A Laser and Topical Treatment Combination in the Vulvo-vaginal Atrophy Management in Breast Cancer Patients.

Not Applicable

Not yet recruiting

• Conditions: Female Urogenital Diseases; Breast Cancer Female
• Interventions: Device: C02 microablative laser; Combination Product: Regenerative topical treatment

• Registration Number: NCT05585476
• Lead Sponsor: Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz

Brief Summary

The genito-urinary syndrome of menopause severely affects patients with a history of gynecological cancer, especially those diagnosed with breast cancer. At the present time, we do not have solid scientific evidence on treatments that can be effective and safe to address this pathology. Based on the above, we have developed our working hypothesis where it is postulated that the microfractionated laser treatment of C02, in conjunction with topical regenerative treatment, constitute an effective alternative in the management of vulvo-vaginal atrophy in oncological patients who have contraindicated hormonal treatments.

Detailed Description

Based on the hypothesis set out in the previous section, the main objective of the study will consist of:

-To assess the effectiveness of microfractionated C02 laser therapy in combination with non-hormonal topical regenerative therapy versus laser treatment or non-hormonal topical regenerative treatment (the latter two exclusively) in the management of symptoms derived from vulvovaginal atrophy in cancer patients who are contraindicated to the use of hormonal therapies.

As secondary objectives we have the following:

* To determine the prevalence and incidence of genitourinary syndrome in our population of patients diagnosed with breast cancer and who are undergoing adjuvant or neoadjuvant treatment (with the exception of chemotherapy).

* To assess the impact of genitourinary syndrome on the quality of life of these patients.

* To determine the degree of correlation between intensity of the symptomatology and impact on the quality of life of the same with the presence of characteristic changes of hormonal depletion at the tissue level and vaginal microbiota.

* To evaluate the safety and tolerability of the C02 laser in our group of patients. Special attention will be paid to the occurrence of adverse events that have not been described in the literature at the present time.

* Describe other effects of laser treatment on urinary symptoms that could serve as hypotheses for future studies.

* To evaluate the safety and tolerability of the topical non-hormonal regenerating agent XCM intim in our group of patients.

* To describe the effects of topical non-hormonal regenerative therapy on vulvo-vaginal and urinary symptoms and the impact on the quality of life of these patients.

To carry out all the above, it is proposed to perform a controlled and randomized clinical trial, single blind, in which the patients included will be assigned to one of the 3 existing treatment arms and that we will explain in detail in later sections.

Recruitment is planned to begin in December 2022. The overall duration of the study is estimated at approximately 42 months, from the beginning of the recruitment period to the last follow-up visit. This study is intended to be conducted from December 2022 to January 2026.

All those patients who meet the inclusion criteria and do not present any reason for exclusion will be given the informative document on the study. If they agree to participate, they will deliver said signed document and will be recruited and randomized in a single-blind manner (only the participant), in a 1:1:1 ratio to laser treatment + regenerative topical treatment or to regenerative topical treatment or to laser treatment ( latter 2 in exclusivity). The entire process of selection, inclusion and randomization will be supervised by both the Research Institute and the Clinical Research Ethics Committee of the Jiménez Díaz Foundation, which will carry out regular audits.

The study will be conducted in accordance with the protocol and standards of good clinical practice, as described in: Harmonized Tripartite Standards of ICH E6, for Good Clinical Practice 1996. Law 14/2007 on Biomedical Research Directive 2001/20/EC. Updated Declaration of Helsinki and amendments concerning medical research on human beings. The researcher agrees, with the signing of this protocol, to follow the instructions and procedures described therein and therefore will comply with the principles of Good Clinical Practice on which it is based. Once the protocol has been signed, it should not be modified without the written agreement of both the sponsor and the principal investigator, and with the consent of the Clinical Trials Ethics Committee.

All the information collected will be treated in a strictly confidential manner, in accordance with current regulations (Regulation (EU) 2016/679 of the European Parliament and of the Council, of April 27, 2016 (GDPR), Law 41/2002 on Patient Autonomy, Law 14/1986 General Health and Law 14/2007 on Biomedical Research). The patient will have the right to access, modify, oppose and cancel their data. In addition, they can limit the processing of data that are incorrect, request a copy or transfer to a third party (portability) the data that has been provided for the study. To exercise their rights, the patient must contact the principal investigator of the study. Data cannot be deleted even if the patient stops participating in the trial to ensure the validity of the research and comply with legal duties and drug authorization requirements. Likewise, the patient has the right to contact the Data Protection Agency if they are not satisfied.

It is the investigator's responsibility to document all adverse events that occur during the clinical trial. At each visit/assessment, all adverse events observed by both the investigator and one of his or her clinical collaborators, as well as those reported by the subject spontaneously or in response to a direct question, shall be evaluated by the investigator and noted in the adverse events section of the subject's data collection notebook.

The nature of each event, the time of onset after the intervention, the duration, the severity and relationship to the intervention should be established. The details of its handling must be recorded on the corresponding pages of the data collection notebook. The initial symptomatology should be well documented at the screening visit. It is important to correctly collect the baseline information in order to interpret the data of the following visits.

Investigators should follow up on subjects with adverse events until they have subsided, disappeared, or until the process has stabilized. Reports on the course of the subject's evolution should be sent to the monitor of the clinical trial.

The principal investigator shall report serious and unexpected adverse events to the sponsor by telephone or fax within 24 hours of becoming aware of the adverse event by the investigator, who shall in turn inform the health authorities. The previous report made by telephone or fax shall be followed by a complete report including a copy of the relevant data collected or recorded at the centre or other documents that occur as a result of the adverse event.

The total number of visits for patients in both treatment arms will be 8, leaving the study schedule as follows:

* Consult before treatment.

* First treatment visit (after acceptance and signing of the informed consent): First session of laser treatment and initiation of topical treatment.

* Second treatment visit (one month after the first session): Second session of laser treatment and topical treatment control.

* Third treatment visit (6 weeks after the second session): Third session of laser treatment and topical treatment control.

* Review 1.5 months after the 3rd session.

* Review 6 months after the 3rd session.

* Review 12 months after the 3rd session.

* Review 24 months after the 3rd session.

The tests and studies to be carried out during the study will be the following:

* Anamnesis (in all visits).

* Physical examination (at all visits).

* Gynecological ultrasound (in 1st visit, before starting treatment).

* Validated questionnaires (in all visits).

* Measurements of skin characteristics with cutometer (at all visits).

* Vaginal exudate (in first pretreatment visit, visit of the month and a half of finishing laser treatment, visit of the 6 months after finishing the laser treatment session, visit of the 12 months and visit of the 24 months).

* Vaginal mucosal biopsy (at the 1st visit before starting treatment and a month and a half after the third session).

A digital data collection notebook will be created by the company Xolomon ® to guarantee the quality and reliability of the information. All data will be entered 2 times by 2 different researchers between whom there will be no contact. In the event that there is a discrepancy in the same field, the computer system will send an alert to the main researcher and he will be in charge of clarifying where the error is. Likewise, it will be the principal investigator who verifies the integrity, accuracy and veracity of the data entered, by comparing them with those collected in the clinical history of patient care.

All variables entered in the digital data notebook will have masks, ranges of values and dictionaries depending on the type of variable and the content they must integrate.

Regarding the statistical analysis of the data, a description of the characteristics of the patients will be made. Qualitative variables will be described by frequencies and percentages. The quantitative variables will be described by the mean and the standard deviation, or by the median and the interquartile range, depending on the degree of symmetry presented by the distribution of the data. Comparisons between the two treatment groups referring to the qualitative variables will be made by the Chi-square test, or failing that by Fisher's exact test. In the case of quantitative variables, comparisons will be made by Student's t test, or by Wilcoxon range test, depending on whether or not the data follow a normal distribution. To test normality, the Shapiro-Wilk test will be used. Whenever possible, the difference between the two treatment groups will be quantified, along with their 95% confidence intervals. The treatment of the lost values will be carried out through the Multiple Imputation method, for which, sets of databases will be generated from the original database, which will contain imputed values based on a random selection. The statistical analyses will be carried out by the Biostatistics service of the Jiménez Díaz Foundation University Hospital, through the Statistical Program Stata 14.0.

The sample size has been calculated in order to detect a difference of 2 points, between the means of the symptom intensity scale of the three groups. A maximum standard deviation of 3 points and a loss percentage of 10% are assumed. Under these assumptions, if we set the significance level at 5% and statistical power at 90%, 60 patients in each group would be

Study Timeline

• Study First Submitted: 2022-09-21
• Study First Submitted QC: 2022-10-14
• Study First Posted: 2022-10-18
• Status Verified: 2024-04
• Last Update Submitted: 2024-04-22
• Last Update Posted: 2024-04-23
• Study Start: 2024-06
• Primary Completion: 2024-09
• Study Completion: 2026-06

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: Female
• Target Recruitment: 180

Inclusion Criteria

Patients must meet ALL of the following criteria to be included in the study:

1. Patients over 18 years of age
2. Who have a history of breast malignancy, and are on adjuvant or neoadjuvant treatment with hormone therapy.
3. That they suffer symptoms related to vulvo-vaginal atrophy and thus become evident to the gynecological examination (Vaginal Health Index<ó=15).
4. That this clinic significantly affects your quality of life ( score in Sexual Function-Vaginal Changes Questionnaire less than or equal to 24 points).
5. Who have not received any treatment for vulvo-vaginal atrophy in at least the previous 6 months. Purely moisturizing or emollient treatments that do not contain any regenerating substance (hyaluronic acid, gotu kola, vitamin E or rosehip oil) are not considered exclusive.
6. That they agree to participate and give their written I consent.

Exclusion Criteria

Patients who present ANY of the following criteria may not be selected to participate in this study:

1. Medical or surgical history that at the discretion of the researcher does not allow participation in the study.
2. Refusal to participate in the study and to sign consent.
3. Be on chemotherapy treatment at the time of inclusion in the study.
4. Have completely completed the adjuvant hormonal treatment.
5. Have a history of vulvar, vaginal and/or cervical malignancy.
6. Have received radiation therapy to the pelvic and/or genital region.
7. Sjögren's syndrome and other pathologies that occur with mucosal involvement.
8. Present any type of disease that occurs with alteration of collagenogenesis.
9. Intake of other cytotoxic drugs that lead to mucositis and alterations of tissue regeneration in the last 6 months.
10. Have previously received laser and/or radiofrequency treatment for the treatment of genital atrophy or other pelvic floor dysfunctions.
11. Active urinary and/or genital tract infection.
12. Diagnosis of gestation at the time of recruitment.
13. History of malignant neoplasm of the urinary tract.
14. Have severe stress urinary incontinence (Sandvik test with a score equal to or greater than 8)
15. Diagnosis of pelvic organ prolapse grade III or higher according to the POP-Q classification.
16. Any other condition which, in the opinion of the investigator, means that the patient is not in a position to understand the implication of participating in the study and/or of following the established procedures.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Laser + Regenerative topical treatment	C02 microablative laser	The treatments used in this arm are the following: 1. º Microfractionated laser treatment of C02, through the AcupulseDuo generator of the company Lumenis®. The treatment regimen would consist of three sessions in total with periodicity of 4 weeks, between the first and the second, and 6 weeks between the second and third. The application of laser energy will be carried out by vaginal and vulvar terminals. The dose applied will consist of monopulse shots distributed throughout the vaginal mucosa and vulvar skin of 10 mJ of energy and at a density of 10%. 2. nd Topical treatment: It consists of the application of XCM® intim of the company Mucosa Innovations. The route of administration would be vulvo-vaginal. The dose applied would be 2 ml of total product every 12 hours during 36 months.
Regenerative topical treatment	Regenerative topical treatment	In this arm, only the regenerative treatment of XCM® intim of the company Mucosa Innovations will be used. The route of administration would be vulvo-vaginal. The dose applied would be 2 ml of total product every 12 hours. The total duration of treatment would be 36 months.
Laser + Regenerative topical treatment	Regenerative topical treatment	The treatments used in this arm are the following: 1. º Microfractionated laser treatment of C02, through the AcupulseDuo generator of the company Lumenis®. The treatment regimen would consist of three sessions in total with periodicity of 4 weeks, between the first and the second, and 6 weeks between the second and third. The application of laser energy will be carried out by vaginal and vulvar terminals. The dose applied will consist of monopulse shots distributed throughout the vaginal mucosa and vulvar skin of 10 mJ of energy and at a density of 10%. 2. nd Topical treatment: It consists of the application of XCM® intim of the company Mucosa Innovations. The route of administration would be vulvo-vaginal. The dose applied would be 2 ml of total product every 12 hours during 36 months.
Laser treatment	C02 microablative laser	The treatments used in this arm are the following: 1. º Microfractionated laser treatment of C02, through the AcupulseDuo generator of the company Lumenis®. The treatment regimen would consist of three sessions in total with periodicity of 4 weeks, between the first and the second, and 6 weeks between the second and third. The application of laser energy will be carried out by vaginal and vulvar terminals. The dose applied will consist of monopulse shots distributed throughout the vaginal mucosa and vulvar skin of 10 mJ of energy and at a density of 10%. 2. ºPlacebo vulvo-vaginal topical gel, consisting of a watery base.

Primary Outcome Measures

Name	Time	Method
Presence of symptoms at the vulvovaginal level and their intensity	From prior consultation at the beginning of treatment to 24 months after it ends.	This group will include the following items: * Pain with sexual intercourse (dyspareunia).; * Feeling of vaginal stiffness.; * Dryness.; * Vulvar itching.; * Vulvar and/or vaginal burning.; * Urinary frequency (more than 8 times a day).; * Burning when urinating (dysuria). The way to measure the intensity of these symptoms will be through Visual Analog Scale Of Symptom Intensity, with absolute values ranging from 0 to 10.; We will consider improvement a reduction of 2 or more points in at least 50% of the items. Meeting only this item is already considered an efficacy criterion.
Impact in the quality of life of vulvo-vaginal symptoms.	From prior consultation at the beginning of treatment to 24 months after it ends.	The tool used will be the Sexual Function-Vaginal Changes Questionnaire. Scores equal to or less than 24 points will result in an impact on quality of life. A rise of 3 or more points is considered a significant improvement.; The severity levels of quality of life impairment will be as follows: * Mild (scores between 24 and 17); * Moderate (scores between 16 and 8); * Severe (scores between 7 and 1)
Number of capillaries in vaginal mucosa	From prior consultation at the beginning of treatment to 24 months after it ends.	The collection of samples will consist of taking biopsies of vaginal mucosa using a 4 mm punch as an instrument.; The immunohistochemical technique will be applied with antibodies against CD31 and a quantitative assessment of the number of capillaries / field of 40 increases will be carried out.
Changes in vulvar physical examination	From prior consultation at the beginning of treatment to 24 months after it ends.	We will use the following measurement system: Vulvar Health Index Score. It is based on the macroscopic inspection of the vulva performed through a colposcope. The scores range from 0 to 24, being higher to greater atrophy. It is considered a diagnosis of atrophy scores greater than 8 or having obtained 3 points in any of the items. The degrees of gravity are set as follows: 1. Between 9 and 14 points, mild; 2. Between 15 and 20 points, moderate; 3. Between 21 and 24 points, severe.; A reduction of 3 or more points in the overall score or at least one point will be considered a favorable response if there has been an item with a score of 3.
Quantification of cellular glycogen	From prior consultation at the beginning of treatment to 24 months after it ends.	The collection of the samples will consist of taking biopsies of vaginal mucosa using a 4 mm punch as an instrument.; The sample will undergo the Schiff technique (PAS) and the number of stained cells will be determined.
Amount of Candida spp in vaginal microbiota	From prior consultation at the beginning of treatment to 24 months after it ends.	It will be measured through microbiological study. Samples shall be obtained by vaginal exudate.; The measurements will be made by WERFEN system and PCR technique.
Changes in vaginal physical examination	From prior consultation at the beginning of treatment to 24 months after it ends.	We will use the following measurement systems: Vaginal Health Index Score. It is based on the macroscopic inspection of the vagina performed through a colposcope. Scores range from 5 to 25 points (scores equal to or less than 15 are considered diagnostic of atrophy). It is carried out by assessing different items related to exploratory findings.; We can categorize the scores into different degrees of severity of vulvo-vaginal atrophy objectified to the examination: 1. \>from 15 points, absence of atrophy; 2. Between 15 and 13 points, mild; 3. Between 12 and 9 points, moderate; 4. Between 8 and 5 points, severe; An increase of 2 or more points in the overall score will be considered a favourable response.
Thickness of the vaginal epithelium	From prior consultation at the beginning of treatment to 24 months after it ends.	The collection of the sample will consist of taking biopsy of vaginal mucosa using a 4 mm punch as an instrument.; Once obtained, the sample will be stained with hematoxylin-eosin and subjected to microscopic assessment.; The unit of measurement shall be in nanometers.
Amount of Lactobacillus in vaginal microbiota	From prior consultation at the beginning of treatment to 24 months after it ends.	It will be measured through microbiological study. Samples shall be obtained by vaginal exudate.; The measurements will be made by WERFEN system and PCR technique.
Amount of Gardnerella vaginalis in vaginal microbiota	From prior consultation at the beginning of treatment to 24 months after it ends.	It will be measured through microbiological study. Samples shall be obtained by vaginal exudate.; The measurements will be made by WERFEN system and PCR technique.
Free glycogen detection in vaginal discharge	From prior consultation at the beginning of treatment to 24 months after it ends.	It will be measured through microbiological study. Samples shall be obtained by vaginal exudate.; Free glycogen detection will be performed using a commercial kit.
Vaginal pH	From prior consultation at the beginning of treatment to 24 months after it ends.	It will be measured through microbiological study. Samples shall be obtained by vaginal exudate.
Skin elasticity	From prior consultation at the beginning of treatment to 24 months after it ends.	It will be performed with the Dual cutometer MPA 580 ® and will determine different characteristics of the vulvar skin.; The value will be given in the unit of measurement N / m².
Amount of transdermal water in the skin	From prior consultation at the beginning of treatment to 24 months after it ends.	It will be performed with the Dual cutometer MPA 580 ® and will determine different characteristics of the vulvar skin.; The value will be given in the unit of measurement g/h/m².
Skin pigmentation	From prior consultation at the beginning of treatment to 24 months after it ends.	It will be performed with the Dual cutometer MPA 580 ® and will determine different characteristics of the vulvar skin.; The degree of pigmentation of the skin will be determined based on the concentration of melanin.
Degree of vascularization of the skin	From prior consultation at the beginning of treatment to 24 months after it ends.	It will be performed with the Dual cutometer MPA 580 ® and will determine different characteristics of the vulvar skin.; To determine the degree of vascularization of the skin, specific wavelengths will be used, corresponding to the maximum level of spectral absorption of hemoglobin and avoiding other color influences (for example, bilirubin). The result corresponding will be immediately displayed in the form of index figures, on a scale of 0 - 999.

Secondary Outcome Measures

Name	Time	Method
Presence of urge urinary incontinence	From prior consultation at the beginning of treatment to 24 months after it ends.	The Sandvik Test will be used. It consists of 2 sections whose scores are multiplied. The range of scores goes from 0 to 12, with the only possible values being 0, 1, 2, 3, 4, 6, 8, 9 and 12. The degree of urinary incontinence shall be classified as follows: 0--\>Absence of incontinence 1-2--\>Mild urinary incontinence 3-6--\>Moderate urinary incontinence 8-9--\>Severe urinary incontinence 12--\>Very severe urinary incontinence
Presence of bladder hyperactivity clinic	From prior consultation at the beginning of treatment to 24 months after it ends.	The following questionnaires will be used: Bladder control self-assessment questionnaire.; This scale measures 2 items: Presence of symptoms and discomfort generated by them.; The range of values for each of them goes from 0 to 12, with the severity levels being the following in both cases: 0--\>Absence of symptoms/discomfort. 1-3--\>Mild symptoms/discomfort. 4-6--\>Moderate symptoms/discomfort. 7-9--\>Severe symptoms/discomfort. 10-12--\>Very serious symptoms/discomfort.
Impact of urinary incontinence on quality of life	From prior consultation at the beginning of treatment to 24 months after it ends.	We will use the International Consultation on Incontinence Questionnaire-Short Form.; Of this scale we will only use in section that measures the degree of discomfort caused by incontinence and that reaches the values of 1 to 10.