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Clinical Trial Results:
Multi-center, randomized, comparator-controlled, single-blind, parallel-group study to investigate the pharmacodynamics, pharmacokinetics and safety of an intrauterine system releasing BAY 1007626, as compared with Mirena and Jaydess, in a combined proof-of-concept and dose-finding study in healthy pre-menopausal women treated for 90 days

Summary
EudraCT number	2013-003980-74
Trial protocol	DE GB NL
Global end of trial date	22 Jul 2016

Results information
Results version number	v1(current)
This version publication date	07 Jun 2017
First version publication date	07 Jun 2017
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

BAY1007626/15731

ISRCTN number

US NCT number

NCT02490774

WHO universal trial number (UTN)

Sponsor organisation name

Bayer AG

Sponsor organisation address

Kaiser-Wilhelm-Allee, D-51368 Leverkusen, Germany,

Public contact

Bayer Clinical Trial Contact, Bayer HealthCare AG, clinical-trials-contact@bayerhealthcare.com

Scientific contact

Bayer Clinical Trial Contact, Bayer HealthCare AG, clinical-trials-contact@bayerhealthcare.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 Jul 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

22 Jul 2016

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective of this study was to investigate local and systemic effects of BAY1007626 on: – Number of bleeding and spotting days, – Endometrial histology, – Ovulation (as surrogate for systemic effects).

Protection of trial subjects

The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.

Background therapy

Evidence for comparator

Actual start date of recruitment

22 Jun 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 59

Country: Number of subjects enrolled

United Kingdom: 32

Country: Number of subjects enrolled

Germany: 110

Worldwide total number of subjects

201

EEA total number of subjects

201

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)

201

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 9 study centers in multiple countries: Germany, the Netherlands and the United Kingdom between 22 June 2015 (first subject first visit) and 26 May 2016 (last subject last visit).

Screening details

Overall, 395 subjects were screened, of these 194 subjects were screen failures. A total of 201 subjects were randomized: 19 subjects were never administered study drug and 182 subjects were treated and of them 126 completed the study.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Single blind

Roles blinded

Subject

Are arms mutually exclusive

Yes

BAY1007626, 5 microgram (mcg)

Arm description

Subjects were treated with an intrauterine system with a nominal in vitro release of 5 mcg BAY1007626/day for 90 days.

Arm type

Experimental

Investigational medicinal product name

BAY1007626

Investigational medicinal product code

BAY1007626

Other name

Pharmaceutical forms

Intrauterine delivery system

Routes of administration

Intrauterine use

Dosage and administration details

Subjects were treated with an intrauterine system with a nominal in vitro release of 5 mcg BAY1007626/day for 90 days.

BAY1007626, 15 mcg

Arm description

Subjects were treated with an intrauterine system with a nominal in vitro release of 15 mcg BAY1007626/day for 90 days.

Arm type

Experimental

Investigational medicinal product name

BAY1007626

Investigational medicinal product code

BAY1007626

Other name

Pharmaceutical forms

Intrauterine delivery system

Routes of administration

Intrauterine use

Dosage and administration details

Subjects were treated with an intrauterine system with a nominal in vitro release of 15 mcg BAY1007626/day for 90 days.

BAY1007626, 30 mcg

Arm description

Subjects were treated with an intrauterine system with a nominal in vitro release of 30 mcg BAY1007626/day for 90 days.

Arm type

Experimental

Investigational medicinal product name

BAY1007626

Investigational medicinal product code

BAY1007626

Other name

Pharmaceutical forms

Intrauterine delivery system

Routes of administration

Intrauterine use

Dosage and administration details

Subjects were treated with an intrauterine system with a nominal in vitro release of 30 mcg BAY1007626/day for 90 days.

BAY1007626, 60 mcg

Arm description

Subjects were treated with an intrauterine system with a nominal in vitro release of 60 mcg BAY1007626/day for 90 days.

Arm type

Experimental

Investigational medicinal product name

BAY1007626

Investigational medicinal product code

BAY1007626

Other name

Pharmaceutical forms

Intrauterine delivery system

Routes of administration

Intrauterine use

Dosage and administration details

Subjects were treated with an intrauterine system with a nominal in vitro release of 60 mcg BAY1007626/day for 90 days.

Levonorgestrel (Jaydess, BAY86-5028)

Arm description

Subjects were treated with an intrauterine system with a nominal in vitro release of 12 mcg levonorgestrel/day for 90 days.

Arm type

Active comparator

Investigational medicinal product name

Levonorgestrel

Investigational medicinal product code

BAY86-5028

Other name

Jaydess

Pharmaceutical forms

Intrauterine delivery system

Routes of administration

Intrauterine use

Dosage and administration details

Subjects were treated with an intrauterine system with a nominal in vitro release of 12 mcg levonorgestrel/day for 90 days.

Levonorgestrel (Mirena, BAY86-5028)

Arm description

Subjects were treated with an intrauterine system with a nominal in vitro release of 20 mcg levonorgestrel/day for 90 days.

Arm type

Active comparator

Investigational medicinal product name

Levonorgestrel

Investigational medicinal product code

BAY86-5028

Other name

Mirena

Pharmaceutical forms

Intrauterine delivery system

Routes of administration

Intrauterine use

Dosage and administration details

Subjects were treated with an intrauterine system with a nominal in vitro release of 20 mcg levonorgestrel/day for 90 days.

Number of subjects in period 1	BAY1007626, 5 microgram (mcg)	BAY1007626, 15 mcg	BAY1007626, 30 mcg	BAY1007626, 60 mcg	Levonorgestrel (Jaydess, BAY86-5028)	Levonorgestrel (Mirena, BAY86-5028)
Started	39	36	37	39	12	38
Completed	22	24	26	24	10	24
Not completed	17	12	11	15	2	14
Protocol violation	2	1	1	2	1	1
Adverse event	4	-	1	3	-	3
Study terminated by sponsor	11	9	8	8	1	9
Withdrawal by subject	-	2	1	2	-	1

Baseline characteristics

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Reporting group title

BAY1007626, 5 microgram (mcg)

Reporting group description

Subjects were treated with an intrauterine system with a nominal in vitro release of 5 mcg BAY1007626/day for 90 days.

Reporting group title

BAY1007626, 15 mcg

Reporting group description

Subjects were treated with an intrauterine system with a nominal in vitro release of 15 mcg BAY1007626/day for 90 days.

Reporting group title

BAY1007626, 30 mcg

Reporting group description

Subjects were treated with an intrauterine system with a nominal in vitro release of 30 mcg BAY1007626/day for 90 days.

Reporting group title

BAY1007626, 60 mcg

Reporting group description

Subjects were treated with an intrauterine system with a nominal in vitro release of 60 mcg BAY1007626/day for 90 days.

Reporting group title

Levonorgestrel (Jaydess, BAY86-5028)

Reporting group description

Subjects were treated with an intrauterine system with a nominal in vitro release of 12 mcg levonorgestrel/day for 90 days.

Reporting group title

Levonorgestrel (Mirena, BAY86-5028)

Reporting group description

Subjects were treated with an intrauterine system with a nominal in vitro release of 20 mcg levonorgestrel/day for 90 days.

Reporting group values	BAY1007626, 5 microgram (mcg)	BAY1007626, 15 mcg	BAY1007626, 30 mcg	BAY1007626, 60 mcg	Levonorgestrel (Jaydess, BAY86-5028)	Levonorgestrel (Mirena, BAY86-5028)	Total
Number of subjects	39	36	37	39	12	38	201
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	29.9 ( 6.2 )	27.8 ( 5.4 )	30.7 ( 5.1 )	29.9 ( 5.3 )	29.4 ( 6 )	29.1 ( 5.3 )	-
Gender categorical
Units: Subjects
Female	39	36	37	39	12	38	201

End points

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Reporting group title

BAY1007626, 5 microgram (mcg)

Reporting group description

Subjects were treated with an intrauterine system with a nominal in vitro release of 5 mcg BAY1007626/day for 90 days.

Reporting group title

BAY1007626, 15 mcg

Reporting group description

Subjects were treated with an intrauterine system with a nominal in vitro release of 15 mcg BAY1007626/day for 90 days.

Reporting group title

BAY1007626, 30 mcg

Reporting group description

Subjects were treated with an intrauterine system with a nominal in vitro release of 30 mcg BAY1007626/day for 90 days.

Reporting group title

BAY1007626, 60 mcg

Reporting group description

Subjects were treated with an intrauterine system with a nominal in vitro release of 60 mcg BAY1007626/day for 90 days.

Reporting group title

Levonorgestrel (Jaydess, BAY86-5028)

Reporting group description

Subjects were treated with an intrauterine system with a nominal in vitro release of 12 mcg levonorgestrel/day for 90 days.

Reporting group title

Levonorgestrel (Mirena, BAY86-5028)

Reporting group description

Subjects were treated with an intrauterine system with a nominal in vitro release of 20 mcg levonorgestrel/day for 90 days.

Subject analysis set title

Safety analysis set (SAF)

Subject analysis set type

Safety analysis

Subject analysis set description

SAF (N= 182) included all subjects who received study medication.

Subject analysis set title

Pharmacodynamic analysis set 1 (PDS1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

PDS1 (N= 134) included all subjects within the safety analysis set without major protocol deviations who were non completers with at least 60 days of treatment, and for whom not more than 9 entries in the bleeding diary were missing during the treatment period.

Subject analysis set title

Pharmacodynamic analysis set 2 (PDS2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

PDS2 (N= 44) included all subjects who received study medication, without major protocol violations for whom the pharmacodynamics biopsy was evaluated.

Subject analysis set title

Pharmacodynamic analysis set 3 (PDS3)

Subject analysis set type

Sub-group analysis

Subject analysis set description

PDS3 (N= 167) included all subjects from the safety analysis set without major protocol deviations who were treated for at least 40 days (a time span that would cover at least one menstrual cycle in an untreated woman), and for whom weekly measurements of progesterone were performed as outlined in the protocol.

Primary: Number of Bleeding and Spotting Days During the 90 Days Treatment Period

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End point title

Number of Bleeding and Spotting Days During the 90 Days Treatment Period

End point description

The total number of bleeding and spotting days per subject under treatment were determined as the total number of days for which a code greater than (>) 1 had been observed. The following codes 1,2,3,4,5 were given for the below mentioned categories. 1) None: no bleeding 2) Spotting: less than associated with normal menstruation relative to the subject’s experience, with no need for sanitary protection (except for panty liners) 3) Light: less than associated with normal menstruation relative to the subject’s experience, with need for sanitary protection 4) Normal: like normal menstruation relative to the subject’s experience 5) Heavy: more than normal menstruation relative to the subject’s experience

End point type

Primary

End point timeframe

Day 1 to Day 90

End point values	BAY1007626, 5 microgram (mcg)	BAY1007626, 15 mcg	BAY1007626, 30 mcg	BAY1007626, 60 mcg	Levonorgestrel (Jaydess, BAY86-5028)	Levonorgestrel (Mirena, BAY86-5028)
Number of subjects analysed	19 ^[1]	17 ^[2]	22 ^[3]	20 ^[4]	9 ^[5]	20 ^[6]
Units: days
arithmetic mean (standard deviation)	38.0526 ( 18.0045 )	36.2353 ( 16.1072 )	49.8636 ( 15.3973 )	42.35 ( 19.2826 )	40.1111 ( 15.8623 )	37.3 ( 12.2178 )

Notes
[1] - PDS1 with number of subjects evaluable for this specific endpoint
[2] - PDS1 with number of subjects evaluable for this specific endpoint
[3] - PDS1 with number of subjects evaluable for this specific endpoint
[4] - PDS1 with number of subjects evaluable for this specific endpoint
[5] - PDS1 with number of subjects evaluable for this specific endpoint
[6] - PDS1 with number of subjects evaluable for this specific endpoint

Statistical analysis 1

Statistical analysis description

Number of bleeding and spotting days during the 90 days of treatment were analyzed assuming a normal distribution. BAY1007626, 5 mcg treatment arm was compared with the Mirena arm. Point estimates as well as two-sided 95 percent (%) confidence interval (CI) estimates were given for the mean difference between Mirena and BAY1007626, 5 mcg arm. Point and CI estimates were determined by using a Bayesian analysis.

Comparison groups

Levonorgestrel (Mirena, BAY86-5028) v BAY1007626, 5 microgram (mcg)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference

Point estimate

2.3

Confidence interval

level

95%

sides

2-sided

lower limit

-6.7

upper limit

11.6

Statistical analysis 2

Statistical analysis description

Number of bleeding and spotting days during the 90 days of treatment were analyzed assuming a normal distribution. BAY1007626, 15 mcg treatment arm was compared with the Mirena arm. Point estimates as well as two-sided 95% CI estimates were given for the mean difference between Mirena and BAY1007626, 15 mcg arm. Point and CI estimates were determined by using a Bayesian analysis.

Comparison groups

Levonorgestrel (Mirena, BAY86-5028) v BAY1007626, 15 mcg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-8.3

upper limit

9.5

Statistical analysis 3

Statistical analysis description

Number of bleeding and spotting days during the 90 days of treatment were analyzed assuming a normal distribution. BAY1007626, 30 mcg treatment arm was compared with the Mirena arm. Point estimates as well as two-sided 95% CI estimates were given for the mean difference between Mirena and BAY1007626, 30 mcg arm. Point and CI estimates were determined by using a Bayesian analysis.

Comparison groups

Levonorgestrel (Mirena, BAY86-5028) v BAY1007626, 30 mcg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference

Point estimate

14.2

Confidence interval

level

95%

sides

2-sided

lower limit

6.9

upper limit

21.6

Statistical analysis 4

Statistical analysis description

Number of bleeding and spotting days during the 90 days of treatment were analyzed assuming a normal distribution. BAY1007626, 60 mcg treatment arm was compared with the Mirena arm. Point estimates as well as two-sided 95% CI estimates were given for the mean difference between Mirena and BAY1007626, 60 mcg arm. Point and CI estimates were determined by using a Bayesian analysis.

Comparison groups

Levonorgestrel (Mirena, BAY86-5028) v BAY1007626, 60 mcg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference

Point estimate

6.6

Confidence interval

level

95%

sides

2-sided

lower limit

-2.8

upper limit

16.2

Primary: Number of Subjects With Endometrium Proliferative

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End point title

Number of Subjects With Endometrium Proliferative ^[7]

End point description

Endometrial histology was evaluated in endometrial biopsy specimen taken. The histology of the specimen was evaluated by blinded reading. As the study was terminated prematurely, biopsies were only assessed by blinded read assessment in a few subjects. Endometrial biopsies were taken between Days 41 and 90 during treatment and on Day 9 during follow-up. In the below table, "n" indicates the number of subjects analysed for the specified parameter at given time point for each arm, respectively.

End point type

Primary

End point timeframe

Treatment (between Days 41 and 90), post-treatment, follow-up (Day 9 during follow-up)

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, no inferential statistical analyses were performed.

End point values	BAY1007626, 5 microgram (mcg)	BAY1007626, 15 mcg	BAY1007626, 30 mcg	BAY1007626, 60 mcg	Levonorgestrel (Jaydess, BAY86-5028)	Levonorgestrel (Mirena, BAY86-5028)
Number of subjects analysed	4 ^[8]	7 ^[9]	11 ^[10]	8 ^[11]	7 ^[12]	6 ^[13]
Units: subjects
Treatment (n= 4,7,11,8,7,6)	0	0	0	0	0	1
Post-treatment (n= 0,1,0,0,0,0)	0	0	0	0	0	0
Follow-up (n= 2,1,4,0,3,2)	2	1	4	0	3	1

Notes
[8] - PDS2
[9] - PDS2
[10] - PDS2
[11] - PDS2
[12] - PDS2
[13] - PDS2

No statistical analyses for this end point

Primary: Number of Subjects With Ovulation During Treatment

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End point title

Number of Subjects With Ovulation During Treatment ^[14]

End point description

Ovulation activity is defined as: In the weekly visit group: frequency of ovulation (based on assessments of progesterone serum levels > 5 nanomoles/liter) In the dense visit group: frequency of ovulation (based on evaluation of Hoogland score of 6).

End point type

Primary

End point timeframe

Day 1 to Day 90

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: EudraCT database does not allow to report only one treatment group in statistical analyses section. Due to this format constraint, charts have been uploaded with the accurate details of statistical analyses for this endpoint. Please find the statistical analyses in the attachment below.

End point values	BAY1007626, 5 microgram (mcg)	BAY1007626, 15 mcg	BAY1007626, 30 mcg	BAY1007626, 60 mcg	Levonorgestrel (Jaydess, BAY86-5028)	Levonorgestrel (Mirena, BAY86-5028)
Number of subjects analysed	31 ^[15]	31 ^[16]	31 ^[17]	32 ^[18]	11 ^[19]	31 ^[20]
Units: subjects	28	29	29	19	10	19

Attachments

15731_Statistical Analysis_Primary OM

Notes
[15] - PDS3
[16] - PDS3
[17] - PDS3
[18] - PDS3
[19] - PDS3
[20] - PDS3

No statistical analyses for this end point

Secondary: Endometrial Thickness

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End point title

Endometrial Thickness

End point description

Endometrium is the tissue lining the inner cavity of the uterus. Endometrial thickness was measured by transvaginal ultrasound (TVU). TUV examination was performed by a trained qualified member of the investigation team. The endometrial thickness was measured in the medio-sagittal section as double layer in millimetres. As an interim analysis had shown that the primary endpoints could not be met, the study was discontinued permanently and therefore, endometrial thickness was not measured.

End point type

Secondary

End point timeframe

From start of treatment until end of study

End point values	BAY1007626, 5 microgram (mcg)	BAY1007626, 15 mcg	BAY1007626, 30 mcg	BAY1007626, 60 mcg	Levonorgestrel (Jaydess, BAY86-5028)	Levonorgestrel (Mirena, BAY86-5028)
Number of subjects analysed	0 ^[21]	0 ^[22]	0 ^[23]	0 ^[24]	0 ^[25]	0 ^[26]
Units: subjects

Notes
[21] - As the primary endpoints could not be met, the study was discontinued permanently.
[22] - As the primary endpoints could not be met, the study was discontinued permanently.
[23] - As the primary endpoints could not be met, the study was discontinued permanently.
[24] - As the primary endpoints could not be met, the study was discontinued permanently.
[25] - As the primary endpoints could not be met, the study was discontinued permanently.
[26] - As the primary endpoints could not be met, the study was discontinued permanently.

No statistical analyses for this end point

Secondary: Bleeding Characterization (Intensity and Pattern)

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End point title

Bleeding Characterization (Intensity and Pattern)

End point description

A bleeding/spotting episode is defined as day(s) with bleeding/spotting preceded and followed by at least 2 bleed-free days. For bleeding pattern the following dichotomous variables were analysed: a) Irregular bleeding: 3 to 5 bleeding/spotting episodes and less than 3 bleeding/spotting-free intervals of 14 or more days. b) Prolonged bleeding: any bleeding/spotting episode lasting more than 14 days. c) Frequent bleeding: more than 5 bleeding/spotting episodes.

End point type

Secondary

End point timeframe

Day 1 to Day 90

End point values	BAY1007626, 5 microgram (mcg)	BAY1007626, 15 mcg	BAY1007626, 30 mcg	BAY1007626, 60 mcg	Levonorgestrel (Jaydess, BAY86-5028)	Levonorgestrel (Mirena, BAY86-5028)
Number of subjects analysed	19 ^[27]	17 ^[28]	22 ^[29]	20 ^[30]	9 ^[31]	20 ^[32]
Units: subjects
Irregular bleeding	8	8	12	13	7	11
Prolonged bleeding	9	7	14	13	4	11
Frequent bleeding	4	6	3	2	0	5

Notes
[27] - PDS with number of subjects evaluable for this specific endpoint
[28] - PDS with number of subjects evaluable for this specific endpoint
[29] - PDS with number of subjects evaluable for this specific endpoint
[30] - PDS
[31] - PDS
[32] - PDS with number of subjects evaluable for this specific endpoint

No statistical analyses for this end point

Secondary: Serum Levels of Hormones (Estradiol, Progesterone, Luteinizing Hormone, Follicle-Stimulating Hormone)

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End point title

Serum Levels of Hormones (Estradiol, Progesterone, Luteinizing Hormone, Follicle-Stimulating Hormone)

End point description

Blood samples for the determination of estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone levels in serum were taken during the treatment period and the follow-up period. As an interim analysis had shown that the primary endpoints could not be met, the study was discontinued permanently and therefore serum levels of hormones in blood were not evaluated.

End point type

Secondary

End point timeframe

From start of treatment until end of study

End point values	BAY1007626, 5 microgram (mcg)	BAY1007626, 15 mcg	BAY1007626, 30 mcg	BAY1007626, 60 mcg	Levonorgestrel (Jaydess, BAY86-5028)	Levonorgestrel (Mirena, BAY86-5028)
Number of subjects analysed	0 ^[33]	0 ^[34]	0 ^[35]	0 ^[36]	0 ^[37]	0 ^[38]
Units: subjects

Notes
[33] - As the primary endpoints could not be met, the study was discontinued permanently.
[34] - As the primary endpoints could not be met, the study was discontinued permanently.
[35] - As the primary endpoints could not be met, the study was discontinued permanently.
[36] - As the primary endpoints could not be met, the study was discontinued permanently.
[37] - As the primary endpoints could not be met, the study was discontinued permanently.
[38] - As the primary endpoints could not be met, the study was discontinued permanently.

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

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End point title

Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

End point description

An adverse event (AE) was any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly and another medical important serious event as judged by investigator. AE/SAEs that started or worsened after study drug treatment were recorded as TEAE/TESAEs.

End point type

Secondary

End point timeframe

From start of study treatment until end of study

End point values	BAY1007626, 5 microgram (mcg)	BAY1007626, 15 mcg	BAY1007626, 30 mcg	BAY1007626, 60 mcg	Levonorgestrel (Jaydess, BAY86-5028)	Levonorgestrel (Mirena, BAY86-5028)
Number of subjects analysed	36 ^[39]	33 ^[40]	33 ^[41]	34 ^[42]	11 ^[43]	35 ^[44]
Units: subjects
TEAEs	32	28	28	32	11	33
TESAEs	2	0	0	0	0	0

Notes
[39] - SAF
[40] - SAF
[41] - SAF
[42] - SAF
[43] - SAF
[44] - SAF

No statistical analyses for this end point

Secondary: Maximum Observed Drug Concentration of BAY1007626 After Insertion of Intrauterine System (Cmax) in Plasma

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End point title

Maximum Observed Drug Concentration of BAY1007626 After Insertion of Intrauterine System (Cmax) in Plasma

End point description

Maximum observed drug concentration of BAY1007626 after insertion of intrauterine system in plasma. As an interim analysis had shown that the primary endpoints could not be met, the study was discontinued permanently and therefore pharmacokinetic parameters were not evaluated.

End point type

Secondary

End point timeframe

Pre-dose (30 minutes prior on Day 1) to post-dose on Day 90

End point values	BAY1007626, 5 microgram (mcg)	BAY1007626, 15 mcg	BAY1007626, 30 mcg	BAY1007626, 60 mcg	Levonorgestrel (Jaydess, BAY86-5028)	Levonorgestrel (Mirena, BAY86-5028)
Number of subjects analysed	0 ^[45]	0 ^[46]	0 ^[47]	0 ^[48]	0 ^[49]	0 ^[50]
Units: microgram per liter (mcg/L)
geometric mean (geometric coefficient of variation)	( )	( )	( )	( )	( )	( )

Notes
[45] - As the primary endpoints could not be met, the study was discontinued permanently.
[46] - As the primary endpoints could not be met, the study was discontinued permanently.
[47] - As the primary endpoints could not be met, the study was discontinued permanently.
[48] - As the primary endpoints could not be met, the study was discontinued permanently.
[49] - As the primary endpoints could not be met, the study was discontinued permanently.
[50] - As the primary endpoints could not be met, the study was discontinued permanently.

No statistical analyses for this end point

Secondary: Area Under the Concentration Versus Time Curve (AUC) of BAY1007626 in Plasma After Insertion of Intrauterine System

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End point title

Area Under the Concentration Versus Time Curve (AUC) of BAY1007626 in Plasma After Insertion of Intrauterine System

End point description

Area under the concentration versus time curve of BAY1007626 in plasma after insertion of intrauterine system. As an interim analysis had shown that the primary endpoints could not be met, the study was discontinued permanently and therefore pharmacokinetic parameters were not evaluated.

End point type

Secondary

End point timeframe

Pre-dose (30 minutes prior on Day 1) to post-dose on Day 90

End point values	BAY1007626, 5 microgram (mcg)	BAY1007626, 15 mcg	BAY1007626, 30 mcg	BAY1007626, 60 mcg	Levonorgestrel (Jaydess, BAY86-5028)	Levonorgestrel (Mirena, BAY86-5028)
Number of subjects analysed	0 ^[51]	0 ^[52]	0 ^[53]	0 ^[54]	0 ^[55]	0 ^[56]
Units: microgramhour per liter (mcgh/L)
geometric mean (geometric coefficient of variation)	( )	( )	( )	( )	( )	( )

Notes
[51] - As the primary endpoints could not be met, the study was discontinued permanently.
[52] - As the primary endpoints could not be met, the study was discontinued permanently.
[53] - As the primary endpoints could not be met, the study was discontinued permanently.
[54] - As the primary endpoints could not be met, the study was discontinued permanently.
[55] - As the primary endpoints could not be met, the study was discontinued permanently.
[56] - As the primary endpoints could not be met, the study was discontinued permanently.

No statistical analyses for this end point

Secondary: Half-life Associated With the Terminal Slope (t1/2) of BAY1007626 in Plasma

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End point title

Half-life Associated With the Terminal Slope (t1/2) of BAY1007626 in Plasma

End point description

Half-life associated with the terminal slope of BAY1007626 in plasma. As an interim analysis had shown that the primary endpoints could not be met, the study was discontinued permanently and therefore pharmacokinetic parameters were not evaluated.

End point type

Secondary

End point timeframe

Pre-dose (30 minutes prior on Day 1) to post-dose on Day 90

End point values	BAY1007626, 5 microgram (mcg)	BAY1007626, 15 mcg	BAY1007626, 30 mcg	BAY1007626, 60 mcg	Levonorgestrel (Jaydess, BAY86-5028)	Levonorgestrel (Mirena, BAY86-5028)
Number of subjects analysed	0 ^[57]	0 ^[58]	0 ^[59]	0 ^[60]	0 ^[61]	0 ^[62]
Units: hours
geometric mean (geometric coefficient of variation)	( )	( )	( )	( )	( )	( )

Notes
[57] - As the primary endpoints could not be met, the study was discontinued permanently.
[58] - As the primary endpoints could not be met, the study was discontinued permanently.
[59] - As the primary endpoints could not be met, the study was discontinued permanently.
[60] - As the primary endpoints could not be met, the study was discontinued permanently.
[61] - As the primary endpoints could not be met, the study was discontinued permanently.
[62] - As the primary endpoints could not be met, the study was discontinued permanently.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From start of study treatment until end of study

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

BAY1007626, 5 mcg

Reporting group description

Subjects were treated with an intrauterine system with a nominal in vitro release of 5 mcg BAY1007626/day for 90 days.

Reporting group title

BAY1007626, 15 mcg

Reporting group description

Subjects were treated with an intrauterine system with a nominal in vitro release of 15 mcg BAY1007626/day for 90 days.

Reporting group title

BAY1007626, 30 mcg

Reporting group description

Subjects were treated with an intrauterine system with a nominal in vitro release of 30 mcg BAY1007626/day for 90 days.

Reporting group title

BAY1007626, 60 mcg

Reporting group description

Subjects were treated with an intrauterine system with a nominal in vitro release of 60 mcg BAY1007626/day for 90 days.

Reporting group title

Levonorgestrel (Jaydess, BAY86-5028)

Reporting group description

Subjects were treated with an intrauterine system with a nominal in vitro release of 12 mcg levonorgestrel/day for 90 days.

Reporting group title

Levonorgestrel (Mirena, BAY86-5028)

Reporting group description

Subjects were treated with an intrauterine system with a nominal in vitro release of 20 mcg levonorgestrel/day for 90 days.

Serious adverse events	BAY1007626, 5 mcg	BAY1007626, 15 mcg	BAY1007626, 30 mcg	BAY1007626, 60 mcg	Levonorgestrel (Jaydess, BAY86-5028)	Levonorgestrel (Mirena, BAY86-5028)
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 36 (5.56%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Injury, poisoning and procedural complications
Animal bite
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	BAY1007626, 5 mcg	BAY1007626, 15 mcg	BAY1007626, 30 mcg	BAY1007626, 60 mcg	Levonorgestrel (Jaydess, BAY86-5028)	Levonorgestrel (Mirena, BAY86-5028)
Total subjects affected by non serious adverse events
subjects affected / exposed	32 / 36 (88.89%)	28 / 33 (84.85%)	28 / 33 (84.85%)	32 / 34 (94.12%)	11 / 11 (100.00%)	33 / 35 (94.29%)
Surgical and medical procedures
Mole excision
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Dental care
subjects affected / exposed	1 / 36 (2.78%)	1 / 33 (3.03%)	1 / 33 (3.03%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	1	1	1	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Chest pain
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0
Fatigue
subjects affected / exposed	3 / 36 (8.33%)	1 / 33 (3.03%)	1 / 33 (3.03%)	0 / 34 (0.00%)	1 / 11 (9.09%)	1 / 35 (2.86%)
occurrences all number	3	1	1	0	1	1
Feeling hot
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Hangover
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Influenza like illness
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0	0
Malaise
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	1	0	0
Pyrexia
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0	0
Peripheral swelling
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	1 / 36 (2.78%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	1	0	0	0	0
Social circumstances
Tattoo
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0	0
Reproductive system and breast disorders
Breast enlargement
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	2 / 34 (5.88%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	2	0	0
Breast pain
subjects affected / exposed	2 / 36 (5.56%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	4	0	1	0	0	1
Breast tenderness
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	2 / 34 (5.88%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	2	0	0
Dysmenorrhoea
subjects affected / exposed	7 / 36 (19.44%)	3 / 33 (9.09%)	1 / 33 (3.03%)	4 / 34 (11.76%)	2 / 11 (18.18%)	2 / 35 (5.71%)
occurrences all number	11	3	2	6	2	2
Dyspareunia
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0
Galactorrhoea
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Menorrhagia
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0	0
Metrorrhagia
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Nipple pain
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0	0
Ovarian cyst
subjects affected / exposed	1 / 36 (2.78%)	2 / 33 (6.06%)	6 / 33 (18.18%)	17 / 34 (50.00%)	2 / 11 (18.18%)	14 / 35 (40.00%)
occurrences all number	3	2	8	24	2	21
Ovulation pain
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0
Pelvic pain
subjects affected / exposed	4 / 36 (11.11%)	1 / 33 (3.03%)	3 / 33 (9.09%)	1 / 34 (2.94%)	3 / 11 (27.27%)	4 / 35 (11.43%)
occurrences all number	13	2	3	2	4	5
Uterine polyp
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0	0
Vaginal discharge
subjects affected / exposed	0 / 36 (0.00%)	2 / 33 (6.06%)	1 / 33 (3.03%)	3 / 34 (8.82%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	1	3	0	0
Vaginal odour
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0
Vulvovaginal discomfort
subjects affected / exposed	1 / 36 (2.78%)	1 / 33 (3.03%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	1	1	0	0	0
Uterine cyst
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0
Breast discomfort
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	3 / 33 (9.09%)	4 / 34 (11.76%)	1 / 11 (9.09%)	3 / 35 (8.57%)
occurrences all number	0	1	4	4	1	4
Vulvovaginal pruritus
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Haemorrhagic ovarian cyst
subjects affected / exposed	1 / 36 (2.78%)	4 / 33 (12.12%)	2 / 33 (6.06%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	5	2	1	0	0
Vulvovaginal burning sensation
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0
Vulvovaginal erythema
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 36 (0.00%)	2 / 33 (6.06%)	1 / 33 (3.03%)	0 / 34 (0.00%)	2 / 11 (18.18%)	1 / 35 (2.86%)
occurrences all number	0	2	1	0	3	1
Dysphonia
subjects affected / exposed	0 / 36 (0.00%)	2 / 33 (6.06%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	0	0	0	0
Epistaxis
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	1
Oropharyngeal pain
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	3 / 35 (8.57%)
occurrences all number	0	1	1	0	0	3
Psychiatric disorders
Affective disorder
subjects affected / exposed	0 / 36 (0.00%)	2 / 33 (6.06%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	1	0	0	0
Depression
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Insomnia
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Irritability
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	1
Libido decreased
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	1 / 33 (3.03%)	1 / 34 (2.94%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	1	1	1	0	1
Listless
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	2 / 33 (6.06%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	2	0	0	0
Mood altered
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	1 / 34 (2.94%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	1	1	0	2
Mood swings
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	0	0	0	1
Sleep disorder
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	1
Suicidal ideation
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	1
Affect lability
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0
Product issues
Device expulsion
subjects affected / exposed	3 / 36 (8.33%)	0 / 33 (0.00%)	1 / 33 (3.03%)	2 / 34 (5.88%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	3	0	1	2	0	1
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0
Alanine aminotransferase increased
subjects affected / exposed	1 / 36 (2.78%)	2 / 33 (6.06%)	2 / 33 (6.06%)	1 / 34 (2.94%)	2 / 11 (18.18%)	1 / 35 (2.86%)
occurrences all number	1	2	2	1	2	1
Aspartate aminotransferase increased
subjects affected / exposed	1 / 36 (2.78%)	2 / 33 (6.06%)	3 / 33 (9.09%)	1 / 34 (2.94%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	2	3	1	0	1
Blood bilirubin increased
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0
Blood cholesterol increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0	0
Blood potassium increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Blood prolactin increased
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Blood triglycerides increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	1 / 11 (9.09%)	1 / 35 (2.86%)
occurrences all number	0	0	0	3	3	1
Blood urine present
subjects affected / exposed	3 / 36 (8.33%)	4 / 33 (12.12%)	2 / 33 (6.06%)	3 / 34 (8.82%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	4	4	2	3	0	1
Haemoglobin decreased
subjects affected / exposed	1 / 36 (2.78%)	1 / 33 (3.03%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	2	0	1	0	0
Lymphocyte count decreased
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	2 / 34 (5.88%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	3	0	0
Monocyte count increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	2 / 33 (6.06%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	2	1	0	0
Neutrophil count decreased
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0
Neutrophil count increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	1	0	0
Red blood cell count decreased
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Serum ferritin decreased
subjects affected / exposed	2 / 36 (5.56%)	3 / 33 (9.09%)	0 / 33 (0.00%)	1 / 34 (2.94%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	2	3	0	1	1	0
White blood cell count decreased
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0
White blood cells urine positive
subjects affected / exposed	2 / 36 (5.56%)	1 / 33 (3.03%)	2 / 33 (6.06%)	1 / 34 (2.94%)	0 / 11 (0.00%)	3 / 35 (8.57%)
occurrences all number	2	1	2	1	0	3
Urine bilirubin increased
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	1	0	0
Nitrite urine present
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	1	0	0	0	1
Platelet count increased
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	1	0	0	0	1
Protein urine present
subjects affected / exposed	2 / 36 (5.56%)	1 / 33 (3.03%)	1 / 33 (3.03%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	2	1	1	1	0	0
Lymph node palpable
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Waist circumference increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0
Bilirubin urine present
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0
Injury, poisoning and procedural complications
Animal bite
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	1	0	1
Ligament sprain
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	3 / 35 (8.57%)
occurrences all number	0	0	0	0	0	3
Traumatic haematoma
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0	0
Contusion
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0
Thermal burn
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	1	0	0
Limb injury
subjects affected / exposed	0 / 36 (0.00%)	2 / 33 (6.06%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	0	0	0	0
Procedural pain
subjects affected / exposed	4 / 36 (11.11%)	5 / 33 (15.15%)	5 / 33 (15.15%)	7 / 34 (20.59%)	2 / 11 (18.18%)	12 / 35 (34.29%)
occurrences all number	4	7	5	10	2	13
Ligament rupture
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Procedural nausea
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	2 / 34 (5.88%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	2	0	0
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 36 (0.00%)	4 / 33 (12.12%)	1 / 33 (3.03%)	1 / 34 (2.94%)	1 / 11 (9.09%)	1 / 35 (2.86%)
occurrences all number	0	4	1	1	1	1
Headache
subjects affected / exposed	14 / 36 (38.89%)	14 / 33 (42.42%)	14 / 33 (42.42%)	15 / 34 (44.12%)	10 / 11 (90.91%)	11 / 35 (31.43%)
occurrences all number	21	31	35	22	28	12
Hemiparesis
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Muscle contractions involuntary
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0
Paraesthesia
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Sciatica
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Sinus headache
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0
Syncope
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	0	0	0	1
Visual field defect
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Hemianaesthesia
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	1	0	1
Microcytic anaemia
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0
Eye disorders
Ocular hyperaemia
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 36 (2.78%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	1	0	0	0	0
Abdominal pain
subjects affected / exposed	3 / 36 (8.33%)	5 / 33 (15.15%)	5 / 33 (15.15%)	3 / 34 (8.82%)	1 / 11 (9.09%)	5 / 35 (14.29%)
occurrences all number	3	13	7	4	1	6
Abdominal pain lower
subjects affected / exposed	8 / 36 (22.22%)	11 / 33 (33.33%)	11 / 33 (33.33%)	17 / 34 (50.00%)	7 / 11 (63.64%)	10 / 35 (28.57%)
occurrences all number	20	29	34	38	18	17
Abdominal pain upper
subjects affected / exposed	1 / 36 (2.78%)	2 / 33 (6.06%)	0 / 33 (0.00%)	0 / 34 (0.00%)	1 / 11 (9.09%)	1 / 35 (2.86%)
occurrences all number	1	2	0	0	1	2
Constipation
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Dental caries
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0	0
Diarrhoea
subjects affected / exposed	1 / 36 (2.78%)	1 / 33 (3.03%)	3 / 33 (9.09%)	2 / 34 (5.88%)	1 / 11 (9.09%)	1 / 35 (2.86%)
occurrences all number	1	1	4	2	1	1
Dyspepsia
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	0	0	0	2
Flatulence
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	1	0
Gastrointestinal pain
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	1
Nausea
subjects affected / exposed	4 / 36 (11.11%)	2 / 33 (6.06%)	1 / 33 (3.03%)	3 / 34 (8.82%)	1 / 11 (9.09%)	1 / 35 (2.86%)
occurrences all number	4	2	1	3	1	2
Toothache
subjects affected / exposed	2 / 36 (5.56%)	0 / 33 (0.00%)	3 / 33 (9.09%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	2	0	3	1	0	0
Vomiting
subjects affected / exposed	2 / 36 (5.56%)	1 / 33 (3.03%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	3	1	1	0	0	1
Chapped lips
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	3 / 36 (8.33%)	1 / 33 (3.03%)	4 / 33 (12.12%)	2 / 34 (5.88%)	1 / 11 (9.09%)	3 / 35 (8.57%)
occurrences all number	3	2	4	2	1	4
Alopecia
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	2 / 33 (6.06%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	2	0	0	0
Dry skin
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Eczema
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	1	0	1
Hair texture abnormal
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Hirsutism
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0
Night sweats
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Pruritus
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	1 / 33 (3.03%)	2 / 34 (5.88%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	1	2	0	0
Psoriasis
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Rash
subjects affected / exposed	1 / 36 (2.78%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	1	1	0	0	1	0
Rash papular
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	0	0	0	2
Rosacea
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Skin discolouration
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0
Skin disorder
subjects affected / exposed	0 / 36 (0.00%)	2 / 33 (6.06%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	0	0	0	0
Skin irritation
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0
Renal and urinary disorders
Bilirubinuria
subjects affected / exposed	1 / 36 (2.78%)	1 / 33 (3.03%)	2 / 33 (6.06%)	2 / 34 (5.88%)	1 / 11 (9.09%)	4 / 35 (11.43%)
occurrences all number	1	1	2	4	2	6
Dysuria
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	1
Haematuria
subjects affected / exposed	1 / 36 (2.78%)	1 / 33 (3.03%)	2 / 33 (6.06%)	2 / 34 (5.88%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	1	1	2	2	3	0
Ketonuria
subjects affected / exposed	1 / 36 (2.78%)	2 / 33 (6.06%)	1 / 33 (3.03%)	5 / 34 (14.71%)	1 / 11 (9.09%)	1 / 35 (2.86%)
occurrences all number	2	2	1	5	1	3
Pollakiuria
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0
Proteinuria
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	2	0
Renal pain
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Urobilinuria
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0
Leukocyturia
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	1 / 33 (3.03%)	4 / 34 (11.76%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	1	5	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Back pain
subjects affected / exposed	3 / 36 (8.33%)	5 / 33 (15.15%)	0 / 33 (0.00%)	3 / 34 (8.82%)	2 / 11 (18.18%)	4 / 35 (11.43%)
occurrences all number	3	7	0	3	2	4
Joint swelling
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0
Musculoskeletal pain
subjects affected / exposed	1 / 36 (2.78%)	1 / 33 (3.03%)	0 / 33 (0.00%)	1 / 34 (2.94%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	1	1	0	1	1	0
Myalgia
subjects affected / exposed	1 / 36 (2.78%)	2 / 33 (6.06%)	2 / 33 (6.06%)	1 / 34 (2.94%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	2	4	2	1	0	1
Myositis
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Neck pain
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	1 / 34 (2.94%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	0	0	1	1	1	0
Pain in extremity
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	2	0	0
Synovial cyst
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	1
Musculoskeletal stiffness
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0
Infections and infestations
Abscess oral
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Bacterial vaginosis
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0	0
Conjunctivitis
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	2	0
Cystitis
subjects affected / exposed	1 / 36 (2.78%)	2 / 33 (6.06%)	3 / 33 (9.09%)	3 / 34 (8.82%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	3	4	3	0	0
Diarrhoea infectious
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Ear infection
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0	0
Eye infection
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Folliculitis
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0
Fungal skin infection
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0
Furuncle
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	2	0
Gastroenteritis
subjects affected / exposed	3 / 36 (8.33%)	1 / 33 (3.03%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	3	1	0	1	0	1
Gastroenteritis viral
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	1	0	0	0
Gastrointestinal infection
subjects affected / exposed	1 / 36 (2.78%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	1	0	0	0	0
Gingivitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0	0
Influenza
subjects affected / exposed	6 / 36 (16.67%)	6 / 33 (18.18%)	3 / 33 (9.09%)	1 / 34 (2.94%)	2 / 11 (18.18%)	0 / 35 (0.00%)
occurrences all number	8	8	3	2	2	0
Laryngitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0	0
Nasopharyngitis
subjects affected / exposed	14 / 36 (38.89%)	11 / 33 (33.33%)	13 / 33 (39.39%)	13 / 34 (38.24%)	6 / 11 (54.55%)	13 / 35 (37.14%)
occurrences all number	20	14	18	18	7	19
Otitis media
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	1
Paronychia
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	1	0	1
Pharyngitis
subjects affected / exposed	1 / 36 (2.78%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	1	0	0	0	0
Sinusitis
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Skin infection
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0	0
Tonsillitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	1 / 34 (2.94%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	1	0	1
Urinary tract infection
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Vaginal infection
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	2 / 34 (5.88%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	2	0	0
Vulvovaginal candidiasis
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	2 / 33 (6.06%)	3 / 34 (8.82%)	1 / 11 (9.09%)	0 / 35 (0.00%)
occurrences all number	0	1	2	3	1	0
Tooth infection
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	0	0
Vaginitis bacterial
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 33 (3.03%)	1 / 34 (2.94%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	1	0	0
Respiratory tract infection
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	1
Oral herpes
subjects affected / exposed	2 / 36 (5.56%)	0 / 33 (0.00%)	2 / 33 (6.06%)	0 / 34 (0.00%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	4	0	2	0	0	2
Metabolism and nutrition disorders
Increased appetite
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	1 / 11 (9.09%)	1 / 35 (2.86%)
occurrences all number	1	0	0	0	1	1
Decreased appetite
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0	0
Food intolerance
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 33 (0.00%)	0 / 34 (0.00%)	0 / 11 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	0	1

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
26 May 2016	The underlying clinical development program had been discontinued permanently. An interim analysis had shown that one of the primary endpoints (reduction in number of bleeding and spotting days compared to Mirena during the first 90 days of treatment) could not be met. Without demonstrating superiority of this primary variable a further development of an IUS releasing BAY1007626 intended to reduce initial bleeding/ spotting after IUS insertion did not make sense and the development program was discontinued.	-

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

The study was discontinued permanently as the primary endpoints could not be met. Decimal places were automatically truncated if last decimal equals zero.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Bleeding and Spotting Days During the 90 Days Treatment Period

Primary: Number of Bleeding and Spotting Days During the 90 Days Treatment Period

Primary: Number of Subjects With Endometrium Proliferative

Primary: Number of Subjects With Endometrium Proliferative

Primary: Number of Subjects With Ovulation During Treatment

Primary: Number of Subjects With Ovulation During Treatment

Secondary: Endometrial Thickness

Secondary: Endometrial Thickness

Secondary: Bleeding Characterization (Intensity and Pattern)

Secondary: Bleeding Characterization (Intensity and Pattern)

Secondary: Serum Levels of Hormones (Estradiol, Progesterone, Luteinizing Hormone, Follicle-Stimulating Hormone)

Secondary: Serum Levels of Hormones (Estradiol, Progesterone, Luteinizing Hormone, Follicle-Stimulating Hormone)

Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

Secondary: Maximum Observed Drug Concentration of BAY1007626 After Insertion of Intrauterine System (Cmax) in Plasma

Secondary: Maximum Observed Drug Concentration of BAY1007626 After Insertion of Intrauterine System (Cmax) in Plasma

Secondary: Area Under the Concentration Versus Time Curve (AUC) of BAY1007626 in Plasma After Insertion of Intrauterine System

Secondary: Area Under the Concentration Versus Time Curve (AUC) of BAY1007626 in Plasma After Insertion of Intrauterine System

Secondary: Half-life Associated With the Terminal Slope (t1/2) of BAY1007626 in Plasma

Secondary: Half-life Associated With the Terminal Slope (t1/2) of BAY1007626 in Plasma

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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