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Vestibulodynia: Understanding Pathophysiology and Determining Appropriate Treatments

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ClinicalTrials.gov Identifier: NCT03844412
Recruitment Status : Not yet recruiting
First Posted : February 18, 2019
Last Update Posted : February 18, 2019
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Duke University

Brief Summary:
Vestibulodynia (VBD) is a complex chronic vulvar pain condition that impairs the psychological, physical, and sexual health of 1 in 6 reproductive aged women in the United States. Here, the investigators plan to conduct a randomized, double-blinded, placebo-controlled clinical trial to 1) compare the efficacy of peripheral (lidocaine/estradiol cream), centrally-targeted (nortriptyline), and combined treatments in alleviating pain and improving patient-reported outcomes and 2) determine cytokine and microRNA biomarkers that predict treatment response in women with distinct VBD subtypes. Positive findings from this study will readily translate to improved patient care, permitting the millions of women with VBD, their partners, and their clinicians to make more informed decisions about pain management.

Condition or disease Intervention/treatment Phase
Vestibulodynia Temporomandibular Disorder Fibromyalgia Syndrome Irritable Bowel Syndrome Migraines Tension Headache Endometriosis Interstitial Cystitis Back Pain Chronic Fatigue Syndrome Drug: 5% lidocaine/5 mg/ml estradiol compound cream Drug: Nortriptyline Drug: Placebo cream Drug: Placebo pill Phase 2

Detailed Description:
Vestibulodynia (VBD) is a chronic pelvic pain condition that affects 1 in 6 reproductive aged women, yet remains ineffectively treated by standard trial-and-error approaches. The investigators have identified two distinct VBD subtypes that may benefit from different types of treatment: 1) VBD peripheral (VBD-p) subtype characterized by localized pain specific to the vulvar vestibule, and 2) VBD central (VBD-c) subtype characterized by pain at both vaginal and remote body regions. Preliminary data further demonstrate that VBD-p and VBD-c subtypes differ with respect to patient reported outcomes (e.g., physical and mental health), production of cytokines (intracellular proteins that regulate the activity of pain nerves and inflammatory processes), and expression of microRNAs (small non-coding RNA molecules that regulate gene expression). Women with VBD-p exhibit normal psychological profiles; balanced circulating pro- and anti-inflammatory cytokines; and dysregulation in microRNAs that regulate the expression of genes in estrogen pathways. In contrast, women with VBD-c report decreased functional status and increased somatization; increased pro-inflammatory but not anti-inflammatory cytokines; and dysregulation in microRNAs that regulate the expression of genes relevant to muscle, nerve, and immune cell function. Based on these data, the investigators hypothesize that two VBD-p and VBD-c subtypes will preferentially respond to peripheral, central, or combined treatments and can be distinguished by cytokine and microRNA profiles. These hypotheses will be tested in a phase III clinical trial that evaluates diverse treatment strategies in women with VBD-p and VBD-c. Participants will be randomly assigned to one of four parallel arms: peripheral treatment with 5% lidocaine + 0.5 mg/ml estradiol compound cream, 2) central treatment with the tricyclic antidepressant nortriptyline, 3) combined peripheral and central treatments, or 4) placebo. The treatment phase will last 4 months (with a 6-week titration at treatment initiation and 2-week taper period at 4 months), with outcome measures and biomarkers assessed at 4 time points (0, 2, 4, and 6 months). First, the investigators will compare the efficacy of treatments in alleviating pain among women with VBD-p and VBD-c using standardized tampon insertion with a numeric rating scale and self-reported pain on the McGill Pain Questionnaire. Next, the investigators will compare the efficacy of treatments in improving perceived physical, mental, and sexual health among women with VBD-p and VBD-c using standardized questionnaires. Finally, investigators will measure cytokines and microRNAs in women with VBD-p versus VBD-c using multiplex assays and RNA sequencing, and determine the ability of these biomarkers to predict treatment response. Successful completion of the proposed work will provide new insights into the mechanisms that drive pain perception and treatment response in two distinct VBD subtypes, and determine the efficacy of peripheral, central, and combined therapies in reversing this pain. Such findings will readily translate to improved patient care, permitting the millions of women with VBD, their partners, and clinicians to make more informed decisions about pain management.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Intervention Model Description: Two-center, randomized, double-blind, placebo-controlled 2x2 factorial study enrolling 400 women to participate for 24-week duration.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Vestibulodynia: Understanding Pathophysiology and Determining Appropriate Treatments
Estimated Study Start Date : April 1, 2019
Estimated Primary Completion Date : October 1, 2022
Estimated Study Completion Date : December 1, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: peripheral treatment
5% lidocaine/5 mg/ml estradiol compound cream
Drug: 5% lidocaine/5 mg/ml estradiol compound cream
Lidocaine/estradiol cream targets peripheral nerves and tissues affected in VBD. Participants will be provided with a diagram and written instructions, detailing how to apply the cream to the vaginal vestibule daily for weeks 1-16. Treatment with lidocaine/estradiol or placebo cream will be terminated at week 16 (end of month 4).

Drug: Placebo pill
The comparison treatment will be an identical-appearing placebo pill

Active Comparator: central treatment
tricyclic antidepressant nortriptyline pill
Drug: Nortriptyline
Nortriptyline is a centrally-acting tricyclic antidepressant that is FDA-approved for treatment of neuropathic pain. Dosing will begin with one 10 mg pill nightly for week 1, then two 10 mg pills nightly for week 2, three 10 mg pills nightly for week 3, four 10 mg pills nightly for week 4, five 10 mg pills nightly for week 5, and six 10 mg pills nightly for weeks 6-16. Treatment with nortriptyline or placebo pill will be tapered off over weeks 16-18.

Drug: Placebo cream
The comparison treatment will be an identical-appearing placebo Moisturel™ cream
Other Name: Moisturel cream

Active Comparator: combined peripheral and central treatments
5% lidocaine/5 mg/ml estradiol compound cream and tricyclic antidepressant nortriptyline pill
Drug: 5% lidocaine/5 mg/ml estradiol compound cream
Lidocaine/estradiol cream targets peripheral nerves and tissues affected in VBD. Participants will be provided with a diagram and written instructions, detailing how to apply the cream to the vaginal vestibule daily for weeks 1-16. Treatment with lidocaine/estradiol or placebo cream will be terminated at week 16 (end of month 4).

Drug: Nortriptyline
Nortriptyline is a centrally-acting tricyclic antidepressant that is FDA-approved for treatment of neuropathic pain. Dosing will begin with one 10 mg pill nightly for week 1, then two 10 mg pills nightly for week 2, three 10 mg pills nightly for week 3, four 10 mg pills nightly for week 4, five 10 mg pills nightly for week 5, and six 10 mg pills nightly for weeks 6-16. Treatment with nortriptyline or placebo pill will be tapered off over weeks 16-18.

Placebo Comparator: placebo
placebo cream and placebo pill
Drug: Placebo cream
The comparison treatment will be an identical-appearing placebo Moisturel™ cream
Other Name: Moisturel cream

Drug: Placebo pill
The comparison treatment will be an identical-appearing placebo pill




Primary Outcome Measures :
  1. Change in pain score during the tampon test [ Time Frame: Baseline, 16 weeks ]
    The Tampon Test will provide a self-reported numeric rating scale of pain with self-tampon insertion, performed by the patient and reported to the research nurse. Participants will be asked to verbally rate the pain on a scale of 0-10, with 0 meaning no pain and 10 meaning the worst possible pain.

  2. Change in self-reported pain via the Short Form- McGill Pain Questionnaire (SF-MPQ) [ Time Frame: Baseline, 16 weeks ]
    The SF-MPQ will be used to create a summary score. The SF-MPQ measures perceived sensory qualities of pain using 11 describers and affective qualities related to pain using 5 describers. Responses on 4-point scales are summed to compute scores for each section.

  3. Change in self-reported physical/mental health via SF-12 Health Survey (SF12v2) [ Time Frame: Baseline, 16 weeks ]
    The SF-12 assesses 6 domains: global health, physical functioning, physical roles, emotional functioning, emotional roles and pain interference using an algorithm based on answers to 12 physical and mental health-related questions.

  4. Change in sexual health via Patient-Reported Outcomes Measurement Information System (PROMIS) [ Time Frame: Baseline, 16 weeks ]
    The PROMIS score is based on a 96-item form developed by the NIH that measures 11 domains of biopsychosocial function and includes an assessment of sexual function measures (e.g., desire, frequency, fear, and pain) related to sexual intercourse.

  5. Change in inflammation as measured by cytokine expression levels [ Time Frame: Baseline, 16 weeks ]
    Cytokine expression levels will be measured via mesoscale discovery assays.

  6. Change in regulators of pro-pain and pro-inflammatory genes, as measured by microRNA expression levels [ Time Frame: Baseline, 16 weeks ]
    MicroRNA expression levels will be measured via sequencing read.


Secondary Outcome Measures :
  1. Change in pain level as measured by Vaginal Vestibule pressure pain threshold (PPT) [ Time Frame: Baseline, 16 weeks ]
    Vaginal Vestibule PPT will be determined using a digital vestibular algometer applied to 3 externally-accessed sites (2 and 10 o'clock on the upper vestibule and 6 o'clock on the lower vestibule) beginning at 1N and increasing until the participant's first sensation of pain.

  2. Change in pain level as measured by Perineal Complex PPT [ Time Frame: Baseline, 16 weeks ]
    Perineal Complex PPT will be determined by applying an algometer externally to the perineal muscle complex (6 o'clock) beginning at 1N and increasing until the participant's first sensation of pain.

  3. Change in pain level as measured by Levator Muscle PPT [ Time Frame: Baseline, 16 weeks ]
    Levator Muscle PPT will be determined by applying the algometer externally to the right and left puborectalis levator muscles sites (5 and 7 o'clock) just lateral to the perineum beginning at 1N and increasing until the participant's first sensation of pain.

  4. Change in pain level as measured by Remote Bodily PPTs [ Time Frame: Baseline, 16 weeks ]
    Remote Bodily PPTs will be determined by applying the algometer to 3 'neutral' non-pelvic body sites (deltoid, shin, and trapezius), right and left, beginning at 1N and increasing until the participant's first sensation of pain. A composite score will be calculated.

  5. Change in degree of overlapping pain, as measured by COPC follow-up survey [ Time Frame: Baseline, 16 weeks ]
    The COPC survey consists of 2 questions used to determine the change in degree of overlapping pain.

  6. Change in mood as measured by the Symptom Checklist-27 (SCL-27) [ Time Frame: Baseline, 16 weeks ]
  7. Change in somatic awareness via Pennebaker Index of Limbic Languidness (PILL) [ Time Frame: Baseline, 16 weeks ]
    Pennebaker Index of Limbic Languidness (PILL) is used to create a summary score of somatic symptoms (e.g., itchy eyes, dizziness). Symptom frequency is recorded on a five-point Likert scale ranging from "never" to "more than once a week".

  8. Change in perceived stress via Perceived Stress Scale (PSS) [ Time Frame: Baseline, 16 weeks ]
    The Perceived stress scale (PSS) is a 10-item scale that measures the impact of personal stress on thoughts and feelings.

  9. Change in sleep as measured by the sleep scale [ Time Frame: Baseline, 16 weeks ]
    The sleep scale is a 12-item scale that measures amount of sleep and ease/difficulty of initiating and maintaining sleep.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Female
  2. Age 18-50 years
  3. English-literate
  4. Meeting criteria for diagnosis of VBD based on:

    1. self-report of 3 continuous months of insertional (entryway) dyspareunia, and/or pain to touch/tampon insertion
    2. pain score of > 4 on the tampon insertion test
  5. Willingness to provide informed consent

Exclusion Criteria:

  1. Use of daily topical lidocaine, or estradiol, or lidocaine/estradiol to the vulvar vestibule within the past year
  2. Use of nortriptyline or other TCA medications within the past year
  3. Presence of active dermatologic vulvar disease or vaginal infection
  4. Untreated atrophic vaginitis (participants may undergo treatment and re-evaluation for enrollment if the condition is resolved)
  5. Previous vestibulectomy
  6. Pregnant, breastfeeding, or planning on becoming pregnant during the study period.
  7. Active incarceration
  8. Cancer within the past year.
  9. Chemotherapy and/or radiation treatment within the past year.
  10. Unstable medical condition (e.g., renal impairment, significant hematological disease, cardiovascular disease, hepatic insufficiency, neurological disorder, autoimmune disease, or respiratory illness)
  11. Clear inflammatory states (e.g., morbid obesity)
  12. History of intolerance to nortriptyline, topical lidocaine, or topical estradiol
  13. Contraindications to use of nortriptyline: current use of MAOIs, SSRIs, SNRIs, recent (within the past year) myocardial infarction, active psychotic or suicidal thoughts, narrow angle closure glaucoma
  14. Contraindications to the use of lidocaine or local anesthetics
  15. Contraindications to the use of topical estrogen therapy
  16. Post-menopausal, defined as no menses for 12 consecutive months

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03844412


Locations
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United States, California
University of California, Los Angeles Not yet recruiting
Los Angeles, California, United States, 90095
Contact: Andrea Rapkin, MD    310-825-6963    arapkin@mednet.ucla.edu   
United States, North Carolina
University of North Carolina at Chapel Hill Not yet recruiting
Chapel Hill, North Carolina, United States, 27278
Contact: Erin Carey, MD, MSCR    919-966-4717    erin_carey@med.unc.edu   
Contact: Elizabeth Geller, MD       elizabeth_geller@med.unc.edu   
Sponsors and Collaborators
Duke University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
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Principal Investigator: Andrea Nackley, PhD Duke University

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Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT03844412     History of Changes
Other Study ID Numbers: Pro00100678
1R01HD096331-01 ( U.S. NIH Grant/Contract )
First Posted: February 18, 2019    Key Record Dates
Last Update Posted: February 18, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The investigators will share data in a manner consistent with NIH's policy NOT-OD-14-124, found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-124.html, released August 28, 2014. Genotypic data (e.g. microRNA and protein expression) and relevant phenotypic data (e.g. pain scores) from 400 participants will be posted on the dbGaP website.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: The PI expects data release up to 6 months after data submission is initiated or at the time of acceptance of initial publication, whichever occurs first.
Access Criteria: Requests to download individual unit-record datasets should be submitted to the PI and require approval from a Data Access Committee convened by the NIH/NICHD.
URL: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-124.html

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Duke University:
Pelvic pain
Lidocaine
Estradiol
Nortriptyline
Chronic pain

Additional relevant MeSH terms:
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Syndrome
Back Pain
Fatigue
Headache
Fibromyalgia
Irritable Bowel Syndrome
Endometriosis
Cystitis
Cystitis, Interstitial
Fatigue Syndrome, Chronic
Temporomandibular Joint Disorders
Temporomandibular Joint Dysfunction Syndrome
Myofascial Pain Syndromes
Vulvodynia
Vulvar Vestibulitis
Tension-Type Headache
Disease
Pathologic Processes
Pain
Neurologic Manifestations
Signs and Symptoms
Muscular Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Neuromuscular Diseases
Nervous System Diseases
Colonic Diseases, Functional
Colonic Diseases
Intestinal Diseases
Gastrointestinal Diseases