Investigation to Minimize Prolapse Recurrence of the Vagina Using Estrogen (IMPROVE)

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.

Study Overview

• Status: Completed
• Conditions: Pelvic Organ Prolapse; Pelvic Floor Disorders; Cystocele; Uterine Prolapse; Vaginal Vault Prolapse; Vaginal Prolapse; Urogenital Prolapse
• Intervention / Treatment: Drug: Conjugated Estrogens Cream; Drug: Placebo Cream

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.

• Study Type: Interventional
• Enrollment (Actual): 206
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama at Birmingham
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Women & Infants Hospital of Rhode Island
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 48 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo Cream; Placebo cream	Drug: 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.
Experimental: Estrogen Cream; Conjugated Estrogens cream	Drug: 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.; Other Names: Premarin Vaginal Cream

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	12 months
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)	12 months
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.	12 months
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 of surgery
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.	12 months
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 of surgery
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.	12 months
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 of surgery
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.	12 months
Number of Participants With Adverse Events	Number of participants reporting any adverse events from baseline randomization to 12 months postoperatively	12 months

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: Pfizer; University of Alabama at Birmingham; Women and Infants Hospital of Rhode Island
• Investigators: Principal Investigator: David D Rahn, MD, University of Texas Southwestern Medical Center

Publications and helpful links

General Publications

• Rahn DD, Richter HE, Sung VW, Larsen WI, Hynan LS. Design of a Randomized Clinical Trial of Perioperative Vaginal Estrogen Versus Placebo With Transvaginal Native Tissue Apical Prolapse Repair (Investigation to Minimize Prolapse Recurrence of the Vagina using Estrogen: IMPROVE). Female Pelvic Med Reconstr Surg. 2021 Jan 1;27(1):e227-e233. doi: 10.1097/SPV.0000000000000899.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2016
• Primary Completion (Actual): November 29, 2021
• Study Completion (Actual): May 17, 2023

Study Registration Dates

• First Submitted: April 23, 2015
• First Submitted That Met QC Criteria: April 27, 2015
• First Posted (Estimated): May 1, 2015

Study Record Updates

• Last Update Posted (Estimated): September 6, 2023
• Last Update Submitted That Met QC Criteria: August 23, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Pelvic Organ Prolapse; Pelvic Floor Disorders; Therapy, Estrogen Replacement; Estrogens, Conjugated
• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Urinary Bladder Diseases; Uterine Diseases; Disease Attributes; Pathological Conditions, Anatomical; Pregnancy Complications; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Recurrence; Prolapse; Pelvic Organ Prolapse; Pelvic Floor Disorders; Cystocele; Uterine Prolapse; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Estrogens, Conjugated (USP)
• Other Study ID Numbers: STU 022015-117