Clinical trial NCT05000957: Pelvic Organs Prolapse Treatment Using Neodymium Laser
Official title: Low Intensity Nanosecond Neodymium Laser for Complex Treatment of Pelvic Organs Prolapse
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Pelvic Organ Prolapse
Female Urogenital Diseases
Keywords: Pelvic Organ Prolapse
Colporrhaphy
Neodymium Laser
Laser Treatment
Nanosecond
Laser
Vaginal
Female Urogenital Diseases
Lead sponsor: MeLSyTech, Ltd
Sponsor class: INDUSTRY
First posted: 2021-08-11
Enrollment: 129
Sex: FEMALE
Minimum age (years): 35
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The aim of this prospective study is investigation of efficiency and safety of medical device "Magic Max" ("Magic Gyno" from August 2024) for preoperative treatment of pelvic organs prolapse I-II degree of severity. To assess the condition of the vaginal walls and vulva before and after laser treatment, the following methods will be used: ultrasonography with Doppler ultrasonography, vaginal health index, histological examination, immunohistochemical examination, optical coherence tomography (OCT) (elastography). Pelvic Floor Distress Inventory Questionnaire (PFDI-20), The Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12), International Consultation on Incontinence Questionnaire - Short Form (ICIQ-SF), Pelvic Floor Impact Questionnaire (PFIQ-7) will be used to collect feedback on changes in the participants life quality. Genetic testing of 12 gene variants will be carried out. Correlation of genes variants and treatment efficacy will be assessed. Total up to 135 participants with pelvic organs prolapse I-II degree of severity, or any other pathology of pelvic organs, which require surgical intervention will be involved in the study. Participants will be divided into three groups: group with anterior and/or posterior (A/P) colporrhaphy and laser preoperative treatment (laser treatment group), group with A/P colporrhaphy only (control group 1), and group with any other surgical intervention of pelvic area (control group 2), by 45 participants in each. The time intervals between tests will be the same for groups with A/P colporrhaphy, group with any other surgical intervention will be examined before and on the day of surgery without further observation. The main hypothesis of the study is improvement in condition of the vaginal walls after laser preoperative treatment compared with the control group 1.

Detailed description: The principle of participant distribution into groups is the type of surgical intervention and preoperative preparation. Total up to 135 participants with pelvic organs prolapse I-II degree of severity, or any other pathology of pelvic organs, which require surgical intervention will be involved in the study. Participants will be divided into three groups: group with anterior and/or posterior (A/P) colporrhaphy and laser preoperative treatment (laser treatment group), group with A/P colporrhaphy only (control group 1), and group with any other surgical intervention of pelvic area with obtaining a biopsy of the vaginal wall (control group 2), by 45 participants in each group.

The types of examination of each group are the same and include:

General methods: physical examination, clinical blood analysis including glucose determination, clinical urine test, vaginal smear for flora and oncocytology, pelvic ultrasound, tests for hepatitis B, C viruses, human immunodeficiency viruses and syphilis, blood clotting tests, blood type and rhesus factor determination, electrocardiography, colposcopy, consultation of a therapist about the absence of contraindications for surgical treatment.

Special methods: filling out the questionnaire (Pelvic Floor Distress Inventory Questionnaire, The Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire, International Consultation on Incontinence Questionnaire - Short Form, Pelvic Floor Impact Questionnaire), Vaginal Health Index determination, Doppler ultrasonography of vagina, histological examination, immunohistochemical examination, optical coherence tomography (OCT) (elastography).

The treatment procedure of this study is the laser treatment of the vagina and vulva with a "Magic Max" laser ("Magic Gyno" from August 2024) with subsequent monitoring.

Genetic testing: genetic testing for the following markers will be carried out:

ESR1 rs2234693 (estrogen receptor 1), ESR1 rs2228480 (estrogen receptor 1), COL3A1 rs1800255 (collagen type III alpha 1 chain), COL14A1 rs4870723 (collagen type XIV alpha 1 chain), MMP9 rs3918253 (matrix metallopeptidase 9), MMP10 rs17435959 (matrix metallopeptidase 10), LOXL1 rs2304719 (lysyl oxidase like 1), WNT4 rs3820282 (Wnt family member 4), MMP2 rs243865 (matrix metalloproteinase type 2), TIMP2 rs2277698 (tissue inhibitor of metalloproteinase-2), CD31 / PECAM1 rs1131012 (platelet-endothelial cell adhesion molecule 1), Ki67 rs11016076 (proliferation marker Ki67).

Treatment Technique:

Laser treatment procedure will be carried out in three stages. In total, three procedures will be performed with an interval of 4 weeks. Colporrhaphy will be carried out 1 month after last treatment. Three follow-up visits will follow: 1, 6 and 12 months after colporrhaphy.

During the procedure, the following sequence of actions will be performed:

1. st Stage - vaginal processing with a conical mirror handpiece,
2. nd Stage - vaginal processing with a corner mirror handpiece,
3. rd Stage - external vulva and paraurethral region processing with a switched beam diameter handpiece.

Laser radiation is emitted by a series of pulses following each other through a pause. The duration of one pulse is 20-200 nanoseconds (ns), the pause between pulses is 30 microseconds (us). The energy of one pulse is about 1.5 millijoule (mJ). The procedure is performed without anesthesia. The doctor always focuses on the participant's feeling of warmth.

Participants of all groups will be tested with the general methods necessary to include the participant in the study at the first visit.

Control Technique:

In the control groups general surgery preparation protocol (sanitation of vagina) will be used as a therapeutic tool. After completing of preparation course, the operation will be performed.

Operation technique:

A part of the stretched vaginal wall in the posterior fornix area including the mucous membrane and muscle layer will be excised with its further suturing during colporrhaphy surgery (the excised material will be examined). This will allow comparing the vaginal walls state at the time of surgery after laser treatment and without it, and with the age norm.

Participants of all groups will be tested with the general methods necessary to include the patient in the study at the first visit.

For the laser treatment group: Studies will be carried out using filling out the questionnaires, Vaginal Health Index determination, and Doppler ultrasonography, and then laser treatment of the vagina, vulva and paraurethral region will be performed during the 2nd, 3d, and 4th visits. Filling out the questionnaires, Vaginal Health Index determination, and Doppler ultrasonography will be repeated during the 5th visit (1 month after last laser treatment and 1 day before colporrhaphy). Vaginal biopsy for histological examination, immunohistochemical examination, and optical coherence tomography (elastography) will be carried out during A/P colporrhaphy in the 6th visit. Physical examination only will be carried out during the 7th (follow-up) visit - 1 month after colporrhaphy. Filling out the questionnaires, Vaginal Health Index determination, and Doppler ultrasonography will be carried out during 8th and 9th (follow-up) visits - 6 and 12 months after colporrhaphy.

For control group 1: Studies will be carried out using filling out the questionnaires, Vaginal Health Index determination, and Doppler ultrasonography during the 1st visit after including patient. Vaginal biopsy for histological examination, immunohistochemical examination, and optical coherence tomography (elastography) will be carried out during A/P colporrhaphy in the 2nd visit. Physical examination only will be carried out during the 3th (follow-up) visit - 1 month after colporrhaphy. Filling out the questionnaire, Vaginal Health Index determination, and Doppler ultrasonography will be carried out during 4th and 5th (follow-up) visits - 6 and 12 months after colporrhaphy. Buccal smear collection will be carried out during 4th follow up visit (6 months after colporrhaphy).

Thus, a direct comparison between laser preoperational treatment and lack of preoperational treatment will be made during the investigation, 6 and 12 months after the end of each type of treatment.

For control group 2: Studies will be carried out using filling out the questionnaires, Vaginal Health Index determination, and Doppler ultrasonography during the 1st visit after including participant. Vaginal biopsy for histological examination, immunohistochemical examination, and optical coherence tomography (elastography) will be carried out during A/P colporrhaphy in the 2nd visit (no more than 1 month after 1st visit). The obtained data will allow to study the tissues of the vaginal wall in normal conditions.

The study will be carried out with the participation of several clinics:

(recruting, filling out IRC - Individual Registration Cards, buccal smear collection) (colporrhaphy and biopsy)

1. Privolzhsky Research Medical University (main scientific coordinator, histological examination, immunohistochemical examination, and optical coherence tomography (elastography)), genetic examination,
2. LLC "Medical Center" AIST "" (location of laser equipment, recruiting, filling out IRC - Individual Registration Cards laser treatment, special tests, buccal smear collection),
3. State Budgetary Institution of Health Care of the Nizhny Novgorod Region "Nizhny Novgorod Regional Clinical Oncological Dispensary" (colporrhaphy and biopsy, buccal smear collection),
4. Clinic "Preventamed", LLC "Aesthetic Medicine" (recruting, filling out IRC - Individual Registration Cards, buccal smear collection),
5. State-Funded Healthcare Institution of the Nizhny Novgorod region "Nizhny Novgorod Regional Clinical Hospital named after N.A. Semashko" (recruting, filling out IRC - Individual Registration Cards, buccal smear collection),
6. Birth house №4 of the Leninskiy District of Nizhny Novgorod named after A.F. Dobrotina (colporrhaphy and biopsy) All data obtained during the study will be transferred to the manufacturer of laser equipment "MeLSyTech" Ltd.

The study will be monitored by "MeLSyTech" Ltd as follows:

* Once a month, monitoring of provided documents (copies of individual registration records of participants, informed consent, test results) for the complete filling of the forms; the clarity of filling out forms, the possibility of systematizing information from the forms of their assessment;
* Once every six months, monitoring will be conducted with a coordinator visit of the research center and analysis activities, such as participants recruitment, data collection, data management, data analysis, reporting for adverse events, and change management;
* Once a year, the investigator submits a clinical evaluation report to the sponsor.

Statistics

The analysis will be carried out both between groups of participants receiving different types of therapy (analysis of independent groups) and within groups at different time intervals (analysis of matched groups).

Before performing statistical analysis of the data, the distribution type of the variables will be assessed. To assess the normality of distribution for each variable, histograms of frequency distributions will be visually evaluated, indicators of skewness, kurtosis, and the D'Agostino-Pearson normality test will be used.

In addition to checking the type of distribution of variables, the equality of variances of the studied groups will be assessed using the methods of analysis of variance, in particular the Brown-Forsythe test.

Methods of descriptive analysis will be used depending on the type of distribution of the variable. With a normal distribution, the mean (M) and standard deviation (SD) will be calculated. In case of an nongaussian distribution, the median (Me) and interquartile range will be calculated. Different algorithms of statistical analysis will be applied depending on the type of distribution of variables.

Comparison of the paired and unpaired groups with a normal distribution, in case of the equality of the variances, will be carried out by the methods of analysis of variance ANOVA. Comparison of groups in pairs will be performed using the post-hoc method of posterior multiple comparisons (Tukey test).

Comparison of groups in which variables do not follow the normal distribution will be carried out using the methods of nonparametric analysis of variations: the Kruskal-Wallis test (ANOVA tests) for independent groups and the Friedman test for matched groups. Dunn's multiple comparison test will be used to assess intergroup differences.

Before assessing intergroup differences, the initial samples (1 visit) will be analyzed for identity using ANOVA or nonparametric Kruskal-Wallis tests (depending on the type of data). In case of significant differences in the samples, the search and removal of extremely deviating values (outliers) will be carried out.

Differences will be considered statistically significant if the significance P values are \<0.05.

Eligibility criteria: Inclusion Criteria:

* Age 35-50 years old;
* Participants diagnosed with pelvic organ prolapse of I-II degree of severity or any non vaginal diseases which require surgical intervention by the method of laparotomy;
* Participants were examined according to the proposed protocol;
* Participants who signed informed consent and fully informed about the purpose of the study.

Exclusion Criteria:

* Age of under 35 and over 50 years old;
* History of oncological diseases;
* Active tuberculosis;
* Inflammatory diseases of the vulva and vagina including genital herpes in the acute stage;
* Urinary tract infections;
* Damage to the vaginal mucosa;
* Pregnancy;
* Tendency to photoallergy including taking photosensitizing drugs (diuretics, antihistamines, antipsychotics);
* Porphyria;
* Cardiac deficiency of 2-3 degrees;
* Chronic renal disease;
* Diabetes mellitus (type I, II);
* Participants with greater than 2nd grade vaginal prolapse;
* Women after childbirth up to 8 weeks;
* Participants who, according to the doctor, are not able to complete the study;
* Protocol non-compliance of laser exposure sessions;
* Voluntary refusal to participate in the study;
* Violation of recommendations for the management of the period after laser treatment;
* Adverse events that occurred during laser processing and research, and associated with them.
* The occurrence of adverse events or other symptoms that are contraindications to laser procedures, as well as the occurrence of cases described in the exclusion criteria.

Primary outcomes:
measure: Mean Difference from Control Groups of Collagen Fibers Thickness in Vaginal Wall
timeFrame: day of colporrhaphy or any surgery (laser treatment group: 1 month after last laser treatment - visit 6, control groups - no more than a month after the participant was included in the study - visit 2).
measure: Mean Difference from Control Groups of Collagen Fibers Length in Vaginal Wall
timeFrame: day of colporrhaphy or any surgery (laser treatment group: 1 month after last laser treatment - visit 6, control groups - no more than a month after the participant was included in the study - visit 2).
measure: Mean Difference from Control Groups of Thickness of the Vaginal Wall
timeFrame: day of colporrhaphy or any surgery (laser treatment group: 1 month after last laser treatment - visit 6, control groups - no more than a month after the participant was included in the study - visit 2).
Secondary outcomes:
measure: Mean Change from Baseline of Artery Perfusion Index
timeFrame: before any intervention: laser treatment, colporrhaphy, or any surgery; before colporrhaphy - 1 month after last laser treatment (for laser treatment group); 6 and 12 months after any colporrhaphy or any surgery.
measure: Mean Difference from Control Groups of Number of Fibroblasts in Vaginal Wall
timeFrame: day of colporrhaphy or any surgery (laser treatment group: 1 month after last laser treatment - visit 6, control groups - no more than a month after the participant was included in the study - visit 2).
Other outcomes:
measure: Mean Change from Baseline of Thickness of the Vaginal Wall
timeFrame: before any intervention: laser treatment, colporrhaphy, or any surgery; before colporrhaphy - 1 month after last laser treatment (for laser treatment group); 6 and 12 months after any colporrhaphy or any surgery.
measure: Mean Change from Baseline of Pulsatility Index of Uterine Arteries
timeFrame: before any intervention: laser treatment, colporrhaphy, or any surgery; before colporrhaphy - 1 month after last laser treatment (for laser treatment group); 6 and 12 months after any colporrhaphy or any surgery.
measure: Mean Change from Baseline of Volumetric Blood Flow of Uterine Arteries
timeFrame: before any intervention: laser treatment, colporrhaphy, or any surgery; before colporrhaphy - 1 month after last laser treatment (for laser treatment group); 6 and 12 months after any colporrhaphy or any surgery.
measure: Mean Change from Baseline of Resistive Index of Uterine Arteries
timeFrame: before any intervention: laser treatment, colporrhaphy, or any surgery; before colporrhaphy - 1 month after last laser treatment (for laser treatment group); 6 and 12 months after any colporrhaphy or any surgery.
measure: Mean Change from Baseline of Vaginal Health Index Score
timeFrame: before any intervention: laser treatment, colporrhaphy, or any surgery; before colporrhaphy - 1 month after last laser treatment (for laser treatment group); 6 and 12 moths after any colporrhaphy or any surgery.
measure: Mean Difference from Control Groups of Vascular Density in Vaginal Wall
timeFrame: day of colporrhaphy or any surgery (laser treatment group: 1 month after last laser treatment - visit 6, control groups - no more than a month after the participant was included in the study - visit 2).
measure: Mean Difference from Control Groups of Matrix Metalloproteinase-2 (MMP-2) Percentage in the Vaginal Wall
timeFrame: day of colporrhaphy or any surgery (laser treatment group: 1 month after last laser treatment - visit 6, control groups - no more than a month after the participant was included in the study - visit 2).
measure: Mean Difference from Control Groups of Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) Percentage in the Vaginal Wall
timeFrame: day of colporrhaphy or any surgery (laser treatment group: 1 month after last laser treatment - visit 6, control groups - no more than a month after the participant was included in the study - visit 2).
measure: Mean Difference from Control Groups of Cluster of Differentiation 31 (CD 31+) Percentage in the Vaginal Wall
timeFrame: day of colporrhaphy or any surgery (laser treatment group: 1 month after last laser treatment - visit 6, control groups - no more than a month after the participant was included in the study - visit 2).
measure: Mean Difference from Control Groups of Marker of Proliferating Cells (Ki 67) Percentage in the Vaginal Wall
timeFrame: day of colporrhaphy or any surgery (laser treatment group: 1 month after last laser treatment - visit 6, control groups - no more than a month after the participant was included in the study - visit 2).
measure: Mean Difference from Control Groups of Stiffness of Vaginal Wall
timeFrame: day of colporrhaphy or any surgery (laser treatment group: 1 month after last laser treatment - visit 6, control groups - no more than a month after the participant was included in the study - visit 2).
measure: Mean Change from Baseline of "Sexual Function in Women with Urinary Incontinence and/or Pelvic Organ Prolapse" Score on Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire
timeFrame: before any intervention: laser treatment, colporrhaphy, or any surgery; before colporrhaphy - 1 month after last laser treatment (for laser treatment group); 6 and 12 months after any colporrhaphy or any surgery.
measure: Mean Change from Baseline of Total Score on International Consultation on Incontinence Questionnaire - Short Form
timeFrame: before any intervention: laser treatment, colporrhaphy, or any surgery; before colporrhaphy - 1 month after last laser treatment (for laser treatment group); 6 and 12 months after any colporrhaphy or any surgery.
measure: Mean Change from Baseline of "Pelvic Organ Prolapse Distress Inventory" on Pelvic Floor Distress Inventory Questionnaire
timeFrame: before any intervention: laser treatment, colporrhaphy, or any surgery; before colporrhaphy - 1 month after last laser treatment (for laser treatment group); 6 and 12 months after any colporrhaphy or any surgery.
measure: Mean Change from Baseline of "Colorectal-Anal Distress Inventory" on Pelvic Floor Distress Inventory Questionnaire
timeFrame: before any intervention: laser treatment, colporrhaphy, or any surgery; before colporrhaphy - 1 month after last laser treatment (for laser treatment group); 6 and 12 months after any colporrhaphy or any surgery.
measure: Mean Change from Baseline of "Urinary Distress Inventory" on Pelvic Floor Distress Inventory Questionnaire
timeFrame: before any intervention: laser treatment, colporrhaphy, or any surgery; before colporrhaphy - 1 month after last laser treatment (for laser treatment group); 6 and 12 months after any colporrhaphy or any surgery.
measure: Mean Change from Baseline of "Bladder or Urine" on Pelvic Floor Distress Inventory Questionnaire
timeFrame: before any intervention: laser treatment, colporrhaphy, or any surgery; before colporrhaphy - 1 month after last laser treatment (for laser treatment group); 6 and 12 months after any colporrhaphy or any surgery.
measure: Mean Change from Baseline of "Bowel or Rectum" on Pelvic Floor Distress Inventory Questionnaire
timeFrame: before any intervention: laser treatment, colporrhaphy, or any surgery; before colporrhaphy - 1 month after last laser treatment (for laser treatment group); 6 and 12 months after any colporrhaphy or any surgery.
measure: Mean Change from Baseline of "Vagina or Pelvis" on Pelvic Floor Distress Inventory Questionnaire
timeFrame: before any intervention: laser treatment, colporrhaphy, or any surgery; before colporrhaphy - 1 month after last laser treatment (for laser treatment group); 6 and 12 months after any colporrhaphy or any surgery.
measure: Association of Marker COL3A1 rs1800255 with Changes of Collagen Fibers
timeFrame: 6 months after colporrhaphy.
measure: Association of Marker COL14A1 rs4870723 with Changes of Collagen Fibers
timeFrame: 6 months after colporrhaphy.
measure: Association of Marker ESR1 rs2234693 with Changes of Collagen Fibers
timeFrame: 6 months after colporrhaphy.
measure: Association of Marker ESR1 rs2228480 with Changes of Collagen Fibers
timeFrame: 6 months after colporrhaphy.
measure: Association of Marker MMP9 rs3918253 with Changes of Collagen Fibers
timeFrame: 6 months after colporrhaphy.
measure: Association of Marker MMP10 rs17435959 with Changes of Collagen Fibers
timeFrame: 6 months after colporrhaphy.
measure: Association of Marker LOXL1 rs2304719 with Vascular Density in Vaginal Wall
timeFrame: 6 months after colporrhaphy.
measure: Association of Marker LOXL1 rs2304719 with Stiffness of Vaginal Wall
timeFrame: 6 months after colporrhaphy.
measure: Association of Marker WNT4 rs3820282 with Changes of Collagen Fibers
timeFrame: 6 months after colporrhaphy.
measure: Association of Marker MMP2 rs243865 with Changes in Expression Level of MMP2
timeFrame: 6 months after colporrhaphy.
measure: Association of Marker TIMP2 rs2277698 with Changes in Expression Level of TIMP2
timeFrame: 6 months after colporrhaphy.
measure: Association of Marker CD31 / PECAM1 rs1131012 with Changes in Expression Level of CD31+
timeFrame: 6 months after colporrhaphy.
measure: Association of Marker Ki67 rs11016076 with Changes in Expression Level of Ki67
timeFrame: 6 months after colporrhaphy.
Locations:
city: Nizhny Novgorod
country: Russian Federation
facility: Federal State Budgetary Educational Institution of Higher Education "Privolzhsky Research Medical University" of the Ministry of Health of the Russian Federation
Study officials:
affiliation: Privolzhsky Research Medical University
name: Gennadij O Grechkanev, M.D.
role: PRINCIPAL_INVESTIGATOR
References: