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Regenerative Treatment of Female Genital Atrophy (RETREAT-FUGA)

A

AndreiaAntunes

Status and phase

Completed
Phase 2
Phase 1

Conditions

Vulvo Vaginal Atrophy

Treatments

Biological: Mesotherapy with Autologous Platelet-Rich Plasma (PRP) to vulvovaginal area
Biological: Platelet-Poor Plasma Gel
Other: Mesotherapy with saline solution

Study type

Interventional

Funder types

Other

Identifiers

NCT07306611
27/2024 CE ULS-RL
PHD SCHOLARSHIP 2021. 07973.BD (Other Grant/Funding Number)

Details and patient eligibility

About

Vulvovaginal health is a key aspect of active and healthy aging for all women. Hormonal deprivation that occurs during menopause significantly affects the anatomy and function of urogenital tissues, leading to their atrophy. Vaginal creams and suppositories containing estrogens are the standard treatment and can improve this condition. However, they require continuous application, which often makes adherence to treatment challenging. Additionally, women with hormone-dependent tumors, such as most breast cancers and many gynecological cancers, are even more affected by this issue. These women are often treated with anti-estrogen medications, undergo radio or chemotherapy, and are frequently younger, with the added complication that the standard treatment is contraindicated for them.

To address this important issue, the study titled "Regenerative Treatment of Female Genital Atrophy" was developed. If you meet the required criteria, we would like to invite you to participate.

Inclusion Criteria:

  • Clinical complaints of genital atrophy (e.g., dryness, burning, itching, discomfort, or pain during intercourse).
  • Contraindication to standard local hormonal treatment (e.g., allergy, bothersome side effects, lack of improvement with standard treatment, history of hormone-dependent cancer, or thrombotic event treated at least two years ago).

This study focuses on Regenerative Medicine, which aims to support the regeneration of cells, tissues, or organs in the human body to restore normal function. This field holds significant curative and preventive potential. The selected regenerative treatment, widely used in various medical fields (such as dentistry and orthopedics), is derived from the patient's own body, making it a natural and safe option with minimal side effects. This treatment, known as platelet-rich plasma (PRP), has shown effectiveness in improving the firmness, elasticity, hydration, and thickness of the vulva and vagina. However, further research is required to assess the effectiveness of PRP specifically in the external female genital area.

What is PRP - Platelet-Rich Plasma? PRP is a substance obtained from the patient's own blood. Blood is composed of several components, including red blood cells, white blood cells, plasma, and platelets. Platelets are small cell fragments that play a crucial role in blood clotting and wound healing. PRP is created by taking a small sample of the patient's blood and processing it in a centrifuge to concentrate the platelets within the plasma. This concentrated plasma, rich in growth factors and proteins, is then injected into the target area to stimulate tissue regeneration and repair. Because PRP is derived from the patient's own body, it is considered a natural and safe treatment with a very low risk of adverse reactions.

PRP is obtained by collecting a small amount of the patient's blood. After a carefully standardized preparation process, the PRP is injected into the vulvovaginal area under local anesthesia.

Study Location: Gynecology Department of Santo André Hospital, Leiria, at the Genital Atrophy Clinic.

Study Protocol:

  • Initial evaluation consultation.
  • First treatment intervention.
  • Follow up approximately one month after the first treatment and second treatment intervention.
  • Another follow-up approximately one month after the second treatment.
  • Final evaluation six months after the start of the study. Participants are divided into two groups: one group receives PRP treatment, while the other receives a placebo (serum). At the end of the study, participants in the placebo group will have the option to undergo PRP treatment.

This is a double-blind study designed to evaluate the efficacy of PRP in the female external genital area.

Full description

Introduction:

Vulvovaginal atrophy (VVA) is a condition associated with lower urinary tract dysfunction caused by decreased levels of estrogen and androgens, collectively referred to as genitourinary syndrome of menopause (GSM). Approximately 50% of postmenopausal women experience symptoms related to urogenital atrophy, which significantly impacts sexual function and quality of life (QoL) worldwide. These symptoms include vaginal dryness, irritation, dyspareunia, and recurrent infections, leading to discomfort, reduced intimacy, and emotional distress.

VVA symptoms are associated with decrements in quality of life that may be comparable to serious conditions such as arthritis, chronic obstructive pulmonary disease, asthma, and irritable bowel syndrome.

Contrary to vasomotor symptoms of menopause, which tend to diminish over time, GSM symptoms often worsen, leading to a greater impact on QoL and negatively affecting patients' confidence and intimacy with their partners. Current standard treatments, such as low-dose vaginal estrogens, are effective in alleviating symptoms but require continuous application, which can hinder adherence. Furthermore, these treatments are contraindicated in women with hormone-dependent cancers or a history of thrombotic events, leaving a significant population without effective therapeutic options.

Regenerative options include injection of materials into the vaginal such as PRP, fat graft, hyaluronic acid, botulinum toxin, and collagen, seems promising options, but to date their efficacy has not been reviewed, so further studies are required, and the procedures should be standardized to benefit more patients.

PRP is the most common autologous regenerative treatment used in different medical fields (maxillo-facial, dermatology, cardiac surgery, pediatric surgery, gynecology, urology, plastic surgery, and ophthalmology)and poses a low risk adverse events.

Platelets contain an abundance of growth factors and cytokines that can affect inflammation, angiogenesis, stem cell migration, and cell proliferation. Based on histological evidence, PRP injected in human deep dermis and sub-cutaneous tissue induces soft-tissue augmentation, activation of fibroblasts, and new collagen deposition, as well as new blood vessels and adipose tissue formation, induction of dermal collagenases, angiogenesis, and adipogenesis in human skin by injection of platelet-rich fibrin matrix. PRP is more than just a platelet concentrate; it also contains proteins to cell adhesion that allow the use of PRP product into a biologic gel cream for surface application.

Objectives:

The primary objective of this study is to evaluate the efficacy and safety of autologous PRP for the treatment of VVA in women with contraindications or inefficacy to local hormonal treatments. Specifically, the study aims to:

  1. Assess the ability of PRP to restore vaginal tissue integrity, including firmness, elasticity, hydration, and thickness.
  2. Evaluate the improvement of VVA symptoms, such as dryness, irritation, and dyspareunia.
  3. Measure the impact of PRP treatment on patients' quality of life and sexual function.
  4. Monitor and document any adverse effects associated with PRP treatment.

Study Protocol:

Participants will be randomly assigned to one group:

  1. PRP Group: Patients will receive autologous PRP injections into the vulvovaginal area.
  2. Placebo Group: Patients will receive placebo (saline solution) injections.

The study will follow a standardized protocol:

  • T0 (Baseline): Initial evaluation, including medical history, gynecological examination, and baseline symptom assessment.
  • T1 (1 Month): First treatment session.
  • T2 (2 Months): Follow-up and second treatment session.
  • T3 (3 Months): Follow-up evaluation.
  • T4 (6 Months): Final evaluation, including symptom assessment, quality of life questionnaires, and laboratory tests.

Data Collection

Data will be collected at multiple times (T0, T1, T2, T3, and T4) using both clinical assessments and patient-reported outcome measures (PROMs). The following variables and tools will be used:

  1. - Clinical Report Form (CRF):

    • Demographic and Health Data: Age, years since menopause, education level, occupation, body mass index (BMI), smoking habits, parity, medical history, current medications, and history of hormonal treatments.
    • Gynecological Examination:

    Visual assessment of the perineum, vulva, and vagina for signs of atrophy (e.g., pallor, petechiae, friability, narrowing of the vaginal opening).

    Cotton swab test to assess tissue sensitivity. Vaginal opening flexibility, measured in centimeters. Vulvovaginal Visual Examination Tool (VVET): A validated scale to assess vulvovaginal health, including color, epithelial integrity, surface thickness, and secretions. These ratings were summed and re-scaled to range from 0 to 12 to create a vaginal exam composite index. A score of 0 indicates normal vulva-vaginal characteristics and higher scores indicate greater degrees of vulva-vaginal atrophy

  2. - Laboratory Investigations:

    • Vaginal Maturation Index (VMI): Cytological analysis of epithelial cells to assess atrophy.
    • Vaginal Maturation Value (VMV): Calculated using the formula: (0.2 × % parabasal cells) + (0.6 × % intermediate cells) + (1.0 × % superficial cells). A VMV ≤50 indicates atrophy.
    • Vaginal pH: Measured using pH strips, with values <5 indicating normal hormonal patterns.
  3. - Patient-Reported Outcome Measures (PROMs):

    • Patient self-assessed symptoms of vulva and vaginal atrophy (VVA)• Vaginal • Vaginal and/or vulva irritation/itching/discomfort (none, mild, moderate or severe) • Dysuria/pain with urination (none, mild, moderate or severe) • Vaginal pain associated with sexual activity/pain with sex (none, mild, moderate or severe) • Vaginal bleeding associated with sexual activity (presence vs. absence) and identification of the most bothersome symptom.
    • EQ-5D: A generic instrument for measuring health-related quality of life, validated for European Portuguese.
    • Female Sexual Function Index (FSFI-6): A validated questionnaire assessing six domains of sexual function: desire, arousal, lubrication, orgasm, satisfaction, and pain.
    • The King´s Health Questionnaire (KHQ) assesses the impact of urinary incontinence on the QoL.
    • Day-to-Day Impact of Vaginal Aging (DIVA): A self-report measure of the impact of vaginal symptoms on daily life, emotional well-being, and sexual function.
    • Visual Analog Scale (VAS): Used to assess pain and discomfort during and after treatment.
    • Side Effects Questionnaire: Participants will report any side effects (e.g., pain, swelling, bruising) one week after each treatment.
    • Satisfaction Questionnaire: At the final visit (T4), participants will rate their overall satisfaction with the treatment and perceived improvement compared to baseline.

Feasibility: After each treatment, the co-investigator will be asked to evaluate the ease of treatment using a 5-point Likert scale.

Safety Measures

The safety of PRP treatment will be closely monitored throughout the study. Participants will be asked to document any side effects in a daily diary and report them during follow-up visits or phone interviews. The most common expected side effects include:

  • Localized pain or discomfort.
  • Swelling or edema.
  • Bruising at the injection site. These side effects are expected to be mild, temporary, and self-limiting. Serious adverse events are not anticipated based on previous studies of PRP in gynecological and other medical applications.

Adverse Events Monitoring All adverse events will be documented in the source documents and the patient report form (PRF). The clinical course of each event will be followed until resolution or stabilization. If a participant experiences significant discomfort during the procedure (measured using the Visual Analog Scale), the intervention will be suspended, and appropriate medical care will be provided.

Participants will have access to the principal investigator via phone or email for immediate reporting of any concerns or adverse events.

Goals:

Primary endpoints Goal 1: The efficacy analyses demonstrate a statistically significant improvement from baseline T0 to T4, of treatment in following parameters: 1. Maturation Index of vaginal cytology (decrease of parabasal vulvovaginal cells and increase in superficial cells) 2. Lowering of the vaginal PH.

Goal 2: A statistically significant improvement of VVA symptoms self-identified by subjects as the most bothersome VVA symptom to her at baseline.

Goal 3: A statistically significant improvement of quantitative assessment of genital health with the VVET scale.

Secondary endpoints Secondary efficacy variables include the significant improvement of the other symptoms of VVA self-assessed by questionnaires and satisfaction with the treatment evaluated by the significant improve in the quality of life evaluated with several dimensional PROMs.

Ethical Considerations This study will be conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines, and relevant European and Portuguese legislation. Ethical approval will be obtained from the Ethics Committee of Santo André Hospital and the Ethics Subcommittee for Life and Health Sciences of the University of Minho.

Informed Consent All participants will provide written informed consent before enrollment. They will be informed about the study objectives, procedures, potential risks, and benefits. Participants will have the right to withdraw from the study at any time without any impact on their medical care.

Confidentiality Participant confidentiality will be strictly maintained. Personal data will be anonymized and stored securely in password-protected systems and locked cabinets. Only authorized personnel will have access to identifiable information. Data will be managed in compliance with the EU General Data Protection Regulation (GDPR) and Portuguese Law nº 58/2019.

Harms The suspension of the intervention will occur through the verification of significant levels of discomfort during the procedure (Visual Analogue Scale). In case of events occurrence such as urinary tract infection, vulvovaginitis, irritation and vaginal injury after treatment. In these cases, an appropriate medical treatment will be offered. Nevertheless, we don´t expect any serious harms according to previous studies, being the most expected; pain, swelling or hematoma all of it temporary and auto limited.

Minorities This study intends to include all eligible women regardless of race, ethnic origin, or sexual orientation. VVA has been well studied in the USA, Europe, the Mid East, and Asian countries. A review of the literature has not revealed any differences in either diagnosis or treatment effects between racial or ethnic groups. The study is a preliminary investigation of regenerative treatment effects of PRP graft in all women pooled, regardless of ethnic or racial group.

Financial Issues and Resources

This study will not impose additional costs on the participating institution or patients. The following resources will be provided free of charge:

  • Consumables (e.g., anesthetics, syringes, blood collection tubes, pH strips).
  • Laboratory services for cytology and platelet count analysis. The estimated cost of the study is €6,000, which will be covered by the research team through funding from the Portuguese Science and Technology Foundation - FCT Medical PhD Scholarship and other sources.

Conflict of Interest The researchers declare no conflicts of interest related to the implementation of this study.

Communication and Use of Results

The results of this study will be disseminated through:

  • Presentations at national and international scientific conferences.
  • Publications in peer-reviewed scientific journals.
  • Inclusion in the principal investigator's doctoral thesis. If the study yields positive results, it may serve as a basis for a Phase 3 clinical trial, contributing to the development of new therapeutic options for VVA with minimal environmental impact.

Enrollment

30 patients

Sex

Female

Ages

25 to 80 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

  • At least one clinical complaint of VVA.

    • Dryness
    • Burning
    • Itching
    • Discomfort (soreness, irritation)
    • Dyspareunia (sexual impaired function)
    • With or without urinary problems (incontinence, urgency, dysuria). Must report a contra-indication with the standard local hormonal treatment.
    • Allergy
    • Burden side effects
    • Non-improvement with standard treatment
    • Hormonal cancer survivors must be in remission for two years after the last oncologic treatment.
    • Thrombotic disease patients must have the disease controlled and have passed 2 years after the thrombotic event.

Must have a cervicovaginal cytology confirming the atrophy, having ≤ 5% of superficial cells on vaginal smear. Moreover, a normal morphologic cytology besides the inflammatory or atrophy change is mandatory.

Must have a vaginal pH above 5 at baseline. Must have a normal mammography (American College of Radiology BI-RADS 1 or 2) within 12 months of study starts (Day 1), and normal breast examination.

Willing to participate in the study and sign an informed consent.

Exclusion criteria

  • Life expectancy < 6 months due to concomitant illnesses.
  • Exposure to any investigational drug or procedure within 1 month prior to study entry or enrolled in a concurrent study that may confound results of this study.
  • Active infectious disease. Patients known to have tested positive for HIV, HTLV, HBV, HCV, CMV (IgM > IgG) and/or syphilis will have an expert consultation as to patient eligibility based on the patient's infectious status.
  • Any illness which, in the Investigator's judgment, will interfere with the patient's ability to comply with the protocol, compromise patient safety, or interfere with the interpretation of the study results.
  • Patients on chronic immunosuppressive transplant therapy.
  • Known drug or alcohol dependence or any other factors which will interfere with the study conduct or interpretation of the results or who in the opinion of the investigator are not suitable to participate.
  • Used oral, transdermal, vaginal, intrauterine, implants/injectables drugs that contained either oestrogens, progestins, androgens, or selective oestrogen receptor modulators (SERMs) before the study (a washout period of 4 weeks is required). Use of prescription and non-prescription medications and remedies known to alleviate VVA, discomfort including vaginal lubricants and moisturizers, are allowed during the study.
  • Any allergic reaction to local anaesthetics.
  • Unwilling and/or not able to give written informed consent.

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

Triple Blind

30 participants in 2 patient groups, including a placebo group

PRP Group
Active Comparator group
Description:
GROUP A (18 patients) random assign from enrolled patients: Participants receive intradermal injections of autologous platelet-rich plasma (PRP) into the vulvar vestibule, followed by topical application of platelet-poor plasma (PPP) gel for 5 days.
Treatment:
Biological: Platelet-Poor Plasma Gel
Biological: Mesotherapy with Autologous Platelet-Rich Plasma (PRP) to vulvovaginal area
Placebo Group
Placebo Comparator group
Description:
GROUP B (12 patients) random assign from enrolled patients: Participants receive intradermal injections of saline solution into the vulvar vestibule, followed by topical application of platelet-poor plasma (PPP) gel for 5 days.
Treatment:
Other: Mesotherapy with saline solution
Biological: Platelet-Poor Plasma Gel

Trial contacts and locations

1

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Data sourced from clinicaltrials.gov

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