Endometrial Safety Study

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00522873
• Collaborator: Laboratorium für Klinische Forschung (Other), Diagnostic Cytology Laboratory (Other), University of California, San Francisco (Other)
• Enrollment: 662
• Locations: 59
• Arms: 2
• Duration (Months): 24
• Patients Per Site: 11.2
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The study is designed to investigate the safety of the investigational product for the lining of the uterus (endometrium).

Condition or Disease	Intervention/Treatment	Phase
Postmenopause	Drug: 0.25mg DRSP / 0.5mg E2 (BAY86-4891); Drug: 0.5mg NETA / 1.0mg E2 (Activella)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 662 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Randomized, Multi-center Study to Investigate the Endometrial Safety of a Continuous, Combined, Oral Estrogen/Progestin Preparation (17b-estradiol [E2] / Drospirenone [DRSP]) and to Compare the Bleeding Pattern of Subjects Treated With E2 / DRSP With the Bleeding Pattern of Subjects Treated With E2 / Norethisterone Acetate (NETA) When Used for Hormone Therapy (HT) for 1 Year in Post-menopausal Women
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Aug 1, 2009
• Actual Study Completion Date: Aug 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 0.25mg DRSP / 0.5mg E2 (BAY86-4891) One capsule [0.25mg drospirenone/0.5mg 17β-estradiol (DRSP/E2)] per day taken orally for 13 cycles (28 days per cycle).	Drug: 0.25mg DRSP / 0.5mg E2 (BAY86-4891); One capsule [0.25mg drospirenone/0.5mg 17β-estradiol (DRSP/E2)] per day taken orally for 13 cycles (28 days per cycle).
Active Comparator: 0.5mg NETA / 1.0mg E2 (Activella) One capsule [0.5mg norethisterone acetate/1.0mg 17β-estradiol (NETA/E2)] per day taken orally for 13 cycles (28 days per cycle).	Drug: 0.5mg NETA / 1.0mg E2 (Activella); One capsule [0.5mg norethisterone acetate/1.0mg 17β-estradiol (NETA/E2)] per day taken orally for 13 cycles (28 days per cycle).

Outcome Measures

Primary Outcome Measures

1. Number of Participants in the DRSP/E2 Group With an Assessment of Endometrial Hyperplasia or Worse at End of Study (EoS) (1 Year of Treatment) [Up to one year]

   The number of women who had a biopsy classified as 'hyperplasia or worse' at any time during the study. According to the protocol this endpoint was defined as primary for the DRSP/E2 group only.

Secondary Outcome Measures

1. Number of Participants With Amenorrhea During Month 1 to 3 of Treatment [Month 1 to Month 3]

   The women were to record daily in a diary, indicating 'no bleeding', 'spotting', 'light bleeding', 'normal bleeding' or 'heavy bleeding'. Women were considered to have amenorrhea if they had no bleeding and no spotting day within the given time interval.

2. Number of Participants With Amenorrhea During Month 10 to 12 of Treatment [Month 10 to Month 12]

   The women were to record any bleeding daily in a diary, indicating 'no bleeding', 'spotting', 'light bleeding', 'normal bleeding' or 'heavy bleeding'. Women were considered to have amenorrhea if they had no bleeding and no spotting day within the given time interval.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 65 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Postmenopausal women between 40 and 65 years of age with hormone therapy indication (symptoms and need for treatment)

• Non-hysterectomized women.

Exclusion Criteria:

• Usual exclusion criteria for hormone therapy apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Chandler	Arizona	United States	85224
2		San Diego	California	United States	92103
3		San Diego	California	United States	92108
4		Denver	Colorado	United States	80218
5		Greenwood Village	Colorado	United States	80111
6		Boynton Beach	Florida	United States	33437
7		Clearwater	Florida	United States	33759
8		Boise	Idaho	United States	83704
9		Amite	Louisiana	United States	70422
10		Marrero	Louisiana	United States	70072
11		Las Vegas	Nevada	United States	89122
12		Cleveland	Ohio	United States	44122
13		Philadelphia	Pennsylvania	United States	19114
14		Columbia	South Carolina	United States	29201
15		Corpus Christi	Texas	United States	78414
16		Richmond	Virginia	United States	23294
17		Seattle	Washington	United States	98105
18		Lanus Oeste	Buenos Aires	Argentina	1824
19		San Isidro	Buenos Aires	Argentina	B1642CLN
20		Buenos Aires	Ciudad Auton. de Buenos Aires	Argentina	C1117ABH
21		Buenos Aires	Ciudad Auton. de Buenos Aires	Argentina	C1280AEB
22		Mödling	Niederösterreich	Austria	2340
23		Wiener Neustadt	Niederösterreich	Austria	2700
24		Fuerstenfeld	Steiermark	Austria	8280
25		Wörgl	Tirol	Austria	6300
26		Bregenz	Vorarlberg	Austria	6900
27		Innsbruck		Austria	6020
28		Klagenfurt		Austria	9020
29		Mürzzuschlag		Austria	8680
30		St. Poelten		Austria	3100
31		Wien		Austria	1030
32		Wien		Austria	1060
33		Wien		Austria	1090
34		Wien		Austria	1200
35		Zeltweg		Austria	8740
36		Goiania	Goiás	Brazil	74175-080
37		Curitiba	Parana	Brazil	80030-220
38		Porto Alegre	Rio Grande do Sul	Brazil	90035-001
39		Sao Paulo		Brazil	04062-003
40		Alborg		Denmark	9000
41		Ballerup		Denmark	2750
42		Vejle		Denmark	7100
43		Bologna		Italy	40138
44		Cagliari		Italy	09124
45		Modena		Italy	41124
46		Novara		Italy	28100
47		Parma		Italy	43100
48		Pisa		Italy	56126
49		Sassari		Italy	07100
50		Siena		Italy	53100
51		Mexico	Distrito Federal	Mexico
52		Mexico		Mexico	06700
53		Monterrey		Mexico	64460
54		México, D.F.		Mexico	14050
55		Moscow		Russian Federation	117415
56		Moscow		Russian Federation	177997
57		Moskva		Russian Federation	101000
58		Moskva		Russian Federation	113093
59		Moskva		Russian Federation	117997

Sponsors and Collaborators

• Bayer
• Laboratorium für Klinische Forschung
• Diagnostic Cytology Laboratory
• University of California, San Francisco

Investigators

• Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• click here and search for Bayer Product information provided by the EMA

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT00522873
• Other Study ID Numbers: 91508; 2006-006199-39; 310523
• First Posted: Aug 30, 2007
• Last Update Posted: Dec 31, 2014
• Last Verified: Dec 1, 2014

• Keywords provided by Bayer: Postmenopausal Symptoms e.g.; Hot flushes; Sweating episodes; Vaginal dryness

Study Results

Participant Flow

Recruitment Details	Only non-hysterectomized, postmenopausal women could take part in this study. The women had to have symptoms requiring hormone therapy in the opinion of the investigator. An endometrial biopsy at screening was to show no evidence of endometrial hyperplasia or cancer.
Pre-assignment Detail	944 women screened, 661 treated. 282 failed screening: consent withdrawn (55), in-/exclusion criteria not met (209), lost to follow-up (3), other (15). 1 woman was randomized but not treated (own decision). 5 women completed the study but not study medication, i.e. they stopped medication early but remained in the study for final assessments.

Arm/Group Title	0.25mg DRSP / 0.5mg E2 (BAY86-4891)	0.5mg NETA / 1.0mg E2 (Activella)
Arm/Group Description	One capsule [0.25mg drospirenone/0.5mg 17β-estradiol (DRSP/E2)] per day taken orally for 13 cycles (28 days per cycle).	One capsule [0.5mg norethisterone acetate/1.0mg 17β-estradiol (NETA/E2)] per day taken orally for 13 cycles (28 days per cycle).
Period Title: Overall Study
STARTED	490	172
Received Treatment	489	172
COMPLETED	394	128
NOT COMPLETED	96	44

Baseline Characteristics

Arm/Group Title	0.25mg DRSP / 0.5mg E2 (BAY86-4891)	0.5mg NETA / 1.0mg E2 (Activella)	Total
Arm/Group Description	One capsule [0.25mg drospirenone/0.5mg 17β-estradiol (DRSP/E2)] per day taken orally for 13 cycles (28 days per cycle).	One capsule [0.5mg norethisterone acetate/1.0mg 17β-estradiol (NETA/E2)] per day taken orally for 13 cycles (28 days per cycle).	Total of all reporting groups
Overall Participants	489	172	661
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	53.5 (5.1)	53.5 (4.5)	53.5 (4.9)
Sex: Female, Male (Count of Participants)
Female	489 100%	172 100%	661 100%
Male	0 0%	0 0%	0 0%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.315 (4.851)	26.020 (5.476)	26.184 (5.008)
Number of participants with hysterectomy/oophorectomy (Number) [Number]
Hysterectomized	0 0%	0 0%	0 0%
Oophorectomized	25 5.1%	5 2.9%	30 4.5%
Years since last menstruation at baseline (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	5.109 (4.528)	4.807 (4.287)	5.031 (4.465)

Outcome Measures

1. Primary Outcome

Title	Number of Participants in the DRSP/E2 Group With an Assessment of Endometrial Hyperplasia or Worse at End of Study (EoS) (1 Year of Treatment)
Description	The number of women who had a biopsy classified as 'hyperplasia or worse' at any time during the study. According to the protocol this endpoint was defined as primary for the DRSP/E2 group only.
Time Frame	Up to one year

Outcome Measure Data

Analysis Population Description

For the DRSP/E2 group only - Primary analysis set (PAS): All subjects from the full analysis set (FAS) who either had a biopsy result classified as 'normal' or 'hyperplasia or worse' after a year of treatment or who prematurely discontinued the study before Cycle 13 with a biopsy classified as 'hyperplasia or worse'.

Arm/Group Title	0.25mg DRSP / 0.5mg E2 (BAY86-4891)
Arm/Group Description	One capsule [0.25mg drospirenone/0.5mg 17β-estradiol (DRSP/E2)] per day taken orally for 13 cycles (28 days per cycle).
Measure Participants	309
Number [Participants]	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.25mg DRSP / 0.5mg E2 (BAY86-4891)
	Comments	Exact 95% confidence interval for proportion of participants with hyperplasia or worse at EoS
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	proportion
	Estimated Value	0.0000
	Confidence Interval	(2-Sided) 95%; 0.0000 to 0.0119
	Parameter Dispersion	Type: Value:
	Estimation Comments	The number of women who had a biopsy classified as 'hyperplasia or worse' was divided by the number of women with an evaluable biopsy (i.e. classified as 'normal' after 1 year of treatment or as 'hyperplasia or worse' at any time during the study).

2. Secondary Outcome

Title	Number of Participants With Amenorrhea During Month 1 to 3 of Treatment
Description	The women were to record daily in a diary, indicating 'no bleeding', 'spotting', 'light bleeding', 'normal bleeding' or 'heavy bleeding'. Women were considered to have amenorrhea if they had no bleeding and no spotting day within the given time interval.
Time Frame	Month 1 to Month 3

Outcome Measure Data

Analysis Population Description

Per protocol set (PPS): All subjects from the FAS who had at least 75% overall study drug compliance and no major protocol violations

Arm/Group Title	0.25mg DRSP / 0.5mg E2 (BAY86-4891)	0.5mg NETA / 1.0mg E2 (Activella)
Arm/Group Description	One capsule [0.25mg drospirenone/0.5mg 17β-estradiol (DRSP/E2)] per day taken orally for 13 cycles (28 days per cycle).	One capsule [0.5mg norethisterone acetate/1.0mg 17β-estradiol (NETA/E2)] per day taken orally for 13 cycles (28 days per cycle).
Measure Participants	371	113
Number [Participants]	255 52.1%	67 39%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.25mg DRSP / 0.5mg E2 (BAY86-4891)
	Comments	exact 95% confidence intervall (Clopper-Pearson) for proportion of participants with amenorrhea
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	proportion
	Estimated Value	0.687
	Confidence Interval	(2-Sided) 95%; 0.637 to 0.734
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.5mg NETA / 1.0mg E2 (Activella)
	Comments	exact 95% confidence intervall (Clopper-Pearson) for proportion of participants with amenorrhea
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	proportion
	Estimated Value	0.593
	Confidence Interval	(2-Sided) 95%; 0.496 to 0.684
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Participants With Amenorrhea During Month 10 to 12 of Treatment
Description	The women were to record any bleeding daily in a diary, indicating 'no bleeding', 'spotting', 'light bleeding', 'normal bleeding' or 'heavy bleeding'. Women were considered to have amenorrhea if they had no bleeding and no spotting day within the given time interval.
Time Frame	Month 10 to Month 12

Outcome Measure Data

Analysis Population Description

Per protocol set (PPS): All subjects from the FAS who had at least 75% overall study drug compliance and no major protocol violations

Arm/Group Title	0.25mg DRSP / 0.5mg E2 (BAY86-4891)	0.5mg NETA / 1.0mg E2 (Activella)
Arm/Group Description	One capsule [0.25mg drospirenone/0.5mg 17β-estradiol (DRSP/E2)] per day taken orally for 13 cycles (28 days per cycle).	One capsule [0.5mg norethisterone acetate/1.0mg 17β-estradiol (NETA/E2)] per day taken orally for 13 cycles (28 days per cycle).
Measure Participants	355	106
Number [Participants]	280 57.3%	89 51.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.25mg DRSP / 0.5mg E2 (BAY86-4891)
	Comments	exact 95% confidence intervall (Clopper-Pearson) for proportion of participants with amenorrhea
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	proportion
	Estimated Value	0.789
	Confidence Interval	(2-Sided) 95%; 0.743 to 0.830
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.5mg NETA / 1.0mg E2 (Activella)
	Comments	exact 95% confidence intervall (Clopper-Pearson) for proportion of participants with amenorrhea
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	proportion
	Estimated Value	0.840
	Confidence Interval	(2-Sided) 95%; 0.756 to 0.904
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	0.25mg DRSP / 0.5mg E2 (BAY86-4891)		0.5mg NETA / 1.0mg E2 (Activella)
Arm/Group Description	One capsule [0.25mg drospirenone/0.5mg 17β-estradiol (DRSP/E2)] per day taken orally for 13 cycles (28 days per cycle).		One capsule [0.5mg norethisterone acetate/1.0mg 17β-estradiol (NETA/E2)] per day taken orally for 13 cycles (28 days per cycle).
All Cause Mortality
	0.25mg DRSP / 0.5mg E2 (BAY86-4891)		0.5mg NETA / 1.0mg E2 (Activella)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	0.25mg DRSP / 0.5mg E2 (BAY86-4891)		0.5mg NETA / 1.0mg E2 (Activella)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/489 (3.3%)		6/172 (3.5%)
Blood and lymphatic system disorders
Lymphadenopathy	1/489 (0.2%)		0/172 (0%)
Ear and labyrinth disorders
Deafness neurosensory	0/489 (0%)		1/172 (0.6%)
Endocrine disorders
Hyperparathyroidism	0/489 (0%)		1/172 (0.6%)
Eye disorders
Retinal vascular thrombosis	0/489 (0%)		1/172 (0.6%)
Gastrointestinal disorders
Abdominal pain lower	1/489 (0.2%)		0/172 (0%)
Constipation	1/489 (0.2%)		0/172 (0%)
Faecaloma	1/489 (0.2%)		0/172 (0%)
Large intestinal haemorrhage	1/489 (0.2%)		0/172 (0%)
Pancreatitis acute	1/489 (0.2%)		0/172 (0%)
Hepatobiliary disorders
Cholecystitis	1/489 (0.2%)		0/172 (0%)
Cholelithiasis	1/489 (0.2%)		0/172 (0%)
Infections and infestations
Appendicitis	0/489 (0%)		1/172 (0.6%)
Cellulitis	1/489 (0.2%)		0/172 (0%)
Pneumonia	1/489 (0.2%)		0/172 (0%)
Injury, poisoning and procedural complications
Splenic rupture	1/489 (0.2%)		0/172 (0%)
Metabolism and nutrition disorders
Hyperglycaemia	1/489 (0.2%)		0/172 (0%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/489 (0.2%)		0/172 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/489 (0%)		1/172 (0.6%)
Colon adenoma	1/489 (0.2%)		0/172 (0%)
Colon cancer	1/489 (0.2%)		0/172 (0%)
Lung neoplasm malignant	1/489 (0.2%)		0/172 (0%)
Lymphoma	1/489 (0.2%)		0/172 (0%)
Salivary gland adenoma	1/489 (0.2%)		0/172 (0%)
Nervous system disorders
Carpal tunnel syndrome	1/489 (0.2%)		0/172 (0%)
Grand mal convulsion	0/489 (0%)		1/172 (0.6%)
Transient ischaemic attack	1/489 (0.2%)		0/172 (0%)
Psychiatric disorders
Anxiety	1/489 (0.2%)		0/172 (0%)
Self-injurious ideation	1/489 (0.2%)		0/172 (0%)
Renal and urinary disorders
Urinary incontinence	1/489 (0.2%)		0/172 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/489 (0.2%)		0/172 (0%)
Surgical and medical procedures
Hip arthroplasty	1/489 (0.2%)		0/172 (0%)
Other (Not Including Serious) Adverse Events
	0.25mg DRSP / 0.5mg E2 (BAY86-4891)		0.5mg NETA / 1.0mg E2 (Activella)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	172/489 (35.2%)		63/172 (36.6%)
Gastrointestinal disorders
Abdominal pain	6/489 (1.2%)		4/172 (2.3%)
Infections and infestations
Influenza	21/489 (4.3%)		6/172 (3.5%)
Nasopharyngitis	18/489 (3.7%)		2/172 (1.2%)
Urinary tract infection	9/489 (1.8%)		4/172 (2.3%)
Investigations
Weight increased	17/489 (3.5%)		3/172 (1.7%)
Musculoskeletal and connective tissue disorders
Back pain	17/489 (3.5%)		2/172 (1.2%)
Pain in extremity	12/489 (2.5%)		0/172 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma	16/489 (3.3%)		4/172 (2.3%)
Nervous system disorders
Headache	32/489 (6.5%)		7/172 (4.1%)
Psychiatric disorders
Depression	9/489 (1.8%)		6/172 (3.5%)
Reproductive system and breast disorders
Breast pain	21/489 (4.3%)		10/172 (5.8%)
Breast tenderness	9/489 (1.8%)		5/172 (2.9%)
Cervical dysplasia	11/489 (2.2%)		7/172 (4.1%)
Endometrial hypertrophy	13/489 (2.7%)		4/172 (2.3%)
Postmenopausal haemorrhage	14/489 (2.9%)		9/172 (5.2%)
Vascular disorders
Hypertension	15/489 (3.1%)		5/172 (2.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.