Low-dose Hormone Therapy for Relief of Vasomotor Symptoms

This study has been completed.

Sponsor:

Information provided by:

Bayer

ClinicalTrials.gov Identifier:

NCT00446199

First received: March 9, 2007

Last updated: April 16, 2013

Last verified: April 2013

History of Changes

Results First Received: March 23, 2012

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Treatment
Conditions:	Vasomotor Symptoms Hot Flashes
Interventions:	Drug: 0.5mg DRSP / 0.5mg E2 (BAY86-4891) Drug: 0.25mg DRSP / 0.5mg E2 (BAY86-4891) Drug: Estradiol (E2 0.3mg) Drug: Placebo

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
The study was conducted at 79 centers in the United States from 26 Mar 2007 (date of first participant's first visit) to 03 Nov 2008 (date of last participant's last visit)

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
2457 Screened; 1722 Screen Failures; 735 randomized; 726 treated (Safety Analysis Set, SAF); 710 Full Analysis Set (FAS, randomized subjects with Baseline vasomotor symptom (VMS) data, took ≥1 study dose plus ≥1 VMS data day postdose); 569 Per Protocol Set (PPS, all subjects in FAS with ≥75% study drug compliance and no major protocol violations).

Reporting Groups

	Description
0.5mg DRSP / 0.5mg E2 (BAY86-4891)	One tablet [0.5mg drospirenone/0.5mg 17β-estradiol (DRSP/E2)] per day taken orally for 3 cycles (28 days per cycle).
0.25mg DRSP / 0.5mg E2 (BAY86-4891)	One tablet [0.25mg drospirenone/0.5mg 17β-estradiol (DRSP/E2)] per day taken orally for 3 cycles (28 days per cycle).
Estradiol (E2 0.3mg)	One tablet [17β-estradiol (E2 0.3mg)] per day taken orally for 3 cycles (28 days per cycle).
Placebo	Matching placebo tablet per day taken orally for 3 cycles (28 days per cycle).

Participant Flow: Overall Study

	0.5mg DRSP / 0.5mg E2 (BAY86-4891)	0.25mg DRSP / 0.5mg E2 (BAY86-4891)	Estradiol (E2 0.3mg)	Placebo
STARTED	183	184	185	183
Participants Received Treatment	181 ^[1]	183 ^[1]	182 ^[1]	180 ^[1]
Baseline and Postdose VMS Data Available	178 ^[2]	177 ^[2]	179 ^[2]	176 ^[2]
COMPLETED	160	164	158	153
NOT COMPLETED	23	20	27	30
Adverse Event	7	4	6	4
Lost to Follow-up	4	5	2	6
Protocol Violation	1	2	1	3
Withdrawal by Subject	2	5	9	10
Site termination	2	0	0	1
Randomization in Error	2	0	1	1
Lack of Efficacy	1	0	0	1
Non-compliant with study drug	1	0	5	0
Non-compliant with visit schedule	1	1	1	2
Hormone fear	0	0	0	1
Lost interest in study participation	0	1	0	0
In-/Exclusion criterion violated	2	1	2	1
Move	0	1	0	0

[1]	SAF=all randomized participants who took at least 1 dose of study medication.
[2]	FAS=all randomized participants with Baseline VMS data and at least 1 day VMS data postdose.

Baseline Characteristics

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Reporting Groups

	Description
0.5mg DRSP / 0.5mg E2 (BAY86-4891)	One tablet [0.5mg drospirenone/0.5mg 17β-estradiol (DRSP/E2)] per day taken orally for 3 cycles (28 days per cycle).
0.25mg DRSP / 0.5mg E2 (BAY86-4891)	One tablet [0.25mg drospirenone/0.5mg 17β-estradiol (DRSP/E2)] per day taken orally for 3 cycles (28 days per cycle).
Estradiol (E2 0.3mg)	One tablet [17β-estradiol (E2 0.3mg)] per day taken orally for 3 cycles (28 days per cycle).
Placebo	Matching placebo tablet per day taken orally for 3 cycles (28 days per cycle).
Total	Total of all reporting groups

Baseline Measures

	0.5mg DRSP / 0.5mg E2 (BAY86-4891)	0.25mg DRSP / 0.5mg E2 (BAY86-4891)	Estradiol (E2 0.3mg)	Placebo	Total
Number of Participants [units: participants]	178	177	179	176	710
Age ^[1] [units: years] Mean ± Standard Deviation	53.8 ± 5.61	53.5 ± 5.77	53.3 ± 6.05	53.4 ± 6.46	53.5 ± 5.97
Gender ^[1] [units: participants]
Female	178	177	179	176	710
Male	0	0	0	0	0
Number of participants with hysterectomy/oophorectomy ^[1] [units: Participants]
hysterectomized	98	91	98	99	386
oophorectomized	61	61	63	59	244
Body Mass Index (BMI) ^[1] [units: kg/sqm] Mean ± Standard Deviation	29.070 ± 6.0636	28.190 ± 5.6965	29.080 ± 5.7410	27.882 ± 5.7859	28.543 ± 5.8370
Years since last menstruation at baseline ^[1] [units: years] Mean ± Standard Deviation	9.913 ± 8.6719	8.784 ± 7.9947	9.214 ± 8.1892	9.509 ± 8.9693	9.355 ± 8.4560

[1]	The population included all randomized participants with Baseline VMS data and at least 1 day VMS data postdose. Full Analysis Set (FAS).

Outcome Measures

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1. Primary:

Change From Baseline to Week 12 in Weekly Frequency of Moderate to Severe Hot Flushes (Median Value) [ Time Frame: Baseline until 12 weeks of treatment ]

Show Outcome Measure 1

2. Primary:

Change From Baseline to Week 4 in Weekly Frequency of Moderate to Severe Hot Flushes (Median Value) [ Time Frame: Baseline until 4 weeks of treatment ]

Show Outcome Measure 2

3. Primary:

Change From Baseline to Week 12 in Weekly Mean Daily Severity of Moderate to Severe Hot Flushes (Median Value) [ Time Frame: Baseline until 12 weeks of treatment ]

Show Outcome Measure 3

4. Primary:

Change From Baseline to Week 4 in Weekly Mean Daily Severity of Moderate to Severe Hot Flushes (Median Value) [ Time Frame: Baseline until 4 weeks of treatment ]

Show Outcome Measure 4

5. Secondary:

Change From Baseline to Week 12 in Vaginal pH [ Time Frame: Baseline until 12 weeks of treatment ]

Show Outcome Measure 5

6. Secondary:

Change From Baseline to Week 12 in Vaginal Maturation Value [ Time Frame: Baseline until 12 weeks of treatment ]

Show Outcome Measure 6

7. Secondary:

Symptoms of Vulvar and Vaginal Atrophy: Severity of Symptom 'Vaginal Dryness' [ Time Frame: After 12 weeks of treatment ]

Show Outcome Measure 7

8. Secondary:

Symptoms of Vulvar and Vaginal Atrophy: Severity of Symptom 'Vaginal and/or Vulvar Irritation/Itching' [ Time Frame: After 12 weeks of treatment ]

Show Outcome Measure 8

9. Secondary:

Symptoms of Vulvar and Vaginal Atrophy: Severity of Symptom 'Dysuria' [ Time Frame: After 12 weeks of treatment ]

Show Outcome Measure 9

10. Secondary:

Symptoms of Vulvar and Vaginal Atrophy: Severity of Symptom 'Vaginal Pain Associated With Sexual Activity' [ Time Frame: After 12 weeks of treatment ]

Show Outcome Measure 10

11. Secondary:

Symptoms of Vulvar and Vaginal Atrophy: Severity of Symptom 'Vaginal Bleeding Associated With Sexual Activity' [ Time Frame: After 12 weeks of treatment ]

Show Outcome Measure 11

12. Secondary:

Urogenital Symptoms: Number of Participants With Symptom 'Frequent Urination' [ Time Frame: After 12 weeks of treatment ]

Show Outcome Measure 12

13. Secondary:

Urogenital Symptoms: Number of Participants With Symptom 'Involuntary Urination When Laughing or Coughing' [ Time Frame: After 12 weeks of treatment ]

Show Outcome Measure 13

14. Secondary:

Urogenital Symptoms: Number of Participants With Symptom 'Urination at Night' [ Time Frame: After 12 weeks of treatment ]

Show Outcome Measure 14

15. Other Pre-specified:

Change From Baseline to Week 12 in Weekly Frequency of Moderate to Severe Hot Flushes (Mean Value) [ Time Frame: Baseline until 12 weeks of treatment ]

Show Outcome Measure 15

16. Other Pre-specified:

Change From Baseline to Week 4 in Weekly Frequency of Moderate to Severe Hot Flushes (Mean Value) [ Time Frame: Baseline until 4 weeks of treatment ]

Show Outcome Measure 16

17. Other Pre-specified:

Change From Baseline to Week 12 in Weekly Mean Daily Severity of Moderate to Severe Hot Flushes (Mean Value) [ Time Frame: Baseline until 12 weeks of treatment ]

Show Outcome Measure 17

18. Other Pre-specified:

Change From Baseline to Week 4 in Weekly Mean Daily Severity of Moderate to Severe Hot Flushes (Mean Value) [ Time Frame: Baseline until 4 weeks of treatment ]

Hide Outcome Measure 18

Measure Type	Other Pre-specified
Measure Title	Change From Baseline to Week 4 in Weekly Mean Daily Severity of Moderate to Severe Hot Flushes (Mean Value)
Measure Description	Subjects record daily on the diary cards the frequency and severity of hot flushes during the treatment period as none, mild, moderate or severe. Daily score is calculated as [(2 x number of moderate hot flushes) + (3 x number of severe hot flushes)] / (total number of moderate to severe hot flushes on that day). Range = 0 (lowest severity) to 3 (highest severity). Absolute change calculated as week 4 severity moderate to severe hot flushes minus baseline severity.
Time Frame	Baseline until 4 weeks of treatment
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set (ITT) with last observation carried forward approach (LOCF). Numbers differ from the complete full analysis set due to missing Week 1 data.

Reporting Groups

	Description
0.5mg DRSP / 0.5mg E2 (BAY86-4891)	One tablet [0.5mg drospirenone/0.5mg 17β-estradiol (DRSP/E2)] per day taken orally for 3 cycles (28 days per cycle).
0.25mg DRSP / 0.5mg E2 (BAY86-4891)	One tablet [0.25mg drospirenone/0.5mg 17β-estradiol (DRSP/E2)] per day taken orally for 3 cycles (28 days per cycle).
Estradiol (E2 0.3mg)	One tablet [17β-estradiol (E2 0.3mg)] per day taken orally for 3 cycles (28 days per cycle).
Placebo	Matching placebo tablet per day taken orally for 3 cycles (28 days per cycle).

Measured Values

	0.5mg DRSP / 0.5mg E2 (BAY86-4891)	0.25mg DRSP / 0.5mg E2 (BAY86-4891)	Estradiol (E2 0.3mg)	Placebo
Number of Participants Analyzed [units: participants]	177	174	177	176
Change From Baseline to Week 4 in Weekly Mean Daily Severity of Moderate to Severe Hot Flushes (Mean Value) [units: scores on a scale] Mean ± Standard Deviation	-0.8347 ± 1.02226	-0.5859 ± 0.89106	-0.4033 ± 0.73774	-0.1926 ± 0.63585

Statistical Analysis 1 for Change From Baseline to Week 4 in Weekly Mean Daily Severity of Moderate to Severe Hot Flushes (Mean Value)

Groups ^[1]	0.5mg DRSP / 0.5mg E2 (BAY86-4891) vs. Placebo
Method ^[2]	ANCOVA
P Value ^[3]	<0.0001
Mean Difference (Final Values) ^[4]	-0.635
95% Confidence Interval	( -0.813 to -0.458 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison between DRSP/E2 (0.5mg/0.5mg) and Placebo with respect to a shift in the distribution of the end point. Null hypothesis: The mean change from baseline to week 4 is identical in both arms, alternative: there is a difference in the mean change from baseline.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Treatment, Center, and Baseline value used as covariate
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Significance level of 1.7% is used to adjust (Bonferroni) for the comparison of three active arms with Placebo.
[4]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change From Baseline to Week 4 in Weekly Mean Daily Severity of Moderate to Severe Hot Flushes (Mean Value)

Groups ^[1]	0.25mg DRSP / 0.5mg E2 (BAY86-4891) vs. Placebo
Method ^[2]	ANCOVA
P Value ^[3]	<0.0001
Mean Difference (Final Values) ^[4]	-0.382
95% Confidence Interval	( -0.560 to -0.205 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison between DRSP/E2 (0.25mg/0.5mg) and Placebo with respect to a shift in the distribution of the end point. Null hypothesis: The mean change from baseline to week 4 is identical in both arms, alternative: there is a difference in the mean change from baseline.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Treatment, Center, and Baseline value used as covariate
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Significance level of 1.7% is used to adjust (Bonferroni) for the comparison of three active arms with Placebo.
[4]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Change From Baseline to Week 4 in Weekly Mean Daily Severity of Moderate to Severe Hot Flushes (Mean Value)

Groups ^[1]	Estradiol (E2 0.3mg) vs. Placebo
Method ^[2]	ANCOVA
P Value ^[3]	0.0233
Mean Difference (Final Values) ^[4]	-0.204
95% Confidence Interval	( -0.381 to -0.028 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison between E2 (0.3) and Placebo with respect to a shift in the distribution of the end point. Null hypothesis: The mean change from baseline to week 4 is identical in both arms, alternative: there is a difference in the mean change from baseline.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Treatment, Center, and Baseline value used as covariate
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Significance level of 1.7% is used to adjust (Bonferroni) for the comparison of three active arms with Placebo.
[4]	Other relevant estimation information:
	No text entered.

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	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.
	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 more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: (A) PI will provide copy to Sponsor at least (30) days prior to date of planned submission or presentation. Sponsor will have thirty (30) days to review and provide feedback. If proposed publication presents material adverse effect on the confidentiality of Sponsor's information, then PI shall delay or prevent such publication. (B) In a multi-center trial, the investigative data will be pooled and published as a collaborative effort with consent from all parties including the Sponsor.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: Therapeutic Area Head
Organization: BAYER
e-mail: clinical-trials-contact@bayerhealthcare.com

No publications provided

Responsible Party:	Therapeutic Area Head, Bayer HealthCare Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:	NCT00446199 History of Changes
Other Study ID Numbers:	91493, 310184
Study First Received:	March 9, 2007
Results First Received:	March 23, 2012
Last Updated:	April 16, 2013
Health Authority:	United States: Food and Drug Administration

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