Breast Cancer, Vaginal Dryness
Conditions
Keywords
sexuality and reproductive issues, sexual dysfunction, 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
Brief summary
RATIONALE: Pilocarpine may decrease vaginal dryness and improve quality of life in patients with breast cancer It is not yet known whether pilocarpine is more effective than a placebo in treating vaginal dryness in patients with breast cancer. PURPOSE: This randomized phase III trial is studying pilocarpine to see how well it works compared to a placebo in treating vaginal dryness in patients with breast cancer.
Detailed description
OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to age (18 to 45 vs 46 to 55 vs 56 to 65 vs \> 65), concurrent tamoxifen therapy (yes vs no vs unknown \[e.g., on a blinded clinical study\]), concurrent aromatase inhibitor therapy (yes vs no vs unknown \[e.g., on a blinded clinical study\]), and perception of severity of vaginal symptoms at baseline (mild vs moderate vs severe). Patients are randomized to 1 of 4 treatment arms. The primary and secondary objectives of the study are described below. OBJECTIVES: Primary * Determine the effectiveness of pilocarpine hydrochloride for alleviation of vaginal dryness in patients with breast cancer. Secondary * Evaluate any toxicities arising from pilocarpine hydrochloride in these patients. * Evaluate quality of life of these patients treated with pilocarpine hydrochloride. Quality of life was assessed at baseline and then weekly for 6 weeks.
Interventions
Given orally
OTHERplacebo
Given orally
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Required Characteristics: 1. Adult post menopausal women or women with no childbearing potential (≥ 18 years) with a history of breast cancer (currently no evidence of disease) or women who do not want to take vaginal estrogen for a fear of an increased risk of breast cancer. Postmenopausal status will be determined by the primary physician. 2. Significant vaginal complaints defined as persistent vaginal dryness and/or itching of sufficient severity to make a patient desire therapeutic intervention. Symptoms should have been present ≥ 2 months prior to randomization. 3. Life expectancy \> 6 months 4. Ability to complete questionnaire(s) by themselves or with assistance. Contraindications: 1. Initiation or discontinuation of tamoxifen or aromatase inhibitors ≤2 months prior to randomization or plans to initiate or discontinue any of these medications during the 6-week study. 2. Active vaginal infection 3. Concurrent chemotherapy 4. Acute iritis 5. Current or past use of pilocarpine (regardless of purpose) 6. Planned use of any vaginal preparations during the study period (including any over the counter or herbal preparations). Note: Lubricants used during sexual intercourse are permitted. 7. Use of any vaginal preparations ≤ 1 week prior to study entry (Exception: If patient has used vaginal preparations during the previous week but will stop, then they can be placed on study with plans to start with pretreatment questionnaire one week later). Note: Lubricants used during sexual intercourse are permitted. 8. Current (≤ 4weeks prior to randomization), or planned during the study period, use of any estrogen product. 9. A diagnosis of asthma, COPD, CAD or narrow angle glaucoma, or known cholelithiasis. 10. Hepatic or renal insufficiency defined as a history of an elevation of SGOT ≥1.5 x ULN or creatinine ≥ 1.5 x ULN within the past year. 11. Concurrent use of other anticholinergics 12. Use of pharmacologic soy preparations 13. Known history of cardiac arrhythmia. (Patients with occasional PVC's or PAC's that do not require treatment are eligible.) 14. Prior or concurrent pelvic radiation therapy 15. Prior radical pelvic surgery (TAH/BSO is allowed) 16. Use of beta adrenergic antagonists 17. Diagnosis of any of the following conditions: * Vulvar and vaginal dysplasia * Essential vulvodynia * Vulvar vestibulitis * Vaginal prolapse * Bartholin cyst/abscess * History of Bartholin gland surgery * Lichen sclerosis * Lichen planus of the vulvovaginal region * Desquamative vaginitis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Average Vaginal Dryness Scores Via Area Under the Curve (AUC) Summary Statistics | Baseline to Week 6 | Vaginal dryness was measured by the numerical analogue scale at baseline and through the six weeks of treatment. The item scores was transformed into 0 to 100 scales with 0=poor quality of life (QOL) and 100=best possible QOL. The average AUC values were calculated by dividing 6 from AUC values for participants who completed item on all 6 weeks. If a participant completed the item at baseline, week 1, 2 and 3 but did not complete the item at week 4 to week 6, the AUC values of the item was prorated, which is (((AUC values \* 6) / 3) / 6). The average pro-rated AUC for vaginal dryness scores was compared in each of the Pilocarpine arms against the collective placebo arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity as Measured by Common Terminology Criteria for Adverse Events (CTCAE) 3.0 | End of 6 weeks | CTCAE Grading: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening, Grade 5=Death. |
| Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Baseline to Week 6 | The impact of vaginal dryness for activities of daily living (ADL) were measured by the numerical analogue scales at baseline and through the six weeks of treatment. The item scores was transformed into 0 to 100 scales with 0=poor quality of life (QOL) and 100=best possible QOL. The average AUC values were calculated by dividing 6 from AUC values for participants who completed item on all 6 weeks. If a participant completed the item at baseline, week 1, 2 and 3 but did not complete the item at week 4 to week 6, the AUC values of the item was prorated, which is (((AUC values \* 6) / 3) / 6). The average pro-rated AUC scores was compared in each of the Pilocarpine arms against the collective placebo arm. |
| Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Baseline and Week 6 | The impact of vaginal dryness for activities of daily living (ADL) were measured by the numerical analogue scales at baseline and through the six weeks of treatment. The item scores was transformed into 0 to 100 scales with 0=poor quality of life (QOL) and 100=best possible QOL. The change from baseline scores was calculated by subtracting the baseline item scores from the scores at 6 week. |
Countries
United States
Participant flow
Recruitment details
Two-hundred and one (201) participants were recruited between December 2006 and May 2009 from 22 North Central Cancer Treatment Group (NCCTG) member sites.
Pre-assignment details
Five participants (2 collective placebo, 2 Pilocarpine 2 times per day, 1 Pilocarpine 4 times per day) canceled prior to study medication begins and one Pilocarpine 2 times per day participant was ineligible. These six participants were excluded from all analysis.
Participants by arm
| Arm | Count |
|---|---|
| Collective Placebo Patients receive 1 capsule of placebo 2 times per day for 6 weeks and; patients receive 1 capsule of placebo 4 times per day for 6 weeks. | 64 |
| Pilocarpine 2 Times Per Day Patients receive 5mg of Pilocarpine 2 times per day for 6 weeks. | 65 |
| Pilocarpine 4 Times Per Day Patients receive 5mg of Pilocarpine 4 times per day for 6 weeks. | 66 |
| Total | 195 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 10 | 7 |
| Overall Study | Other Reason Not Specified | 1 | 2 | 4 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 6 |
Baseline characteristics
| Characteristic | Total | Collective Placebo | Pilocarpine 2 Times Per Day | Pilocarpine 4 Times Per Day |
|---|---|---|---|---|
| Age, Continuous | 54.8 years STANDARD_DEVIATION 7.74 | 54.6 years STANDARD_DEVIATION 7.93 | 55.1 years STANDARD_DEVIATION 8.14 | 54.7 years STANDARD_DEVIATION 7.25 |
| Breast cancer history No | 23 participants | 9 participants | 6 participants | 8 participants |
| Breast cancer history Yes | 172 participants | 55 participants | 59 participants | 58 participants |
| Current aromatase inhibitor No | 82 participants | 28 participants | 27 participants | 27 participants |
| Current aromatase inhibitor Unknown | 2 participants | 0 participants | 1 participants | 1 participants |
| Current aromatase inhibitor Yes | 111 participants | 36 participants | 37 participants | 38 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 3 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 188 Participants | 60 Participants | 63 Participants | 65 Participants |
| Region of Enrollment United States | 195 participants | 64 participants | 65 participants | 66 participants |
| Severity of vaginal symptoms Mild | 18 participants | 6 participants | 6 participants | 6 participants |
| Severity of vaginal symptoms Moderate | 90 participants | 30 participants | 30 participants | 30 participants |
| Severity of vaginal symptoms Severe | 87 participants | 28 participants | 29 participants | 30 participants |
| Sex/Gender, Customized Female | 195 participants | 64 participants | 65 participants | 66 participants |
| Tamoxifen use No | 164 participants | 54 participants | 54 participants | 56 participants |
| Tamoxifen use Unknown | 2 participants | 0 participants | 1 participants | 1 participants |
| Tamoxifen use Yes | 29 participants | 10 participants | 10 participants | 9 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 48 / 65 | 47 / 66 | 33 / 63 |
| serious Total, serious adverse events | 0 / 65 | 0 / 66 | 0 / 63 |
Outcome results
Primary
Average Vaginal Dryness Scores Via Area Under the Curve (AUC) Summary Statistics
Vaginal dryness was measured by the numerical analogue scale at baseline and through the six weeks of treatment. The item scores was transformed into 0 to 100 scales with 0=poor quality of life (QOL) and 100=best possible QOL. The average AUC values were calculated by dividing 6 from AUC values for participants who completed item on all 6 weeks. If a participant completed the item at baseline, week 1, 2 and 3 but did not complete the item at week 4 to week 6, the AUC values of the item was prorated, which is (((AUC values \* 6) / 3) / 6). The average pro-rated AUC for vaginal dryness scores was compared in each of the Pilocarpine arms against the collective placebo arm.
Time frame: Baseline to Week 6
Population: Includes all participants that reported a baseline value and at least one value after baseline (i.e. week 3, 4, 5 or 6).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Collective Placebo | Average Vaginal Dryness Scores Via Area Under the Curve (AUC) Summary Statistics | 63.6 units on a scale | Standard Deviation 24.04 |
| Pilocarpine 2 Times Per Day | Average Vaginal Dryness Scores Via Area Under the Curve (AUC) Summary Statistics | 55.8 units on a scale | Standard Deviation 27.69 |
| Pilocarpine 4 Times Per Day | Average Vaginal Dryness Scores Via Area Under the Curve (AUC) Summary Statistics | 66.0 units on a scale | Standard Deviation 21.38 |
p-value: 0.1675Kruskal-Wallis
p-value: 0.5974Kruskal-Wallis
Secondary
Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living
The impact of vaginal dryness for activities of daily living (ADL) were measured by the numerical analogue scales at baseline and through the six weeks of treatment. The item scores was transformed into 0 to 100 scales with 0=poor quality of life (QOL) and 100=best possible QOL. The average AUC values were calculated by dividing 6 from AUC values for participants who completed item on all 6 weeks. If a participant completed the item at baseline, week 1, 2 and 3 but did not complete the item at week 4 to week 6, the AUC values of the item was prorated, which is (((AUC values \* 6) / 3) / 6). The average pro-rated AUC scores was compared in each of the Pilocarpine arms against the collective placebo arm.
Time frame: Baseline to Week 6
Population: Includes all participants that reported a baseline value and at least one value after baseline (i.e. week 3, 4, 5 or 6).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Collective Placebo | Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Interfered with general activity | 87.9 units on a scale | Standard Deviation 15.77 |
| Collective Placebo | Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Interfered with mood | 85.4 units on a scale | Standard Deviation 17.17 |
| Collective Placebo | Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Interfered with normal work | 91.5 units on a scale | Standard Deviation 14.08 |
| Collective Placebo | Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Interfered with relations with other people | 82.2 units on a scale | Standard Deviation 20.62 |
| Collective Placebo | Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Interfered with sleep | 93.0 units on a scale | Standard Deviation 13.46 |
| Collective Placebo | Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Interfered with enjoyment of life | 77.8 units on a scale | Standard Deviation 24.24 |
| Pilocarpine 2 Times Per Day | Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Interfered with enjoyment of life | 68.7 units on a scale | Standard Deviation 27.84 |
| Pilocarpine 2 Times Per Day | Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Interfered with general activity | 87.1 units on a scale | Standard Deviation 15.36 |
| Pilocarpine 2 Times Per Day | Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Interfered with relations with other people | 77.9 units on a scale | Standard Deviation 25.92 |
| Pilocarpine 2 Times Per Day | Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Interfered with sleep | 92.3 units on a scale | Standard Deviation 15.81 |
| Pilocarpine 2 Times Per Day | Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Interfered with mood | 75.8 units on a scale | Standard Deviation 24.16 |
| Pilocarpine 2 Times Per Day | Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Interfered with normal work | 93.0 units on a scale | Standard Deviation 11.77 |
| Pilocarpine 4 Times Per Day | Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Interfered with mood | 81.8 units on a scale | Standard Deviation 17.65 |
| Pilocarpine 4 Times Per Day | Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Interfered with normal work | 92.3 units on a scale | Standard Deviation 10.8 |
| Pilocarpine 4 Times Per Day | Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Interfered with enjoyment of life | 76.4 units on a scale | Standard Deviation 23.08 |
| Pilocarpine 4 Times Per Day | Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Interfered with relations with other people | 80.6 units on a scale | Standard Deviation 21.27 |
| Pilocarpine 4 Times Per Day | Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Interfered with general activity | 87.0 units on a scale | Standard Deviation 15.72 |
| Pilocarpine 4 Times Per Day | Average AUC Summary Statistics for the Impact of Vaginal Dryness for Activities of Daily Living | Interfered with sleep | 93.3 units on a scale | Standard Deviation 9.28 |
Secondary
Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores
The impact of vaginal dryness for activities of daily living (ADL) were measured by the numerical analogue scales at baseline and through the six weeks of treatment. The item scores was transformed into 0 to 100 scales with 0=poor quality of life (QOL) and 100=best possible QOL. The change from baseline scores was calculated by subtracting the baseline item scores from the scores at 6 week.
Time frame: Baseline and Week 6
Population: Includes all participants who completed both baseline and week 6 assessments.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Collective Placebo | Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Interfered with general activity | 17.8 units on a scale | Standard Deviation 26.23 |
| Collective Placebo | Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Interfered with mood | 18.3 units on a scale | Standard Deviation 29.03 |
| Collective Placebo | Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Interfered with normal work | 11.0 units on a scale | Standard Deviation 23.15 |
| Collective Placebo | Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Interfered with relations with other people | 23.0 units on a scale | Standard Deviation 37.41 |
| Collective Placebo | Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Interfered with sleep | 5.6 units on a scale | Standard Deviation 19.27 |
| Collective Placebo | Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Interfered with enjoyment of life | 26.7 units on a scale | Standard Deviation 35.17 |
| Pilocarpine 2 Times Per Day | Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Interfered with enjoyment of life | 21.1 units on a scale | Standard Deviation 36.11 |
| Pilocarpine 2 Times Per Day | Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Interfered with general activity | 16.0 units on a scale | Standard Deviation 28.77 |
| Pilocarpine 2 Times Per Day | Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Interfered with relations with other people | 18.5 units on a scale | Standard Deviation 33.02 |
| Pilocarpine 2 Times Per Day | Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Interfered with sleep | 5.1 units on a scale | Standard Deviation 12.75 |
| Pilocarpine 2 Times Per Day | Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Interfered with mood | 17.8 units on a scale | Standard Deviation 29.44 |
| Pilocarpine 2 Times Per Day | Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Interfered with normal work | 6.0 units on a scale | Standard Deviation 18.16 |
| Pilocarpine 4 Times Per Day | Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Interfered with mood | 18.9 units on a scale | Standard Deviation 34.62 |
| Pilocarpine 4 Times Per Day | Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Interfered with normal work | 9.1 units on a scale | Standard Deviation 22.17 |
| Pilocarpine 4 Times Per Day | Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Interfered with enjoyment of life | 30.2 units on a scale | Standard Deviation 33.14 |
| Pilocarpine 4 Times Per Day | Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Interfered with relations with other people | 24.3 units on a scale | Standard Deviation 41.15 |
| Pilocarpine 4 Times Per Day | Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Interfered with general activity | 16.1 units on a scale | Standard Deviation 27.02 |
| Pilocarpine 4 Times Per Day | Change From Baseline to Week 6 on the Impact of Vaginal Dryness for Activities of Daily Living Scores | Interfered with sleep | 10.8 units on a scale | Standard Deviation 21.99 |
Secondary
Toxicity as Measured by Common Terminology Criteria for Adverse Events (CTCAE) 3.0
CTCAE Grading: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening, Grade 5=Death.
Time frame: End of 6 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Collective Placebo | Toxicity as Measured by Common Terminology Criteria for Adverse Events (CTCAE) 3.0 | Grade 1 or 2 rigors | 2 participants |
| Collective Placebo | Toxicity as Measured by Common Terminology Criteria for Adverse Events (CTCAE) 3.0 | Grade 1 or 2 urinary frequency | 12 participants |
| Collective Placebo | Toxicity as Measured by Common Terminology Criteria for Adverse Events (CTCAE) 3.0 | Grade 1 or 2 nausea | 7 participants |
| Collective Placebo | Toxicity as Measured by Common Terminology Criteria for Adverse Events (CTCAE) 3.0 | Grade 1 or 2 sweating | 19 participants |
| Pilocarpine 2 Times Per Day | Toxicity as Measured by Common Terminology Criteria for Adverse Events (CTCAE) 3.0 | Grade 1 or 2 sweating | 29 participants |
| Pilocarpine 2 Times Per Day | Toxicity as Measured by Common Terminology Criteria for Adverse Events (CTCAE) 3.0 | Grade 1 or 2 rigors | 14 participants |
| Pilocarpine 2 Times Per Day | Toxicity as Measured by Common Terminology Criteria for Adverse Events (CTCAE) 3.0 | Grade 1 or 2 nausea | 16 participants |
| Pilocarpine 2 Times Per Day | Toxicity as Measured by Common Terminology Criteria for Adverse Events (CTCAE) 3.0 | Grade 1 or 2 urinary frequency | 21 participants |
| Pilocarpine 4 Times Per Day | Toxicity as Measured by Common Terminology Criteria for Adverse Events (CTCAE) 3.0 | Grade 1 or 2 sweating | 33 participants |
| Pilocarpine 4 Times Per Day | Toxicity as Measured by Common Terminology Criteria for Adverse Events (CTCAE) 3.0 | Grade 1 or 2 urinary frequency | 29 participants |
| Pilocarpine 4 Times Per Day | Toxicity as Measured by Common Terminology Criteria for Adverse Events (CTCAE) 3.0 | Grade 1 or 2 nausea | 20 participants |
| Pilocarpine 4 Times Per Day | Toxicity as Measured by Common Terminology Criteria for Adverse Events (CTCAE) 3.0 | Grade 1 or 2 rigors | 17 participants |
Comparison: Comparison of Rigors among arms.p-value: 0.002Kruskal-Wallis
Comparison: Comparison of Urinary Frequency among armsp-value: 0.006Kruskal-Wallis
Comparison: Comparison of nausea among armsp-value: 0.03Kruskal-Wallis
Comparison: Comparison of sweating among armsp-value: 0.062Kruskal-Wallis