Clinical trial NCT03844412: Vestibulodynia: Understanding Pathophysiology and Determining Appropriate Treatments
Official title: Vestibulodynia: Understanding Pathophysiology and Determining Appropriate Treatments
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Vestibulodynia
Temporomandibular Disorder
Fibromyalgia Syndrome
Irritable Bowel Syndrome
Migraines
Tension Headache
Endometriosis
Interstitial Cystitis
Back Pain
Chronic Fatigue Syndrome
Keywords: Pelvic pain
Lidocaine
Estradiol
Nortriptyline
Chronic pain
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2019-02-18
Enrollment: 223
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: Two-center, randomized, double-blind, placebo-controlled 2x2 factorial study enrolling 400 women to participate for 24-week duration.
Primary purpose: TREATMENT

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.

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 0.02% 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.

Eligibility criteria: Inclusion Criteria

1. Female
2. Age 18-50 years
3. English-literate
4. Willingness to provide informed consent
5. 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 ≥ 3 on the tampon insertion test

Exclusion Criteria

1. Use of daily topical lidocaine, or estradiol, or lidocaine/estradiol to the vulvar vestibule within the past three months
2. Use of nortriptyline or other TCA medications within the past three months
3. Use of pregabalin or gabapentin within the past three months
4. Presence of active dermatologic vulvar disease or vaginal infection
5. Untreated atrophic vaginitis (participants may undergo treatment and re-evaluation for enrollment if the condition is resolved)
6. Previous vestibulectomy
7. Pregnant or planning on becoming pregnant during the study period. Within the first six months of the postpartum period. Currently breastfeeding/lactating, or within three months of discontinuing breastfeeding/lactation.
8. Active incarceration
9. Cancer within the past year.
10. Chemotherapy and/or radiation treatment within the past year.
11. Unstable medical condition (e.g., renal impairment, significant hematological disease, cardiovascular disease, hepatic insufficiency, neurological disorder, autoimmune disease, or respiratory illness)
12. Clear inflammatory states (e.g., morbid obesity)
13. Use of immunosuppressant medications
14. History of intolerance to nortriptyline, topical lidocaine, or topical estradiol
15. Contraindications to use of nortriptyline: current use, or use within the past 3 months, of MAOIs, SSRIs, SNRIs, NDRIs; recent (within the past year) myocardial infarction, active psychotic or suicidal thoughts, narrow angle closure glaucoma
16. Contraindications to the use of lidocaine or local anesthetics
17. Contraindications to the use of topical estrogen therapy
18. Post-menopausal, defined as no menses for 12 consecutive months or surgical removal of both ovaries. (Hysterectomy is not an exclusion)
19. Have not had Botox of the pelvic floor muscles in the last 12 months, or pelvic nerve blocks in the last three months.
20. Are not currently enrolled or planning to enroll in another clinical trial during the course of this trial.
21. Are not currently receiving pelvic physical therapy

Primary outcomes:
measure: Change in pain score during the tampon test
timeFrame: Baseline, 16 weeks
measure: Change in self-reported pain via the Short Form- McGill Pain Questionnaire (SF-MPQ)
timeFrame: Baseline, 16 weeks
measure: Change in self-reported physical/mental health via SF-12 Health Survey (SF12v2)
timeFrame: Baseline, 16 weeks
measure: Change in sexual health via Patient-Reported Outcomes Measurement Information System (PROMIS)
timeFrame: Baseline, 16 weeks
measure: Change in inflammation as measured by cytokine expression levels
timeFrame: Baseline, 16 weeks
measure: Change in regulators of pro-pain and pro-inflammatory genes, as measured by microRNA expression levels
timeFrame: Baseline, 16 weeks
Secondary outcomes:
measure: Change in pain level as measured by Vaginal Vestibule Pressure Pain Intensities (PPI)
timeFrame: Baseline, 8 weeks, 16 weeks, and 24 weeks
measure: Levator Muscle Complex Pressure Pain Thresholds (PPTs)
timeFrame: Baseline, 8 weeks, 16 weeks, and 24 weeks
measure: Change in pain level as measured by Remote Bodily PPTs
timeFrame: Baseline, 8 weeks, 16 weeks, and 24 weeks
measure: Change in degree of overlapping pain, as measured by COPC follow-up survey
timeFrame: Baseline, 8 weeks, 16 weeks, and 24 weeks
measure: Change in mood as measured by the Symptom Checklist-27 (SCL-27)
timeFrame: Baseline, 8 weeks, 16 weeks, and 24 weeks
measure: Change in somatic awareness via Pennebaker Index of Limbic Languidness (PILL)
timeFrame: Baseline, 8 weeks, 16 weeks, and 24 weeks
measure: Change in perceived stress via Perceived Stress Scale (PSS)
timeFrame: Baseline, 8 weeks, 16 weeks, and 24 weeks
measure: Change in sleep as measured by the sleep scale
timeFrame: Baseline, 8 weeks, 16 weeks, and 24 weeks
measure: Change in in pain score during the tampon test at other time points
timeFrame: 8 weeks and 24 weeks
measure: Change in in pain score via the SF-MPQ at other time points
timeFrame: 8 weeks and 24 weeks
measure: Change in self-reported health on the SF12v2 at other time points
timeFrame: 8 weeks and 24 weeks
measure: Change in self-reported health on the PROMIS at other time points
timeFrame: 8 weeks and 24 weeks
measure: Change in cytokine biomarkers at other time points
timeFrame: 8 weeks and 24 weeks
measure: Change in microRNA biomarkers at other time points
timeFrame: 8 weeks and 24 weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
Study officials:
affiliation: Duke University
name: Andrea Nackley, PhD
role: PRINCIPAL_INVESTIGATOR
References: