Clinical trial NCT06660212: Biomodulation and Rehabilitation Interventions to TarGet Pelvic Health
Official title: Is Multimodal Physiotherapy And/or Photobiomodulation Therapy Effective for Pain Reduction Among Those Who Experience Provoked Vestibulodynia: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Vulvodynia
Provoked Vestibulodynia
Dyspareunia
Keywords: Provoked vestibulodynia
Intervention
Vulvodynia
Double-blinded
Pelvic floor
laser
Vulvar pain
Lead sponsor: University of Ottawa
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: University of Laval, Quebec City, Canada
name: BioFlexTM Laser Therapy
First posted: 2024-10-28
Enrollment: 240
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: 2x2 factorial
Primary purpose: TREATMENT

Brief summary: This trial will provide evidence for the effective management of pain and pain-related domains among those who experience provoked vestibulodynia (PVD) using photobiomodulation (PBM) and multimodal physiotherapy (mPT) in a randomized controlled trial (RCT). PVD is the most common subcategory of vulvovaginal pain experienced during sexual and non-sexual activities, affects the psychological and sexual health of an astounding one in five Canadian women, yet access to evidence-informed management approaches is limited. We will employ four intervention groups: PBM, sham PBM (control), PBM combined with mPT, and mPT with sham PBM to evaluate the effectiveness of each approach on its own and the two approaches in combination.

Among those who experience PVD, we seek to answer:

1. Relative to baseline and to sham PBM, does a 14-week intervention involving PBM, mPT, or a combination of mPT and PMB reduce vulvar pain severity reported on the Vulvar Pain Assessment Questionnaire (VPAQ)?
2. Is a combined mPT and PBM intervention more effective than mPT or PMB alone when considering vulvar pain severity and/or related domains as measured through VPAQ?
3. Are positive changes in vulvar pain severity and related domains observed following a 14-week intervention involving PBM, mPT or a combination of PBM and mPT retained at 6 months and at 1 year?

Secondary objectives include determining the effectiveness of PBM, mPT, and mPT combined with PBM relative to sham PBM on: Patient Global Impression of Change (PGIC), pain sensitivity measured using provocative tests, the other domains of the VPAQ, sexual function, as well as investigating mediating effects of psychosocial variables (central sensitization index, chronic pain acceptance), gender identity, and the presence of vaginismus on patient response to mPT, PBM and mPT combined with PBM. Lastly we will monitor patient satisfaction with the interventions, adherence to the interventions, and any adverse events.

Detailed description: Despite its high prevalence, surprisingly little is known about vulvovaginal pain in general and PVD more specifically. It is characterized by severe sharp and/or burning pain at the entrance to the vagina (i.e. the vulvar vestibule) when pressure is applied to it and it has been primarily attributed to inflammatory processes, hyper-innervation, and pelvic floor muscle (PFM) overactivity.

While it remains under-reported due to embarrassment and shame, the prevalence of PVD in premenopausal women is estimated at 12%, who account for 87% of cases. PVD pain can be intense and can last for days following attempts at sexual and non-sexual (e.g., tampon insertion) activities. It negatively impacts the physical, social and sexual health of women who experience it, and it can have major implications for reproductive health including functional infertility when those affected are unable to have penetrative intercourse, and delayed detection of cervical or uterine pathologies when gynaecological exams are avoided due to pain.

Current management of PVD involves multidisciplinary teams (including physicians, psychologists, sex therapists, and physical therapists) aiming to change the vulvar pain experience through analgesia, cognitive reframing, PFM relaxation and/or stretching and the reduction of vulvar sensitivity. Multimodal physiotherapy (mPT), in the form of education, biofeedback, manual therapies, and the vaginal insertion of dilators is recommended in clinical guidelines as a first-line treatment for PVD. The investigators have published two studies on the effectiveness of mPT intervention for women with PVD; both with positive results; yet their impact was limited since they were preliminary - the first was a prospective cohort study and the second was a pilot randomized controlled trial (RCT). Elsewhere in the literature, the first large-scale RCT on mPT compared the effectiveness of mPT to topical lidocaine for pain reduction and improved sexual function among women with PVD. The results were very promising; 79% of females in a mPT group reported being much or very much improved compared with 39% in a topical lidocaine group, coincident with reporting reduced pain during intercourse and improved sexual function. However, due to the lack of a comparable control group, the evidence for mPT was rated as "low" in systematic reviews, highlighting the need for further research.

A different, and likely complementary, treatment avenue for PVD is to focus interventions on the vulvar tissues themselves. One therapeutic option is photobiomodulation (PBM, aka low-level laser therapy, cold laser). PBM involves irradiation of tissue with a combination of red and near infrared light. PBM is theorized to initiate a series of physiological reactions within the cells exposed to light at specific wavelengths, leading to the restoration of normal cell structure and function. Although the mechanisms of action of PBM are not fully understood, positive effects of PBM have been found in clinical populations with chronic neuropathic pain, including carpal tunnel syndrome and trigeminal neuralgia. Recent evidence shows elevated bradykinin signaling (one of the most potent inducers of inflammatory pain) on the surface of vestibular fibroblasts collected from sites of intense pain in patients with PVD. The fibroblasts, in turn, respond vigorously to bradykinin, producing IL-6, which has strong expression in numerous pain conditions. Given our current understanding of PVD pathophysiology, and the suspected mechanistic actions of PBM, this intervention may provide an effective, non-invasive, approach to the management of PVD through reducing inflammation, promoting cell repair, and producing anesthesia.

The available evidence suggests that both mPT and PBM may be effective interventions for PVD; it is plausible that combining these two therapies may result in an additive effect and may result in a more effective approach than either intervention alone. The investigators have just completed a sham-controlled pilot RCT (NCT04234542) using a comprehensive PBM intervention, and the results are extremely promising. Those who received the real PBM improved by 25% on the pain severity domain of the Vulvar Pain Assessment Questionnaire (VPAQ), which was significantly greater than the sham PBM group. They also reported significant improvements in emotional responses to pain and sexual interference relative to baseline. Thirty-eight percent of participants who received the real PBM intervention reported \>30% improvement in their condition. And while the sham PBM group did not demonstrate significant reductions in pain sensitivity, the real PBM group demonstrated a 59% increase in pressure pain threshold (PPThresh) at the vulvar vestibule. A full RCT is clearly warranted.

The proposed trial will evaluate each intervention separately as well as a combined intervention group, as it is essential that we find effective, comprehensive, physiologically focused interventions that reduce vulvar pain severity and also improve the emotional, cognitive and functional burdens experienced by those who live with PVD. This will be a double-blind, multicenter RCT designed according to the Consolidated Standards of Reporting Trials (CONSORT) statement. The design will involve PBM (real, sham) and mPT (yes, no), resulting in four study groups: real PBM, sham PBM, PBM combined with mPT, and sham PBM combined with mPT. We did not include a sham mPT intervention due to existing RCT evidence supporting mPT's effectiveness, the lack of a validated sham mPT intervention for PVD, and the challenges in ensuring blinding with complex behavioral interventions like mPT.

mPT- The mPT protocol is largely based on the investigator's previously published protocol, including a greater focus on chronic pain education. It is very similar to that used in the RCT by Morin et al. (2021). At each site, the same physiotherapists (PTs) will provide all mPT treatments. The PTs have postgraduate certification in Women's Health physiotherapy, including advanced courses in pelvic pain, and \>5 years of practice experience.

The goals of the mPT intervention are to educate the participant (vulvar anatomy and physiology, PVD pathophysiology, chronic pain pathophysiology, and self-care for chronic pain), increase flexibility of the tissue surrounding the vaginal opening, decrease pain sensitivity at the vulvar vestibule, decrease fear and anxiety towards vaginal penetration, increase control and relaxation of the PFMs upon vaginal penetration, and provide the participants with techniques to prevent and manage their vulvar pain. These goals are representative of clinical practice in Canada and the United States.

Participants will attend weekly mPT sessions for the first 8 weeks of the 14-week intervention period then every two weeks thereafter, for a total of 10 sessions. Sessions will last 45 minutes each, and, for combination therapy groups, will be scheduled wherever possible at the same visit as the PBM sessions described below. While standardized to a large extent, to approximate clinical practice, the protocol will be tailored to allow participants to progress at their own pace. For example, participants will only move up to the next dilator circumference when their pain on insertion is rated at ≤4/10 using the dilator they have been given. Participants will be offered the opportunity to bring a partner or other individual with them to a treatment session (8, 9 and/or 10) to learn how to perform basic manual stretches of the vagina that could be conducted before engaging in penetrative activities, and to receive further recommendations regarding pain and sexual activity. At the completion of the 14th treatment session, participants will be provided with a personalized home exercise program to continue on their own. At each mPT visit, adherence to the home program in the preceding week will be reported by the participant through an on-line portal (RedCAP) which is inaccessible to the PT to minimize reporting bias. Missed/cancelled mPT visits will be rescheduled wherever possible.

Real PBM/sham PBM- The PBM treatment protocol will be delivered through a Bioflex Laser Therapy (Toronto, Canada) system by the PT at each site. The participants and the PT delivering the PBM intervention will remain blinded to real/ sham PBM by having an independent researcher not involved in the study, program the real and the sham (all outputs set to 1%) PBM protocols into the PBM system, labelling one as protocol A the other as protocol B, while making program data inaccessible to the PT. This independent researcher will not disclose to participants or any member of the study team which protocol is real and which is sham until the end of the study, including following data analysis, with one exception. The study biostatistician will learn which group received the real vs sham PBM after completing the interim analysis only if the analysis reveals that the futility criteria may have been met; which will subsequently be disclosed to the Trial Steering Committee.

The precise PBM protocol, was developed in collaboration with the scientific advisor to BioFlex Laser Therapy and was used in the investigator's pilot RCT. Fifteen real/sham PBM treatments will be provided by the study PT over a 14- week period. The treatment is delivered in a progressive fashion, treating sites at the vulvar vestibule locally using a focal probe, and the perineum using an array. The dosage of the laser is increased progressively, while monitoring patient response and adjusting as necessary. Each treatment will last approximately 20 minutes and will be scheduled at the participant's convenience and in coordination with the mPT visits where relevant. Missed visits will be rescheduled wherever possible. Participants will progress through five treatment levels at their own rate. Patients randomized to the sham-PBM group will be offered the real PBM at the end of the study.

All groups - Regardless of assigned intervention group, participants will be asked not to engage in vaginal penetrative activities while undergoing the first 8 weeks of the intervention. After 8 weeks of the intervention period, participants will be advised that they may, if desired, engage in penetrative activities, both sexual and not (e.g., internal pelvic examination, tampon insertion), but to stop a given attempt if perceived pain exceeds a NRS of 4/10. This time point will coincide with an invitation being extended to the participant to invite a partner or other individual to participate in the mPT treatment. Adherence to all intervention visits (mPT, PBM) and any adverse events will be recorded by the study PT, the latter being reported to the NPA and the Trial Steering Committee within 2 days of occurrence.

Participants will be randomly allocated (1:1:1:1) to one of the four intervention groups using a concealed, computer-generated, permuted block randomization (block size= 4) stratified by PVD type (primary/ secondary) and site (Ottawa/ Quebec City) only after they have consented to participate and have completed the baseline assessment. The allocation sequence will be managed by an independent investigator not associated with the project. It will be concealed from the study team through storage in a password protected file on an encrypted computer, backed up in a password-protected directory on MSSharepoint. Group allocation will be revealed only to the recruitment officer, who will inform the PT who will deliver the intervention and the participant. Since all participants will be pre-menopausal, no stratification by age will be performed. While gender will be recorded and sub-analyses will be performed by gender if possible, the investigators will not stratify by gender because PVD prevalence by gender is unknown.

Eligibility criteria: Inclusion Criteria:

* Willing to travel to Ottawa area or Quebec City area
* Biologically born female older than eighteen years
* Pre-menopausal
* Not currently pregnant or pregnancy/given birth in the past six months
* Experiencing signs and symptoms consistent with provoked vestibulodynia alone or provoked vestibulodynia plus vaginismus

Exclusion Criteria:

* gynaecologist cannot insert a single digit intravaginally and thus the participant would be unlikely able to tolerate the assessment procedures
* other gynaecologic conditions such as lichen sclerosus, fissures, endometriosis, adenomyosis, or pelvic organ prolapse

Primary outcomes:
measure: Vulvar Pain Assessment Questionnaire - Pain Severity
timeFrame: Baseline
measure: Vulvar Pain Assessment Questionnaire - Pain Severity
timeFrame: Within 2 weeks of the end of intervention
measure: Vulvar Pain Assessment Questionnaire - Pain Severity
timeFrame: 6 months post start of intervention
measure: Vulvar Pain Assessment Questionnaire - Pain Severity
timeFrame: 12 months post start of intervention
Secondary outcomes:
measure: Tampon Test
timeFrame: Baseline
measure: Tampon Test
timeFrame: Within 2 weeks of the end of the intervention
measure: Tampon Test
timeFrame: 6 months post start of the intervention
measure: Tampon Test
timeFrame: 12 months post start of the intervention
measure: Provoked vulvar pain sensitivity
timeFrame: Baseline
measure: Provoked vulvar pain sensitivity
timeFrame: 2 weeks post intervention
measure: Provoked vulvar pain sensitivity
timeFrame: 6 months post start of the intervention
measure: Provoked vulvar pain sensitivity
timeFrame: 12 months post start of the intervention
measure: Vulvar pain assessment questionnaire - full inventory
timeFrame: Baseline
measure: Vulvar pain assessment questionnaire - full inventory
timeFrame: Within 2 weeks post intervention
measure: Vulvar pain assessment questionnaire - full inventory
timeFrame: 6 months post start of the intervention
measure: Vulvar pain assessment questionnaire - full inventory
timeFrame: 12 months post start of the intervention
measure: Pain Catastrophizing Scale
timeFrame: Baseline
measure: Pain Catastrophizing Scale
timeFrame: Within 2 weeks post-intervention
measure: Pain Catastrophizing Scale
timeFrame: 6 months post start of intervention
measure: Pain Catastrophizing Scale
timeFrame: 12-months post start of intervention
measure: Female sexual function index
timeFrame: Baseline
measure: Female sexual function index
timeFrame: Within 2 weeks post intervention
measure: Female sexual function index
timeFrame: 6 months post start of intervention
measure: Female sexual function index
timeFrame: 12 months post start of intervention
measure: Central sensitization inventory
timeFrame: Baseline
measure: Central sensitization inventory
timeFrame: Within 2 weeks post-intervention
measure: Central sensitization inventory
timeFrame: 6 months post start of intervention,
measure: Central sensitization inventory
timeFrame: 12 months post start of intervention
measure: Chronic Pain Acceptance Questionnaire
timeFrame: Baseline
measure: Chronic Pain Acceptance Questionnaire
timeFrame: 2 weeks post intervention
measure: Chronic Pain Acceptance Questionnaire
timeFrame: 6 months post start of the intervention
measure: Chronic Pain Acceptance Questionnaire
timeFrame: 12 months post start of the intervention
measure: Non-sexual insertional pain
timeFrame: Baseline
measure: Non-sexual insertional pain
timeFrame: 2 weeks post intervention
measure: Non-sexual insertional pain
timeFrame: 6 months post start of the intervention
measure: Non-sexual insertional pain
timeFrame: 12 months post start of the intervention
measure: Sexual Insertion pain
timeFrame: Baseline
measure: Sexual Insertion pain
timeFrame: 2 weeks post intervention
measure: Sexual Insertion pain
timeFrame: 6 months post start of the intervention
measure: Sexual Insertion pain
timeFrame: 12 months post start of the intervention
measure: Patient global impression of change
timeFrame: 2 weeks post intervention
measure: Patient global impression of change
timeFrame: 6 months post start of intervention
measure: Patient global impression of change
timeFrame: 12 months post start of intervention
Other outcomes:
Locations:
city: Ottawa
country: Canada
facility: Motor Function Measurement Lab
state: Ontario
city: Quebec City
country: Canada
facility: Bernard Lab
state: Quebec
Study officials:
affiliation: University of Ottawa
name: Linda McLean, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Laval
name: Stephanie Bernard, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dargie E, Holden RR, Pukall CF. The Vulvar Pain Assessment Questionnaire: Factor Structure, Preliminary Norms, Internal Consistency, and Test-Retest Reliability. J Sex Med. 2017 Dec;14(12):1585-1596. doi: 10.1016/j.jsxm.2017.10.072.
citation: Vowles KE, Kruger ES, Bailey RW, Sowden G, Ashworth J, Hickman J, McCracken LM. Initial evaluation of the Chronic Pain Acceptance Questionnaire - 2. Eur J Pain. 2020 Nov;24(10):2027-2036. doi: 10.1002/ejp.1650. Epub 2020 Sep 21.
citation: Vandyken C, Hilton S. Physical Therapy in the Treatment of Central Pain Mechanisms for Female Sexual Pain. Sex Med Rev. 2017 Jan;5(1):20-30. doi: 10.1016/j.sxmr.2016.06.004. Epub 2016 Aug 3.
citation: LePage K, Selk A. What Do Patients Want? A Needs Assessment of Vulvodynia Patients Attending a Vulvar Diseases Clinic. Sex Med. 2016 Dec;4(4):e242-e248. doi: 10.1016/j.esxm.2016.06.003. Epub 2016 Jul 30.
citation: Bergeron S, Binik YM, Khalife S, Pagidas K, Glazer HI, Meana M, Amsel R. A randomized comparison of group cognitive--behavioral therapy, surface electromyographic biofeedback, and vestibulectomy in the treatment of dyspareunia resulting from vulvar vestibulitis. Pain. 2001 Apr;91(3):297-306. doi: 10.1016/S0304-3959(00)00449-8.
citation: Lev-Sagie A, Kopitman A, Brzezinski A. Low-Level Laser Therapy for the Treatment of Provoked Vestibulodynia-A Randomized, Placebo-Controlled Pilot Trial. J Sex Med. 2017 Nov;14(11):1403-1411. doi: 10.1016/j.jsxm.2017.09.004. Epub 2017 Sep 29.
citation: Dargie EE, Chamberlain SM, Pukall CF. Provoked Vestibulodynia: Diagnosis, Self-Reported Pain, and Presentation During Gynaecological Examinations. J Obstet Gynaecol Can. 2017 Mar;39(3):145-151. doi: 10.1016/j.jogc.2017.01.001.
citation: McLean L, Thibault-Gagnon S, Brooks K, Goldfinger C, Pukall C, Chamberlain S. Differences in Pelvic Morphology Between Women With and Without Provoked Vestibulodynia. J Sex Med. 2016 Jun;13(6):963-71. doi: 10.1016/j.jsxm.2016.04.066.
citation: Morin M, Bergeron S, Khalife S, Mayrand MH, Binik YM. Morphometry of the pelvic floor muscles in women with and without provoked vestibulodynia using 4D ultrasound. J Sex Med. 2014 Mar;11(3):776-85. doi: 10.1111/jsm.12367. Epub 2013 Nov 6.
citation: Gentilcore-Saulnier E, McLean L, Goldfinger C, Pukall CF, Chamberlain S. Pelvic floor muscle assessment outcomes in women with and without provoked vestibulodynia and the impact of a physical therapy program. J Sex Med. 2010 Feb;7(2 Pt 2):1003-22. doi: 10.1111/j.1743-6109.2009.01642.x. Epub 2010 Jan 6.
citation: Reissing ED, Brown C, Lord MJ, Binik YM, Khalife S. Pelvic floor muscle functioning in women with vulvar vestibulitis syndrome. J Psychosom Obstet Gynaecol. 2005 Jun;26(2):107-13. doi: 10.1080/01443610400023106.
citation: Mayer TG, Neblett R, Cohen H, Howard KJ, Choi YH, Williams MJ, Perez Y, Gatchel RJ. The development and psychometric validation of the central sensitization inventory. Pain Pract. 2012 Apr;12(4):276-85. doi: 10.1111/j.1533-2500.2011.00493.x. Epub 2011 Sep 27.
citation: Meyer-Bahlburg HF, Dolezal C. The female sexual function index: a methodological critique and suggestions for improvement. J Sex Marital Ther. 2007 May-Jun;33(3):217-24. doi: 10.1080/00926230701267852.
citation: Rosen R, Brown C, Heiman J, Leiblum S, Meston C, Shabsigh R, Ferguson D, D'Agostino R Jr. The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther. 2000 Apr-Jun;26(2):191-208. doi: 10.1080/009262300278597.
citation: Pukall CF, Young RA, Roberts MJ, Sutton KS, Smith KB. The vulvalgesiometer as a device to measure genital pressure-pain threshold. Physiol Meas. 2007 Dec;28(12):1543-50. doi: 10.1088/0967-3334/28/12/008. Epub 2007 Dec 3.
citation: Goldstein AT, Pukall CF, Brown C, Bergeron S, Stein A, Kellogg-Spadt S. Vulvodynia: Assessment and Treatment. J Sex Med. 2016 Apr;13(4):572-90. doi: 10.1016/j.jsxm.2016.01.020. Epub 2016 Mar 25.
citation: Spoelstra SK, Dijkstra JR, van Driel MF, Weijmar Schultz WC. Long-term results of an individualized, multifaceted, and multidisciplinary therapeutic approach to provoked vestibulodynia. J Sex Med. 2011 Feb;8(2):489-96. doi: 10.1111/j.1743-6109.2010.01941.x.
citation: Harlow BL, Stewart EG. A population-based assessment of chronic unexplained vulvar pain: have we underestimated the prevalence of vulvodynia? J Am Med Womens Assoc (1972). 2003 Spring;58(2):82-8.