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Clinical Trial Results:
A Multicentre Dose-Finding, Randomised, Double-Blind, Placebo-Controlled Study to Select the Daily Oral Dose of Estetrol (E4) for the Treatment of Vasomotor Symptoms in Post-Menopausal Women

Summary
EudraCT number	2015-004018-44
Trial protocol	BE NL PL GB CZ IE
Global end of trial date	22 Jan 2018

Results information
Results version number	v1(current)
This version publication date	07 Nov 2019
First version publication date	07 Nov 2019
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-Do0001-C201

ISRCTN number

US NCT number

NCT02834312

WHO universal trial number (UTN)

Sponsor organisation name

Mithra Pharmaceuticals SA

Sponsor organisation address

Rue Saint-Georges 5-7, Liege, Belgium, 4000

Public contact

Mithra Pharmaceuticals SA Pharma Department, Mithra Pharmaceuticals SA, +32 43492822, clinicaltrials@mithra.com

Scientific contact

Mithra Pharmaceuticals SA Pharma Department, Mithra Pharmaceuticals SA, +32 43492822, clinicaltrials@mithra.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

22 Jan 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

22 Jan 2018

Global end of trial reached?

Yes

Global end of trial date

22 Jan 2018

Was the trial ended prematurely?

Main objective of the trial

To define the minimum effective dose (MED) of the oral dose of estetrol (E4) by evaluating changes in frequency and in severity of moderate to severe vasomotor symptoms (VMS).

Protection of trial subjects

The study was conducted in accordance with the ethical principles set out in the Declaration of Helsinki, Good Clinical Practice (GCP) as defined in the International Council for Harmonisation (ICH), and all applicable national laws and regulations including but not limited to country-specific GCP.

Background therapy

Evidence for comparator

Actual start date of recruitment

29 Feb 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 28

Country: Number of subjects enrolled

Czech Republic: 45

Country: Number of subjects enrolled

United Kingdom: 18

Country: Number of subjects enrolled

Ireland: 1

Country: Number of subjects enrolled

Poland: 168

Worldwide total number of subjects

260

EEA total number of subjects

260

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)

260

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 609 participants were screened, with 349 resulting in screen failures. A total of 260 participants were enrolled across 35 sites in 5 European countries, with 257 participants receiving at least one dose of study drug. Each participant was randomly allocated to one of 5 treatment groups in a 1:1:1:1:1 ratio.

Period 1 title

Overall Study (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

Are arms mutually exclusive

Yes

E4 2.5 mg

Arm description

Estetrol (E4) 2.5 mg was administered orally via a capsule, once daily.

Arm type

Experimental

Investigational medicinal product name

Estetrol

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Participants received 2.5, 5, 10 or 15 mg of estetrol (E4) capsule orally, once daily for 12 consecutive weeks.

E4 5 mg

Arm description

Estetrol (E4) 5 mg was administered orally via a capsule, once daily.

Arm type

Experimental

Investigational medicinal product name

Estetrol

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Participants received 2.5, 5, 10 or 15 mg of estetrol (E4) capsule orally, once daily for 12 consecutive weeks.

E4 10 mg

Arm description

Estetrol (E4) 10 mg was administered orally via a capsule, once daily.

Arm type

Experimental

Investigational medicinal product name

Estetrol

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Participants received 2.5, 5, 10 or 15 mg of estetrol (E4) capsule orally, once daily for 12 consecutive weeks.

E4 15 mg

Arm description

Estetrol (E4) 15 mg was administered orally via a capsule, once daily.

Arm type

Experimental

Investigational medicinal product name

Estetrol

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Participants received 2.5, 5, 10 or 15 mg of estetrol (E4) capsule orally, once daily for 12 consecutive weeks.

Placebo

Arm description

Matching placebo was administered orally via a capsule, once daily.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Matching placebo capsule, administered orally once daily for 12 consecutive weeks.

Number of subjects in period 1 ^[1]	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Started	52	47	54	49	55
Completed	43	36	39	41	41
Not completed	9	11	15	8	14
Consent withdrawn by subject	4	4	6	3	7
Adverse event, non-fatal	-	2	3	1	1
Deterioration of clinical condition	-	-	1	-	-
Miscellaneous	1	1	3	2	3
Protocol deviation	4	4	2	2	3

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 260 participants were randomized to treatment groups, but 3 participants did not receive study drug. Only participants who received study drug are included in the baseline period.

Baseline characteristics

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Reporting group title

E4 2.5 mg

Reporting group description

Estetrol (E4) 2.5 mg was administered orally via a capsule, once daily.

Reporting group title

E4 5 mg

Reporting group description

Estetrol (E4) 5 mg was administered orally via a capsule, once daily.

Reporting group title

E4 10 mg

Reporting group description

Estetrol (E4) 10 mg was administered orally via a capsule, once daily.

Reporting group title

E4 15 mg

Reporting group description

Estetrol (E4) 15 mg was administered orally via a capsule, once daily.

Reporting group title

Placebo

Reporting group description

Matching placebo was administered orally via a capsule, once daily.

Reporting group values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo	Total
Number of subjects	52	47	54	49	55	257
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0
Adults (18-64 years)	52	47	54	49	55	257
From 65-84 years	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	54.0 ( 4.42 )	53.8 ( 4.75 )	54.3 ( 4.44 )	55.2 ( 4.03 )	53.7 ( 4.41 )	-
Gender categorical
Units: Subjects
Female	52	47	54	49	55	257
Male	0	0	0	0	0	0
Race
Units: Subjects
White	52	47	54	49	55	257
Smoker
Units: Subjects
No	46	43	43	47	47	226
Yes	6	4	11	2	8	31

End points

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Reporting group title

E4 2.5 mg

Reporting group description

Estetrol (E4) 2.5 mg was administered orally via a capsule, once daily.

Reporting group title

E4 5 mg

Reporting group description

Estetrol (E4) 5 mg was administered orally via a capsule, once daily.

Reporting group title

E4 10 mg

Reporting group description

Estetrol (E4) 10 mg was administered orally via a capsule, once daily.

Reporting group title

E4 15 mg

Reporting group description

Estetrol (E4) 15 mg was administered orally via a capsule, once daily.

Reporting group title

Placebo

Reporting group description

Matching placebo was administered orally via a capsule, once daily.

Primary: Change in Weekly Frequency of Moderate to Severe Vasomotor Symptoms (VMS) from Baseline to Week 4

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End point title

Change in Weekly Frequency of Moderate to Severe Vasomotor Symptoms (VMS) from Baseline to Week 4

End point description

The severity scoring system of VMS was documented by the participants in the participant's diary using the following scores: None (0) = no VMS symptoms Mild (1) = Sensation of heat without sweating Moderate (2) = Sensation of heat with sweating. Able to continue activity Severe (3) = Sensation of heat with sweating. Causes cessation of activity The weekly frequency of moderate to severe VMS at baseline and week 4 is defined as the total number of all recorded moderate to severe VMS experienced during the 7 day periods days -7 to -1 (baseline) and days 22 to 28 (week 4), respectively. Change = total No. of moderate & severe VMS at week 4 - total No. of moderate & severe VMS at baseline. A negative change from baseline score indicates a reduction in the frequency of moderate to severe VMS per week. Reported value are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Primary

End point timeframe

Baseline and Week 4

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[1]	47 ^[2]	53 ^[3]	49 ^[4]	55 ^[5]
Units: Weekly Frequency
arithmetic mean (standard deviation)	-35.9 ( 31.57 )	-27.6 ( 22.47 )	-36.4 ( 22.62 )	-41.4 ( 21.60 )	-32.9 ( 23.14 )

Notes
[1] - ITT N = 53 ITT set with baseline and week 4 data, last observation carried forward [LOCF] approach
[2] - ITT set with baseline and week 4 data, last observation carried forward [LOCF] approach
[3] - ITT set with baseline and week 4 data, last observation carried forward [LOCF] approach
[4] - ITT set with baseline and week 4 data, last observation carried forward [LOCF] approach
[5] - ITT set with baseline and week 4 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9986

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.97

Confidence interval

level

95%

sides

2-sided

lower limit

-10.16

upper limit

12.11

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.5389

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

5.78

Confidence interval

level

95%

sides

2-sided

lower limit

-5.58

upper limit

17.14

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9673

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-2.22

Confidence interval

level

95%

sides

2-sided

lower limit

-13.24

upper limit

8.8

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0683

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-10.71

Confidence interval

level

95%

sides

2-sided

lower limit

-21.98

upper limit

0.57

Primary: Change in Weekly Frequency of Moderate to Severe Vasomotor Symptoms (VMS) from Baseline to Week 12

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End point title

Change in Weekly Frequency of Moderate to Severe Vasomotor Symptoms (VMS) from Baseline to Week 12

End point description

The severity scoring system of VMS was documented by the participants in the participants diary using the following scores: None (0) = no VMS symptoms Mild (1) = Sensation of heat without sweating Moderate (2) = Sensation of heat with sweating. Able to continue activity Severe (3) = Sensation of heat with sweating. Causes cessation of activity The weekly frequency of moderate to severe VMS at baseline and week 12 is defined as the total number of all recorded moderate to severe VMS experienced during the 7 day periods days -7 to -1 (baseline) and days 78 to 84 (week 12) respectively. Change = total No. of moderate & severe VMS at week 12 - total No. of moderate & severe VMS at baseline. A negative change from baseline score indicates a reduction in the frequency of moderate to severe VMS per week. Reported value are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Primary

End point timeframe

Baseline and Week 12

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[6]	47 ^[7]	53 ^[8]	49 ^[9]	55 ^[10]
Units: Weekly frequency
arithmetic mean (standard deviation)	-45.0 ( 38.91 )	-40.6 ( 24.37 )	-47.2 ( 22.87 )	-50.9 ( 18.38 )	-43.0 ( 22.31 )

Notes
[6] - ITT N = 53 ITT set with baseline and week 12 data, last observation carried forward [LOCF] approach
[7] - ITT set with baseline and week 12 data, last observation carried forward [LOCF] approach
[8] - ITT set with baseline and week 12 data, last observation carried forward [LOCF] approach
[9] - ITT set with baseline and week 12 data, last observation carried forward [LOCF] approach
[10] - ITT set with baseline and week 12 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.8986

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

3.25

Confidence interval

level

95%

sides

2-sided

lower limit

-8.24

upper limit

14.73

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9326

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

2.92

Confidence interval

level

95%

sides

2-sided

lower limit

-8.8

upper limit

14.63

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9491

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-2.6

Confidence interval

level

95%

sides

2-sided

lower limit

-13.97

upper limit

8.76

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0706

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-10.98

Confidence interval

level

95%

sides

2-sided

lower limit

-22.6

upper limit

0.65

Primary: Change in Mean Severity of Moderate to Severe Vasomotor Symptoms (VMS) from Baseline to Week 4

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End point title

Change in Mean Severity of Moderate to Severe Vasomotor Symptoms (VMS) from Baseline to Week 4

End point description

The severity scoring system of VMS was documented by the participants in the participants diary using the following scores: None (0) = no VMS symptoms Mild (1) = Sensation of heat without sweating Moderate (2) = Sensation of heat with sweating. Able to continue activity Severe (3) = Sensation of heat with sweating. Causes cessation of activity Change in the severity of VMS from baseline to week 4 is defined as arithmetic mean of the recorded severity score of VMS (mild, moderate and severe) observed during day 22 & 28 (week 4) - the arithmetic mean of recorded severity scores values of VMS (moderate or severe) observed during -7 to -1 prior to treatment (baseline). A negative change from baseline score indicates improvement in symptoms. Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Primary

End point timeframe

Baseline and Week 4

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[11]	47 ^[12]	53 ^[13]	49 ^[14]	55 ^[15]
Units: Score on a Scale
arithmetic mean (standard deviation)	-0.3 ( 0.55 )	-0.2 ( 0.46 )	-0.5 ( 0.60 )	-0.6 ( 0.64 )	-0.3 ( 0.41 )

Notes
[11] - ITT N = 53 ITT set with baseline and week 4 data, last observation carried forward [LOCF] approach
[12] - ITT set with baseline and week 4 data, last observation carried forward [LOCF] approach
[13] - ITT set with baseline and week 4 data, last observation carried forward [LOCF] approach
[14] - ITT set with baseline and week 4 data, last observation carried forward [LOCF] approach
[15] - ITT set with baseline and week 4 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9998

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.27

upper limit

0.24

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.8253

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.17

upper limit

0.35

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.3767

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.41

upper limit

0.1

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0486

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.26

Confidence interval

level

95%

sides

2-sided

lower limit

-0.52

upper limit

Primary: Change in Mean Severity of Moderate to Severe Vasomotor Symptoms (VMS) from Baseline to Week 12

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End point title

Change in Mean Severity of Moderate to Severe Vasomotor Symptoms (VMS) from Baseline to Week 12

End point description

The severity scoring system of VMS was documented by the participants in the participants diary using the following scores: None (0) = no VMS symptoms Mild (1) = Sensation of heat without sweating Moderate (2) = Sensation of heat with sweating. Able to continue activity Severe (3) = Sensation of heat with sweating. Causes cessation of activity Change in the severity of VMS from baseline to week 12 is defined as arithmetic mean of the recorded severity score of VMS (mild, moderate and severe) observed during day 78 to 84 (week 12) - the arithmetic mean of recorded severity scores values of VMS (moderate or severe) observed during -7 to -1 prior to treatment (baseline). A negative change from baseline score indicates improvement in symptoms. Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Primary

End point timeframe

Baseline and Week 12

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[16]	47 ^[17]	53 ^[18]	49 ^[19]	55 ^[20]
Units: Score on a Scale
arithmetic mean (standard deviation)	-0.6 ( 0.79 )	-0.4 ( 0.67 )	-0.7 ( 0.80 )	-1.0 ( 0.87 )	-0.7 ( 0.78 )

Notes
[16] - ITT N = 53 ITT set with baseline and week 12 data, last observation carried forward [LOCF] approach
[17] - ITT set with baseline and week 12 data, last observation carried forward [LOCF] approach
[18] - ITT set with baseline and week 12 data, last observation carried forward [LOCF] approach
[19] - ITT set with baseline and week 12 data, last observation carried forward [LOCF] approach
[20] - ITT set with baseline and week 12 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9992

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.35

upper limit

0.4

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.3062

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.26

Confidence interval

level

95%

sides

2-sided

lower limit

-0.13

upper limit

0.64

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9981

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.41

upper limit

0.34

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0489

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.38

Confidence interval

level

95%

sides

2-sided

lower limit

-0.77

upper limit

Secondary: Change in Genitourinary Syndrome of Menopause (GSM) from Baseline to Week 13

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End point title

Change in Genitourinary Syndrome of Menopause (GSM) from Baseline to Week 13

End point description

The following GSM symptoms were assessed: Vaginal dryness Vaginal and/or irritation/itching Dysuria Vaginal pain associated with sexual activity These GSM symptoms were graded by the participants using the following scale: [0] none, [1] mild, [2] moderate, or [3] severe. A negative change from baseline score indicates improvement in symptoms. Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[21]	47 ^[22]	53 ^[23]	48 ^[24]	55 ^[25]
Units: Score on a Scale
arithmetic mean (standard deviation)
Vaginal dryness	-0.4 ( 0.82 )	-0.7 ( 0.98 )	-0.5 ( 0.80 )	-0.6 ( 0.98 )	-0.4 ( 1.01 )
Vaginal and/or vulvar irritation/itching	-0.5 ( 0.80 )	-0.2 ( 1.00 )	-0.4 ( 0.88 )	-0.1 ( 0.86 )	-0.3 ( 0.91 )
Dysuria	-0.2 ( 0.57 )	-0.1 ( 0.58 )	-0.2 ( 0.58 )	-0.0 ( 0.64 )	-0.1 ( 0.66 )
Vaginal pain associated with sexual activity	-0.2 ( 0.62 )	-0.6 ( 1.02 )	-0.4 ( 0.75 )	-0.4 ( 0.77 )	-0.2 ( 0.91 )

Notes
[21] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[22] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[23] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[24] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[25] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

Vaginal Dryness: E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.3345

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-0.58

upper limit

0.13

Vaginal Dryness: E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.1202

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.66

upper limit

0.05

Vaginal Dryness: E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0798

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.32

Confidence interval

level

95%

sides

2-sided

lower limit

-0.67

upper limit

0.03

Vaginal Dryness: E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0291

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.76

upper limit

-0.03

Irritation/Itching: E4 2.5 mg vs Placebo

Statistical analysis description

Vaginal and/or vulvar irritation/itching

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.1717

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

0.06

Irritation/Itching: E4 5 mg vs Placebo

Statistical analysis description

Vaginal and/or vulvar irritation/itching

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9618

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.37

upper limit

0.24

Irritation/Itching: E4 10 mg vs Placebo

Statistical analysis description

Vaginal and/or vulvar irritation/itching

Comparison groups

Placebo v E4 10 mg

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.2487

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-0.51

upper limit

0.09

Irritation/Itching: E4 15 mg vs Placebo

Statistical analysis description

Vaginal and/or vulvar irritation/itching

Comparison groups

Placebo v E4 15 mg

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.931

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.38

upper limit

0.23

Dysuria: E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.2942

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.31

upper limit

0.06

Dysuria: E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.3488

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.31

upper limit

0.07

Dysuria: E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.3386

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

0.07

Dysuria: E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.643

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

0.27

Vaginal Pain: E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0763

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-0.56

upper limit

0.02

Vaginal Pain: E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0246

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.33

Confidence interval

level

95%

sides

2-sided

lower limit

-0.62

upper limit

-0.03

Vaginal Pain: E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0004

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.47

Confidence interval

level

95%

sides

2-sided

lower limit

-0.76

upper limit

-0.18

Vaginal Pain: E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0006

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.47

Confidence interval

level

95%

sides

2-sided

lower limit

-0.77

upper limit

-0.17

Secondary: Change in Vaginal Bleeding Associated with Sexual Activity from Baseline to Week 13

Top of page

End point title

Change in Vaginal Bleeding Associated with Sexual Activity from Baseline to Week 13

End point description

Vaginal bleeding (a genitourinary syndrome of menopasure [GSM]) associated with sexual activity was documented using 3 categories: [0] absent, [1] present, or not applicable. Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[26]	47 ^[27]	53 ^[28]	49 ^[29]	55 ^[30]
Units: Participants
Baseline: Presence	0	3	0	0	2
Baseline: Absence	53	43	53	47	51
Baseline: Not Applicable	0	1	0	1	2
Week 13: Presence	0	0	0	2	2
Week 13: Absence	53	47	53	46	53
Week 13: Not Applicable	0	0	0	0	0

Notes
[26] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[27] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[28] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[29] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[30] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

Vaginal Bleeding: 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9958

Method

Regression, Logistic

Parameter type

Mean difference (final values)

Point estimate

-1.24

Confidence interval

level

95%

sides

2-sided

lower limit

-459.49

upper limit

457.01

Vaginal Bleeding: 5 mg vs Placebo

Comparison groups

Placebo v E4 5 mg

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.903

Method

Regression, Logistic

Parameter type

Mean difference (final values)

Point estimate

-30.98

Confidence interval

level

95%

sides

2-sided

lower limit

-529.01

upper limit

467.05

Vaginal Bleeding: 10 mg vs Placebo

Comparison groups

Placebo v E4 10 mg

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9955

Method

Regression, Logistic

Parameter type

Mean difference (final values)

Point estimate

-1.34

Confidence interval

level

95%

sides

2-sided

lower limit

-461.01

upper limit

458.34

Vaginal Bleeding: 15 mg vs Placebo

Comparison groups

Placebo v E4 15 mg

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9308

Method

Regression, Logistic

Parameter type

Mean difference (final values)

Point estimate

10.38

Confidence interval

level

95%

sides

2-sided

lower limit

-223.76

upper limit

244.51

Secondary: Change in Menopause Rating Scale (MRS) Score from Baseline to Week 5

Top of page

End point title

Change in Menopause Rating Scale (MRS) Score from Baseline to Week 5

End point description

MRS consists of 11 items (severity expressed in 0 to 4 points in each item). The total score of the MRS ranges between 0 (asymptomatic) to 44 (highest degree of complaints). A negative change from baseline indicates an improvement in symptoms. Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 5

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[31]	47 ^[32]	53 ^[33]	48 ^[34]	55 ^[35]
Units: Score on a Scale
arithmetic mean (standard deviation)	-6.2 ( 5.67 )	-6.0 ( 6.21 )	-6.0 ( 6.44 )	-7.8 ( 7.56 )	-5.4 ( 6.46 )

Notes
[31] - ITT N = 53 ITT set with baseline and week 5 data, last observation carried forward [LOCF] approach
[32] - ITT set with baseline and week 5 data, last observation carried forward [LOCF] approach
[33] - ITT set with baseline and week 5 data, last observation carried forward [LOCF] approach
[34] - ITT set with baseline and week 5 data, last observation carried forward [LOCF] approach
[35] - ITT set with baseline and week 5 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.4352

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-1.44

Confidence interval

level

95%

sides

2-sided

lower limit

-3.98

upper limit

1.09

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.4808

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-1.41

Confidence interval

level

95%

sides

2-sided

lower limit

-4.02

upper limit

1.19

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.8994

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.71

Confidence interval

level

95%

sides

2-sided

lower limit

-3.23

upper limit

1.81

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0113

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-3.15

Confidence interval

level

95%

sides

2-sided

lower limit

-5.74

upper limit

-0.56

Secondary: Change in Menopause Rating Scale (MRS) Score from Baseline to Week 13

Top of page

End point title

Change in Menopause Rating Scale (MRS) Score from Baseline to Week 13

End point description

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[36]	47 ^[37]	53 ^[38]	48 ^[39]	55 ^[40]
Units: Score on a Scale
arithmetic mean (standard deviation)	-7.0 ( 6.29 )	-5.5 ( 7.23 )	-7.9 ( 8.30 )	-8.3 ( 7.90 )	-6.8 ( 8.67 )

Notes
[36] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[37] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[38] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[39] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[40] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

Placebo v E4 2.5 mg

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.5283

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-1.61

Confidence interval

level

95%

sides

2-sided

lower limit

-4.74

upper limit

1.52

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9965

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.35

Confidence interval

level

95%

sides

2-sided

lower limit

-3.51

upper limit

2.81

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.4726

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-1.69

Confidence interval

level

95%

sides

2-sided

lower limit

-4.77

upper limit

1.39

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0694

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-3.07

Confidence interval

level

95%

sides

2-sided

lower limit

-6.32

upper limit

0.17

Secondary: Change in Vaginal pH from Baseline to Week 13

Top of page

End point title

Change in Vaginal pH from Baseline to Week 13

End point description

Vaginal pH was performed on-site by an investigator or qualified site personnel using a standardized vaginal pH paper test. Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[41]	47 ^[42]	53 ^[43]	49 ^[44]	55 ^[45]
Units: pH
arithmetic mean (standard deviation)	-0.16 ( 0.746 )	-0.22 ( 1.173 )	-0.08 ( 0.780 )	-0.12 ( 0.550 )	0.12 ( 0.719 )

Notes
[41] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[42] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[43] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[44] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[45] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.2294

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.22

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

0.08

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9948

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.35

upper limit

0.27

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9818

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.36

upper limit

0.25

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.3352

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.52

upper limit

0.11

Secondary: Change in Vaginal Maturation Value (MV) from Baseline to Week 13

Top of page

End point title

Change in Vaginal Maturation Value (MV) from Baseline to Week 13

End point description

A vaginal MV is a parameter derived from the maturation index (MI). The MI is a ratio obtained through performing a random count of three major cell types (parabasal cells, intermediate cells and superficial cells) that are shed from squamous epithelium. The cell count is expressed as a percentage that reads as follows: MI = % parabasal cells, % intermediate cells, % superficial cells. The vaginal MV is calculated as follows: MV = 0.0 x parabasal cells [%] + 0.5 x intermediate cells [%] + 1.0 x superficial cells [%] Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[46]	44 ^[47]	52 ^[48]	47 ^[49]	54 ^[50]
Units: Maturation value
arithmetic mean (standard deviation)	16.1 ( 24.63 )	26.6 ( 29.31 )	26.5 ( 27.89 )	30.1 ( 28.98 )	6.7 ( 16.21 )

Notes
[46] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[47] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[48] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[49] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[50] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0003

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

14.59

Confidence interval

level

95%

sides

2-sided

lower limit

5.71

upper limit

23.48

E4 5 mg vs Placebo

Comparison groups

Placebo v E4 5 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

19.16

Confidence interval

level

95%

sides

2-sided

lower limit

9.93

upper limit

28.38

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

23.61

Confidence interval

level

95%

sides

2-sided

lower limit

14.72

upper limit

32.49

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

22.51

Confidence interval

level

95%

sides

2-sided

lower limit

13.43

upper limit

31.59

Secondary: Change in Serum Concentration of Triglycerides from Baseline to Week 13

Top of page

End point title

Change in Serum Concentration of Triglycerides from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[51]	47 ^[52]	53 ^[53]	49 ^[54]	55 ^[55]
Units: mmol/L
arithmetic mean (standard deviation)	-0.0392 ( 0.48013 )	-0.0146 ( 0.79080 )	0.0320 ( 0.90955 )	0.2018 ( 0.80108 )	0.0070 ( 0.77504 )

Notes
[51] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[52] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[53] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[54] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[55] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.4821

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-0.47

upper limit

0.14

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.8945

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

0.22

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 1

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

0.3

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.6721

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.18

upper limit

0.44

Secondary: Change in Serum Concentration of High Density Lipoprotein (HDL) Cholesterol from Baseline to Week 13

Top of page

End point title

Change in Serum Concentration of High Density Lipoprotein (HDL) Cholesterol from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[56]	47 ^[57]	53 ^[58]	49 ^[59]	55 ^[60]
Units: mmol/L
arithmetic mean (standard deviation)	0.1169 ( 0.20512 )	0.1113 ( 0.28608 )	0.1496 ( 0.24857 )	0.1596 ( 0.23372 )	0.0146 ( 0.21852 )

Notes
[56] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[57] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[58] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[59] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[60] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

Placebo v E4 2.5 mg

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0481

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.11

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.22

E4 5 mg vs Placebo

Comparison groups

Placebo v E4 5 mg

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0451

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.11

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.22

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0076

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.03

upper limit

0.24

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0025

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.15

Confidence interval

level

95%

sides

2-sided

lower limit

0.04

upper limit

0.26

Secondary: Change in Serum Concentration of Low Density Lipoprotein (LDL) Cholesterol from Baseline to Week 13

Top of page

End point title

Change in Serum Concentration of Low Density Lipoprotein (LDL) Cholesterol from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[61]	47 ^[62]	53 ^[63]	49 ^[64]	55 ^[65]
Units: mmol/L
arithmetic mean (standard deviation)	0.2263 ( 0.58921 )	0.2805 ( 0.66790 )	0.1763 ( 0.75712 )	0.0835 ( 0.43864 )	0.0989 ( 0.55484 )

Notes
[61] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[62] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[63] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[64] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[65] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.8037

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.18

upper limit

0.38

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.4627

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-0.13

upper limit

0.44

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.952

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.22

upper limit

0.34

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9308

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.35

upper limit

0.21

Secondary: Change in Total Cholesterol from Baseline to Week 13

Top of page

End point title

Change in Total Cholesterol from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[66]	47 ^[67]	53 ^[68]	49 ^[69]	55 ^[70]
Units: mmol/L
arithmetic mean (standard deviation)	0.2175 ( 0.64351 )	0.2165 ( 0.83013 )	0.2614 ( 0.85508 )	0.1285 ( 0.71395 )	0.0010 ( 0.70271 )

Notes
[66] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[67] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[68] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[69] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[70] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.5863

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-0.17

upper limit

0.5

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.5027

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.16

upper limit

0.53

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.3051

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.22

Confidence interval

level

95%

sides

2-sided

lower limit

-0.11

upper limit

0.55

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9873

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.29

upper limit

0.39

Secondary: Change in Fasting Glucose from Baseline to Week 13

Top of page

End point title

Change in Fasting Glucose from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[71]	46 ^[72]	52 ^[73]	49 ^[74]	53 ^[75]
Units: mmol/L
arithmetic mean (standard deviation)	-0.013 ( 0.3704 )	-0.038 ( 0.6564 )	-0.157 ( 0.5321 )	0.019 ( 0.5131 )	0.006 ( 0.4195 )

Notes
[71] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[72] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[73] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[74] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[75] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.983

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.19

upper limit

0.27

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9983

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.26

upper limit

0.21

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.7535

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.32

upper limit

0.14

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 1

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.22

upper limit

0.24

Secondary: Change in Insulin Levels from Baseline to Week 13

Top of page

End point title

Change in Insulin Levels from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[76]	47 ^[77]	53 ^[78]	49 ^[79]	55 ^[80]
Units: mIU/L
arithmetic mean (standard deviation)	-0.86 ( 11.667 )	-0.83 ( 21.145 )	-1.82 ( 9.382 )	-1.40 ( 7.146 )	2.55 ( 8.912 )

Notes
[76] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[77] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[78] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[79] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[80] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.5945

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-2.46

Confidence interval

level

95%

sides

2-sided

lower limit

-7.61

upper limit

2.7

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.4737

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-2.89

Confidence interval

level

95%

sides

2-sided

lower limit

-8.19

upper limit

2.4

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.325

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-3.32

Confidence interval

level

95%

sides

2-sided

lower limit

-8.47

upper limit

1.83

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.1255

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-4.42

Confidence interval

level

95%

sides

2-sided

lower limit

-9.67

upper limit

0.82

Secondary: Change in Serum Concentration of Glycated Hemoglobin from Baseline to Week 13

Top of page

End point title

Change in Serum Concentration of Glycated Hemoglobin from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[81]	47 ^[82]	53 ^[83]	49 ^[84]	55 ^[85]
Units: mmol/mol
arithmetic mean (standard deviation)	0.02 ( 0.222 )	0.00 ( 0.190 )	-0.08 ( 0.175 )	-0.14 ( 0.225 )	0.02 ( 0.194 )

Notes
[81] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[82] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[83] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[84] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[85] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9988

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-1.12

upper limit

0.94

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9768

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-1.25

upper limit

0.87

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0272

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-1.12

Confidence interval

level

95%

sides

2-sided

lower limit

-2.15

upper limit

-0.1

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0001

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-1.78

Confidence interval

level

95%

sides

2-sided

lower limit

-2.83

upper limit

-0.74

Secondary: Change in Homeostatis Model Assessment-Estimated Insulin Resistance (HOMA-IR) from Baseline to Week 13

Top of page

End point title

Change in Homeostatis Model Assessment-Estimated Insulin Resistance (HOMA-IR) from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[86]	45 ^[87]	53 ^[88]	49 ^[89]	55 ^[90]
Units: Index
arithmetic mean (standard deviation)	-0.08 ( 2.585 )	-0.52 ( 6.815 )	-0.42 ( 2.204 )	-0.36 ( 1.845 )	0.58 ( 2.179 )

Notes
[86] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[87] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[88] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[89] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[90] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.8842

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.41

Confidence interval

level

95%

sides

2-sided

lower limit

-1.82

upper limit

0.99

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.4794

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-2.26

upper limit

0.67

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.6434

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.63

Confidence interval

level

95%

sides

2-sided

lower limit

-2.04

upper limit

0.78

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.2155

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-1.05

Confidence interval

level

95%

sides

2-sided

lower limit

-2.48

upper limit

0.38

Secondary: Change in Serum Concentration of Prothrombin Fragment 1 + 2 from Baseline to Week 13

Top of page

End point title

Change in Serum Concentration of Prothrombin Fragment 1 + 2 from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[91]	46 ^[92]	53 ^[93]	49 ^[94]	54 ^[95]
Units: pmol/L
arithmetic mean (standard deviation)	4.53 ( 201.865 )	43.30 ( 333.608 )	17.44 ( 287.119 )	30.07 ( 309.723 )	-33.20 ( 395.547 )

Notes
[91] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[92] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[93] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[94] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[95] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.8345

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-39.94

Confidence interval

level

95%

sides

2-sided

lower limit

-160.16

upper limit

80.28

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9997

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-7.11

Confidence interval

level

95%

sides

2-sided

lower limit

-128.17

upper limit

113.95

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9197

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

30.9

Confidence interval

level

95%

sides

2-sided

lower limit

-86.92

upper limit

148.72

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9515

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

27.52

Confidence interval

level

95%

sides

2-sided

lower limit

-94.61

upper limit

149.64

Secondary: Change in Serum Concentration of D-dimers from Baseline to Week 13

Top of page

End point title

Change in Serum Concentration of D-dimers from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[96]	46 ^[97]	53 ^[98]	49 ^[99]	54 ^[100]
Units: mcg/L
arithmetic mean (standard deviation)	5.8 ( 158.93 )	80.4 ( 327.02 )	50.9 ( 139.54 )	108.2 ( 293.57 )	127.8 ( 542.68 )

Notes
[96] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[97] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[98] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[99] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[100] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.1827

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-122.76

Confidence interval

level

95%

sides

2-sided

lower limit

-282.11

upper limit

36.59

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.8116

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-56.93

Confidence interval

level

95%

sides

2-sided

lower limit

-220.78

upper limit

106.93

E4 10 mg vs Placebo

Comparison groups

Placebo v E4 10 mg

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.579

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-76.75

Confidence interval

level

95%

sides

2-sided

lower limit

-235.08

upper limit

81.57

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.998

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-15.35

Confidence interval

level

95%

sides

2-sided

lower limit

-176.73

upper limit

146.04

Secondary: Change in Serum Concentration of Sex-Hormone Binding Globulin from Baseline to Week 13

Top of page

End point title

Change in Serum Concentration of Sex-Hormone Binding Globulin from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	51 ^[101]	46 ^[102]	53 ^[103]	49 ^[104]	54 ^[105]
Units: nmol/L
arithmetic mean (standard deviation)	4.26 ( 15.874 )	11.33 ( 14.233 )	28.97 ( 26.846 )	40.63 ( 32.658 )	1.98 ( 13.080 )

Notes
[101] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[102] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[103] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[104] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[105] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.973

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

2.02

Confidence interval

level

95%

sides

2-sided

lower limit

-8.61

upper limit

12.65

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.1092

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

9.32

Confidence interval

level

95%

sides

2-sided

lower limit

-1.41

upper limit

20.05

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

26.72

Confidence interval

level

95%

sides

2-sided

lower limit

16.34

upper limit

37.1

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

38.41

Confidence interval

level

95%

sides

2-sided

lower limit

27.87

upper limit

48.95

Secondary: Change in Serum Concentration of Antithrombin from Baseline to Week 13

Top of page

End point title

Change in Serum Concentration of Antithrombin from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[106]	46 ^[107]	53 ^[108]	49 ^[109]	54 ^[110]
Units: percent
arithmetic mean (standard deviation)	-3.7 ( 16.02 )	-2.5 ( 14.51 )	-4.8 ( 15.27 )	-4.6 ( 17.96 )	-1.9 ( 12.49 )

Notes
[106] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[107] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[108] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[109] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[110] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

Placebo v E4 2.5 mg

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9999

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.24

Confidence interval

level

95%

sides

2-sided

lower limit

-5.76

upper limit

6.23

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.7691

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

2.27

Confidence interval

level

95%

sides

2-sided

lower limit

-3.78

upper limit

8.33

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.6119

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-2.75

Confidence interval

level

95%

sides

2-sided

lower limit

-8.64

upper limit

3.14

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9548

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-1.35

Confidence interval

level

95%

sides

2-sided

lower limit

-7.46

upper limit

4.76

Secondary: Change in Serum Concentration of Protein-C from Baseline to Week 13

Top of page

End point title

Change in Serum Concentration of Protein-C from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[111]	46 ^[112]	53 ^[113]	49 ^[114]	54 ^[115]
Units: percent
arithmetic mean (standard deviation)	-1.7 ( 14.53 )	-2.0 ( 15.77 )	-1.9 ( 15.51 )	-2.5 ( 15.02 )	-5.2 ( 14.11 )

Notes
[111] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[112] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[113] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[114] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[115] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9774

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

1.31

Confidence interval

level

95%

sides

2-sided

lower limit

-5.91

upper limit

8.53

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.6022

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

3.49

Confidence interval

level

95%

sides

2-sided

lower limit

-3.9

upper limit

10.87

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9741

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

1.35

Confidence interval

level

95%

sides

2-sided

lower limit

-5.82

upper limit

8.53

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.884

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

2.19

Confidence interval

level

95%

sides

2-sided

lower limit

-5.23

upper limit

9.6

Secondary: Change in Serum Concentration of Free Protein-S from Baseline to Week 13

Top of page

End point title

Change in Serum Concentration of Free Protein-S from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[116]	46 ^[117]	53 ^[118]	49 ^[119]	54 ^[120]
Units: percent
arithmetic mean (standard deviation)	-1.04 ( 12.227 )	-3.00 ( 11.234 )	-5.65 ( 10.148 )	-9.20 ( 11.194 )	-4.01 ( 13.473 )

Notes
[116] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[117] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[118] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[119] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[120] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.7798

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

1.99

Confidence interval

level

95%

sides

2-sided

lower limit

-3.42

upper limit

7.39

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9693

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

1.09

Confidence interval

level

95%

sides

2-sided

lower limit

-4.45

upper limit

6.63

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.8984

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-1.51

Confidence interval

level

95%

sides

2-sided

lower limit

-6.86

upper limit

3.84

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0292

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-5.91

Confidence interval

level

95%

sides

2-sided

lower limit

-11.38

upper limit

-0.45

Secondary: Change in Serum Concentration of Factor VIII from Baseline to Week 13

Top of page

End point title

Change in Serum Concentration of Factor VIII from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[121]	46 ^[122]	53 ^[123]	49 ^[124]	54 ^[125]
Units: percent
arithmetic mean (standard deviation)	4.3 ( 30.03 )	-0.5 ( 35.28 )	0.5 ( 31.80 )	6.7 ( 46.46 )	6.0 ( 29.97 )

Notes
[121] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[122] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[123] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[124] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[125] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.304

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-9.82

Confidence interval

level

95%

sides

2-sided

lower limit

-24.67

upper limit

5.04

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.2206

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-11.04

Confidence interval

level

95%

sides

2-sided

lower limit

-26.13

upper limit

4.05

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.1189

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-12.58

Confidence interval

level

95%

sides

2-sided

lower limit

-27.33

upper limit

2.17

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.8135

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-5.3

Confidence interval

level

95%

sides

2-sided

lower limit

-20.56

upper limit

9.96

Secondary: Change in Serum Concentration of Free Tissue Factor Pathway Inhibitor (TFPI) from Baseline to Week 13

Top of page

End point title

Change in Serum Concentration of Free Tissue Factor Pathway Inhibitor (TFPI) from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[126]	46 ^[127]	53 ^[128]	49 ^[129]	54 ^[130]
Units: ug/L
arithmetic mean (standard deviation)	0.97 ( 8.357 )	0.76 ( 8.347 )	0.10 ( 10.928 )	-3.05 ( 10.320 )	0.54 ( 9.069 )

Notes
[126] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[127] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[128] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[129] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[130] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.6298

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-1.92

Confidence interval

level

95%

sides

2-sided

lower limit

-6.12

upper limit

2.28

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9916

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.59

Confidence interval

level

95%

sides

2-sided

lower limit

-4.84

upper limit

3.66

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9925

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-0.56

Confidence interval

level

95%

sides

2-sided

lower limit

-4.71

upper limit

3.58

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.2657

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-2.99

Confidence interval

level

95%

sides

2-sided

lower limit

-7.32

upper limit

1.33

Secondary: Change in Activated protein C sensitivity ratio (APCsr) (Endogenous Thrombin Potential [ETP] - Based) from Baseline to Week 13

Top of page

End point title

Change in Activated protein C sensitivity ratio (APCsr) (Endogenous Thrombin Potential [ETP] - Based) from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline to Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	0 ^[131]	0 ^[132]	0 ^[133]	0 ^[134]	0 ^[135]
Units: Ratio
arithmetic mean (standard deviation)	( )	( )	( )	( )	( )

Notes
[131] - Data for this factor are not yet available.
[132] - Data for this factor are not yet available.
[133] - Data for this factor are not yet available.
[134] - Data for this factor are not yet evaluable.
[135] - Data for this factor are not yet available.

No statistical analyses for this end point

Secondary: Change in Serum Concentration of Osteocalcin from Baseline to Week 13

Top of page

End point title

Change in Serum Concentration of Osteocalcin from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	51 ^[136]	46 ^[137]	53 ^[138]	49 ^[139]	54 ^[140]
Units: µg/L
arithmetic mean (standard deviation)	2.93 ( 7.080 )	-0.43 ( 5.967 )	-0.63 ( 7.806 )	0.08 ( 6.467 )	2.44 ( 8.223 )

Notes
[136] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[137] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[138] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[139] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[140] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.904

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

0.87

Confidence interval

level

95%

sides

2-sided

lower limit

-2.27

upper limit

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.2154

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-2.37

Confidence interval

level

95%

sides

2-sided

lower limit

-5.59

upper limit

0.85

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.1345

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-2.58

Confidence interval

level

95%

sides

2-sided

lower limit

-5.69

upper limit

0.53

E4 15 mg vs Placebo

Comparison groups

E4 15 mg v Placebo

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0474

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-3.19

Confidence interval

level

95%

sides

2-sided

lower limit

-6.36

upper limit

-0.03

Secondary: Change in Serum Concentration of C-Terminal Telopeptide (CTX-1) from Baseline to Week 13

Top of page

End point title

Change in Serum Concentration of C-Terminal Telopeptide (CTX-1) from Baseline to Week 13

End point description

Reported values are for the intent-to-treat (ITT) analysis set, which is inclusive of all participants who received at least one dose of study drug on the planned treatment.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	51 ^[141]	46 ^[142]	53 ^[143]	49 ^[144]	54 ^[145]
Units: ng/L
arithmetic mean (standard deviation)	-28.0 ( 181.90 )	-83.3 ( 170.60 )	-127.3 ( 171.11 )	-95.3 ( 429.60 )	17.9 ( 200.84 )

Notes
[141] - ITT N = 53 ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[142] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[143] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[144] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach
[145] - ITT set with baseline and week 13 data, last observation carried forward [LOCF] approach

E4 2.5 mg vs Placebo

Comparison groups

E4 2.5 mg v Placebo

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.9547

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-23.27

Confidence interval

level

95%

sides

2-sided

lower limit

-128.72

upper limit

82.19

E4 5 mg vs Placebo

Comparison groups

E4 5 mg v Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0711

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-101.67

Confidence interval

level

95%

sides

2-sided

lower limit

-209.51

upper limit

6.16

E4 10 mg vs Placebo

Comparison groups

E4 10 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0038

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-140.87

Confidence interval

level

95%

sides

2-sided

lower limit

-245.08

upper limit

-36.67

E4 15 mg vs Placebo

Comparison groups

Placebo v E4 15 mg

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0634

Method

ANCOVA by Dunnett's test

Parameter type

Mean difference (final values)

Point estimate

-102.11

Confidence interval

level

95%

sides

2-sided

lower limit

-208.26

upper limit

4.05

Secondary: Number of Participants Who Experienced a Treatment-Emergent Adverse Event (TEAE)

Top of page

End point title

Number of Participants Who Experienced a Treatment-Emergent Adverse Event (TEAE)

End point description

An AE is any untoward medical occurrence in a participant of a clinical trial, which does not necessarily have any causal relationship with the product under investigation. A treatment-emergent adverse event (TEAE) is defined as an AE with an onset that occurs after receiving study drug. All safety outcomes were analyzed using the safety analysis (SA) set: The SA set differs from the intent-to-treat (ITT) set as one participant randomized to the 2.5 mg E4 group received 10 mg by error. Therefore, the participant was allocated to the highest dose received, the 10 mg group, for analysis in the SA set.

End point type

Secondary

End point timeframe

Baseline to end of trial, a maximum of 119 days

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[146]	47 ^[147]	54 ^[148]	49 ^[149]	55 ^[150]
Units: Participants	30	25	30	31	26

Notes
[146] - SA set N = 52 SA set: All randomized participants who received at least 1 dose of study drug
[147] - SA set: All randomized participants who received at least 1 dose of study drug
[148] - SA set: All randomized participants who received at least 1 dose of study drug
[149] - SA set: All randomized participants who received at least 1 dose of study drug
[150] - SA set: All randomized participants who received at least 1 dose of study drug

No statistical analyses for this end point

Secondary: Number of Participants Who Experienced a Serious Adverse Event (SAE)

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End point title

Number of Participants Who Experienced a Serious Adverse Event (SAE)

End point description

A SAE was defined as an AE that met one or more of the following outcomes which were classified as serious: • Results in death • Is life-threatening (The term "life-threatening" refers to an event in which the subject is at risk of death at the time of the event; it does not refer to an event which hypothetically may cause death if it is more severe.) • Requires subject hospitalization or prolongation of existing hospitalization • Results in persistent or significant disability/incapacity • Is a congenital birth defect • Medically important condition • Requires intervention to prevent one or more of the outcomes listed in the definition above All safety outcomes were analyzed using the safety analysis (SA) set: The SA set differs from the intent-to-treat (ITT) set as one participant randomized to the 2.5 mg E4 group received 10 mg by error. Therefore, the participant was allocated to the highest dose received, the 10 mg group, for analysis in the SA set.

End point type

Secondary

End point timeframe

Baseline to end of trial, a maximum of 119 days

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[151]	47 ^[152]	54 ^[153]	49 ^[154]	55 ^[155]
Units: Participants	0	0	0	2	1

Notes
[151] - SA set N = 52 SA set: All randomized participants who received at least 1 dose of study drug
[152] - SA set: All randomized participants who received at least 1 dose of study drug
[153] - SA set: All randomized participants who received at least 1 dose of study drug
[154] - SA set: All randomized participants who received at least 1 dose of study drug
[155] - SA set: All randomized participants who received at least 1 dose of study drug

No statistical analyses for this end point

Secondary: Number of Participants Who Experienced a Treatment Related Adverse Event

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End point title

Number of Participants Who Experienced a Treatment Related Adverse Event

End point description

A treatment-related AE was defined as an AE related to the study drug or related to the study procedure as assessed by the principle investigator. All safety outcomes were analyzed using the safety analysis (SA) set: The SA set differs from the intent-to-treat (ITT) set as one participant randomized to the 2.5 mg E4 group received 10 mg by error. Therefore, the participant was allocated to the highest dose received, the 10 mg group, for analysis in the SA set.

End point type

Secondary

End point timeframe

Baseline to end of trial, a maximum of 119 days

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[156]	47 ^[157]	54 ^[158]	49 ^[159]	55 ^[160]
Units: Participants
Related to study drug	14	12	21	25	13
Related to study procedure	3	2	2	5	0

Notes
[156] - SA set N = 52 SA set: All randomized participants who received at least 1 dose of study drug
[157] - SA set: All randomized participants who received at least 1 dose of study drug
[158] - SA set: All randomized participants who received at least 1 dose of study drug
[159] - SA set: All randomized participants who received at least 1 dose of study drug
[160] - SA set: All randomized participants who received at least 1 dose of study drug

No statistical analyses for this end point

Secondary: Number of Participants Who Experienced a Clinically Significant Clinical Laboratory Measurement

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End point title

Number of Participants Who Experienced a Clinically Significant Clinical Laboratory Measurement

End point description

Laboratory measurements included hematology, chemistry and urinalysis. All safety outcomes were analyzed using the safety analysis (SA) set: The SA set differs from the intent-to-treat (ITT) set as one participant randomized to the 2.5 mg E4 group received 10 mg by error. Therefore, the participant was allocated to the highest dose received, the 10 mg group, for analysis in the SA set.

End point type

Secondary

End point timeframe

Baseline to end of trial, a maximum of 119 days

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[161]	47 ^[162]	54 ^[163]	49 ^[164]	55 ^[165]
Units: Participants
Aspartate aminotransferase increased	0	0	1	0	0
Blood cholesterol increased	0	0	0	1	0
Blood creatine phosphokinase increased	0	0	1	0	0
Blood triglycerides increased	0	0	0	1	0
Low density lipoprotein increased	0	0	0	1	0

Notes
[161] - SA set N = 52 SA set: All randomized participants who received at least 1 dose of study drug
[162] - SA set: All randomized participants who received at least 1 dose of study drug
[163] - SA set: All randomized participants who received at least 1 dose of study drug
[164] - SA set: All randomized participants who received at least 1 dose of study drug
[165] - SA set: All randomized participants who received at least 1 dose of study drug

No statistical analyses for this end point

Secondary: Mean Endometrial Thickness at Each Study Visit

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End point title

Mean Endometrial Thickness at Each Study Visit

End point description

Endometrial thickness assessment was done by the investigator, gynaecologist or designee at each study visit, planned or unplanned. All safety outcomes were analyzed using the safety analysis (SA) set: The SA set differs from the intent-to-treat (ITT) set as one participant randomized to the 2.5 mg E4 group received 10 mg by error. Therefore, the participant was allocated to the highest dose received, the 10 mg group, for analysis in the SA set.

End point type

Secondary

End point timeframe

Screening, Baseline, Week 5, Week 13, and Week 16

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	44 ^[166]	43 ^[167]	49 ^[168]	40 ^[169]	49 ^[170]
Units: millimeter(s)
arithmetic mean (standard deviation)
Screening	2.6 ( 1.00 )	2.7 ( 0.96 )	2.4 ( 1.05 )	2.6 ( 1.00 )	2.6 ( 1.01 )
Baseline	2.7 ( 1.13 )	2.4 ( 1.06 )	2.5 ( 1.09 )	2.7 ( 1.08 )	2.5 ( 1.11 )
Week 5	3.9 ( 1.86 )	5.4 ( 3.13 )	6.2 ( 3.07 )	6.2 ( 3.94 )	4.0 ( 2.49 )
Week 13	4.5 ( 2.80 )	5.5 ( 3.10 )	6.3 ( 3.24 )	7.9 ( 4.04 )	3.4 ( 2.10 )
Week 16	3.3 ( 1.62 )	3.6 ( 2.02 )	3.0 ( 0.93 )	3.1 ( 2.04 )	3.0 ( 1.58 )

Notes
[166] - Screening N = 44 Baseline N = 44 Week 5 N = 38 Week 13 N = 43 Week 16 N = 41
[167] - Screening N = 43 Baseline N = 43 Week 5 N = 39 Week 13 N = 42 Week 16 N = 40
[168] - Screening N = 49 Baseline N = 49 Week 5 N = 42 Week 13 N = 46 Week 16 N = 42
[169] - Screening N = 40 Baseline N = 40 Week 5 N = 36 Week 13 N = 38 Week 16 N = 38
[170] - Screening N = 49 Baseline N = 49 Week 5 N = 41 Week 13 N = 48 Week 16 N = 44

No statistical analyses for this end point

Secondary: Number of Participants Who Experienced Abnormal Uterine Bleeding at Each Study Visit

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End point title

Number of Participants Who Experienced Abnormal Uterine Bleeding at Each Study Visit

End point description

Abnormal uterine bleeding was defined as the occurrence of vaginal bleeding or spotting on a daily basis reported using the scale below: 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. All safety outcomes were analyzed using the safety analysis (SA) set: The SA set differs from the intent-to-treat (ITT) set as one participant randomized to the 2.5 mg E4 group received 10 mg by error. Therefore, the participant was allocated to the highest dose received, the 10 mg group, for analysis in the SA set.

End point type

Secondary

End point timeframe

Screening to Week 16

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	44 ^[171]	43 ^[172]	49 ^[173]	40 ^[174]	49 ^[175]
Units: Participants
Screening	0	0	0	0	0
Baseline	0	0	0	0	0
Week 5	0	0	1	0	2
Week 13	4	2	7	9	2
Week 16	1	2	3	4	0

Notes
[171] - Screening N = 44 Baseline N = 43 Week 5 N = 37 Week 13 N = 43 Week 16 N = 42
[172] - Screening N = 43 Baseline N = 43 Week 5 N = 39 Week 13 N = 42 Week 16 N = 41
[173] - Screening N = 49 Baseline N = 48 Week 5 N = 42 Week 13 N = 46 Week 16 N = 44
[174] - Screening N = 39 Baseline N = 39 Week 5 N = 35 Week 13 N = 38 Week 16 N = 39
[175] - Screening N = 48 Baseline N = 48 Week 5 N = 41 Week 13 N = 47 Week 16 N = 45

No statistical analyses for this end point

Secondary: Number of Participants Who Experienced a Clinically Significant Physical Examination Measurement

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End point title

Number of Participants Who Experienced a Clinically Significant Physical Examination Measurement

End point description

The physical examination included an examination of general appearance, head, eyes, nose, throat, skin, neck, lungs, breasts, lymph nodes, abdomen, and the cardiovascular, musculoskeletal and neurological systems. All safety outcomes were analyzed using the safety analysis (SA) set: The SA set differs from the intent-to-treat (ITT) set as one participant randomized to the 2.5 mg E4 group received 10 mg by error. Therefore, the participant was allocated to the highest dose received, the 10 mg group, for analysis in the SA set. Data produced from the shift table analysis. Inclusive of all participants with baseline and week 13 data. The number of participants per treatment group with available data varied for each system. The number of participants with available data in each arm is as follows: 2.5 mg E4: up to 51 participants 5 mg E4: up to 46 participants 10 mg E4: up to 50 participants 15 mg E4: up to 47 participants Placebo: up to 54 participants

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[176]	47 ^[177]	53 ^[178]	49 ^[179]	55 ^[180]
Units: Participants
General appearance	0	0	0	0	0
Head	0	0	0	0	0
Eyes	0	0	0	0	0
Ears	0	0	0	0	0
Nose	0	0	0	0	0
Throat	0	0	0	0	0
Skin	1	0	0	0	0
Neck	0	0	0	0	0
Lungs	0	0	0	0	0
Lymph nodes	0	0	0	0	0
Abdomen	0	0	0	0	0
Cardiovascular	1	0	0	0	0
Musculoskeletal	0	0	0	0	0
Neurological	0	0	0	0	0

Notes
[176] - SA set N = 52 SA set: All randomized participants who received at least 1 dose of study drug
[177] - SA set: All randomized participants who received at least 1 dose of study drug
[178] - SA set: All randomized participants who received at least 1 dose of study drug
[179] - SA set: All randomized participants who received at least 1 dose of study drug
[180] - SA set: All randomized participants who received at least 1 dose of study drug

No statistical analyses for this end point

Secondary: Number of Participants Who Experienced a Clinically Significant Gynaecological Examination

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End point title

Number of Participants Who Experienced a Clinically Significant Gynaecological Examination

End point description

Gynecological examination included inspection of breast, adnexa, cervix, uterus, vagina and external genitalia. All safety outcomes were analyzed using the safety analysis (SA) set: The SA set differs from the intent-to-treat (ITT) set as one participant randomized to the 2.5 mg E4 group received 10 mg by error. Therefore, the participant was allocated to the highest dose received, the 10 mg group, for analysis in the SA set. Data produced from the shift table analysis. Inclusive of all participants with baseline and visit 5 (end of trial visit) data.

End point type

Secondary

End point timeframe

Baseline and end of trial (up to a maximum of 119 days)

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[181]	47 ^[182]	54 ^[183]	49 ^[184]	55 ^[185]
Units: Participants
Breast	0	0	0	0	0
Adnexa	0	0	0	0	0
Cervix	0	0	0	0	0
Uterus	0	0	0	0	0
Vagina	0	0	0	0	0
External Genitalia	0	0	0	0	0

Notes
[181] - Breast N = 40 Adnexa N = 39 Cervix N = 39 Uterus N = 38 Vagina N = 41 External Genitalia N = 41
[182] - Breast N = 39 Adnexa N = 38 Cervix N = 40 Uterus N = 40 Vagina N = 40 External Genitalia N = 40
[183] - Breast N = 42 Adnexa N = 42 Cervix N = 42 Uterus N = 39 Vagina N = 42 External Genitalia N = 42
[184] - Breast N = 39 Adnexa N = 39 Cervix N = 39 Uterus N = 39 Vagina N = 39 External Genitalia N = 39
[185] - Breast N = 43 Adnexa N = 42 Cervix N = 43 Uterus N = 43 Vagina N = 43 External Genitalia N = 43

No statistical analyses for this end point

Secondary: Number of Participants that Experienced a Clinically Significant Electrocardiogram (ECG) Result

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End point title

Number of Participants that Experienced a Clinically Significant Electrocardiogram (ECG) Result

End point description

The ECG interpretation scheme included the analysis of the morphology, rhythm, conduction, ST segment, PR, QRS, QT and QTc intervals, T waves, U waves and the presence or absence of any pathological changes. All safety outcomes were analyzed using the safety analysis (SA) set: The SA set differs from the intent-to-treat (ITT) set as one participant randomized to the 2.5 mg E4 group received 10 mg by error. Therefore, the participant was allocated to the highest dose received, the 10 mg group, for analysis in the SA set.

End point type

Secondary

End point timeframe

Baseline to Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	52 ^[186]	47 ^[187]	54 ^[188]	49 ^[189]	55 ^[190]
Units: Participants	0	1	1	0	1

Notes
[186] - SA set N = 52 SA set: All randomized participants who received at least 1 dose of study drug
[187] - SA set: All randomized participants who received at least 1 dose of study drug
[188] - SA set: All randomized participants who received at least 1 dose of study drug
[189] - SA set: All randomized participants who received at least 1 dose of study drug
[190] - SA set: All randomized participants who received at least 1 dose of study drug

No statistical analyses for this end point

Secondary: Change in Body Mass Index (BMI) from Baseline to Week 13

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End point title

Change in Body Mass Index (BMI) from Baseline to Week 13

End point description

All safety outcomes were analyzed using the safety analysis (SA) set: The SA set differs from the intent-to-treat (ITT) set as one participant randomized to the 2.5 mg E4 group received 10 mg by error. Therefore, the participant was allocated to the highest dose received, the 10 mg group, for analysis in the SA set.

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	51 ^[191]	46 ^[192]	50 ^[193]	47 ^[194]	54 ^[195]
Units: kg/m2
arithmetic mean (standard deviation)	0.12 ( 0.765 )	0.28 ( 0.574 )	0.33 ( 0.654 )	0.11 ( 0.714 )	0.09 ( 0.618 )

Notes
[191] - SA N: 52 Randomized participants, received ≥1 dose of study drug, with data at baseline and week 13
[192] - SA: All participants who recieved at least 1 dose of study drug with data at baseline and week 13
[193] - SA: All participants who recieved at least 1 dose of study drug with data at baseline and week 13
[194] - SA: All participants who recieved at least 1 dose of study drug with data at baseline and week 13
[195] - SA: All participants who recieved at least 1 dose of study drug with data at baseline and week 13

No statistical analyses for this end point

Secondary: Change in Blood Pressure from Baseline to Week 13

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End point title

Change in Blood Pressure from Baseline to Week 13

End point description

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	51 ^[196]	46 ^[197]	51 ^[198]	47 ^[199]	54 ^[200]
Units: mmHg
arithmetic mean (standard deviation)
Systolic Blood Pressure	-0.24 ( 9.768 )	4.67 ( 9.942 )	1.49 ( 10.961 )	6.06 ( 12.858 )	2.31 ( 10.522 )
Diastolic Blood Pressure	-0.25 ( 7.954 )	2.74 ( 7.347 )	1.08 ( 8.724 )	1.36 ( 6.391 )	2.35 ( 8.294 )

Notes
[196] - SA N: 52 Randomized participants, received ≥1 dose of study drug, with data at baseline and week 13
[197] - SA: All participants who received at least 1 dose of study drug with data at baseline and week 13
[198] - SA: All participants who received at least 1 dose of study drug with data at baseline and week 13
[199] - SA: All participants who received at least 1 dose of study drug with data at baseline and week 13
[200] - SA: All participants who received at least 1 dose of study drug with data at baseline and week 13

No statistical analyses for this end point

Secondary: Change in Pulse Rate from Baseline to Week 13

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End point title

Change in Pulse Rate from Baseline to Week 13

End point description

End point type

Secondary

End point timeframe

Baseline and Week 13

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Number of subjects analysed	51 ^[201]	46 ^[202]	51 ^[203]	47 ^[204]	54 ^[205]
Units: beats/min
arithmetic mean (standard deviation)	-1.43 ( 8.031 )	1.04 ( 7.510 )	0.18 ( 9.427 )	-0.47 ( 10.032 )	0.22 ( 8.316 )

Notes
[201] - SA N: 52 Randomized participants, received ≥1 dose of study drug, with data at baseline and week 13
[202] - SA: All participants who recieved at least 1 dose of study drug with data at baseline and week 13
[203] - SA: All participants who recieved at least 1 dose of study drug with data at baseline and week 13
[204] - SA: All participants who recieved at least 1 dose of study drug with data at baseline and week 13
[205] - SA: All participants who recieved at least 1 dose of study drug with data at baseline and week 13

No statistical analyses for this end point

Secondary: Estetrol (E4) Concentrations in Plasma

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End point title

Estetrol (E4) Concentrations in Plasma ^[206]

End point description

Analyzed using the pharmacokinetic (PK) set: All participants who received at least one dose of study drug and had at least one post-baseline plasma sample collected. One participant was randomized to receive 2.5 mg but also received 10 mg by error. The participant was allocated to the highest dose received, 10 mg group, for the analysis in the PK set.

End point type

Secondary

End point timeframe

Baseline, Week 5 and Week 13

Notes
[206] - 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: PK analysis was only planned for participants receiving E4.

End point values	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg
Number of subjects analysed	52 ^[207]	47 ^[208]	52 ^[209]	47 ^[210]
Units: nmol/L
arithmetic mean (standard deviation)
Week 5	1.710 ( 1.3752 )	4.159 ( 4.2086 )	6.599 ( 4.3100 )	13.324 ( 9.6068 )
Week 13	1.639 ( 1.8015 )	3.593 ( 4.2321 )	5.894 ( 5.2996 )	8.645 ( 10.0393 )

Notes
[207] - PK: All participants with at least 1 post baseline sample of PK data Week 5 N = 46 Week 13 N = 51
[208] - PK: All participants with at least 1 post baseline sample of PK data Week 5 N = 43 Week 13 N = 46
[209] - PK: All participants with at least 1 post baseline sample of PK data Week 5 N = 47 Week 13 N = 50
[210] - PK: All participants with at least 1 post baseline sample of PK data Week 5 N = 45 Week 13 N = 46

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline to end of study, a maximum of 119 days

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

E4 2.5 mg

Reporting group description

Estetrol (E4) 2.5 mg was administered orally via a capsule, once daily.

Reporting group title

E4 5 mg

Reporting group description

Estetrol (E4) 5 mg was administered orally via a capsule, once daily.

Reporting group title

E4 10 mg

Reporting group description

Estetrol (E4) 10 mg was administered orally via a capsule, once daily.

Reporting group title

E4 15 mg

Reporting group description

Estetrol (E4) 15 mg was administered orally via a capsule, once daily.

Reporting group title

Placebo

Reporting group description

Matching placebo was administered orally via a capsule, once daily.

Serious adverse events	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 52 (0.00%)	0 / 47 (0.00%)	0 / 54 (0.00%)	2 / 49 (4.08%)	1 / 55 (1.82%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Reproductive system and breast disorders
Dysfunctional uterine bleeding
subjects affected / exposed	0 / 52 (0.00%)	0 / 47 (0.00%)	0 / 54 (0.00%)	1 / 49 (2.04%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 52 (0.00%)	0 / 47 (0.00%)	0 / 54 (0.00%)	0 / 49 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 52 (0.00%)	0 / 47 (0.00%)	0 / 54 (0.00%)	1 / 49 (2.04%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	30 / 52 (57.69%)	25 / 47 (53.19%)	30 / 54 (55.56%)	31 / 49 (63.27%)	26 / 55 (47.27%)
Nervous system disorders
Headache
subjects affected / exposed	4 / 52 (7.69%)	3 / 47 (6.38%)	4 / 54 (7.41%)	4 / 49 (8.16%)	6 / 55 (10.91%)
occurrences all number	4	9	8	8	9
Reproductive system and breast disorders
Vaginal haemorrhage
subjects affected / exposed	3 / 52 (5.77%)	4 / 47 (8.51%)	12 / 54 (22.22%)	10 / 49 (20.41%)	3 / 55 (5.45%)
occurrences all number	3	9	24	16	6
Uterine haemorrhage
subjects affected / exposed	3 / 52 (5.77%)	2 / 47 (4.26%)	4 / 54 (7.41%)	4 / 49 (8.16%)	2 / 55 (3.64%)
occurrences all number	4	2	5	4	2
Breast pain
subjects affected / exposed	3 / 52 (5.77%)	1 / 47 (2.13%)	5 / 54 (9.26%)	4 / 49 (8.16%)	1 / 55 (1.82%)
occurrences all number	3	1	6	4	1
Endometrial hypertrophy
subjects affected / exposed	0 / 52 (0.00%)	0 / 47 (0.00%)	0 / 54 (0.00%)	3 / 49 (6.12%)	0 / 55 (0.00%)
occurrences all number	0	0	0	3	0
Gastrointestinal disorders
Abdominal pain lower
subjects affected / exposed	0 / 52 (0.00%)	0 / 47 (0.00%)	3 / 54 (5.56%)	1 / 49 (2.04%)	0 / 55 (0.00%)
occurrences all number	0	0	5	1	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 52 (1.92%)	1 / 47 (2.13%)	0 / 54 (0.00%)	1 / 49 (2.04%)	3 / 55 (5.45%)
occurrences all number	1	1	0	1	4
Infections and infestations
Viral upper respiratory tract infection
subjects affected / exposed	4 / 52 (7.69%)	0 / 47 (0.00%)	3 / 54 (5.56%)	2 / 49 (4.08%)	0 / 55 (0.00%)
occurrences all number	5	0	4	3	0
Urinary tract infection
subjects affected / exposed	0 / 52 (0.00%)	3 / 47 (6.38%)	0 / 54 (0.00%)	1 / 49 (2.04%)	1 / 55 (1.82%)
occurrences all number	0	3	0	1	1
Influenza
subjects affected / exposed	0 / 52 (0.00%)	1 / 47 (2.13%)	3 / 54 (5.56%)	1 / 49 (2.04%)	1 / 55 (1.82%)
occurrences all number	0	1	3	1	1

More information

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Were there any global substantial amendments to the protocol? Yes

26 Jul 2016

•Exclusion criteria number 8 was updated to clarify that participants with glucose laboratory values outside the normal ranges and glycated hemoglobin above 7% were not allowed to participate in the trial. •Exclusion criteria number 9 was updated to only include participants who were in the low or moderate cardiovascular risk category according to the SCORE chart issued by the European Association for Cardiovascular Prevention and Rehabilitation. •Instructions were added in regards to progestin treatment, that had to be followed in case of occurrences of abnormal uterine bleeding or endometrial thickness ≥15 mm. •"Presence of endometrial hyperplasia" was added as a reason for premature discontinuation to emphasize that endometrial hyperplasia is an absolute reason for a participant's discontinuation. •The statistical model for the analysis of "vaginal bleeding associated with sexual activity" (logistic regression) was specified. •Two analysis populations were added to initially planned study populations, the modified intent-to-treat and the modified per-protocol set, to allow analyzing the primary objective in participants who did not receive any progestin therapy during E4/placebo treatment.

09 Jan 2017

•Exclusion criteria 9 was amended to use the atherosclerotic cardiovascular disease score recommended by the North American Menopause Society rather than the European SCORE to evaluate the eligibility of the participants. The goal was 2-fold: firstly, to use the most recent and robust epidemiological evidence and the most recent recommendations in the menopausal field, secondly to give the investigator an easier and more user-friendly tool to evaluate the cardiovascular risk, limiting at the maximum the risk of mistakes. •Analysis of covariance was performed instead of mixed effect model repeat measurement for the analysis of the efficacy endpoints.

14 Mar 2017

Ireland-specific amendment. •Exclusion criteria number 15 was updated to "Acute or chronic renal impairment, including severe renal impairment" and exclusion criteria number 24 was updated to include "porphyria", following a request from Ireland Competent Authorities.

28 Apr 2017

•The population of eligible individuals was expanded to include hysterectomized women, and the age limit was decreased from 45 years to 40 years. •The inclusion criteria for postmenopausal status was revised as it seemed clinically relevant to consider as postmenopausal the subjects presenting 6 months of spontaneous amenorrhea associated with an absence of ovarian function (translated in a circulating level of estradiol <20 pg/mL). •The exclusion criteria "participants with QTc prolongation (QTcB and QTcF values >450 msec)" was removed. •"Use of >1 ml/day of nicotine-containing liquid for electronic cigarette" was added as an exclusion criteria. •The use of clonidine was added to the list of prohibited anti-hot-flush treatments. •A new exclusion criteria was added to exclude participants treated with drugs that might affect the occurrence of vasomotor symptoms.

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 reported

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Clinical trials

Clinical Trial Results: A Multicentre Dose-Finding, Randomised, Double-Blind, Placebo-Controlled Study to Select the Daily Oral Dose of Estetrol (E4) for the Treatment of Vasomotor Symptoms in Post-Menopausal Women

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in Weekly Frequency of Moderate to Severe Vasomotor Symptoms (VMS) from Baseline to Week 4

Primary: Change in Weekly Frequency of Moderate to Severe Vasomotor Symptoms (VMS) from Baseline to Week 4

Primary: Change in Weekly Frequency of Moderate to Severe Vasomotor Symptoms (VMS) from Baseline to Week 12

Primary: Change in Weekly Frequency of Moderate to Severe Vasomotor Symptoms (VMS) from Baseline to Week 12

Primary: Change in Mean Severity of Moderate to Severe Vasomotor Symptoms (VMS) from Baseline to Week 4

Primary: Change in Mean Severity of Moderate to Severe Vasomotor Symptoms (VMS) from Baseline to Week 4

Primary: Change in Mean Severity of Moderate to Severe Vasomotor Symptoms (VMS) from Baseline to Week 12

Primary: Change in Mean Severity of Moderate to Severe Vasomotor Symptoms (VMS) from Baseline to Week 12

Secondary: Change in Genitourinary Syndrome of Menopause (GSM) from Baseline to Week 13

Secondary: Change in Genitourinary Syndrome of Menopause (GSM) from Baseline to Week 13

Secondary: Change in Vaginal Bleeding Associated with Sexual Activity from Baseline to Week 13

Secondary: Change in Vaginal Bleeding Associated with Sexual Activity from Baseline to Week 13

Secondary: Change in Menopause Rating Scale (MRS) Score from Baseline to Week 5

Secondary: Change in Menopause Rating Scale (MRS) Score from Baseline to Week 5

Secondary: Change in Menopause Rating Scale (MRS) Score from Baseline to Week 13

Secondary: Change in Menopause Rating Scale (MRS) Score from Baseline to Week 13

Secondary: Change in Vaginal pH from Baseline to Week 13

Secondary: Change in Vaginal pH from Baseline to Week 13

Secondary: Change in Vaginal Maturation Value (MV) from Baseline to Week 13

Secondary: Change in Vaginal Maturation Value (MV) from Baseline to Week 13

Secondary: Change in Serum Concentration of Triglycerides from Baseline to Week 13

Secondary: Change in Serum Concentration of Triglycerides from Baseline to Week 13

Secondary: Change in Serum Concentration of High Density Lipoprotein (HDL) Cholesterol from Baseline to Week 13

Secondary: Change in Serum Concentration of High Density Lipoprotein (HDL) Cholesterol from Baseline to Week 13

Secondary: Change in Serum Concentration of Low Density Lipoprotein (LDL) Cholesterol from Baseline to Week 13

Secondary: Change in Serum Concentration of Low Density Lipoprotein (LDL) Cholesterol from Baseline to Week 13

Secondary: Change in Total Cholesterol from Baseline to Week 13

Secondary: Change in Total Cholesterol from Baseline to Week 13

Secondary: Change in Fasting Glucose from Baseline to Week 13

Secondary: Change in Fasting Glucose from Baseline to Week 13

Secondary: Change in Insulin Levels from Baseline to Week 13

Secondary: Change in Insulin Levels from Baseline to Week 13

Secondary: Change in Serum Concentration of Glycated Hemoglobin from Baseline to Week 13

Secondary: Change in Serum Concentration of Glycated Hemoglobin from Baseline to Week 13

Secondary: Change in Homeostatis Model Assessment-Estimated Insulin Resistance (HOMA-IR) from Baseline to Week 13

Secondary: Change in Homeostatis Model Assessment-Estimated Insulin Resistance (HOMA-IR) from Baseline to Week 13

Secondary: Change in Serum Concentration of Prothrombin Fragment 1 + 2 from Baseline to Week 13

Secondary: Change in Serum Concentration of Prothrombin Fragment 1 + 2 from Baseline to Week 13

Secondary: Change in Serum Concentration of D-dimers from Baseline to Week 13

Secondary: Change in Serum Concentration of D-dimers from Baseline to Week 13

Secondary: Change in Serum Concentration of Sex-Hormone Binding Globulin from Baseline to Week 13

Secondary: Change in Serum Concentration of Sex-Hormone Binding Globulin from Baseline to Week 13

Secondary: Change in Serum Concentration of Antithrombin from Baseline to Week 13

Secondary: Change in Serum Concentration of Antithrombin from Baseline to Week 13

Secondary: Change in Serum Concentration of Protein-C from Baseline to Week 13

Secondary: Change in Serum Concentration of Protein-C from Baseline to Week 13

Secondary: Change in Serum Concentration of Free Protein-S from Baseline to Week 13

Secondary: Change in Serum Concentration of Free Protein-S from Baseline to Week 13

Secondary: Change in Serum Concentration of Factor VIII from Baseline to Week 13

Secondary: Change in Serum Concentration of Factor VIII from Baseline to Week 13

Secondary: Change in Serum Concentration of Free Tissue Factor Pathway Inhibitor (TFPI) from Baseline to Week 13

Secondary: Change in Serum Concentration of Free Tissue Factor Pathway Inhibitor (TFPI) from Baseline to Week 13

Secondary: Change in Activated protein C sensitivity ratio (APCsr) (Endogenous Thrombin Potential [ETP] - Based) from Baseline to Week 13

Secondary: Change in Activated protein C sensitivity ratio (APCsr) (Endogenous Thrombin Potential [ETP] - Based) from Baseline to Week 13

Secondary: Change in Serum Concentration of Osteocalcin from Baseline to Week 13

Secondary: Change in Serum Concentration of Osteocalcin from Baseline to Week 13

Secondary: Change in Serum Concentration of C-Terminal Telopeptide (CTX-1) from Baseline to Week 13

Secondary: Change in Serum Concentration of C-Terminal Telopeptide (CTX-1) from Baseline to Week 13

Secondary: Number of Participants Who Experienced a Treatment-Emergent Adverse Event (TEAE)

Secondary: Number of Participants Who Experienced a Treatment-Emergent Adverse Event (TEAE)

Secondary: Number of Participants Who Experienced a Serious Adverse Event (SAE)

Secondary: Number of Participants Who Experienced a Serious Adverse Event (SAE)

Secondary: Number of Participants Who Experienced a Treatment Related Adverse Event

Secondary: Number of Participants Who Experienced a Treatment Related Adverse Event

Secondary: Number of Participants Who Experienced a Clinically Significant Clinical Laboratory Measurement

Secondary: Number of Participants Who Experienced a Clinically Significant Clinical Laboratory Measurement

Secondary: Mean Endometrial Thickness at Each Study Visit

Secondary: Mean Endometrial Thickness at Each Study Visit

Secondary: Number of Participants Who Experienced Abnormal Uterine Bleeding at Each Study Visit

Secondary: Number of Participants Who Experienced Abnormal Uterine Bleeding at Each Study Visit

Clinical Trial Results:
A Multicentre Dose-Finding, Randomised, Double-Blind, Placebo-Controlled Study to Select the Daily Oral Dose of Estetrol (E4) for the Treatment of Vasomotor Symptoms in Post-Menopausal Women