint belongs to the Safety Study Part, which is single arm (Arm 4).

End point values	E4 20 mg + P4 100 mg
Number of subjects analysed	325 ^[19]
Units: subjects
Benign Endometrium	324
Simple Hyperplasia Without Atypia	0
Complex Hyperplasia Without Atypia	1
Simple Hyperplasia With Atypia	0
Complex Hyperplasia With Atypia	0
Carcinoma	0

Notes
[19] - No. of subjects in the Endometrial Safety Analysis Set with an available Final/Consensus Diagnosis

No statistical analyses for this end point

Primary: 6_Incidence (percentage) of endometrial hyperplasia with up to 12 months of treatment based on endometrial biopsies -- Safety Study Part

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End point title

6_Incidence (percentage) of endometrial hyperplasia with up to 12 months of treatment based on endometrial biopsies -- Safety Study Part ^[20] ^[21]

End point description

Safety Study Part Incidence (percentage (95% CI)) of endometrial hyperplasia with up to 12 months of treatment based on endometrial biopsies. The denominator for the computation of percentages and 95% CIs is the number of subjects in the Endometrial Safety Analysis Set with an available Final/Consensus Diagnosis. For details, refer to the description text of the previous endpoint.

End point type

Primary

End point timeframe

Week 0 (Baseline) and Week 55 (Follow-Up).

Notes
[20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The Safety Study Part is single arm.
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint belongs to the Safety Study Part, which is single arm (Arm 4).

End point values	E4 20 mg + P4 100 mg
Number of subjects analysed	325 ^[22]
Units: percentage
number (confidence interval 95%)
Benign Endometrium	99.7 (98.3 to 100.0)
Simple Hyperplasia Without Atypia	0 (0.0 to 1.1)
Complex Hyperplasia Without Atypia	0.3 (0.0 to 1.7)
Simple Hyperplasia With Atypia	0 (0.0 to 1.1)
Complex Hyperplasia With Atypia	0 (0.0 to 1.1)
Carcinoma	0 (0.0 to 1.1)

Notes
[22] - No. of subjects in the Endometrial Safety Analysis Set with an available Final/Consensus Diagnosis

No statistical analyses for this end point

Secondary: 7_Proportion of Subjects with 50% and 75% Reduction in Frequency of VMS from Baseline -- Efficacy Study Part

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End point title

7_Proportion of Subjects with 50% and 75% Reduction in Frequency of VMS from Baseline -- Efficacy Study Part ^[23]

End point description

Efficacy Study Part The percentage of subjects with >=50% and >=75% reduction in frequency of moderate to severe VMS from Baseline is presented for each treatment group.

End point type

Secondary

End point timeframe

Week 0 (Baseline) and Week 12.

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint belongs to the Efficacy Study Part and statistics are presented for all arms of the Efficacy Study Part, i.e., Arms 1-3.

End point values	E4 15 mg	E4 20 mg	Placebo
Number of subjects analysed	166 ^[24]	161 ^[25]	167 ^[26]
Units: percentage of subjects
number (not applicable)
>=50%	82.5	87.0	60.5
>=75%	63.3	74.5	39.5

Notes
[24] - ITT
[25] - ITT
[26] - ITT

1_50% at week 12, E4 15 mg vs placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

333

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

22.1

Confidence interval

level

95%

sides

2-sided

lower limit

12.7

upper limit

31.5

2_50% at week 12, E4 20 mg vs placebo

Comparison groups

E4 20 mg v Placebo

Number of subjects included in analysis

328

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

26.5

Confidence interval

level

95%

sides

2-sided

lower limit

17.4

upper limit

35.5

3_75% at week 12, E4 15 mg vs placebo

Comparison groups

Placebo v E4 15 mg

Number of subjects included in analysis

333

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

23.7

Confidence interval

level

95%

sides

2-sided

lower limit

13.3

upper limit

34.2

4_75% at week 12, E4 20 mg vs placebo

Comparison groups

E4 20 mg v Placebo

Number of subjects included in analysis

328

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: 8_Percentage of subjects with a clinically important difference (CID) compared to Baseline, Week 4 -- Efficacy Study Part

Top of page

End point title

8_Percentage of subjects with a clinically important difference (CID) compared to Baseline, Week 4 -- Efficacy Study Part ^[27]

End point description

Efficacy Study Part Percentage of subjects with a CID compared to Baseline in the weekly frequency of moderate to severe VMS at Week 4 using the Clinical Global Impression (CGI) questionnaire. CGI questionnaire: questionnaire in which subjects were to answer the question “Rate the total improvement, whether or not in your judgement it is due entirely to drug treatment. Compared to your condition at administration to the study, how much has it changed?”. The options were: very much improved, much improved, minimally improved, no change, minimally worse, much worse, and very much worse. CID (=Clinically Important Difference) = much improved + very much improved; MCID (=Minimally Clinically Important Difference) = minimally improved.

End point type

Secondary

End point timeframe

Week 4

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint belongs to the Efficacy Study Part and statistics are presented for all arms of the Efficacy Study Part, i.e., Arms 1-3.

End point values	E4 15 mg	E4 20 mg	Placebo
Number of subjects analysed	189 ^[28]	184 ^[29]	190 ^[30]
Units: percentage of subjects
number (not applicable)
CID	52.9	59.8	27.9
MCID	34.9	28.8	39.5
Worsen/No Change	12.2	11.4	32.6

Notes
[28] - ITT
[29] - ITT
[30] - ITT

1_Week 4, CID, E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

379

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

15.5

upper limit

34.6

2_Week 4, CID, E4 20 mg vs Placebo

Comparison groups

E4 20 mg v Placebo

Number of subjects included in analysis

374

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

31.9

Confidence interval

level

95%

sides

2-sided

lower limit

22.4

upper limit

41.4

3_Week 4, MCID, E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

379

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3592

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

-4.6

Confidence interval

level

95%

sides

2-sided

lower limit

-14.3

upper limit

5.2

4_Week 4, MCID, E4 20 mg vs Placebo

Comparison groups

E4 20 mg v Placebo

Number of subjects included in analysis

374

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0297

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

-10.7

Confidence interval

level

95%

sides

2-sided

lower limit

-20.2

upper limit

-1.1

5_Week 4, Worsen/No change, E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

379

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

-20.5

Confidence interval

level

95%

sides

2-sided

lower limit

-28.6

upper limit

-12.3

6_Week 4, Worsen/No change, E4 20 mg vs Placebo

Comparison groups

E4 20 mg v Placebo

Number of subjects included in analysis

374

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

-21.2

Confidence interval

level

95%

sides

2-sided

lower limit

-29.3

upper limit

-13.1

Secondary: 9_Percentage of subjects with a clinically important difference (CID) compared to baseline, Week 12 -- Efficacy Study Part

Top of page

End point title

9_Percentage of subjects with a clinically important difference (CID) compared to baseline, Week 12 -- Efficacy Study Part ^[31]

End point description

Efficacy Study Part Percentage of subjects with a CID compared to Baseline in the weekly frequency of moderate to severe VMS at Week 12 using the Clinical Global Impression (CGI) questionnaire. CGI questionnaire, CID, MCID: see description above.

End point type

Secondary

End point timeframe

Week 12.

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint belongs to the Efficacy Study Part and statistics are presented for all arms of the Efficacy Study Part, i.e., Arms 1-3.

End point values	E4 15 mg	E4 20 mg	Placebo
Number of subjects analysed	165 ^[32]	158 ^[33]	166 ^[34]
Units: percentage of subjects
number (not applicable)
CID	73.3	77.8	47.0
MCID	20.0	14.6	27.7
Worsen/No Change	6.7	7.6	25.3

Notes
[32] - ITT
[33] - ITT
[34] - ITT

1_Week 12, CID, E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

331

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

26.3

Confidence interval

level

95%

sides

2-sided

lower limit

16.2

upper limit

36.5

2_Week 12, CID, E4 20 mg vs Placebo

Comparison groups

E4 20 mg v Placebo

Number of subjects included in analysis

324

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

30.9

Confidence interval

level

95%

sides

2-sided

lower limit

20.9

upper limit

40.8

3_Week 12, MCID, E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

331

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0999

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

-7.7

Confidence interval

level

95%

sides

2-sided

lower limit

-16.9

upper limit

1.4

4_Week 12, MCID, E4 20 mg vs Placebo

Comparison groups

E4 20 mg v Placebo

Number of subjects included in analysis

324

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0038

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

-13.2

Confidence interval

level

95%

sides

2-sided

lower limit

-21.9

upper limit

-4.4

5_Week 12, Worsen/No change, E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

331

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

-18.6

Confidence interval

level

95%

sides

2-sided

lower limit

-26.3

upper limit

-11

6_Week 12, Worsen/No change, E4 20 mg v Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

331

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

-17.7

Confidence interval

level

95%

sides

2-sided

lower limit

-25.5

upper limit

-9.9

Secondary: 10_Change from Baseline to Week 12 in VVA symptoms (subject self-assessment) using VVA questionnaire -- Efficacy Study Part

Top of page

End point title

10_Change from Baseline to Week 12 in VVA symptoms (subject self-assessment) using VVA questionnaire -- Efficacy Study Part ^[35]

End point description

Efficacy Study Part Change from Baseline to Week 12 in VVA symptoms (subject self-assessment) using VVA questionnaire. Vulvovaginal atrophy (VVA) questionnaire and scoring system: questionnaire about the following symptoms: vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, and vaginal bleeding associated with sexual activity. All symptoms except vaginal bleeding associated with sexual activity were graded by the subject using the following scale: 0 = none, 1 = mild, 2 = moderate, or 3 = severe. Vaginal bleeding associated with sexual activity was documented as [0] absent or [1] present. The proportion of subjects with vaginal bleeding associated with sexual activity was low in the E4 treatment arms and placebo at Baseline so that no reliable conclusions could be drawn. Dyspareunia=Vaginal Pain Associated with Sexual Activity

End point type

Secondary

End point timeframe

Week 0 (Baseline) and Week 12.

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint belongs to the Efficacy Study Part and statistics are presented for all arms of the Efficacy Study Part, i.e., Arms 1-3.

End point values	E4 15 mg	E4 20 mg	Placebo
Number of subjects analysed	163 ^[36]	158 ^[37]	158 ^[38]
Units: score
arithmetic mean (confidence interval 95%)
Vaginal Dryness	-0.8 (-0.9 to -0.6)	-0.6 (-0.7 to -0.4)	-0.4 (-0.5 to -0.2)
Vaginal and/or Vulvar Irritation/Itching	-0.3 (-0.5 to -0.1)	-0.3 (-0.5 to -0.2)	-0.3 (-0.5 to -0.2)
Dysuria	-0.2 (-0.3 to -0.1)	-0.2 (-0.3 to -0.1)	-0.2 (-0.3 to -0.1)
Dyspareunia	-0.7 (-0.9 to -0.5)	-0.4 (-0.6 to -0.3)	-0.3 (-0.5 to -0.2)

Notes
[36] - ITT N=162 for Vaginal and/or Vulvar Irritation/Itching
[37] - ITT N=159 Vaginal and/or Vulvar Irritation/Itching
[38] - ITT N=160 Vaginal and/or Vulvar Irritation/Itching; N=160 Dysuria

1_Week 12, Vaginal Dryness, E4 15 mg vs Placebo

Statistical analysis description

Model-Adjusted Change from Baseline vs. Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

-0.31

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

-0.09

2_Week 12, Vaginal Dryness, E4 20 mg vs Placebo

Statistical analysis description

Model-Adjusted Change from Baseline vs. Placebo

Comparison groups

E4 20 mg v Placebo

Number of subjects included in analysis

316

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1067

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

-0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

0.03

3_Week 12, Vaginal/Vulvar Irr, E4 15 mg vs Placebo

Statistical analysis description

Model-Adjusted Change from Baseline vs. Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6868

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.13

upper limit

0.26

4_Week 12, Vaginal/Vulvar Irr, E4 20 mg vs Placebo

Statistical analysis description

Model-Adjusted Change from Baseline vs. Placebo

Comparison groups

Placebo v E4 20 mg

Number of subjects included in analysis

316

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9757

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.18

upper limit

0.21

5_Week 12, Dysuria, E4 15 mg vs Placebo

Statistical analysis description

Model-Adjusted Change from Baseline vs. Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1983

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.03

upper limit

0.2

6_Week 12, Dysuria, E4 20 mg vs Placebo

Statistical analysis description

Model-Adjusted Change from Baseline vs. Placebo

Comparison groups

E4 20 mg v Placebo

Number of subjects included in analysis

316

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5349

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.07

upper limit

0.16

7_Week 12, Dyspareunia, E4 15 mg vs Placebo

Statistical analysis description

Model-Adjusted Change from Baseline vs. Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0142

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

-0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-0.41

upper limit

-0.04

8_Week 12, Dyspareunia, E4 20 mg vs Placebo

Statistical analysis description

Model-Adjusted Change from Baseline vs. Placebo

Comparison groups

E4 20 mg v Placebo

Number of subjects included in analysis

316

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5313

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.26

upper limit

0.1

Secondary: 11_Change from Baseline to Week 12 in HRQoL using the Menopause-specific Quality of Life (MENQOL) questionnaire -- Efficacy Study Part

Top of page

End point title

11_Change from Baseline to Week 12 in HRQoL using the Menopause-specific Quality of Life (MENQOL) questionnaire -- Efficacy Study Part ^[39]

End point description

Efficacy Study Part Change from Baseline to Week 12 in HRQoL using the MENQOL questionnaire. The MENQOL questionnaire is a 29-item (Q1-Q29) assessment of quality of life designed to capture self-reported information on the presence and bother of symptoms, feelings and experiences in the domains of vasomotor, psychosocial, physical and sexual functioning, among midlife women in the immediate post-menopause period. Lower scores indicate better quality of life. The MENQOL questionnaire administered after study drug administration refers to the symptoms experienced over the past month. (HRQoL=Health-Related Quality of Life; MENQOL=Menopause-specific Quality of Life)

End point type

Secondary

End point timeframe

Week 0 (Baseline) and Week 12.

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint belongs to the Efficacy Study Part and statistics are presented for all arms of the Efficacy Study Part, i.e., Arms 1-3.

End point values	E4 15 mg	E4 20 mg	Placebo
Number of subjects analysed	166 ^[40]	161 ^[41]	169 ^[42]
Units: score
arithmetic mean (confidence interval 95%)
Vasomotor Domain	-3.72 (-4.04 to -3.41)	-3.71 (-4.02 to -3.39)	-2.23 (-2.58 to -1.89)
Psychosocial Domain	-1.79 (-2.07 to -1.52)	-1.87 (-2.15 to -1.59)	-1.32 (-1.57 to -1.07)
Physical Domain	-1.55 (-1.78 to -1.32)	-1.49 (-1.72 to -1.27)	-1.15 (-1.36 to -0.93)
Sexual functioning Domain	-1.81 (-2.13 to -1.49)	-1.91 (-2.26 to -1.56)	-1.01 (-1.29 to -0.73)
Total MENQOL	-2.22 (-2.44 to -2.01)	-2.25 (-2.48 to -2.01)	-1.43 (-1.63 to -1.22)

Notes
[40] - ITT
[41] - ITT N=160 for Vasomotor Domain Score
[42] - ITT

1_Week12, Vasomotor Domain, E4 15 mg vs Placebo

Statistical analysis description

Model-Adjusted Change from Baseline vs. Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

-1.36

Confidence interval

level

95%

sides

2-sided

lower limit

-1.85

upper limit

-0.87

2_Week12, Vasomotor Domain, E4 20 mg vs Placebo

Statistical analysis description

Model-Adjusted Change from Baseline vs. Placebo

Comparison groups

Placebo v E4 20 mg

Number of subjects included in analysis

330

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

-1.26

Confidence interval

level

95%

sides

2-sided

lower limit

-1.75

upper limit

-0.78

3_Week12, Psychosocial Domain, E4 15 mg vs Placebo

Statistical analysis description

Model-Adjusted Change from Baseline vs. Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0024

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

-0.52

Confidence interval

level

95%

sides

2-sided

lower limit

-0.88

upper limit

-0.17

4_Week12, Psychosocial Domain, E4 20 mg vs Placebo

Statistical analysis description

Model-Adjusted Change from Baseline vs. Placebo

Comparison groups

E4 20 mg v Placebo

Number of subjects included in analysis

330

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0003

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

-0.61

Confidence interval

level

95%

sides

2-sided

lower limit

-0.96

upper limit

-0.25

5_Week12, Physical Domain, E4 15 mg vs Placebo

Statistical analysis description

Model-Adjusted Change from Baseline vs. Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0728

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

-0.28

Confidence interval

level

95%

sides

2-sided

lower limit

-0.58

upper limit

0.02

6_Week12, Physical Domain, E4 20 mg vs Placebo

Statistical analysis description

Model-Adjusted Change from Baseline vs. Placebo

Comparison groups

Placebo v E4 20 mg

Number of subjects included in analysis

330

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0479

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

7_Week12, Sexual funct Domain, E4 15 mg vs Placebo

Statistical analysis description

Model-Adjusted Change from Baseline vs. Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0022

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

-0.65

Confidence interval

level

95%

sides

2-sided

lower limit

-1.09

upper limit

-0.21

8_Week12, Sexual funct Domain, E4 20 mg vs Placebo

Statistical analysis description

Model-Adjusted Change from Baseline vs. Placebo

Comparison groups

E4 20 mg v Placebo

Number of subjects included in analysis

330

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0017

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

-0.66

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1

upper limit

-0.22

9_Week12, Total MENQOL, E4 15 mg vs Placebo

Statistical analysis description

Model-Adjusted Change from Baseline vs. Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

-0.71

Confidence interval

level

95%

sides

2-sided

lower limit

-1.01

upper limit

-0.4

10_Week12, Total MENQOL, E4 20 mg vs Placebo

Statistical analysis description

Model-Adjusted Change from Baseline vs. Placebo

Comparison groups

E4 20 mg v Placebo

Number of subjects included in analysis

330

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

-0.72

Confidence interval

level

95%

sides

2-sided

lower limit

-1.02

upper limit

-0.41

Secondary: 12_Number of subjects in the different endometrial categories -- Efficacy Study Part

Top of page

End point title

12_Number of subjects in the different endometrial categories -- Efficacy Study Part ^[43]

End point description

Efficacy Study Part A summary of the Final/Consensus diagnosis of endometrial biopsies across all post-baseline visits is provided. An endometrial biopsy was obtained during the Screening period and at the EOT/Early Discontinuation visit. An additional unscheduled biopsy could have been taken if a subject presented with endometrial thickness >10 mm on TVUS, or persistent and/or recurrent bleeding. Biopsies were read by a panel of 3 independent expert pathologists as per regulatory requirements. The Final/Consensus diagnosis was defined as the concurrence of at least 2 diagnoses from the 3 pathologists, and if there was no agreement among at least 2 pathologists, the most severe pathologic diagnosis was used. The WHO classification which separates endometrial diagnoses into 6 categories (benign endometrium, simple hyperplasia, complex hyperplasia, simple atypical hyperplasia, complex atypical hyperplasia, carcinoma) was applied for the assessment of the Final/Consensus diagnosis.

End point type

Secondary

End point timeframe

Week 0 (Baseline) and Week 15 (Follow-Up).

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Secondary study endpoint; no statistics presented.

End point values	E4 15 mg	E4 20 mg	Placebo
Number of subjects analysed	67 ^[44]	62 ^[45]	56 ^[46]
Units: subjects
Benign Endometrium	65	59	56
Simple Hyperplasia Without Atypia	1	3	0
Complex Hyperplasia Without Atypia	1	0	0
Simple hyperplasia with atypia	0	0	0
Complex hyperplasia with atypia	0	0	0
Carcinoma	0	0	0

Notes
[44] - SAF N=74 with performed post-baseline biopsy N=67 with evaluable post-baseline biopsy
[45] - SAF N=66 with performed post-baseline biopsy N=62 with evaluable post-baseline biopsy
[46] - SAF N=67 with performed post-baseline biopsy N=56 with evaluable post-baseline biopsy

No statistical analyses for this end point

Secondary: 13_Percentage of subjects in the different endometrial categories -- Efficacy Study Part

Top of page

End point title

13_Percentage of subjects in the different endometrial categories -- Efficacy Study Part

End point description

Efficacy Study Part The percentage (95% CI) of subjects in the different endometrial categories is presented. The denominator for the computation of percentages and 95% CIs is the number of subjects with an evaluable post-baseline biopsy in the SAF. For details, refer to the description text of the previous endpoint.

End point type

Secondary

End point timeframe

Week 0 (Baseline) and Week 15 (Follow-Up).

End point values	E4 15 mg Non-Hysterectomized	E4 20 mg Non-Hysterectomized	Placebo Non-Hysterectomized
Number of subjects analysed	67 ^[47]	62 ^[48]	56 ^[49]
Units: percentage
number (confidence interval 95%)
Benign Endometrium	97.0 (89.6 to 99.6)	95.2 (86.5 to 99.0)	100.0 (93.6 to 100.0)
Simple Hyperplasia Without Atypia	1.5 (0.0 to 8.0)	4.8 (1.0 to 13.5)	0 (0.0 to 6.4)
Complex Hyperplasia Without Atypia	1.5 (0.0 to 8.0)	0 (0.0 to 5.8)	0 (0.0 to 6.4)
Simple Hyperplasia With Atypia	0 (0.0 to 5.4)	0 (0.0 to 5.8)	0 (0.0 to 6.4)
Complex Hyperplasia With Atypia	0 (0.0 to 5.4)	0 (0.0 to 5.8)	0 (0.0 to 6.4)
Carcinoma	0 (0.0 to 5.4)	0 (0.0 to 5.8)	0 (0.0 to 6.4)

Notes
[47] - Number of subjects with evaluable post-baseline biopsy in the SAF.
[48] - Number of subjects with evaluable post-baseline biopsy in the SAF.
[49] - Number of subjects with evaluable post-baseline biopsy in the SAF.

No statistical analyses for this end point

Secondary: 14_Frequency of vaginal bleeding and/or spotting by cycle -- Efficacy Study Part

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End point title

14_Frequency of vaginal bleeding and/or spotting by cycle -- Efficacy Study Part ^[50]

End point description

Efficacy Study Part Frequency (percentage) of women with vaginal bleeding and/or spotting during each 28-day cycle of treatment with E4 based on data in the patient diary. The number of non-hysterectomized subjects with available bleeding information in diaries during the cycle is shown for each cycle under the results table.

End point type

Secondary

End point timeframe

Cycle 1 to Cycle 4.

Notes
[50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Secondary study endpoint; no statistics presented.

End point values	E4 15 mg	E4 20 mg	Placebo
Number of subjects analysed	103 ^[51]	103 ^[52]	104 ^[53]
Units: percentage of subjects
number (not applicable)
Cycle 1	10.5	9.4	6.2
Cycle 2	39.6	40.4	1.1
Cycle 3	66.3	67.5	4.5
Cycle 4	34.4	40.8	4.8

Notes
[51] - SAF Cycle 1: N=95 Cycle 2: N=91 Cycle 3: N=83 Cycle 4: N=61
[52] - SAF Cycle 1: N=96 Cycle 2: N=89 Cycle 3: N=83 Cycle 4: N=49
[53] - SAF Cycle 1: N=97 Cycle 2: N=93 Cycle 3: N=88 Cycle 4: N=62

No statistical analyses for this end point

Secondary: 15_Number of days with bleeding and/or spotting during each cycle -- Efficacy Study Part

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End point title

15_Number of days with bleeding and/or spotting during each cycle -- Efficacy Study Part ^[54]

End point description

Efficacy Study Part Number of days with bleeding and/or spotting during each 28-day cycle of treatment based on data in the patient diary. The number of non-hysterectomized subjects with vaginal bleeding and/or spotting is shown for each cycle under the results table.

End point type

Secondary

End point timeframe

Cycle 1 to Cycle 4.

Notes
[54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Secondary study endpoint; no statistics presented.

End point values	E4 15 mg	E4 20 mg	Placebo
Number of subjects analysed	103 ^[55]	103 ^[56]	104 ^[57]
Units: days
arithmetic mean (standard deviation)
Cycle 1	2.7 ( 1.77 )	5.7 ( 7.16 )	4.8 ( 2.71 )
Cycle 2	6.5 ( 5.97 )	7.2 ( 4.94 )	1.0 ( 0.00 )
Cycle 3	9.7 ( 7.09 )	9.4 ( 6.65 )	2.5 ( 1.29 )
Cycle 4	4.0 ( 2.16 )	3.8 ( 2.24 )	1.0 ( 0.00 )

Notes
[55] - SAF Cycle 1: N=10 Cycle 2: N=36 Cycle 3: N=55 Cycle 4: N=21
[56] - SAF Cycle 1: N=9 Cycle 2: N=36 Cycle 3: N=56 Cycle 4: N=20
[57] - SAF Cycle 1: N=6 Cycle 2: N=1 Cycle 3: N=4 Cycle 4: N=3

No statistical analyses for this end point

Secondary: 16_Number of subjects with serious adverse events by Hysterectomy Status (Hysterectomized and Non-Hysterectomized) -- Efficacy Study Part

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End point title

16_Number of subjects with serious adverse events by Hysterectomy Status (Hysterectomized and Non-Hysterectomized) -- Efficacy Study Part

End point description

Efficacy Study Part Number of subjects with serious treatment emergent adverse events belonging to the system organ class (SOC) Reproductive system and breast disorders by hysterectomy status (hysterectomized and non-hysterectomized).

End point type

Secondary

End point timeframe

From Day 1 (first IMP intake) until Week 13 (hysterectomized subjects) or Week 15/16 (non-hysterectomized subjects).

End point values	E4 15 mg Hysterectomized	E4 15 mg Non-Hysterectomized	E4 20 mg Hysterectomized	E4 20 mg Non-Hysterectomized	Placebo Hysterectomized	Placebo Non-Hysterectomized
Number of subjects analysed	110 ^[58]	103 ^[59]	110 ^[60]	103 ^[61]	110 ^[62]	104 ^[63]
Units: N subjects with SAE
Reproductive System and Breast Disorders	0	5	0	8	0	1
Endometrial disorder	0	3	0	4	0	0
Endometrial hyperplasia	0	2	0	3	0	0
Endometrial metaplasia	0	0	0	1	0	0
Hydrosalpinx	0	0	0	0	0	1
Uterine polyp	0	0	0	1	0	0
Vaginal haemorrhage	0	0	0	1	0	0

Notes
[58] - SAF
[59] - SAF For non-hysterectomized, all SAEs of SOC Reproductive system and breast disorders were related.
[60] - SAF
[61] - SAF For non-hysterectomized, all SAEs of SOC Reproductive system and breast disorders were related.
[62] - SAF
[63] - SAF For non-hysterectomized, all SAEs of SOC Reproductive system and breast disorders were related.

No statistical analyses for this end point

Secondary: 17_Number of non-hysterectomized subjects with non-serious adverse events -- Efficacy Study Part

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End point title

17_Number of non-hysterectomized subjects with non-serious adverse events -- Efficacy Study Part

End point description

Efficacy Study Part Number of non-hysterectomized subjects with non-serious treatment emergent adverse events belonging to the system organ class (SOC) Reproductive system and breast disorders. Frequency threshold for reporting non-serious adverse events: 2%.

End point type

Secondary

End point timeframe

From Day 1 (first IMP intake) until Week 15/16.

End point values	E4 15 mg Non-Hysterectomized	E4 20 mg Non-Hysterectomized	Placebo Non-Hysterectomized
Number of subjects analysed	103 ^[64]	103 ^[65]	104 ^[66]
Units: N subjects with non-serious AEs
Reproductive System and Breast Disorders	78	84	24
Vaginal haemorrhage	54	62	14
Endometrial disorder	43	38	4
Endometrial thickening	10	13	0
Breast pain	8	9	2
Breast tenderness	6	4	0
Vaginal discharge	6	5	1
Pelvic pain	1	7	0
Uterine haemorrhage	3	2	0
Breast discomfort	1	3	2
Nipple pain	3	3	0

Notes
[64] - SAF
[65] - SAF
[66] - SAF

No statistical analyses for this end point

Secondary: 18_Number of hysterectomized subjects with non-serious adverse events -- Efficacy Study Part

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End point title

18_Number of hysterectomized subjects with non-serious adverse events -- Efficacy Study Part

End point description

Efficacy Study Part Number of hysterectomized subjects with non-serious treatment emergent adverse events belonging to the system organ class (SOC) Reproductive system and breast disorders. Frequency threshold for reporting non-serious adverse events: 2%.

End point type

Secondary

End point timeframe

From Day 1 (first IMP intake) until Week 13.

End point values	E4 15 mg Hysterectomized	E4 20 mg Hysterectomized	Placebo Hysterectomized
Number of subjects analysed	110 ^[67]	110 ^[68]	110 ^[69]
Units: N subjects with non-serious AEs
Reproductive System and Breast Disorders	20	28	4
Breast pain	10	14	0
Nipple pain	3	6	1
Breast tenderness	3	8	0
Breast discomfort	1	4	0
Vaginal discharge	3	1	0
Vulvovaginal pruritus	3	1	0

Notes
[67] - SAF
[68] - SAF
[69] - SAF

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From Day 1 (first IMP intake) until: Week 13 for Efficacy Study Part: Hysterectomized participants Week 15/16 for Efficacy Study Part: Non Hysterectomized participants Week 55/56 for Safety Study Part: All participants

Adverse event reporting additional description

Treatment-emergent AEs (TEAEs): AEs occurring from time of first IMP intake until last visit or any event already present that worsens (either intensity or frequency) after exposure to the treatment. MedDRA dictionary: version 24.1 for groups E4 15 mg, E4 20 mg, Placebo; version 25.0. for group E4 20 mg + P4 100 mg.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

ESP - E4 15 mg

Reporting group description

Reporting group title

ESP - E4 20 mg

Reporting group description

Reporting group title

ESP - Placebo

Reporting group description

Reporting group title

SSP - E4 20 mg + P4 100 mg

Reporting group description

Serious adverse events	ESP - E4 15 mg	ESP - E4 20 mg	ESP - Placebo	SSP - E4 20 mg + P4 100 mg
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 213 (2.82%)	13 / 213 (6.10%)	1 / 214 (0.47%)	32 / 922 (3.47%)
number of deaths (all causes)	1	0	0	0
number of deaths resulting from adverse events	1	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	1 / 922 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Lower limb fracture
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	2 / 922 (0.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	1 / 922 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	1 / 922 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	1 / 922 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	1 / 922 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine perforation
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	1 / 922 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Superficial vein thrombosis
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	1 / 922 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	1 / 922 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar radiculopathy
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	1 / 922 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Migraine
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	1 / 922 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	1 / 922 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transverse sinus thrombosis
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	1 / 922 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Essential tremor
subjects affected / exposed	0 / 213 (0.00%)	1 / 213 (0.47%)	0 / 214 (0.00%)	0 / 922 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest discomfort
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	1 / 922 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Retinal detachment
subjects affected / exposed	0 / 213 (0.00%)	1 / 213 (0.47%)	0 / 214 (0.00%)	0 / 922 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Endometrial disorder
subjects affected / exposed	3 / 213 (1.41%)	4 / 213 (1.88%)	0 / 214 (0.00%)	7 / 922 (0.76%)
occurrences causally related to treatment / all	3 / 3	4 / 4	0 / 0	7 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal haemorrhage
subjects affected / exposed	0 / 213 (0.00%)	1 / 213 (0.47%)	0 / 214 (0.00%)	5 / 922 (0.54%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectocele
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	1 / 922 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine haemorrhage
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	1 / 922 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endometrial hyperplasia
subjects affected / exposed	2 / 213 (0.94%)	3 / 213 (1.41%)	0 / 214 (0.00%)	0 / 922 (0.00%)
occurrences causally related to treatment / all	2 / 2	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endometrial metaplasia
subjects affected / exposed	0 / 213 (0.00%)	1 / 213 (0.47%)	0 / 214 (0.00%)	0 / 922 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hydrosalpinx
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	1 / 214 (0.47%)	0 / 922 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine polyp
subjects affected / exposed	0 / 213 (0.00%)	1 / 213 (0.47%)	0 / 214 (0.00%)	0 / 922 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Intestinal perforation
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	1 / 922 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal polyp
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	1 / 922 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 213 (0.00%)	0 / 213 (0.00%)	0 / 214 (0.00%)	1 / 922 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	1 / 213 (0.47%)	0 / 213 (0.00%)	0 / 214 (0.00%)	0 / 922 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	0 / 213 (0.00%)	1 / 213 (0.47%)	0 / 214 (0.00%)	0 / 922 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
COVID-19
subjects affected / exposed	1 / 213 (0.47%)	1 / 213 (0.47%)	0 / 214 (0.00%)	4 / 922 (0.43%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Cholecystitis infective
subjects affected / exposed	0 / 213 (0.00%)	1 / 213 (0.47%)	0 / 214 (0.00%)	0 / 922 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 213 (0.00%)	1 / 213 (0.47%)	0 / 214 (0.00%)	0 / 922 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypocalcaemia
subjects affected / exposed	0 / 213 (0.00%)	1 / 213 (0.47%)	0 / 214 (0.00%)	0 / 922 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	ESP - E4 15 mg	ESP - E4 20 mg	ESP - Placebo	SSP - E4 20 mg + P4 100 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	116 / 213 (54.46%)	123 / 213 (57.75%)	44 / 214 (20.56%)	775 / 922 (84.06%)
Investigations
Weight increased
subjects affected / exposed	6 / 213 (2.82%)	1 / 213 (0.47%)	1 / 214 (0.47%)	11 / 922 (1.19%)
occurrences all number	6	1	1	11
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma
subjects affected / exposed	1 / 213 (0.47%)	0 / 213 (0.00%)	0 / 214 (0.00%)	28 / 922 (3.04%)
occurrences all number	1	0	0	29
Vascular disorders
Hypertension
subjects affected / exposed	5 / 213 (2.35%)	2 / 213 (0.94%)	2 / 214 (0.93%)	6 / 922 (0.65%)
occurrences all number	5	2	2	6
Nervous system disorders
Headache
subjects affected / exposed	25 / 213 (11.74%)	18 / 213 (8.45%)	24 / 214 (11.21%)	88 / 922 (9.54%)
occurrences all number	39	22	49	133
Dizziness
subjects affected / exposed	3 / 213 (1.41%)	7 / 213 (3.29%)	2 / 214 (0.93%)	14 / 922 (1.52%)
occurrences all number	3	7	3	14
General disorders and administration site conditions
Fatigue
subjects affected / exposed	4 / 213 (1.88%)	6 / 213 (2.82%)	0 / 214 (0.00%)	8 / 922 (0.87%)
occurrences all number	4	6	0	8
Reproductive system and breast disorders
Vaginal haemorrhage
subjects affected / exposed	55 / 213 (25.82%)	63 / 213 (29.58%)	14 / 214 (6.54%)	616 / 922 (66.81%)
occurrences all number	110	155	22	2382
Endometrial disorder
subjects affected / exposed	43 / 213 (20.19%)	38 / 213 (17.84%)	4 / 214 (1.87%)	145 / 922 (15.73%)
occurrences all number	43	38	4	147
Breast pain
subjects affected / exposed	18 / 213 (8.45%)	23 / 213 (10.80%)	2 / 214 (0.93%)	89 / 922 (9.65%)
occurrences all number	20	23	2	95
Breast tenderness
subjects affected / exposed	9 / 213 (4.23%)	12 / 213 (5.63%)	0 / 214 (0.00%)	64 / 922 (6.94%)
occurrences all number	9	15	0	67
Endometrial thickening
subjects affected / exposed	10 / 213 (4.69%)	13 / 213 (6.10%)	0 / 214 (0.00%)	55 / 922 (5.97%)
occurrences all number	10	13	0	55
Nipple pain
subjects affected / exposed	6 / 213 (2.82%)	9 / 213 (4.23%)	1 / 214 (0.47%)	24 / 922 (2.60%)
occurrences all number	6	11	2	25
Vaginal discharge
subjects affected / exposed	9 / 213 (4.23%)	6 / 213 (2.82%)	1 / 214 (0.47%)	17 / 922 (1.84%)
occurrences all number	9	7	1	21
Breast discomfort
subjects affected / exposed	2 / 213 (0.94%)	7 / 213 (3.29%)	2 / 214 (0.93%)	23 / 922 (2.49%)
occurrences all number	2	7	2	24
Pelvic pain
subjects affected / exposed	1 / 213 (0.47%)	7 / 213 (3.29%)	2 / 214 (0.93%)	10 / 922 (1.08%)
occurrences all number	1	9	2	12
Vulvovaginal pruritus
subjects affected / exposed	5 / 213 (2.35%)	3 / 213 (1.41%)	1 / 214 (0.47%)	8 / 922 (0.87%)
occurrences all number	5	3	1	8
Gastrointestinal disorders
Nausea
subjects affected / exposed	5 / 213 (2.35%)	9 / 213 (4.23%)	3 / 214 (1.40%)	18 / 922 (1.95%)
occurrences all number	8	9	3	19
Abdominal pain
subjects affected / exposed	5 / 213 (2.35%)	6 / 213 (2.82%)	7 / 214 (3.27%)	37 / 922 (4.01%)
occurrences all number	5	6	7	48
Abdominal pain lower
subjects affected / exposed	6 / 213 (2.82%)	7 / 213 (3.29%)	2 / 214 (0.93%)	48 / 922 (5.21%)
occurrences all number	6	10	2	58
Abdominal pain upper
subjects affected / exposed	2 / 213 (0.94%)	0 / 213 (0.00%)	2 / 214 (0.93%)	20 / 922 (2.17%)
occurrences all number	2	0	2	20
Psychiatric disorders
Insomnia
subjects affected / exposed	1 / 213 (0.47%)	6 / 213 (2.82%)	5 / 214 (2.34%)	11 / 922 (1.19%)
occurrences all number	1	6	7	11
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	2 / 213 (0.94%)	7 / 213 (3.29%)	4 / 214 (1.87%)	14 / 922 (1.52%)
occurrences all number	2	8	4	16
Back pain
subjects affected / exposed	4 / 213 (1.88%)	3 / 213 (1.41%)	2 / 214 (0.93%)	23 / 922 (2.49%)
occurrences all number	4	4	3	27
Infections and infestations
COVID-19
subjects affected / exposed	9 / 213 (4.23%)	9 / 213 (4.23%)	6 / 214 (2.80%)	57 / 922 (6.18%)
occurrences all number	9	9	6	58
Upper respiratory tract infection
subjects affected / exposed	1 / 213 (0.47%)	0 / 213 (0.00%)	2 / 214 (0.93%)	19 / 922 (2.06%)
occurrences all number	2	0	2	20

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Were there any global substantial amendments to the protocol? Yes

28 Nov 2019

Amendment 1, leading to version 2.0 of the protocol, date November 28, 2019 Inclusion criterion was added for non hysterectomized subjects regarding uterus with bi-layer endometrial thickness ≤ 4 mm on TVUS. Exclusion criterion regarding diabetes mellitus was changed from "fasting glucose outside the normal ranges and glycated hemoglobin above 7%" To "fasting glucose outside the normal ranges and/or glycated hemoglobin above 7%". Exclusion criterion regarding dyslipoproteinemia was changed from "(LDL >190 mg/dL and triglycerides >300 mg/dL)" to "(LDL >190 mg/dL and/or triglycerides >300 mg/dL)". Exclusion criterion regarding smoking was changed from 5 cigarettes per day to 15 cigarettes per day. The number of packs per week has been deleted. Exclusion criterion was changed from "Inadequately treated hyperthyroidism at screening" to "Inadequately treated hyperthyroidism with abnormal TSH and free T4 at screening. Subjects with low TSH are allowed if free T4 at screening is within normal range."

24 Feb 2020

Amendment 2, leading to version 3.0 of the protocol, date February 24, 2020 Exclusion criterion updated to cover not only "enlarged uterus with myoma" but also "any uterine/endometrial abnormality which in the judgment of the investigator contraindicates the use of estrogen and/or progestin therapy". Exclusion criterion changed for clarification: "Diabetes mellitus with poor glycemic control in the last 6 months assessed by fasting glucose outside the normal ranges and glycated hemoglobin above 7%" was replaced with "Laboratory values of fasting glucose above 125 mg/dL (>6.94 mmol/L) and/or glycated hemoglobin above 7%".

09 Jul 2020

Amendment 3, leading to version 4.0 of the protocol, date July 09, 2020 Inclusion criterion regarding mammography and BI-RADS 0 was adjusted to clarify that a BI-RADS 0 may be acceptable if further assessment is done confirming non clinical significant changes. Addition of a section about Adverse Events of Special Interest (AESIs) to the protocol.

05 Aug 2021

Amendment 4.1, leading to version 5.1 of the protocol, date August 05, 2021 Disordered proliferative endometrium (DPE) removed from the reasons for study discontinuation and exclusion criteria, to align with regulatory approach and based on the available safety information. Extended the maximum screening period; increased the planned number of subjects to be enrolled in Arm 4 based on the available safety information; added information regarding COVID-19 vaccination during the trial, including a recommendation on the timing of vaccination in relation to study assessments. Updated the definition for the hierarchy of the pathologic diagnoses of endometrial tissue. Defined the process for resolution of endometrial events. Increased the number of pathologists who assessed endometrial biopsies and clarified pathologists' roles. Clarified secondary efficacy endpoints regarding frequency and severity of vasomotor symptoms (VMS); added information regarding restart patients on study treatment after study drug interruption. Specified that exclusion criterion about high risk oncogene human papilloma virus (HPV) included subtypes 16 and 18. Endometrial and General Safety Study part: Safety endpoints for endometrial safety were adjusted. Added information text that P4 200 mg may be administered after treatment discontinuation due to vaginal bleeding or endometrial event if deemed necessary by the Investigator.

27 Apr 2022

Amendment 5, leading to version 6.0 of the protocol, date April 27, 2022 Following interaction with FDA regarding the study, disordered proliferative endometrium was reincluded as an exclusion criterion and as a reason for discontinuation.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None.

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Clinical trials

Clinical Trial Results: 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)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 1_Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 4 -- Efficacy Study Part

Primary: 1_Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 4 -- Efficacy Study Part

Primary: 2_Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 12 -- Efficacy Study Part

Primary: 2_Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 12 -- Efficacy Study Part

Primary: 3_Mean change in severity of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 4 -- Efficacy Study Part

Primary: 3_Mean change in severity of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 4 -- Efficacy Study Part

Primary: 4_Mean change in severity of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 12 -- Efficacy Study Part

Primary: 4_Mean change in severity of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 12 -- Efficacy Study Part

Primary: 5_Incidence (number) of endometrial hyperplasia with up to 12 months of treatment based on endometrial biopsies -- Safety Study Part

Primary: 5_Incidence (number) of endometrial hyperplasia with up to 12 months of treatment based on endometrial biopsies -- Safety Study Part

Primary: 6_Incidence (percentage) of endometrial hyperplasia with up to 12 months of treatment based on endometrial biopsies -- Safety Study Part

Primary: 6_Incidence (percentage) of endometrial hyperplasia with up to 12 months of treatment based on endometrial biopsies -- Safety Study Part

Secondary: 7_Proportion of Subjects with 50% and 75% Reduction in Frequency of VMS from Baseline -- Efficacy Study Part

Secondary: 7_Proportion of Subjects with 50% and 75% Reduction in Frequency of VMS from Baseline -- Efficacy Study Part

Secondary: 8_Percentage of subjects with a clinically important difference (CID) compared to Baseline, Week 4 -- Efficacy Study Part

Secondary: 8_Percentage of subjects with a clinically important difference (CID) compared to Baseline, Week 4 -- Efficacy Study Part

Secondary: 9_Percentage of subjects with a clinically important difference (CID) compared to baseline, Week 12 -- Efficacy Study Part

Secondary: 9_Percentage of subjects with a clinically important difference (CID) compared to baseline, Week 12 -- Efficacy Study Part

Secondary: 10_Change from Baseline to Week 12 in VVA symptoms (subject self-assessment) using VVA questionnaire -- Efficacy Study Part

Secondary: 10_Change from Baseline to Week 12 in VVA symptoms (subject self-assessment) using VVA questionnaire -- Efficacy Study Part

Secondary: 11_Change from Baseline to Week 12 in HRQoL using the Menopause-specific Quality of Life (MENQOL) questionnaire -- Efficacy Study Part

Secondary: 11_Change from Baseline to Week 12 in HRQoL using the Menopause-specific Quality of Life (MENQOL) questionnaire -- Efficacy Study Part

Secondary: 12_Number of subjects in the different endometrial categories -- Efficacy Study Part

Secondary: 12_Number of subjects in the different endometrial categories -- Efficacy Study Part

Secondary: 13_Percentage of subjects in the different endometrial categories -- Efficacy Study Part

Secondary: 13_Percentage of subjects in the different endometrial categories -- Efficacy Study Part

Secondary: 14_Frequency of vaginal bleeding and/or spotting by cycle -- Efficacy Study Part

Secondary: 14_Frequency of vaginal bleeding and/or spotting by cycle -- Efficacy Study Part

Secondary: 15_Number of days with bleeding and/or spotting during each cycle -- Efficacy Study Part

Secondary: 15_Number of days with bleeding and/or spotting during each cycle -- Efficacy Study Part

Secondary: 16_Number of subjects with serious adverse events by Hysterectomy Status (Hysterectomized and Non-Hysterectomized) -- Efficacy Study Part

Secondary: 16_Number of subjects with serious adverse events by Hysterectomy Status (Hysterectomized and Non-Hysterectomized) -- Efficacy Study Part

Secondary: 17_Number of non-hysterectomized subjects with non-serious adverse events -- Efficacy Study Part

Secondary: 17_Number of non-hysterectomized subjects with non-serious adverse events -- Efficacy Study Part

Secondary: 18_Number of hysterectomized subjects with non-serious adverse events -- Efficacy Study Part

Secondary: 18_Number of hysterectomized subjects with non-serious adverse events -- Efficacy Study Part

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
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)