Aqua Therapeutics Thermal Therapy Vapor Ablation System (ATTTVAS) Abnormal Uterine Bleeding Safety Study

A Pre-Market, First-In-Human, Pilot, Interventional, Clinical Investigation to Evaluate the Safety of the Aqua Therapeutics Thermal Therapy Vapor Ablation System (ATTTVAS) in Premenopausal Women With Abnormal Uterine Bleeding (AUB).

Abnormal uterine bleeding (AUB) is defined as "flow outside of normal volume, duration, regularity, or frequency". Acute AUB is excessive bleeding that requires immediate intervention to prevent further blood loss. Chronic AUB refers to irregularities in menstrual bleeding for most of the previous 6 months. AUB can be frequent or infrequent, prolonged, irregular, or heavy. Heavy menstrual bleeding (HMB) is defined as "excessive menstrual blood loss which interferes with a woman's physical, social, emotional and/or material quality of life". Causes of AUB are classified as polyps, adenomyosis, leiomyomas (AUB-L), malignancy and premalignant conditions, coagulopathy, ovulatory disorders (AUB-O), endometrial disorders (AUB-E), iatrogenic, and ''not classified'' . AUB affects approximately one in four women between 30 and 50 years of age, with serious implications on woman's quality of life (QoL). Endometrial ablation (EA) is a uterus-preserving procedure that aims to destroy or remove the endometrial tissue in selected women who have no desire for future fertility. EA has become an alternative to hysterectomy in the treatment of AUB because it is less invasive and has a shorter recovery period. At present, many different techniques are available to remove the endometrial tissue. Resectoscopic endometrial ablation (REA) consists of targeted endometrial destruction under direct hysteroscopic visualization. REA techniques include endometrial laser ablation, transcervical resection of the endometrium, and rollerball endometrial ablation. Non-resectoscopic endometrial ablation (NREA) uses a variety of energy sources to non-selectively destroy the endometrial lining and include thermal balloon endometrial ablation, microwave endometrial ablation, hydrothermal ablation, bipolar radiofrequency endometrial ablation, endometrial cryotherapy, and more recently vapor endometrial ablation. NREA technologies require short surgical time and can also be performed in the outpatient setting. Vapor EA is one of the newest approaches in the field. In this context, the Aqua Therapeutics Thermal Therapy Vapor Ablation system (ATTTVAS; AQUA Therapeutics Inc.) is a novel system designed to ablate uterine tissue using vapor thermal therapy technology.

The ATTTVAS is indicated to ablate the endometrial lining of the uterus in premenopausal women with abnormal uterine bleeding (AUB) due to benign causes for whom childbearing is complete. In this Pre-Market, First-In-Human, Pilot, Interventional, Clinical Investigation we aim to evaluate the Safety of the Aqua Therapeutics Thermal Therapy Vapor Ablation System (ATTTVAS) in premenopausal women with AUB.

The Aqua Therapeutics Thermal Therapy Vapor Ablation System (ATTTVAS) is a system designed to ablate uterine tissue by vapor thermal therapy technology. The ATTTVAS consists of a reusable Generator, a DISPOSABLE APPLICATOR, a DISPOSABLE CATHETER and a SYRINGE.

The ATTTVAS is intended for outpatient use although it can easily be utilized in both a surgery centre and the operating room as well. This is a Pre-Market, First-In-Human, Pilot, Interventional, Clinical Investigation to Evaluate the Safety of the Aqua Therapeutics Thermal Therapy Vapor Ablation System (ATTTVAS) in premenopausal women with AUB. For each patient, a total of 6 visits (5 on-site and 1 remote) will be planned according to the flowchart. Unscheduled visit(s) will be planned on-site according to Principal Investigator judgement. Each Subject, after signing the Informed Consent Form (ICF), will enter a screening phase (V-1) during which several assessments (e.g., demographics, medical history, current menstrual condition, blood analysis) will be conducted. At the screening visit, patients will receive a menstrual calendar and a PBAC to be completed. The PBAC score must be recorded as soon as available to confirm that the patient can be enrolled at baseline (PBAC must be ≥150). The PBAC score will also be recorded at the End of Study (EOS) visit. At baseline (V0) and at EOS, on site, patients will also complete the Menorrhagia Impact Questionnaire (MIQ). If the Investigator can complete all the assessments foreseen at baseline visit (V0) and V1-EA in one day, V0 and V1 may coincide. At V1, enrolled Subjects will undergo EA with the ATTTVAS. EA must be performed within 15-20 days from the beginning of the menstrual cycle. EA cannot be performed in the presence of heavy menstrual bleeding, but it can be performed in the presence of light bleeding/spotting. Sedation will be performed before the EA by intravenous administration of propofol and fentanyl. The duration (seconds) of the ablation cycle will be recorded on the CRF. After the procedure is completed, the PI will fill a questionnaire on procedural ease of use. Device deficiencies (if any) will be recorded. At discharge, after 24 hours and 1 week from discharge, patients will be asked to rate pain intensity on a Numeric Rating Scale (NRS). At discharge patients will receive a diary to record AEs and concomitant medications through the study period. Follow-up visits will be performed after 1 week and 6 weeks from discharge. Satisfaction with the procedure will be evaluated using a 5-Likert Scale (completed by patient and PI) at discharge and at EOS. Physical examination, monitoring of vital signs and AEs will be performed at each applicable visit. Current menstrual condition will be monitored during the entire study period. To evaluate the need for surgical or medical intervention to treat AUB after EA, any surgical or medical intervention required to treat AUB after EA will be recorded during the study. An Interim Analysis was performed on the clinical data collected from V-1 to EOS (included) for the first 5 patients enrolled. The primary aim of the interim analysis was to evaluate the safety of the medical device. During the interim analysis, the enrollment of patients stopped. The results of the interim analysis were submitted to the Ethic Committee (EC) and Competent Authority (CA). Based on the interim analysis results and, after EC/CA feedback, the study activities could continue as planned.

Inclusion Criteria:

1. Signed patient informed consent form (ICF).
2. Females aged ≥ 30 years and ≤ 55 years at baseline with no desire to conceive, with or without simple endometrial hyperplasia (without atypia).
3. Diagnosis of AUB.
4. Premenopausal (follicle-stimulating hormone level ≤ 40 mIU/mL), women who don't want to receive hormonal treatment or who have failed to respond to hormonal treatment.
5. Pictorial Blood Loss Assessment Chart (PBAC) score ≥150 at baseline.
6. Normal endometrial biopsy.
7. Negative PAP test.
8. Willingness to follow all study procedures, including attending all site visits, tests, and examinations.

Exclusion Criteria:

1. BMI ≥35
2. Postmenopausal status.
3. Undiagnosed vaginal bleeding.
4. A patient with a history of a prior completed endometrial ablation procedure and/or endometrial resection (including endometrial ablation/resection performed immediately prior to the ATTTVAS Ablation Treatment) regardless of the modality by which it was performed.
5. Previous uterine surgery.
6. Not willing to avoid the use of vaginal ring, hormonal intrauterine device (concomitant IUD such as Essure is not allowed prior to the ATTTVAS Ablation Treatment), oral contraceptives during the study period.
7. Pregnant or breastfeeding.
8. Less than 1-year post-partum.
9. Any contraindication to endometrial ablation.
10. History of previous classical cesarean section or transmural myomectomy, including hysteroscopic and/or laparoscopic myomectomy performed immediately prior to the ATTTVAS Ablation Treatment.
11. Confirmed pelvic inflammatory disease, active/acute endometritis, sexually transmitted disease, bacteremia, sepsis, other active local and/or systemic infection.
12. Active genital or urinary tract infection (e.g., cervicitis, vaginitis, endometritis, salpingitis or cystitis) at the time of treatment.
13. Congenital malformations of the female genital tract.
14. Subjects with suspected or known coagulopathies or receiving anticoagulation therapy.
15. A patient currently on medications that could thin the myometrial muscle, such as long-term steroid use (except for inhaler or nasal therapy for asthma).
16. Documented cervical dysplasia, complex or atypical endometrial hyperplasia, abdominal or pelvic cancer.
17. Presence of any relevant severe condition or clinically relevant abnormal laboratory parameters that in the opinion of the Investigator may interfere with the participation to the study.
18. Presence of any relevant severe organic, systemic, or metabolic disease (particularly significant history of cardiac, renal, neurological, psychiatric, oncology, endocrinology, metabolic or hepatic disease), or abnormal laboratory values that will be deemed clinically significant in Investigator's opinion.
19. Active malignant neoplasm of any type, or history of a malignancy (patients with a history of other malignancies that have been surgically removed and who have no evidence of recurrence for at least five years before study enrollment are also acceptable).
20. Participation in another investigational study within the previous 30 days.
21. Recent history or suspicion of alcohol abuse or drug addiction.
22. Inability to follow study procedures.
23. History of allergic reactions to propofol and/or fentanyl.