NRR: Studying Blood Samples From Women With Breast Cancer or Ductal Carcinoma In Situ Who Are Receiving Tamoxifen

• Sponsor: UNC Lineberger Comprehensive Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00764322
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 501
• Locations: 7
• Arms: 2
• Duration (Months): 36.4
• Patients Per Site: 71.6
• Patients Per Site Per Month: 2

Study Details

Study Description

Brief Summary

RATIONALE: Studying samples of blood from patients with cancer in the laboratory may help doctors learn more about differences in DNA and predict how well patients will respond to treatment and plan better treatment.

PURPOSE: This clinical trial is studying blood samples from women with breast cancer or ductal carcinoma in situ who are receiving tamoxifen.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Menopausal Symptoms	Drug: tamoxifen citrate; Genetic: gene expression analysis; Other: pharmacogenomic studies; Other: questionnaire administration; Procedure: quality-of-life assessment	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To evaluate the change in endoxifen levels after an increase in tamoxifen citrate dose from 20 mg to 40 mg in women with breast cancer or ductal breast carcinoma in situ with intermediate-metabolizing CYP2D6 genotypes.

Secondary

• To evaluate the tolerability of increasing the dose of tamoxifen citrate from 20 to 40 mg per day in these patients.

• To assess the feasibility of obtaining pharmacogenomic information from patients in the clinical setting and using it to guide changes in therapy.

• To examine CYP2D6 allele frequencies and endoxifen levels among African-American women taking tamoxifen citrate.

• To evaluate the change in plasma endoxifen levels after an increase in the tamoxifen citrate dose from 20 mg to 40 mg daily in patients with poor-metabolizing genotypes.

• To study patient understanding of pharmacogenomics and obstacles to participation in clinical trials based upon germline DNA.

OUTLINE: This is a multicenter study.

Blood samples are collected at baseline to determine CYP2D6 genotype and tamoxifen citrate metabolic status: poor-metabolizing (PM), intermediate-metabolizing (IM), or extensive-metabolizing (EM) alleles. Samples are also analyzed for plasma levels of endoxifen and N-desmethyltamoxifen and for endoxifen/N-desmethyltamoxifen ratio. Patients found to be IM or PM are notified to increased tamoxifen citrate to 40 mg/day for 4 months (in the absence of unacceptable toxicity) with repeat endoxifen and N-desmethyltamoxifen levels (and the ratio) at the end of this time.

All patients complete Quality Of Life (QOL) and Menopausal Symptoms Scale (MSS) questionnaires at baseline and after 4 months of treatment. Toxicities are assessed at the end of 4 months. Patients undergo repeat questionnaire assessment of their understanding of the use of pharmacogenomics in clinical decision-making. Some patients also undergo a 30-minute, baseline interview regarding attitudes and experience towards participation in a pharmacogenomics study.

Patients who choose to be informed of the results of their genotyping are contacted by letter, along with their physicians, and offered genetic counseling to discuss the significance of these results.

After completion of study therapy, patients are followed at 3-6 months, including toxicity assessment and QOL and MSS questionnaires.

Study Design

• Study Type: Interventional
• Actual Enrollment: 501 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Validating CYP2D6 Genotype-Guided Tamoxifen Therapy for a Multiracial U.S. Population
• Study Start Date: Jun 18, 2008
• Actual Primary Completion Date: Sep 28, 2010
• Actual Study Completion Date: Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tamoxifen 20 One arm, containing the ultra-rapid and extensive metabolizer genotypes, continues treatment with tamoxifen at 20mg.	Drug: tamoxifen citrate; Women found to be IM or PM will undergo increased tamoxifen to 40 mg/day (20 mg bid). Drug is given orally on a daily basis.; Other Names: Nolvadex Soltamox ; Genetic: gene expression analysis; Genetic analysis of blood sample.; Other: pharmacogenomic studies; Genetic analysis of blood sample.; Other: questionnaire administration; Questionnaire called the survey of participants. Questionnaires is self administered on paper documents and given pre-study, and at 4 months; Procedure: quality-of-life assessment; Self administration of a multiquestion questionnaire called the Functional Assessment of Cancer Therapy -Breast (FACT-B). Given pre-study, at 4 months and at 8-10 months.
Active Comparator: Tamoxifen 40 This arm, containing the intermediate and poor metabolizer genotypes, receives escalated treatment with tamoxifen at 40mg.	Drug: tamoxifen citrate; Women found to be IM or PM will undergo increased tamoxifen to 40 mg/day (20 mg bid). Drug is given orally on a daily basis.; Other Names: Nolvadex Soltamox ; Genetic: gene expression analysis; Genetic analysis of blood sample.; Other: pharmacogenomic studies; Genetic analysis of blood sample.; Other: questionnaire administration; Questionnaire called the survey of participants. Questionnaires is self administered on paper documents and given pre-study, and at 4 months; Procedure: quality-of-life assessment; Self administration of a multiquestion questionnaire called the Functional Assessment of Cancer Therapy -Breast (FACT-B). Given pre-study, at 4 months and at 8-10 months.

Outcome Measures

Primary Outcome Measures

1. Endoxifen Concentrations in Participants Receiving Tamoxifen Citrate Dose of 20 mg or 40 mg Stratified by the Metabolizing CYP2D6 Genotypes [4 months]

   Measurements of plasma concentrations of the key active metabolite of tamoxifen, endoxifen, were measured at baseline and after 4 months of treatment; The most common CYP2D6 alleles have been grouped by functional activity classifications with descending activity: ultra-rapid (UM), extensive (EM), intermediate (IM) or poor (PM) metabolism. A given patient has two alleles, giving them 10 possible allelic combinations, or diplotypes (UM/UM, UM/EM, EM/EM, etc.). These diplotypes are collapsed into four phenotypes, UM, EM, IM or PM.

Secondary Outcome Measures

1. Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer [Approximately ten months from registration to last follow-up]

   The doubling of tamoxifen dose is defined as "unacceptable" (i.e., not tolerable) if the prevalence of Pulmonary embolism (PE), Deep vein thrombosis (DVT), stroke, or endometrial cancer, either individually or in any combination, is greater than 2%.

2. Change in Median Endoxifen Concentrations to Determine Feasibility of Obtaining Pharmacogenomic Information From Patients in the Clinical Setting and Using it to Guide Changes in Therapy [Baseline and 4 months after dose increase]

   If the key active tamoxifen metabolite, endoxifen, could be significantly increased by genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism (by increasing tamoxifen dosing based on CYP2D6 genotype), then the study would be deemed feasible and the accrual expanded.

3. CYP2D6 Allele Frequencies and Endoxifen Levels Among African-American Women Taking Tamoxifen Citrate [baseline]

   Mean endoxifen levels by CYP2D6 genotype among African Americans. Measurements of plasma concentrations of the key active metabolite of tamoxifen, endoxifen, were measured at baseline.The most common CYP2D6 alleles have been grouped by functional activity classifications with descending activity: ultra-rapid (UM), extensive (EM), intermediate (IM) or poor (PM) metabolism. A given patient has two alleles, giving them 10 possible allelic combinations, or diplotypes (UM/UM, UM/EM, EM/EM, etc.). These diplotypes are collapsed into four phenotypes, UM, EM, IM or PM.

4. Change in Plasma Endoxifen Levels After an Increase in Tamoxifen Citrate Dose From 20 mg to 40 mg Daily in Patients With Poor-metabolizing Genotypes [Baseline and 4 months after dose increase]

   The intrapatient change in median endoxifen levels were calculated between baseline and 4 months after the increase in dose of Tamoxifen from 20mg/day to 40 mg/day

5. Patient Understanding of Pharmacogenomics [baseline]

   To examine patients' beliefs about how hypothetical genotype information would affect their perceived recurrence risk and benefits of tamoxifen therapy, participants were given experimentally manipulated 6 vignettes to describe hypothetical tamoxifen treatment (no or yes) and hypothetical genotype (EM, IM or PM). For each vignette, participants gave their perceived recurrence risk (RR; 0-100%)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 120 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion:

Histologically confirmed invasive carcinoma of the breast or ductal breast carcinoma in situ Has been receiving tamoxifen citrate at a dose of 20 mg/day for at least 4 months either for the treatment of invasive or non-invasive carcinoma of the breast or for breast cancer recurrence prevention

• Expected duration of tamoxifen citrate treatment at least 6 months Hormone receptor status not specified Concurrent participation in non-treatment studies allowed provided it will not interfere with participation in this study Menopausal status not specified Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Life expectancy ≥ 6 months Absolute Neutrophil Count (ANC) ≥ 1.0 x 10^{9/L Platelet count ≥ 100 x 10}9/L Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 times Upper Limit of Normal (ULN) Total bilirubin ≤ 2.5 times ULN Creatinine clearance ≥ 50 mL/min Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

• No limitations to number of prior therapies

• No limitations for prior radiotherapy

• More than 14 days since prior and no other concurrent investigational agent

Exclusion:

Not pregnant or nursing No active, serious infection or medical or psychiatric illness likely to preclude study participation No psychiatric conditions that would preclude study compliance or informed consent No history of venous thromboembolism, transient ischemic attack, or cerebral vascular accident No history of allergic reaction to tamoxifen citrate or any of its reagents No concurrent coumadin

No concurrent medications known to inhibit CYP2D6, including any of the following:

• Amiodarone

• Haloperidol

• Indinavir

• Ritonavir

• Quinidine

No concurrent selective serotonin reuptake inhibitors, except the following:

• Venlafaxine

• Citalopram

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina	United States	27599-7295
2	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina	United States	28232-2861
3	Duke Comprehensive Cancer Center	Durham	North Carolina	United States	27710
4	Moses Cone Regional Cancer Center at Wesley Long Community Hospital	Greensboro	North Carolina	United States	27403-1198
5	Leo W. Jenkins Cancer Center at ECU Medical School	Greenville	North Carolina	United States	27834
6	Rex Cancer Center at Rex Hospital	Raleigh	North Carolina	United States	27607
7	Gibbs Regional Cancer Center at Spartanburg Regional Medical Center	Spartanburg	South Carolina	United States	29303

Sponsors and Collaborators

• UNC Lineberger Comprehensive Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Lisa A. Carey, MD, UNC Lineberger Comprehensive Cancer Center
• Principal Investigator: William J. Irvin, MD, Bon Secours Virginia Health System / Bon Secours Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Clinical trial summary from the National Cancer Institute's PDQ® database

Publications

None provided.

• Responsible Party: UNC Lineberger Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT00764322
• Other Study ID Numbers: LCCC 0801; P30CA016086; 08-0483
• First Posted: Oct 2, 2008
• Last Update Posted: Aug 1, 2017
• Last Verified: Jul 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by UNC Lineberger Comprehensive Cancer Center: menopausal symptoms; recurrent breast cancer; stage I breast cancer; stage II breast cancer; stage IIIA breast cancer; stage IIIB breast cancer; stage IIIC breast cancer; stage IV breast cancer; ductal breast carcinoma in situ; breast cancer in situ
• Additional relevant MeSH terms: Breast Neoplasms; Carcinoma in Situ; Tamoxifen

Study Results

Participant Flow

Recruitment Details	Participants were recruited from breast cancer patients at Lineberger Comprehensive Cancer Center who had received tamoxifen for at least 4 months.
Pre-assignment Detail	One patient was a screen failure

Arm/Group Title	Patients Enrolled
Arm/Group Description
Period Title: Overall Study
STARTED	500
COMPLETED	480
NOT COMPLETED	20

Baseline Characteristics

Arm/Group Title	Extensive and Ultra-rapid Metabolizers	Intermediate and Poor Metabolizers	Total
Arm/Group Description	Those with the highest endoxifen concentrations as measured at baseline.	Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.	Total of all reporting groups
Overall Participants	161	319	480
Age (years) [Median (Full Range) ]
Median	51	50	50
Sex: Female, Male (Count of Participants)
Female	161 100%	319 100%	480 100%
Male	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	13 8.1%	61 19.1%	74 15.4%
White	140 87%	250 78.4%	390 81.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	8 5%	8 2.5%	16 3.3%
Region of Enrollment (Count of Participants)
United States	161 100%	319 100%	480 100%
Menopausal status (Count of Participants)
Pre/peri-	70 43.5%	154 48.3%	224 46.7%
Post-	91 56.5%	165 51.7%	256 53.3%
Duration of Tamoxifen treatment (years) (years) [Median (Full Range) ]
Median (Full Range) [years]	0.88	0.98	0.93
Prior chemotherapy (Count of Participants)
Yes	92 57.1%	169 53%	261 54.4%
No	69 42.9%	150 47%	219 45.6%
Tamoxifen indication (Count of Participants)
Invasive Disease	144 89.4%	263 82.4%	407 84.8%
DCIS	17 10.6%	49 15.4%	66 13.8%
Other	0 0%	6 1.9%	6 1.3%

Outcome Measures

1. Primary Outcome

Title	Endoxifen Concentrations in Participants Receiving Tamoxifen Citrate Dose of 20 mg or 40 mg Stratified by the Metabolizing CYP2D6 Genotypes
Description	Measurements of plasma concentrations of the key active metabolite of tamoxifen, endoxifen, were measured at baseline and after 4 months of treatment; The most common CYP2D6 alleles have been grouped by functional activity classifications with descending activity: ultra-rapid (UM), extensive (EM), intermediate (IM) or poor (PM) metabolism. A given patient has two alleles, giving them 10 possible allelic combinations, or diplotypes (UM/UM, UM/EM, EM/EM, etc.). These diplotypes are collapsed into four phenotypes, UM, EM, IM or PM.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

Baseline measurements are reported on all 353 subjects, while the 4 month levels are reported only for patients who completed 4 months of treatment

Arm/Group Title	Ultra-rapid Metabolizers	Extensive Metabolizers	Intermediate Metabolizers	Poor Metabolizers
Arm/Group Description	Those with the highest transformation of the CYP2D6 genotype to allelic activity	Those with the most normal transformation of the CYP2D6 genotype to allelic activity	Those with reduced transformation of the CYP2D6 genotype to allelic activity Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.	Those with no transformation of the CYP2D6 genotype to allelic activity Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.
Measure Participants	5	119	212	17
Baseline endoxifen concentration	8.4 (4.59)	10.00 (6.00)	7.10 (4.77)	3.42 (2.75)
4-Month endoxifen concentration	15.35 (5.48)	9.30 (5.03)	10.74 (7.36)	5.52 (2.57)

2. Secondary Outcome

Title	Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer
Description	The doubling of tamoxifen dose is defined as "unacceptable" (i.e., not tolerable) if the prevalence of Pulmonary embolism (PE), Deep vein thrombosis (DVT), stroke, or endometrial cancer, either individually or in any combination, is greater than 2%.
Time Frame	Approximately ten months from registration to last follow-up

Outcome Measure Data

Analysis Population Description

Incidence of unacceptable adverse events among all patients who completed study

Arm/Group Title	Tamoxifen 20	Tamoxifen 40
Arm/Group Description	One arm, containing the ultra-rapid and extensive metabolizer genotypes, continues treatment with tamoxifen at 20mg. tamoxifen citrate: Women found to be IM or PM will undergo increased tamoxifen to 40 mg/day (20 mg bid). Drug is given orally on a daily basis. gene expression analysis: Genetic analysis of blood sample. pharmacogenomic studies: Genetic analysis of blood sample. questionnaire administration: Questionnaire called the survey of participants. Questionnaires is self administered on paper documents and given pre-study, and at 4 months quality-of-life assessment: Self administration of a multiquestion questionnaire called the Functional Assessment of Cancer Therapy -Breast (FACT-B). Given pre-study, at 4 months and at 8-10 months.	This arm, containing the intermediate and poor metabolizer genotypes, receives escalated treatment with tamoxifen at 40mg. tamoxifen citrate: Women found to be IM or PM will undergo increased tamoxifen to 40 mg/day (20 mg bid). Drug is given orally on a daily basis. gene expression analysis: Genetic analysis of blood sample. pharmacogenomic studies: Genetic analysis of blood sample. questionnaire administration: Questionnaire called the survey of participants. Questionnaires is self administered on paper documents and given pre-study, and at 4 months quality-of-life assessment: Self administration of a multiquestion questionnaire called the Functional Assessment of Cancer Therapy -Breast (FACT-B). Given pre-study, at 4 months and at 8-10 months.
Measure Participants	161	319
Pulmonary embolism (PE)	0 0%	0 0%
Deep vein thrombosis (DVT)	0 0%	0 0%
Stroke	0 0%	0 0%
Endometrial cancer	0 0%	0 0%

3. Secondary Outcome

Title	Change in Median Endoxifen Concentrations to Determine Feasibility of Obtaining Pharmacogenomic Information From Patients in the Clinical Setting and Using it to Guide Changes in Therapy
Description	If the key active tamoxifen metabolite, endoxifen, could be significantly increased by genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism (by increasing tamoxifen dosing based on CYP2D6 genotype), then the study would be deemed feasible and the accrual expanded.
Time Frame	Baseline and 4 months after dose increase

Outcome Measure Data

Analysis Population Description

This was based on the initial 119 subjects enrolled (based on initial sample size of 100) and of those, the 89 that completed 4 months of tamoxifen therapy

Arm/Group Title	Extensive Metabolizers	Intermediate Metabolizers	Poor Metabolizers
Arm/Group Description	Those with the highest endoxifen concentrations as measured at baseline.	Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.	Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.
Measure Participants	29	51	9
Median (Inter-Quartile Range) [ng/mL]	-1.5	7.6	6.1

4. Secondary Outcome

Title	CYP2D6 Allele Frequencies and Endoxifen Levels Among African-American Women Taking Tamoxifen Citrate
Description	Mean endoxifen levels by CYP2D6 genotype among African Americans. Measurements of plasma concentrations of the key active metabolite of tamoxifen, endoxifen, were measured at baseline.The most common CYP2D6 alleles have been grouped by functional activity classifications with descending activity: ultra-rapid (UM), extensive (EM), intermediate (IM) or poor (PM) metabolism. A given patient has two alleles, giving them 10 possible allelic combinations, or diplotypes (UM/UM, UM/EM, EM/EM, etc.). These diplotypes are collapsed into four phenotypes, UM, EM, IM or PM.
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

Only participants who self-identified as African American were included in this analysis

Arm/Group Title	African Americans
Arm/Group Description	Participants who self identified as African American Race
Measure Participants	52
UM	14.58
EM	9.69
IM	7.09
PM	0.8

5. Secondary Outcome

Title	Change in Plasma Endoxifen Levels After an Increase in Tamoxifen Citrate Dose From 20 mg to 40 mg Daily in Patients With Poor-metabolizing Genotypes
Description	The intrapatient change in median endoxifen levels were calculated between baseline and 4 months after the increase in dose of Tamoxifen from 20mg/day to 40 mg/day
Time Frame	Baseline and 4 months after dose increase

Outcome Measure Data

Analysis Population Description

Analysis limited to only those subjects with the Poor Metabolizing (PM) genotype who were evaluable at baseline

Arm/Group Title	Poor Metabolizers
Arm/Group Description	Those with no transformation of the CYP2D6 genotype to allelic activity Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.
Measure Participants	11
Median (Inter-Quartile Range) [ng/mL]	6.1

6. Secondary Outcome

Title	Patient Understanding of Pharmacogenomics
Description	To examine patients' beliefs about how hypothetical genotype information would affect their perceived recurrence risk and benefits of tamoxifen therapy, participants were given experimentally manipulated 6 vignettes to describe hypothetical tamoxifen treatment (no or yes) and hypothetical genotype (EM, IM or PM). For each vignette, participants gave their perceived recurrence risk (RR; 0-100%)
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

Of 377 patients who were eligible to complete the survey, 320 patients completed the survey and 57 returned incomplete surveys

Arm/Group Title	All Participants
Arm/Group Description	All participants in the main study who consented to this additional survey
Measure Participants	320
Perceived RR -No tamoxifen/EM	47
Perceived RR -No tamoxifen/iM	48
Perceived RR -No tamoxifen/PM	53
Perceived RR - tamoxifen/EM	22
Perceived RR -tamoxifen/IM	30
Perceived RR -tamoxifen/PM	40

Adverse Events

Time Frame	Approximately ten months from on-study to last follow-up visit
Arm/Group Title	Ultra-rapid and Extensive Metabolizers		Intermediate Metabolizers		Poor Metabolizers
Arm/Group Description	Those with the highest endoxifen concentrations as measured at baseline.		Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.		Genotype-guided escalation of the tamoxifen dose from 20mg to 40mg/day.
All Cause Mortality
	Ultra-rapid and Extensive Metabolizers		Intermediate Metabolizers		Poor Metabolizers
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/161 (0%)		0/290 (0%)		0/29 (0%)
Serious Adverse Events
	Ultra-rapid and Extensive Metabolizers		Intermediate Metabolizers		Poor Metabolizers
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/161 (0%)		3/290 (1%)		0/29 (0%)
Nervous system disorders
headache	0/161 (0%)	0	1/290 (0.3%)	1	0/29 (0%)	0
Psychiatric disorders
Mood alteration	0/161 (0%)	0	1/290 (0.3%)	1	0/29 (0%)	0
Reproductive system and breast disorders
Hemorrhage, GU	0/161 (0%)	0	1/290 (0.3%)	1	0/29 (0%)	0
Vascular disorders
thrombosis	0/161 (0%)	0	1/290 (0.3%)	1	0/29 (0%)	0
Other (Not Including Serious) Adverse Events
	Ultra-rapid and Extensive Metabolizers		Intermediate Metabolizers		Poor Metabolizers
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	149/161 (92.5%)		274/290 (94.5%)		26/29 (89.7%)
Blood and lymphatic system disorders
Hemorrhage, GU - Vagina	0/161 (0%)		4/290 (1.4%)		2/29 (6.9%)
Hemorrhage/Bleeding - Other (Specify, __)	3/161 (1.9%)		2/290 (0.7%)		0/29 (0%)
Cardiac disorders
Palpitations	4/161 (2.5%)		5/290 (1.7%)		0/29 (0%)
Eye disorders
Cataract	3/161 (1.9%)		8/290 (2.8%)		0/29 (0%)
Ocular/Visual - Other (Specify, __)	2/161 (1.2%)		2/290 (0.7%)		0/29 (0%)
Vision-blurred vision	8/161 (5%)		21/290 (7.2%)		0/29 (0%)
Gastrointestinal disorders
Constipation	8/161 (5%)		18/290 (6.2%)		0/29 (0%)
Diarrhea	5/161 (3.1%)		9/290 (3.1%)		2/29 (6.9%)
Distension/bloating, abdominal	5/161 (3.1%)		9/290 (3.1%)		0/29 (0%)
Gastrointestinal - Other (Specify, __)	2/161 (1.2%)		6/290 (2.1%)		0/29 (0%)
Heartburn/dyspepsia	5/161 (3.1%)		10/290 (3.4%)		0/29 (0%)
Hemorrhoids	2/161 (1.2%)		4/290 (1.4%)		0/29 (0%)
Nausea	6/161 (3.7%)		18/290 (6.2%)		0/29 (0%)
Pain - Abdomen NOS	5/161 (3.1%)		6/290 (2.1%)		0/29 (0%)
General disorders
Edema: limb	10/161 (6.2%)		19/290 (6.6%)		0/29 (0%)
Fatigue (asthenia, lethargy, malaise)	42/161 (26.1%)		64/290 (22.1%)		5/29 (17.2%)
Pain - Other (Specify, __)	4/161 (2.5%)		6/290 (2.1%)		0/29 (0%)
Immune system disorders
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	4/161 (2.5%)		11/290 (3.8%)		0/29 (0%)
Infections and infestations
Infection with unknown ANC	0/161 (0%)		9/290 (3.1%)		0/29 (0%)
Injury, poisoning and procedural complications
Bruising (in absence of Grade 3 or 4 thrombocytopenia)	4/161 (2.5%)		6/290 (2.1%)		0/29 (0%)
Investigations
ALT, SGPT (serum glutamic pyruvic transaminase)	3/161 (1.9%)		3/290 (1%)		0/29 (0%)
AST, SGOT(serum glutamic oxaloacetic transaminase)	5/161 (3.1%)		3/290 (1%)		0/29 (0%)
Weight gain	14/161 (8.7%)		33/290 (11.4%)		4/29 (13.8%)
Musculoskeletal and connective tissue disorders
Arthritis (non-septic)	0/161 (0%)		5/290 (1.7%)		0/29 (0%)
Joint - Function	2/161 (1.2%)		7/290 (2.4%)		0/29 (0%)
Musculoskeletal/Soft Tissue - Other (Specify, __)	5/161 (3.1%)		11/290 (3.8%)		0/29 (0%)
Osteoporosis	0/161 (0%)		3/290 (1%)		0/29 (0%)
Pain - Back	15/161 (9.3%)		28/290 (9.7%)		2/29 (6.9%)
Pain - Bone	4/161 (2.5%)		11/290 (3.8%)		0/29 (0%)
Pain - Breast	13/161 (8.1%)		22/290 (7.6%)		0/29 (0%)
Pain - Buttock	3/161 (1.9%)		2/290 (0.7%)		0/29 (0%)
Pain - Extremity-limb	16/161 (9.9%)		14/290 (4.8%)		3/29 (10.3%)
Pain - Joint	40/161 (24.8%)		58/290 (20%)		5/29 (17.2%)
Pain - Muscle	15/161 (9.3%)		38/290 (13.1%)		2/29 (6.9%)
Pain - Neck	0/161 (0%)		5/290 (1.7%)		0/29 (0%)
Nervous system disorders
Cognitive disturbance	13/161 (8.1%)		27/290 (9.3%)		3/29 (10.3%)
Dizziness	5/161 (3.1%)		14/290 (4.8%)		3/29 (10.3%)
Memory impairment	6/161 (3.7%)		16/290 (5.5%)		0/29 (0%)
Neurology - Other (Specify, __)	0/161 (0%)		7/290 (2.4%)		0/29 (0%)
Neuropathy- sensory	15/161 (9.3%)		22/290 (7.6%)		0/29 (0%)
Pain - Head/headache	15/161 (9.3%)		42/290 (14.5%)		4/29 (13.8%)
Psychiatric disorders
Insomnia	26/161 (16.1%)		42/290 (14.5%)		4/29 (13.8%)
Mood alteration	2/161 (1.2%)		4/290 (1.4%)		0/29 (0%)
Mood alteration - Agitation	5/161 (3.1%)		9/290 (3.1%)		4/29 (13.8%)
Mood alteration - Anxiety	20/161 (12.4%)		17/290 (5.9%)		0/29 (0%)
Mood alteration - Depression	14/161 (8.7%)		13/290 (4.5%)		2/29 (6.9%)
Renal and urinary disorders
Incontinence, urinary	13/161 (8.1%)		28/290 (9.7%)		3/29 (10.3%)
Urinary frequency/urgency	4/161 (2.5%)		2/290 (0.7%)		0/29 (0%)
Reproductive system and breast disorders
Irregular menses (change from baseline)	9/161 (5.6%)		14/290 (4.8%)		0/29 (0%)
Libido	16/161 (9.9%)		24/290 (8.3%)		3/29 (10.3%)
Sexual/Reproductive Function - Other (Specify, __)	9/161 (5.6%)		17/290 (5.9%)		0/29 (0%)
Vaginal discharge (non-infectious)	20/161 (12.4%)		44/290 (15.2%)		2/29 (6.9%)
Vaginal dryness	32/161 (19.9%)		66/290 (22.8%)		8/29 (27.6%)
Vaginitis	3/161 (1.9%)		3/290 (1%)		0/29 (0%)
Vaginitis (not due to infection)	0/161 (0%)		4/290 (1.4%)		0/29 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	10/161 (6.2%)		12/290 (4.1%)		0/29 (0%)
Dyspnea	11/161 (6.8%)		15/290 (5.2%)		0/29 (0%)
Nasal cavity/paranasal sinus reactions	2/161 (1.2%)		4/290 (1.4%)		0/29 (0%)
Pain - Chest/thorax NOS	4/161 (2.5%)		2/290 (0.7%)		0/29 (0%)
Pulmonary/Upper Respiratory - Other (Specify, __)	4/161 (2.5%)		4/290 (1.4%)		0/29 (0%)
Skin and subcutaneous tissue disorders
Hair loss/alopecia (scalp or body)	8/161 (5%)		17/290 (5.9%)		0/29 (0%)
Nail changes	1/161 (0.6%)		7/290 (2.4%)		0/29 (0%)
Pruritus/itching	4/161 (2.5%)		3/290 (1%)		0/29 (0%)
Rash/desquamation	4/161 (2.5%)		6/290 (2.1%)		0/29 (0%)
Rash: acne/acneiform	2/161 (1.2%)		6/290 (2.1%)		2/29 (6.9%)
Sweating (diaphoresis)	6/161 (3.7%)		12/290 (4.1%)		0/29 (0%)
Vascular disorders
Hot flashes/flushes	124/161 (77%)		230/290 (79.3%)		23/29 (79.3%)
Hypertension	3/161 (1.9%)		11/290 (3.8%)		0/29 (0%)
Lymphedema-related fibrosis	0/161 (0%)		5/290 (1.7%)		0/29 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.