Cystocele, Pelvic Floor Disorders, Pelvic Organ Prolapse, Urogenital Prolapse, Uterine Prolapse, Vaginal Prolapse, Vaginal Vault Prolapse
Conditions
Keywords
Pelvic Organ Prolapse, Pelvic Floor Disorders, Therapy, Estrogen Replacement, Estrogens, Conjugated
Brief summary
This study randomizes postmenopausal women with symptomatic pelvic organ prolapse planning native tissue transvaginal surgical repair to 6-8 weeks of preoperative and 1-year continued postoperative vaginal estrogen cream compared to placebo cream. This clinical trial and basic science investigation are designed to understand the mechanisms by which local estrogen treatment affects connective tissues of the pelvic floor and determine whether its use before and after prolapse repair will (i) improve success rates of the surgical intervention and minimize prolapse recurrence and (ii) impact favorably upon symptoms of other pelvic floor disorders.
Detailed description
This is a double-blind randomized trial of intravaginal estrogen (conjugated estrogens, 0.625mg/1g cream) vs. placebo in postmenopausal women (up to n=222 enrolled and randomized in order for 188 to undergo surgery) with symptomatic prolapse beyond the hymen planning transvaginal native tissue repairs. Medication will be started \>5 weeks before surgery and continued for 1 year postoperatively, i.e. until scar remodeling is complete. The investigators aim to determine if pre- and postoperative intravaginal estrogen therapy (i) results in anatomic and patient-reported subjective improvement in pelvic organ support, and (ii) impacts other pelvic floor disorders (overactive bladder and incontinence, sexual function and pain, postoperative cystitis), satisfaction, quality of life, and vaginal wound healing. Finally, (iii) the investigators will determine the potential mechanisms by which local estrogen treatment alters pelvic organ support by examining full-thickness vaginal wall biopsies taken at the time of surgery for histologic, connective tissue, and smooth muscle synthesis and degradative changes. The investigators expect this will highlight other novel targets for future therapies in prolapse repair and prevention.
Interventions
0.625mg/1g cream, 1g applied vaginally nightly for 2 weeks then 2x/week for \>5 weeks before surgery, then 2x/week for 1 year after surgery.
DRUGPlacebo Cream
1g applied vaginally nightly for 2 weeks then 2x/week for \>5 weeks before surgery, then 2x/week for 1 year after surgery.
Sponsors
University of Alabama at Birmingham
Women and Infants Hospital of Rhode Island
Pfizer
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
48 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Postmenopausal: no menses for \>1 year * Minimum age: 48 years * Symptomatic apical and/or anterior vaginal wall prolapse, stage 2 or greater * No estrogen replacement within the last month (may come off current treatment, i.e. wash out, to join the study) * Medically fit for elective surgery * Physically able to apply/insert the study drug * Available for clinic follow-up for minimum 1yr
Exclusion criteria
* Concurrent use of steroid creams for other indications (e.g. lichen sclerosis) * BMI \>35 kg/m2 * Recent history (within last month) of vaginal infection or vaginitis * Contraindications to estrogen therapy (e.g. spontaneous DVT, stroke, breast or endometrial/ hormone-responsive cancer, genital bleeding of unknown cause) * History of connective tissue disease * Any oral or transdermal estrogen, SERM, or other medication impacting vaginal milieu * History of vaginal irradiation * Allergy to Premarin or its constituents * Prior apical repair or use of mesh for prolapse repair * Current tobacco use
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Surgical Failure Defined by (i) Anatomic Assessment of Prolapse, (ii) Presence of Bulge Symptoms, and/or (Iii) Retreatment of Prolapse | 12 months | Cumulative failures, as measured by (i) anatomic assessment of prolapse, (ii) presence of bulge symptoms, and/or (iii) retreatment of pelvic organ prolapse |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Condition Specific (i.e. Pelvic Organ Prolapse) Quality of Life as Measured by Pelvic Floor Impact Questionnaire-7 (PFIQ-7) | 12 months | Questionnaire score at 12 months in overall condition-specific quality of life as measured by Pelvic Floor Impact Questionnaire-7 (PFIQ-7) questionnaire, which is scored from 0-300, higher scores being worse (i.e., more distressing) |
| Generic Quality of Life as Measured by SF-12 Questionnaire | 12 months | Generic (physical component) quality of life as measured by SF-12 questionnaire at 12 months. Scores range from 0-100, with higher scores indicating better physical functioning; the US population average is 50 points. |
| Urinary Symptoms as Measured by Urinary Subscale Questions of the Pelvic Floor Distress Inventory-20 (PFDI-20) Questionnaire, i.e. the Urinary Distress Inventory, UDI-6 | Time of surgery | Urinary symptom bother as measured by urinary subscale questions of the Pelvic Floor Distress Inventory-20 (PFDI-20) questionnaire, i.e. the Urinary Distress Inventory, UDI-6. This is scored from 0-100, with greater scores indicating greater symptom bother. |
| Condition Specific (i.e. Pelvic Organ Prolapse) Symptom Bother as Measured by Pelvic Floor Distress Inventory-20 (PFDI-20) Questionnaire | 12 months | Questionnaire score at 12 months in overall condition-specific symptom bother as measured by Pelvic Floor Distress Inventory-20 (PFDI-20) questionnaire, which is scored from 0-300, higher scores being worse (i.e., more distressing) |
| Sexual Function as Measured by the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR) | Time of surgery | Sexual function in sexually-active women as measured by the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR). The score ranges from 1 (worse sexual experience) to 5 (better sexual experience) with midrange scores commonly seen in women with pelvic floor disorders. |
| Number of Participants With Adverse Events | 12 months | Number of participants reporting any adverse events from baseline randomization to 12 months postoperatively |
| Urinary Symptoms as Measured by Urinary Subscale Questions of the Pelvic Floor Impact Questionnaire (PFIQ-7), i.e. the Urinary Impact Questionnaire | Time of surgery | Urinary symptom impact on quality of life as measured by urinary subscale questions of the Pelvic Floor Impact Questionnaire (PFIQ-7), i.e. the Urinary Impact Questionnaire. This is scored from 0-100, with greater scores indicating worse impact on quality of life. |
Countries
United States
Participant flow
Pre-assignment details
Of the 206 participants consented/enrolled, 7 were not randomized: 4 withdrew consent before randomization, and 3 were found to be ineligible and were not randomized. This left n=199 for randomization.
Participants by arm
| Arm | Count |
|---|---|
| Estrogen Cream Conjugated Estrogens Cream: 0.625mg/1g cream, 1g applied vaginally nightly for 2 weeks then 2x/week for \>5 weeks before surgery, then 2x/week for 1 year after surgery. | 102 |
| Placebo Cream Placebo Cream: 1g applied vaginally nightly for 2 weeks then 2x/week for \>5 weeks before surgery, then 2x/week for 1 year after surgery. | 97 |
| Total | 199 |
Baseline characteristics
| Characteristic | Estrogen Cream | Placebo Cream | Total |
|---|---|---|---|
| Age, Continuous | 64.9 years STANDARD_DEVIATION 6.1 | 65.2 years STANDARD_DEVIATION 7.3 | 65.0 years STANDARD_DEVIATION 6.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 24 Participants | 24 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 78 Participants | 73 Participants | 151 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Gravidity | 3 pregnancies | 2 pregnancies | 3 pregnancies |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 5 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 92 Participants | 89 Participants | 181 Participants |
| Sex: Female, Male Female | 102 Participants | 97 Participants | 199 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Vaginal deliveries | 2 births | 2 births | 2 births |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 102 | 0 / 97 |
| other Total, other adverse events | 56 / 102 | 51 / 97 |
| serious Total, serious adverse events | 10 / 102 | 11 / 97 |
Outcome results
Primary
Surgical Failure Defined by (i) Anatomic Assessment of Prolapse, (ii) Presence of Bulge Symptoms, and/or (Iii) Retreatment of Prolapse
Cumulative failures, as measured by (i) anatomic assessment of prolapse, (ii) presence of bulge symptoms, and/or (iii) retreatment of pelvic organ prolapse
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Estrogen Cream | Surgical Failure Defined by (i) Anatomic Assessment of Prolapse, (ii) Presence of Bulge Symptoms, and/or (Iii) Retreatment of Prolapse | 18 Participants |
| Placebo Cream | Surgical Failure Defined by (i) Anatomic Assessment of Prolapse, (ii) Presence of Bulge Symptoms, and/or (Iii) Retreatment of Prolapse | 8 Participants |
Secondary
Condition Specific (i.e. Pelvic Organ Prolapse) Quality of Life as Measured by Pelvic Floor Impact Questionnaire-7 (PFIQ-7)
Questionnaire score at 12 months in overall condition-specific quality of life as measured by Pelvic Floor Impact Questionnaire-7 (PFIQ-7) questionnaire, which is scored from 0-300, higher scores being worse (i.e., more distressing)
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Estrogen Cream | Condition Specific (i.e. Pelvic Organ Prolapse) Quality of Life as Measured by Pelvic Floor Impact Questionnaire-7 (PFIQ-7) | 8.9 score on a scale | Standard Error 4.5 |
| Placebo Cream | Condition Specific (i.e. Pelvic Organ Prolapse) Quality of Life as Measured by Pelvic Floor Impact Questionnaire-7 (PFIQ-7) | 9.5 score on a scale | Standard Error 4.6 |
Secondary
Condition Specific (i.e. Pelvic Organ Prolapse) Symptom Bother as Measured by Pelvic Floor Distress Inventory-20 (PFDI-20) Questionnaire
Questionnaire score at 12 months in overall condition-specific symptom bother as measured by Pelvic Floor Distress Inventory-20 (PFDI-20) questionnaire, which is scored from 0-300, higher scores being worse (i.e., more distressing)
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Estrogen Cream | Condition Specific (i.e. Pelvic Organ Prolapse) Symptom Bother as Measured by Pelvic Floor Distress Inventory-20 (PFDI-20) Questionnaire | 23.1 score on a scale | Standard Error 4.6 |
| Placebo Cream | Condition Specific (i.e. Pelvic Organ Prolapse) Symptom Bother as Measured by Pelvic Floor Distress Inventory-20 (PFDI-20) Questionnaire | 23.1 score on a scale | Standard Error 4.7 |
Secondary
Generic Quality of Life as Measured by SF-12 Questionnaire
Generic (physical component) quality of life as measured by SF-12 questionnaire at 12 months. Scores range from 0-100, with higher scores indicating better physical functioning; the US population average is 50 points.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Estrogen Cream | Generic Quality of Life as Measured by SF-12 Questionnaire | 52.1 score on a scale | Standard Error 0.9 |
| Placebo Cream | Generic Quality of Life as Measured by SF-12 Questionnaire | 53.2 score on a scale | Standard Error 0.9 |
Secondary
Number of Participants With Adverse Events
Number of participants reporting any adverse events from baseline randomization to 12 months postoperatively
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Estrogen Cream | Number of Participants With Adverse Events | 73 Participants |
| Placebo Cream | Number of Participants With Adverse Events | 68 Participants |
Secondary
Sexual Function as Measured by the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR)
Sexual function in sexually-active women as measured by the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR). The score ranges from 1 (worse sexual experience) to 5 (better sexual experience) with midrange scores commonly seen in women with pelvic floor disorders.
Time frame: Time of surgery
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Estrogen Cream | Sexual Function as Measured by the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR) | 3.13 score on a scale | Standard Error 0.1 |
| Placebo Cream | Sexual Function as Measured by the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR) | 3.12 score on a scale | Standard Error 0.1 |
Secondary
Sexual Function as Measured by the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR)
Sexual function in sexually-active women as measured by the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR). The score ranges from 1 (worse sexual experience) to 5 (better sexual experience) with midrange scores commonly seen in women with pelvic floor disorders.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Estrogen Cream | Sexual Function as Measured by the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR) | 3.55 score on a scale | Standard Error 0.1 |
| Placebo Cream | Sexual Function as Measured by the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR) | 3.70 score on a scale | Standard Error 0.1 |
Secondary
Urinary Symptoms as Measured by Urinary Subscale Questions of the Pelvic Floor Distress Inventory-20 (PFDI-20) Questionnaire, i.e. the Urinary Distress Inventory, UDI-6
Urinary symptom bother as measured by urinary subscale questions of the Pelvic Floor Distress Inventory-20 (PFDI-20) questionnaire, i.e. the Urinary Distress Inventory, UDI-6. This is scored from 0-100, with greater scores indicating greater symptom bother.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Estrogen Cream | Urinary Symptoms as Measured by Urinary Subscale Questions of the Pelvic Floor Distress Inventory-20 (PFDI-20) Questionnaire, i.e. the Urinary Distress Inventory, UDI-6 | 9.8 score on a scale | Standard Error 2.1 |
| Placebo Cream | Urinary Symptoms as Measured by Urinary Subscale Questions of the Pelvic Floor Distress Inventory-20 (PFDI-20) Questionnaire, i.e. the Urinary Distress Inventory, UDI-6 | 9.2 score on a scale | Standard Error 2.2 |
Secondary
Urinary Symptoms as Measured by Urinary Subscale Questions of the Pelvic Floor Distress Inventory-20 (PFDI-20) Questionnaire, i.e. the Urinary Distress Inventory, UDI-6
Urinary symptom bother as measured by urinary subscale questions of the Pelvic Floor Distress Inventory-20 (PFDI-20) questionnaire, i.e. the Urinary Distress Inventory, UDI-6. This is scored from 0-100, with greater scores indicating greater symptom bother.
Time frame: Time of surgery
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Estrogen Cream | Urinary Symptoms as Measured by Urinary Subscale Questions of the Pelvic Floor Distress Inventory-20 (PFDI-20) Questionnaire, i.e. the Urinary Distress Inventory, UDI-6 | 38.2 score on a scale | Standard Error 2.7 |
| Placebo Cream | Urinary Symptoms as Measured by Urinary Subscale Questions of the Pelvic Floor Distress Inventory-20 (PFDI-20) Questionnaire, i.e. the Urinary Distress Inventory, UDI-6 | 37.7 score on a scale | Standard Error 2.8 |
Secondary
Urinary Symptoms as Measured by Urinary Subscale Questions of the Pelvic Floor Impact Questionnaire (PFIQ-7), i.e. the Urinary Impact Questionnaire
Urinary symptom impact on quality of life as measured by urinary subscale questions of the Pelvic Floor Impact Questionnaire (PFIQ-7), i.e. the Urinary Impact Questionnaire. This is scored from 0-100, with greater scores indicating worse impact on quality of life.
Time frame: Time of surgery
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Estrogen Cream | Urinary Symptoms as Measured by Urinary Subscale Questions of the Pelvic Floor Impact Questionnaire (PFIQ-7), i.e. the Urinary Impact Questionnaire | 26.9 score on a scale | Standard Error 1.8 |
| Placebo Cream | Urinary Symptoms as Measured by Urinary Subscale Questions of the Pelvic Floor Impact Questionnaire (PFIQ-7), i.e. the Urinary Impact Questionnaire | 25.2 score on a scale | Standard Error 1.8 |
Secondary
Urinary Symptoms as Measured by Urinary Subscale Questions of the Pelvic Floor Impact Questionnaire (PFIQ-7), i.e. the Urinary Impact Questionnaire
Urinary symptom impact on quality of life as measured by urinary subscale questions of the Pelvic Floor Impact Questionnaire (PFIQ-7), i.e. the Urinary Impact Questionnaire. This is scored from 0-100, with greater scores indicating worse impact on quality of life.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Estrogen Cream | Urinary Symptoms as Measured by Urinary Subscale Questions of the Pelvic Floor Impact Questionnaire (PFIQ-7), i.e. the Urinary Impact Questionnaire | 1.2 score on a scale | Standard Error 1.9 |
| Placebo Cream | Urinary Symptoms as Measured by Urinary Subscale Questions of the Pelvic Floor Impact Questionnaire (PFIQ-7), i.e. the Urinary Impact Questionnaire | 2.6 score on a scale | Standard Error 1.9 |