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

• ClinicalTrials.gov Identifier: NCT02431897
• Recruitment Status: Completed
• First Posted: May 1, 2015
• Results First Posted: December 16, 2022
• Last Update Posted: September 6, 2023
• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: University of Alabama at Birmingham; Women and Infants Hospital of Rhode Island; Pfizer
• Information provided by (Responsible Party): David Rahn, MD, University of Texas Southwestern Medical Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Pelvic Organ Prolapse; Urogenital Prolapse; Vaginal Vault Prolapse; Cystocele; Uterine Prolapse; Vaginal Prolapse; Pelvic Floor Disorders	Drug: Conjugated Estrogens Cream; Drug: Placebo Cream	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 206 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Investigation to Minimize Prolapse Recurrence of the Vagina Using Estrogen
• Actual Study Start Date: December 2016
• Actual Primary Completion Date: November 29, 2021
• Actual Study Completion Date: May 17, 2023

Arms and Interventions

Arm	Intervention/treatment
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 Name: Premarin Vaginal Cream
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.

Outcome Measures

Primary Outcome Measures :

1. Surgical "Failure" Defined by (i) Anatomic Assessment of Prolapse, (ii) Presence of Bulge Symptoms, and/or (Iii) Retreatment of Prolapse [ Time Frame: 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 Outcome Measures :

1. Condition Specific (i.e. Pelvic Organ Prolapse) Symptom Bother as Measured by Pelvic Floor Distress Inventory-20 (PFDI-20) Questionnaire [ Time Frame: 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)
2. Condition Specific (i.e. Pelvic Organ Prolapse) Quality of Life as Measured by Pelvic Floor Impact Questionnaire-7 (PFIQ-7) [ Time Frame: 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)
3. Generic Quality of Life as Measured by SF-12 Questionnaire [ Time Frame: 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.
4. 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 Frame: 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.
5. 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 Frame: 12 months ]
   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.
6. Urinary Symptoms as Measured by Urinary Subscale Questions of the Pelvic Floor Impact Questionnaire (PFIQ-7), i.e. the Urinary Impact Questionnaire [ Time Frame: 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.
7. Urinary Symptoms as Measured by Urinary Subscale Questions of the Pelvic Floor Impact Questionnaire (PFIQ-7), i.e. the Urinary Impact Questionnaire [ Time Frame: 12 months ]
   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.
8. Sexual Function as Measured by the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR) [ Time Frame: 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.
9. Sexual Function as Measured by the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR) [ Time Frame: 12 months ]
   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.
10. Number of Participants With Adverse Events [ Time Frame: 12 months ]
    Number of participants reporting any adverse events from baseline randomization to 12 months postoperatively

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham

Birmingham, Alabama, United States, 35249

United States, Rhode Island

Women & Infants Hospital of Rhode Island

Providence, Rhode Island, United States, 02905

United States, Texas

University of Texas Southwestern Medical Center

Dallas, Texas, United States, 75390

Sponsors and Collaborators

University of Texas Southwestern Medical Center

University of Alabama at Birmingham

Women and Infants Hospital of Rhode Island

Pfizer

Investigators

• Principal Investigator: David D Rahn, MD; University of Texas Southwestern Medical Center

  Study Documents (Full-Text)

Documents provided by David Rahn, MD, University of Texas Southwestern Medical Center:

Study Protocol and Statistical Analysis Plan  [PDF] May 24, 2019

Informed Consent Form  [PDF] May 24, 2019

More Information

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.

• Responsible Party: David Rahn, MD, Associate Professor, Dept. of Obstetrics & Gynecology, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT02431897
• Other Study ID Numbers: STU 022015-117
• First Posted: May 1, 2015
• Results First Posted: December 16, 2022
• Last Update Posted: September 6, 2023
• Last Verified: August 2023

Keywords provided by David Rahn, MD, University of Texas Southwestern Medical Center:

Pelvic Organ Prolapse; Pelvic Floor Disorders; Therapy, Estrogen Replacement; Estrogens, Conjugated

Additional relevant MeSH terms:

Pelvic Floor Disorders; Cystocele; Uterine Prolapse; Recurrence; Prolapse; Pelvic Organ Prolapse; Disease Attributes; Pathologic Processes; Pathological Conditions, Anatomical; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Pregnancy Complications; Male Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Uterine Diseases; Genital Diseases, Female; Genital Diseases; Estrogens; Estrogens, Conjugated (USP); Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs