Vestibulodynia: Understanding Pathophysiology and Determining Appropriate Treatments

NCT03844412 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: Pro001006781R01HD096331-01
• Study Type: interventional
• Target: 209
• Locations: 1 country
• Sites: 2

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.

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

Outcome Measures

Primary Outcomes (5)

• Pain Score During the Tampon Test

  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.

  Baseline, 16 weeks

• Change in Self-reported Pain Via the Short Form- McGill Pain Questionnaire (SF-MPQ)

  The SF-MPQ consists of 15 descriptors which are rated on an intensity scale as 0 = none, 1 = mild, 2 = moderate or 3 = severe. The total score ranges from 0 to 45, where a higher score indicates greater pain. A negative change score indicates a decrease in pain over time.

  Baseline, 16 weeks

• Self-reported Physical Health Via SF-12 Health Survey (SF12v2)

  The SF-12 physical health score has a mean of 50 and a standard deviation of 10 in the general population. Scores above 50 indicate a better-than-average health-related quality of life, while scores below 50 suggest below-average health.

  Prior to randomization

• Self-reported Mental Health Via SF-12 Health Survey (SF12v2)

  The SF-12 mental health score has a mean of 50 and a standard deviation of 10 in the general population. Scores above 50 indicate a better-than-average health-related quality of life, while scores below 50 suggest below-average health.

  Prior to randomization

• Sexual Health Via Patient-Reported Outcomes Measurement Information System (PROMIS)

  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. The PROMIS Sexual Function and Satisfaction (SexFS) measures produce a T-score that summarizes a person's sexual health. The T-score is a standardized score that ranges from 0 to 100, where 50 indicates the population mean with a standard deviation of 10. Higher scores indicate greater satisfaction.

  Baseline, 16 weeks

Secondary Outcomes (7)

• Change in Pain Level as Measured by Vaginal Vestibule Pressure Pain Intensities (PPI)

  Baseline, 8 weeks, and 16 weeks

• Change in Levator Muscle Complex Pressure Pain Threshold (PPT)

  Baseline, 16 weeks

• Change in Pain Level as Measured by Remote Bodily PPTs

  Baseline, 8 weeks, and 16 weeks

• Somatic Awareness Via Pennebaker Index of Limbic Languidness (PILL)

  Baseline, 8 weeks, and 16 weeks

• Change in Sleep as Measured by the Sleep Scale

  Baseline, 8 weeks, 16 weeks, and 24 weeks

Other Outcomes (12)

• Change in Inflammation as Measured by Cytokine Expression Levels

  Baseline, 16 weeks

• Change in Cytokine Biomarkers at Other Time Points

  8 weeks and 24 weeks

• Change in microRNA Biomarkers at Other Time Points

  8 weeks and 24 weeks

Study Arms (4)

peripheral treatment

ACTIVE COMPARATOR

5% lidocaine/5 mg/ml 0.02% estradiol compound cream

Drug: 5% lidocaine/5 mg/ml 0.02% estradiol compound cream; Drug: Placebo pill

central treatment

ACTIVE COMPARATOR

tricyclic antidepressant nortriptyline pill

Drug: Nortriptyline; Drug: Placebo cream

combined peripheral and central treatments

ACTIVE COMPARATOR

5% lidocaine/5 mg/ml 0.02% estradiol compound cream and tricyclic antidepressant nortriptyline pill

Drug: 5% lidocaine/5 mg/ml 0.02% estradiol compound cream; Drug: Nortriptyline

placebo

PLACEBO COMPARATOR

placebo cream and placebo pill

Drug: Placebo cream; Drug: Placebo pill

Interventions

5% lidocaine/5 mg/ml 0.02% estradiol compound cream DRUG

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).

combined peripheral and central treatments; peripheral treatment

Nortriptyline DRUG

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, and five for weeks 5 -16. Treatment with nortriptyline or placebo pill will be tapered off over weeks 16-18, decreasing the dose by 10 mg every 4 days. Participants will be provided with a list of drugs to avoid that are known to interact with nortriptyline.

central treatment; combined peripheral and central treatments

Placebo cream DRUG

The comparison treatment will be an identical-appearing placebo Moisturel™ cream

Also known as: Moisturel cream

central treatment; placebo

Placebo pill DRUG

The comparison treatment will be an identical-appearing placebo pill

peripheral treatment; placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Female
• Age 18-50 years
• English-literate
• Willingness to provide informed consent
• Meeting criteria for diagnosis of VBD based on:
• self-report of 3 continuous months of insertional (entryway) dyspareunia, and/or pain to touch/tampon insertion
• pain score of ≥ 3 on the tampon insertion test

You may not qualify if:

• Use of daily topical lidocaine, or estradiol, or lidocaine/estradiol to the vulvar vestibule within the past three months
• Use of nortriptyline or other TCA medications within the past three months
• Use of pregabalin or gabapentin within the past three months
• Presence of active dermatologic vulvar disease or vaginal infection
• Untreated atrophic vaginitis (participants may undergo treatment and re-evaluation for enrollment if the condition is resolved)
• Previous vestibulectomy
• 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.
• Active incarceration
• Cancer within the past year.
• Chemotherapy and/or radiation treatment within the past year.
• Unstable medical condition (e.g., renal impairment, significant hematological disease, cardiovascular disease, hepatic insufficiency, neurological disorder, autoimmune disease, or respiratory illness)
• Clear inflammatory states (e.g., morbid obesity)
• Use of immunosuppressant medications
• History of intolerance to nortriptyline, topical lidocaine, or topical estradiol
• 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

Sponsors & Collaborators

• Duke University: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (2)

University of California, Los Angeles

Los Angeles, California, 90095, United States

Location

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27278, United States

Location

Related Publications (1)

• Carey ET, Geller EJ, Rapkin A, Farb D, Cutting H, Akaninwor J, Stirling C, Bortsov A, McNulty S, Merrill P, Zakroysky P, DeLaRosa J, Luo S, Nackley AG. Rationale and design of a multicenter randomized clinical trial of vestibulodynia: understanding pathophysiology and determining appropriate treatments (vestibulodynia: UPDATe). Ann Med. 2022 Dec;54(1):2885-2897. doi: 10.1080/07853890.2022.2132531.

  PMID: 36269028 DERIVED

MeSH Terms

Conditions

Vulvodynia; Temporomandibular Joint Disorders; Fibromyalgia; Irritable Bowel Syndrome; Migraine Disorders; Tension-Type Headache; Endometriosis; Cystitis, Interstitial; Back Pain; Fatigue Syndrome, Chronic; Pelvic Pain; Chronic Pain

Interventions

Nortriptyline

Condition Hierarchy (Ancestors)

Vulvar Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Craniomandibular Disorders; Mandibular Diseases; Jaw Diseases; Musculoskeletal Diseases; Joint Diseases; Muscular Diseases; Stomatognathic Diseases; Rheumatic Diseases; Neuromuscular Diseases; Nervous System Diseases; Colonic Diseases, Functional; Colonic Diseases; Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Headache Disorders, Primary; Headache Disorders; Brain Diseases; Central Nervous System Diseases; Cystitis; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Encephalomyelitis; Neuroinflammatory Diseases; Chronic Disease; Disease Attributes; Pathologic Processes

Intervention Hierarchy (Ancestors)

Dibenzocycloheptenes; Benzocycloheptenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Results Point of Contact

• Title: Andrea Nackley, PhD
• Organization: Duke University

andrea.nackley@duke.edu

919-613-5911

Study Officials

• Andrea Nackley, PhD

  Duke University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Two-center, randomized, double-blind, placebo-controlled 2x2 factorial study enrolling 400 women to participate for 24-week duration.

Study Record Dates

• First Submitted: February 15, 2019
• First Posted: February 18, 2019
• Study Start: November 4, 2019
• Primary Completion: March 13, 2024
• Study Completion: May 30, 2024
• Last Updated: March 19, 2026
• Results First Posted: March 19, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, 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.

Locations

US (2)