E-String: Vaginal Testosterone Cream vs ESTRING for Vaginal Dryness or Decreased Libido in Early Stage Breast Cancer Patients

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT00698035
• Collaborator: (none)
• Enrollment: 76
• Location: 1
• Arms: 2
• Duration (Months): 69.1
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

The purpose of this clinical research study is to determine whether the ESTRING or a special preparation of a testosterone cream inserted vaginally are safe for use in breast cancer patients. This study will also evaluate if either of these treatments can improve symptoms of vaginal dryness or decreased sexual interest that are related to your treatment for breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Sexual Dysfunction, Physiological	Drug: Testosterone Cream; Drug: Estring	Phase 2

Detailed Description

There is a growing body of scientific literature to suggest that sexual functioning is one of the most distressing problems experienced by breast cancer survivors. Vaginal dryness, dyspareunia (pain during sexual intercourse), and decreased libido are common complaints among breast cancer patients. With increasing use of aromatase inhibitors which are associated with a higher rate of vaginal dryness than tamoxifen, these problems are becoming even more prominent. This study will evaluate the safety and tolerability of the ESTRING and 1% testosterone cream administered vaginally as treatments for vaginal dryness and/or decreased libido in women receiving an aromatase inhibitor for early stage breast cancer.

Study Design

• Study Type: Interventional
• Actual Enrollment: 76 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: A Phase II Study of Vaginal Testosterone Cream vs. the ESTRING for Vaginal Dryness or Decreased Libido in Early Breast Cancer Patients Treated With Aromatase Inhibitors
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Oct 1, 2012
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Testosterone Cream Testosterone Cream 1% micronized in velvachol - 0.5 gm of cream vaginally each night for two weeks, then 3 times a week for total of 12 weeks of treatment	Drug: Testosterone Cream; 1% micronized in velvachol - 0.5 gm of cream vaginally each night for two weeks, then 3 times a week for total of 12 weeks of treatment; Other Names: intravaginal testosterone cream
Active Comparator: Estring Estring 2mg ring inserted vaginally once every 12 weeks	Drug: Estring; 2mg ring inserted vaginally once every 12 weeks; Other Names: ESTRING Estrodial Vaginal Ring

Outcome Measures

Primary Outcome Measures

1. Persistently Elevated Serum Estradiol Level Outside the Post-menopausal Range [12 Weeks]

   Liquid chromatography tandem mass spectrometry (Quest Diagnostics). Persistently elevated serum estradiol level outside the post-menopausal range was defined as: Serum estradiol >10 pg/dl on two consecutive collections at least 4 weeks apart. 2. If baseline estradiol was >10 pg/dl, subsequent levels >10 pg/ml higher than baseline were considered a significant elevation outside the post-menopausal range.

Secondary Outcome Measures

1. Serum Estradiol (E2) [12 weeks]

   serial measurements of serum estradiol (E2) by liquid chromatography tandem mass spectrometry (Quest Diagnostics)

2. Matched E2 by Commercial and Research (RIA) Analyses [baseline, 4 weeks]

   Serum estradiol assays sent to the UCSF clinical laboratory are sent out to Quest Diagnostics, which uses LC/MS for their ultra-sensitive estradiol assay. Samples were also sent to a specialized research lab in England which has developed an ultrasensitive assay using radioimmunoassay (RIA) after ether extraction (sensitivity limit of 3pmol/l) to quantify low levels of estradiol found in post-menopausal women

3. Total Testosterone Levels [12 weeks]

   By serum ultrasensitive total testosterone test (Quest Diagnostics)

4. Sexual Quality of Life [Baseline, Week 4, Week 12]

   Cancer Rehabilitation Evaluation System (CARES) Sexual Dysfunction (SD) and Sexual Interest (SI) Subscales range from 0 to 4 and measure the severity of problems, with higher scores indicating more difficulty.

5. Sexual Satisfaction [Baseline, Week 4, Week 12]

   Participants were asked to respond to a Sexual Satisfaction One Item Measure which asked "Overall, how satisfactory to you is your sexual relationship with your partner?" Response options range from 1 (Extremely unsatisfactory) to 6 (Extremely satisfactory).

6. Change in Vaginal Epithelium Scores [Baseline, 12 weeks]

   During a gynecologic exam, the vaginal epithelium was assessed by an examiner using the Vaginal Atrophy Scoring Scale to evaluate Rugae (lack of), Pallor (pinkness), Petechiae, Mucosal thinning, Dryness. Scores range from 0 (none) to 3 (severe); higher scores indicate less favorable outcomes.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Histologically or cytologically confirmed Stage I-III breast cancer who are taking an aromatase inhibitor as adjuvant hormonal therapy. Patient must have started the aromatase inhibitor at least 60 days prior to enrolling.

2. Postmenopausal estradiol levels at baseline as measured by standard laboratory analysis.

• Patient may be rendered postmenopausal through the use of a GnRH agonist, but must have confirmed post-menopausal levels of serum estradiol on two lab tests at least one month apart.

• If patient has been rendered post-menopausal by adjuvant chemotherapy but has had a period within the past 12 months, post-menopausal levels of serum estradiol must be documented on two lab tests at least 3 months apart.

1. Age ≥18 and ≤80 years old.

2. ECOG ≤1

3. Adequate hematologic, hepatic, and renal function as defined by:

• Hgb ≥9 g/dL

• Absolute neutrophil count (ANC)/absolute granulocyte count (AGC) ≥1500 cells/mm3

• Platelet count ≥100,000/mm3

• Serum creatinine ≤1.5 mg/dL

• Total bilirubin ≤1.5 times the ULN; and aspartate aminotransferase ≤3 times the ULN

1. Normal thyroid function tested within the past 6 months (Patients with a diagnosis of hypothyroidism and on thyroid supplementation must have had thyroid function tests in the normal range within the past 3 months)

2. Patient must have recovered from the side effects of previous chemotherapy, surgery, or radiation therapy for early breast cancer.

Exclusion Criteria:

1. History of radiation to the vaginal area

2. Concurrent treatment with any type of oral, injectable or topical form of estrogen or androgen therapy including natural supplements marketed as hormone replacement products

3. Initiation of topical moisturizers (for example, Replens), or herbal or alternative medicines to manage the symptoms of vaginal dryness while on study. Patients who were previously using these products may continue them with the same usage pattern while on study.

4. Use of vaginal hormonal products (rings, inserts, creams, gels) containing estrogens or androgens within the past 30 days.

5. History of an abnormal pap smear within the last 12 months

6. History of endometrial or ovarian cancer

7. Any episode of vaginal bleeding in the past 6 months that has not been evaluated by a gynecological exam and/or pelvic ultrasound

8. History of sexual dysfunction prior to diagnosis of breast cancer ( Sexual dysfunction will be defined as loss of libido or inability to achieve orgasm for which patient sought medical attention or which patient felt significantly interfered with quality of life.)

9. Moderate or severe depression for which the patient is receiving ongoing psychological counseling and/or taking antidepressants, and for whom, in the investigators opinion may be interfering in the patients sexual function independent of the side effects of breast cancer and aromatase inhibitor use.

10. Use of any investigational agent for breast cancer within 3 weeks of study entry.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115

Sponsors and Collaborators

• University of California, San Francisco

Investigators

• Principal Investigator: Michelle Melisko, MD, University of California, San Francisco

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT00698035
• Other Study ID Numbers: UCSF-067519
• First Posted: Jun 16, 2008
• Last Update Posted: Jun 2, 2014
• Last Verified: May 1, 2014

• Keywords provided by University of California, San Francisco: Vaginal Testosterone Cream; ESTRING
• Additional relevant MeSH terms: Sexual Dysfunction, Physiological; Methyltestosterone; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Testosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate; Estradiol; Polyestradiol phosphate

Study Results

Participant Flow

Pre-assignment Detail	Of 76 enrolled participants, one participant consented and was assigned to ESTRING, but did not insert ESTRING prior to withdrawing from the study.

Arm/Group Title	Estring	Testosterone Cream
Arm/Group Description	Estring 2mg ring inserted vaginally once every 12 weeks	Testosterone Cream 1% micronized in velvachol - 0.5 gm of cream vaginally each night for two weeks, then 3 times a week for total of 12 weeks of treatment
Period Title: Overall Study
STARTED	39	36
COMPLETED	35	34
NOT COMPLETED	4	2

Baseline Characteristics

Arm/Group Title	Estring	Testosterone Cream	Total
Arm/Group Description	Estring 2mg ring inserted vaginally once every 12 weeks	Testosterone Cream 1% micronized in velvachol - 0.5 gm of cream vaginally each night for two weeks, then 3 times a week for total of 12 weeks of treatment	Total of all reporting groups
Overall Participants	39	36	75
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	56	57	56
Sex: Female, Male (Count of Participants)
Female	39 100%	36 100%	75 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	39 100%	36 100%	75 100%

Outcome Measures

1. Secondary Outcome

Title	Serum Estradiol (E2)
Description	serial measurements of serum estradiol (E2) by liquid chromatography tandem mass spectrometry (Quest Diagnostics)
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Per protocol, participants who completed 12 weeks of assigned treatment

Arm/Group Title	Estring	Testosterone Cream
Arm/Group Description	Estring 2mg ring inserted vaginally once every 12 weeks	Testosterone Cream 1% micronized in velvachol - 0.5 gm of cream vaginally each night for two weeks, then 3 times a week for total of 12 weeks of treatment
Measure Participants	35	34
E2 at baseline	27 (36)	9 (13)
E2 at 4 weeks	5 (5)	10 (20)
E2 at 12 weeks	9 (12)	8 (7)

2. Secondary Outcome

Title	Matched E2 by Commercial and Research (RIA) Analyses
Description	Serum estradiol assays sent to the UCSF clinical laboratory are sent out to Quest Diagnostics, which uses LC/MS for their ultra-sensitive estradiol assay. Samples were also sent to a specialized research lab in England which has developed an ultrasensitive assay using radioimmunoassay (RIA) after ether extraction (sensitivity limit of 3pmol/l) to quantify low levels of estradiol found in post-menopausal women
Time Frame	baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

Patients from both study arms arms with matched pairs of baseline and week 4 E2 performed by both commercial and research labs

Arm/Group Title	E2 by LC/MS	E2 by RIA
Arm/Group Description	A commercially available ultrasensitive E2 level was measured at baseline and 4 weeks (Quest Diagnostics, liquid chromatography tandem mass spectrometry (LC/MS, PM range <10 pg/ml)	Additional measurement of baseline and week 4 E2 by RIA
Measure Participants	63	63
Baseline E2	17.7 (28.5)	17.9 (44.1)
4-week E2	7.8 (15.0)	2.9 (13.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Estring, Testosterone Cream
	Comments	Comparison of baseline estradiol between LC/MS and RIA
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	Significant at p<0.05
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Estring, Testosterone Cream
	Comments	Comparison of week 4 estradiol between LC/MS and RIA
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	singificant at p<0.05
	Method	t-test, 2 sided
	Comments

3. Primary Outcome

Title	Persistently Elevated Serum Estradiol Level Outside the Post-menopausal Range
Description	Liquid chromatography tandem mass spectrometry (Quest Diagnostics). Persistently elevated serum estradiol level outside the post-menopausal range was defined as: Serum estradiol >10 pg/dl on two consecutive collections at least 4 weeks apart. 2. If baseline estradiol was >10 pg/dl, subsequent levels >10 pg/ml higher than baseline were considered a significant elevation outside the post-menopausal range.
Time Frame	12 Weeks

Outcome Measure Data

Analysis Population Description

Per protocol, to be considered evaluable for the Primary Outcome, patients must complete both baseline evaluation and week 4 safety blood draw. 1 participant in the Testosterone arm was not evaluable.

Arm/Group Title	Estring	Testosterone Cream
Arm/Group Description	Estring 2mg ring inserted vaginally once every 12 weeks	Testosterone Cream 1% micronized in velvachol - 0.5 gm of cream vaginally each night for two weeks, then 3 times a week for total of 12 weeks of treatment
Measure Participants	35	33
Number [participants]	0 0%	4 11.1%

4. Secondary Outcome

Title	Total Testosterone Levels
Description	By serum ultrasensitive total testosterone test (Quest Diagnostics)
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Per protocol, participants assigned to the Testosterone arm who completed 12 weeks of assigned treatment and had testosterone measurement at baseline, 4 weeks and 12 weeks.

Arm/Group Title	Testosterone Cream
Arm/Group Description	Testosterone Cream 1% micronized in velvachol - 0.5 gm of cream vaginally each night for two weeks, then 3 times a week for total of 12 weeks of treatment
Measure Participants	27
Testosterone at baseline	33 (19)
Testosterone at 4 weeks	186 (276)
Testosterone at 12 weeks	171 (251)

5. Secondary Outcome

Title	Sexual Quality of Life
Description	Cancer Rehabilitation Evaluation System (CARES) Sexual Dysfunction (SD) and Sexual Interest (SI) Subscales range from 0 to 4 and measure the severity of problems, with higher scores indicating more difficulty.
Time Frame	Baseline, Week 4, Week 12

Outcome Measure Data

Analysis Population Description

Participants who provided responses to SD, SI and SS at 3 time points: Baseline (BL), Week 4 (W4), and Week 12 (W12)

Arm/Group Title	Estring	Testosterone Cream
Arm/Group Description	Estring 2mg ring inserted vaginally once every 12 weeks	Testosterone Cream 1% micronized in velvachol - 0.5 gm of cream vaginally each night for two weeks, then 3 times a week for total of 12 weeks of treatment
Measure Participants	32	30
SI (BL)	1.2 (0.9)	1.4 (0.8)
SI (W4)	1.3 (1.0)	1.2 (0.7)
SI (W12)	0.9 (0.7)	1.0 (0.6)
SD (BL)	2.9 (1.1)	2.9 (0.8)
SD (W4)	2.4 (1.1)	2.1 (1.0)
SD (W12)	2.0 (1.1)	1.9 (1.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Estring
	Comments	Change in SI from BL to W12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.021
	Comments	Significant at p<0.05
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Estring
	Comments	Change in SD from BL to W12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Significant at p<0.05
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Testosterone Cream
	Comments	Change in SI from BL to W12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0228
	Comments	Significant at p<0.05
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Testosterone Cream
	Comments	Change in SD from BL to W12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Significant at p<0.05
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

Title	Sexual Satisfaction
Description	Participants were asked to respond to a Sexual Satisfaction One Item Measure which asked "Overall, how satisfactory to you is your sexual relationship with your partner?" Response options range from 1 (Extremely unsatisfactory) to 6 (Extremely satisfactory).
Time Frame	Baseline, Week 4, Week 12

Outcome Measure Data

Analysis Population Description

Participants who provided responses to SD, SI and SS at all 3 time points: Baseline (BL), Week 4 (W4), and Week 12 (W12)

Arm/Group Title	Estring	Testosterone Cream
Arm/Group Description	Estring 2mg ring inserted vaginally once every 12 weeks	Testosterone Cream 1% micronized in velvachol - 0.5 gm of cream vaginally each night for two weeks, then 3 times a week for total of 12 weeks of treatment
Measure Participants	32	30
SS (BL)	2.5 (1.6)	3.2 (1.6)
SS (W4)	3.5 (1.8)	3.7 (1.6)
SS (W12)	4.0 (1.5)	4.0 (1.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Estring
	Comments	Change in SS from Baseline to Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	Significant at p<0.05
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Testosterone Cream
	Comments	Change in SS from Baseline to Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.139
	Comments	Significant at p<0.05
	Method	t-test, 2 sided
	Comments

7. Secondary Outcome

Title	Change in Vaginal Epithelium Scores
Description	During a gynecologic exam, the vaginal epithelium was assessed by an examiner using the Vaginal Atrophy Scoring Scale to evaluate Rugae (lack of), Pallor (pinkness), Petechiae, Mucosal thinning, Dryness. Scores range from 0 (none) to 3 (severe); higher scores indicate less favorable outcomes.
Time Frame	Baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

Patients with both baseline and week 12 gynecologic exams for evaluation of vaginal atrophy

Arm/Group Title	Estring	Testosterone Cream
Arm/Group Description	Estring 2mg ring inserted vaginally once every 12 weeks	Testosterone Cream 1% micronized in velvachol - 0.5 gm of cream vaginally each night for two weeks, then 3 times a week for total of 12 weeks of treatment
Measure Participants	35	34
Rugae	-1.03 (0.80)	-0.71 (0.84)
Pallor	-0.88 (0.84)	-0.91 (0.75)
Petechiae	-1.0 (1.07)	-0.74 (1.38)
Mucosal thinning	-0.62 (0.49)	-0.88 (0.64)
Dryness	-1.03 (0.80)	-0.71 (0.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Estring
	Comments	Differences in rugae, pallor, petechiae, mucosal thinning and dryness between baseline and week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Significant at p<0.05
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Testosterone Cream
	Comments	Differences in rugae, pallor, mucosal thinning, and dryness from baseline to 12 weeks
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Significant at p<0.05
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Testosterone Cream
	Comments	Difference in petechiae between baseline and week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0061
	Comments	Significant at p<0.05
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	12 weeks
Arm/Group Title	Estring		Testosterone Cream
Arm/Group Description	Estring 2mg ring inserted vaginally once every 12 weeks		Testosterone Cream 1% micronized in velvachol - 0.5 gm of cream vaginally each night for two weeks, then 3 times a week for total of 12 weeks of treatment
All Cause Mortality
	Estring		Testosterone Cream
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Estring		Testosterone Cream
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/39 (0%)		0/36 (0%)
Other (Not Including Serious) Adverse Events
	Estring		Testosterone Cream
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/39 (25.6%)		10/36 (27.8%)
General disorders
Hot flashes	3/39 (7.7%)	3	1/36 (2.8%)	1
Reproductive system and breast disorders
Vaginal discharge	4/39 (10.3%)	4	2/36 (5.6%)	2
Vaginal itching or irritation	4/39 (10.3%)	4	0/36 (0%)	0
Vaginal odor	0/39 (0%)	0	3/36 (8.3%)	3
Skin and subcutaneous tissue disorders
Facial hair growth	1/39 (2.6%)	1	5/36 (13.9%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT 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.