Hormone Replacement Therapy for Use in Postmenopausal Women for Relief of Hot Flushes and Urogenital Symptoms.

• Sponsor: Warner Chilcott (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01070979
• Collaborator: (none)
• Enrollment: 249
• Locations: 32
• Arms: 3
• Duration (Months): 7
• Patients Per Site: 7.8
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

Multicenter, double-blind, controlled, parallel group, randomized study to compare the clinical benefit of Estradiol acetate tablets, estradiol tablets and conjugated equine estrogen tablets, each administered orally, once daily, to postmenopausal women.

Condition or Disease	Intervention/Treatment	Phase
Hormone Replacement Therapy	Drug: Estradiol acetate; Drug: Estradiol; Drug: Conjugated equine estrogens	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 249 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Double-Blind, Controlled, Randomized Study to Compare the Efficacy in Relief of Hot Flushes in Women Receiving Oral Estradiol Acetate Tablets, Oral Estradiol Tablets or Oral Conjugated Equine Estrogens
• Study Start Date: Feb 1, 2003
• Actual Primary Completion Date: Sep 1, 2003
• Actual Study Completion Date: Sep 1, 2003

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Estradiol acetate (E3A)	Drug: Estradiol acetate; Tablet containing 0.9 mg E3A, daily oral administration.
Active Comparator: Estradiol	Drug: Estradiol; Tablet containing 1 mg estradiol, daily oral administration.; Other Names: Estrace
Active Comparator: Conjugated equine estrogens (CEE):	Drug: Conjugated equine estrogens; Tablet containing 0.625 mg CEE, daily oral administration.; Other Names: Premarin

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline in the Number of Moderate to Severe Hot Flushes, Week 4, ITT (Intention to Treat) Population [Baseline to Week 4]

   Severity of hot flush definitions: mild - sensation of heat without perspiration, moderate - sensation of heat with perspiration, able to continue activity, severe - sensation of heat with perspiration, causing the subject to stop activity or awaken from sleep

2. Mean Change From Baseline in the Number of Moderate to Severe Hot Flushes, Week 12, ITT Population [Baseline to Week 12]

   Severity of hot flush definitions: mild - sensation of heat without perspiration, moderate - sensation of heat with perspiration, able to continue activity, severe - sensation of heat with perspiration, causing the subject to stop activity or awaken from sleep

Secondary Outcome Measures

1. Mean Change From Baseline in the Severity of Moderate to Severe Hot Flushes, Week 4, ITT Population [Baseline to Week 4]

   Patient self-reported outcome. Severity of hot flush definitions: mild (1) - sensation of heat without perspiration, moderate (2) - sensation of heat with perspiration, able to continue activity, severe (3) - sensation of heat with perspiration, causing the subject to stop activity or awaken from sleep. Minimum 0/no hot flushes, Maximum 3/all severe hot flushes. Lower the score the greater the improvement in reducing hot flushes.

2. Mean Change From Baseline in the Severity of Moderate to Severe Hot Flushes, Week 12, ITT Population [Baseline to Week 12]

   Patient self-reported outcome. Severity of hot flush definitions: mild (1) - sensation of heat without perspiration, moderate (2) - sensation of heat with perspiration, able to continue activity, severe (3) - sensation of heat with perspiration, causing the subject to stop activity or awaken from sleep. Minimum 0/no hot flushes, Maximum 3/all severe hot flushes. Lower the score the greater the improvement in reducing hot flushes.

3. Mean Change From Baseline in Total Urogenital Symptom Score, Week 4, ITT Population [Baseline to Week 4]

   Urogenital Symptom Severity scored none=0, mild=1, moderate=2, severe=3.

4. Change From Baseline in Total Urogenital Symptom Score, Week 8, ITT Population [Baseline to Week 8]

   Urogenital Symptom Severity scored none=0, mild=1, moderate=2, severe=3.

5. Change From Baseline in Total Urogenital Symptom Score, Week 12, ITT Population [Baseline to Week 12]

   Urogenital Symptom Severity scored none=0, mild=1, moderate=2, severe=3.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 35 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age ≥ 40 years of age; bilateral oophorectomy ≥ 35 years of age.

2. Non-hysterectomized women:

• Amenorrhea for ≥ 12 months or

• Amenorrhea for ≤ 12 months, but longer than 6 months, and serum FSH (follicle stimulating hormone) levels > 40 units/L and serum estradiol levels < 20 pg /mL,

Hysterectomized women:

• Bilateral oophorectomy - subjects may enter the study 6 weeks after surgery or

• History of removal of ovaries may be confirmed by - serum FSH levels > 40 units/L and serum estradiol levels < 20 pg/mL or via surgical report / ultrasound.

1. Seven or more moderate or severe hot flushes daily for 1 week or 60 or more moderate or severe flushes in 1 week during the 2 week screening period prior to study entry.

Exclusion Criteria:

1. Hormone therapy administered via the following routes and during the specified timeframes: oral within 8 weeks, vaginal (rings, creams, gels) within 1 week, transdermal within 4 weeks, intramuscular within 6 weeks, progestational implants, estrogen or estrogen/progestational injectable drug therapy within 3 months, estrogen pellet or progestational injectable within 6 months.

2. Abnormal Pap smear suggestive of low grade squamous intraepithelial lesion (LGSIL) or worse. Enrollment of subjects with an ASCUS (atypical squamous cells of undetermined significance) interpretation must be discussed with the sponsor prior to randomization.

3. Urinary tract infection

4. Congestive heart failure

5. Uncontrolled hypertension; sitting systolic BP ≥ 160 mmHg or diastolic ≥ 95 mmHg

6. History of stroke or transient ischemic attacks

7. Treatment with anticoagulants (heparin or warfarin).

8. Uncontrolled thyroid disorders.

9. Insulin-dependent diabetes mellitus.

10. Increase frequency or severity of headaches including migraines during previous estrogen therapy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Warner Chilcott Investigational Site	Phoenix	Arizona	United States	85031
2	Warner Chilcott Investigational Site	Carmichael	California	United States	95608
3	Warner Chilcott Investigational Site	San Diego	California	United States	92108
4	Warner Chilcott Investigational Site	San Diego	California	United States	92123
5	Warner Chilcott Investigational Site	Aventura	Florida	United States	33180
6	Warner Chilcott Investigational Site	Boynton Beach	Florida	United States	33437
7	Warner Chilcott Investigational Site	Clearwater	Florida	United States	33765
8	Warner Chilcott Investigational Site	Daytona Beach	Florida	United States	32114
9	Warner Chilcott Investigational Site	Gainesville	Florida	United States	32605
10	Warner Chilcott Investigational Site	Longwood	Florida	United States	32779
11	Warner Chilcott Investigational Site	Melbourne	Florida	United States	32935
12	Warner Chilcott Investigational Site	Miami	Florida	United States	33143
13	Warner Chilcott Investigational Site	Palm Springs	Florida	United States	33461
14	Warner Chilcott Investigational Site	Pinellas Park	Florida	United States	33781
15	Warner Chilcott Investigational Site	Sarasota	Florida	United States	34232
16	Warner Chilcott Investigational Site	Venice	Florida	United States	34285
17	Warner Chilcott Investigational Site	Roswell	Georgia	United States	30075
18	Warner Chilcott Investigational Site	Chicago	Illinois	United States	60612
19	Warner Chilcott Investigational Site	Peoria	Illinois	United States	61615
20	Warner Chilcott Investigational Site	Laurel	Maryland	United States	20707
21	Warner Chilcott Investigational Site	Lincoln	Nebraska	United States	68510
22	Warner Chilcott Investigational Site	Raleigh	North Carolina	United States	27612
23	Warner Chilcott Investigational Site	Winston Salem	North Carolina	United States	27103
24	Warner Chilcott Investigational Site	Cleveland	Ohio	United States	44122
25	Warner Chilcott Investigational Site	Columbus	Ohio	United States	43212
26	Warner Chilcott Investigational Site	Mogadore	Ohio	United States	44260
27	Warner Chilcott Investigational Site	Portland	Oregon	United States	97201
28	Warner Chilcott Investigational Site	Pittsburgh	Pennsylvania	United States	15206
29	Warner Chilcott Investigational Site	Nashville	Tennessee	United States	37203
30	Warner Chilcott Investigational Site	Salt Lake City	Utah	United States	84124
31	Warner Chilcott Investigational Site	Spokane	Washington	United States	99201
32	Warner Chilcott Investigational Site	Tacoma	Washington	United States	98405

Sponsors and Collaborators

• Warner Chilcott

Investigators

• Study Director: Herman Ellman, MD, Warner Chilcott

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Warner Chilcott
• ClinicalTrials.gov Identifier: NCT01070979
• Other Study ID Numbers: PR-03602.1
• First Posted: Feb 18, 2010
• Last Update Posted: Apr 22, 2013
• Last Verified: Apr 1, 2013

• Additional relevant MeSH terms: Hot Flashes; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Estradiol; Polyestradiol phosphate; Estrogens; Estrogens, Conjugated (USP)

Study Results

Participant Flow

Recruitment Details	Enrollment of postmenopausal women for relief of hot flushes and urogenital symptoms beginning Feb '03 at 33 sites in the US.
Pre-assignment Detail	Discontinue estrogen/hormone therapy prior to enrollment

Arm/Group Title	Estradiol Acetate (E3A)	Estradiol	Conjugated Equine Estrogens (CEE)
Arm/Group Description	1 tablet daily containing 0.9 mg estradiol acetate	1 tablet daily containing 1 mg estradiol	1 tablet daily containing 0.625 mg conjugated equine estrogen
Period Title: Overall Study
STARTED	79	85	85
COMPLETED	68	73	72
NOT COMPLETED	11	12	13

Baseline Characteristics

Arm/Group Title	Estradiol Acetate (E3A)	Estradiol	Conjugated Equine Estrogens (CEE)	Total
Arm/Group Description	1 tablet daily containing 0.9 mg estradiol acetate	1 tablet daily containing 1 mg estradiol	1 tablet daily containing 0.625 mg conjugated equine estrogen	Total of all reporting groups
Overall Participants	79	85	85	249
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.2 (6.6)	52.3 (7.0)	53.8 (6.3)	52.8 (6.7)
Sex: Female, Male (Count of Participants)
Female	79 100%	85 100%	85 100%	249 100%
Male	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	79 100%	85 100%	85 100%	249 100%

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline in the Number of Moderate to Severe Hot Flushes, Week 4, ITT (Intention to Treat) Population
Description	Severity of hot flush definitions: mild - sensation of heat without perspiration, moderate - sensation of heat with perspiration, able to continue activity, severe - sensation of heat with perspiration, causing the subject to stop activity or awaken from sleep
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

Intention to Treat (ITT) with Last Observation Carried Forward (LOCF)

Arm/Group Title	Estradiol Acetate (E3A)	Estradiol	Conjugated Equine Estrogens (CEE)
Arm/Group Description	1 tablet daily containing 0.9 mg estradiol acetate	1 tablet daily containing 1 mg estradiol	1 tablet daily containing 0.625 mg conjugated equine estrogen
Measure Participants	77	80	84
Least Squares Mean (Standard Error) [Change in Hot Flush Count]	-54.1 (4.5)	-62.0 (4.5)	-54.5 (4.3)

2. Secondary Outcome

Title	Mean Change From Baseline in the Severity of Moderate to Severe Hot Flushes, Week 4, ITT Population
Description	Patient self-reported outcome. Severity of hot flush definitions: mild (1) - sensation of heat without perspiration, moderate (2) - sensation of heat with perspiration, able to continue activity, severe (3) - sensation of heat with perspiration, causing the subject to stop activity or awaken from sleep. Minimum 0/no hot flushes, Maximum 3/all severe hot flushes. Lower the score the greater the improvement in reducing hot flushes.
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

Intention to Treat (ITT) with Last Observation Carried Forward (LOCF)

Arm/Group Title	Estradiol Acetate (E3A)	Estradiol	Conjugated Equine Estrogens (CEE)
Arm/Group Description	1 tablet daily containing 0.9 mg estradiol acetate	1 tablet daily containing 1 mg estradiol	1 tablet daily containing 0.625 mg conjugated equine estrogen
Measure Participants	77	80	84
Least Squares Mean (Standard Error) [Change in Score]	-0.53 (0.106)	-0.51 (0.106)	-0.59 (0.102)

3. Primary Outcome

Title	Mean Change From Baseline in the Number of Moderate to Severe Hot Flushes, Week 12, ITT Population
Description	Severity of hot flush definitions: mild - sensation of heat without perspiration, moderate - sensation of heat with perspiration, able to continue activity, severe - sensation of heat with perspiration, causing the subject to stop activity or awaken from sleep
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Intention to Treat (ITT) with Last Observation Carried Forward (LOCF)

Arm/Group Title	Estradiol Acetate (E3A)	Estradiol	Conjugated Equine Estrogens (CEE)
Arm/Group Description	1 tablet daily containing 0.9 mg estradiol acetate	1 tablet daily containing 1 mg estradiol	1 tablet daily containing 0.625 mg conjugated equine estrogen
Measure Participants	77	80	84
Least Squares Mean (Standard Error) [Change in Hot Flush Count]	-63.6 (4.8)	-72.2 (4.7)	-67.2 (4.6)

4. Secondary Outcome

Title	Mean Change From Baseline in the Severity of Moderate to Severe Hot Flushes, Week 12, ITT Population
Description	Patient self-reported outcome. Severity of hot flush definitions: mild (1) - sensation of heat without perspiration, moderate (2) - sensation of heat with perspiration, able to continue activity, severe (3) - sensation of heat with perspiration, causing the subject to stop activity or awaken from sleep. Minimum 0/no hot flushes, Maximum 3/all severe hot flushes. Lower the score the greater the improvement in reducing hot flushes.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Intention to Treat (ITT) with Last Observation Carried Forward (LOCF)

Arm/Group Title	Estradiol Acetate (E3A)	Estradiol	Conjugated Equine Estrogens (CEE)
Arm/Group Description	1 tablet daily containing 0.9 mg estradiol acetate	1 tablet daily containing 1 mg estradiol	1 tablet daily containing 0.625 mg conjugated equine estrogen
Measure Participants	77	80	84
Least Squares Mean (Standard Error) [Change in Score]	-1.05 (0.127)	-1.34 (0.125)	-1.17 (0.122)

5. Secondary Outcome

Title	Mean Change From Baseline in Total Urogenital Symptom Score, Week 4, ITT Population
Description	Urogenital Symptom Severity scored none=0, mild=1, moderate=2, severe=3.
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

Intention to Treat (ITT) with Last Observation Carried Forward (LOCF)

Arm/Group Title	Estradiol Acetate (E3A)	Estradiol	Conjugated Equine Estrogens (CEE)
Arm/Group Description	1 tablet daily containing 0.9 mg estradiol acetate	1 tablet daily containing 1 mg estradiol	1 tablet daily containing 0.625 mg conjugated equine estrogen
Measure Participants	77	80	84
Least Squares Mean (Standard Error) [Change in Score]	-1.89 (0.413)	-2.26 (0.407)	-1.96 (0.398)

6. Secondary Outcome

Title	Change From Baseline in Total Urogenital Symptom Score, Week 8, ITT Population
Description	Urogenital Symptom Severity scored none=0, mild=1, moderate=2, severe=3.
Time Frame	Baseline to Week 8

Outcome Measure Data

Analysis Population Description

Intention to Treat (ITT) with Last Observation Carried Forward (LOCF)

Arm/Group Title	Estradiol Acetate (E3A)	Estradiol	Conjugated Equine Estrogens (CEE)
Arm/Group Description	1 tablet daily containing 0.9 mg estradiol acetate	1 tablet daily containing 1 mg estradiol	1 tablet daily containing 0.625 mg conjugated equine estrogen
Measure Participants	77	80	84
Least Squares Mean (Standard Error) [Change in Score]	-1.96 (0.432)	-2.58 (0.425)	-2.42 (0.416)

7. Secondary Outcome

Title	Change From Baseline in Total Urogenital Symptom Score, Week 12, ITT Population
Description	Urogenital Symptom Severity scored none=0, mild=1, moderate=2, severe=3.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Intention to Treat (ITT) with Last Observation Carried Forward (LOCF)

Arm/Group Title	Estradiol Acetate (E3A)	Estradiol	Conjugated Equine Estrogens (CEE)
Arm/Group Description	1 tablet daily containing 0.9 mg estradiol acetate	1 tablet daily containing 1 mg estradiol	1 tablet daily containing 0.625 mg conjugated equine estrogen
Measure Participants	77	80	84
Least Squares Mean (Standard Error) [Change in Score]	-2.49 (0.437)	-2.59 (0.431)	-2.52 (0.422)

Adverse Events

Time Frame	7 months
Adverse Event Reporting Description	February 2003 thru September 2003, One subject randomized to estradiol group never took any study drug therefore not included in AE assessment.
Arm/Group Title	Estradiol Acetate (E3A)		Estradiol		Conjugated Equine Estrogens (CEE)
Arm/Group Description	1 tablet daily containing 0.9 mg estradiol acetate		1 tablet daily containing 1 mg estradiol		1 tablet daily containing 0.625 mg conjugated equine estrogen
All Cause Mortality
	Estradiol Acetate (E3A)		Estradiol		Conjugated Equine Estrogens (CEE)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Estradiol Acetate (E3A)		Estradiol		Conjugated Equine Estrogens (CEE)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/79 (0%)		1/84 (1.2%)		0/85 (0%)
Reproductive system and breast disorders
metrorrhagia	0/79 (0%)	0	1/84 (1.2%)	1	0/85 (0%)	0
Other (Not Including Serious) Adverse Events
	Estradiol Acetate (E3A)		Estradiol		Conjugated Equine Estrogens (CEE)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/79 (24.1%)		25/84 (29.8%)		30/85 (35.3%)
Gastrointestinal disorders
Nausea	4/79 (5.1%)		1/84 (1.2%)		2/85 (2.4%)
Abdominal Distention	1/79 (1.3%)		4/84 (4.8%)		2/85 (2.4%)
Infections and infestations
Vaginosis Fungal	0/79 (0%)		1/84 (1.2%)		3/85 (3.5%)
Investigations
Weight Increased	1/79 (1.3%)		1/84 (1.2%)		3/85 (3.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/79 (2.5%)		2/84 (2.4%)		3/85 (3.5%)
Nervous system disorders
Headache	3/79 (3.8%)		5/84 (6%)		6/85 (7.1%)
Nasopharyngitis	1/79 (1.3%)		3/84 (3.6%)		0/85 (0%)
Psychiatric disorders
Anxiety	3/79 (3.8%)		0/84 (0%)		2/85 (2.4%)
Reproductive system and breast disorders
Breast Tenderness	2/79 (2.5%)		5/84 (6%)		5/85 (5.9%)
Metrorrhagia	2/79 (2.5%)		3/84 (3.6%)		4/85 (4.7%)

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.