Patient selection
This study is a prospective, non-randomized, single-arm, multicenter controlled trial using independent core laboratory validation of MRI results. Patients were enrolled from a total of seven sites in three nations: Mexico (one site), The United Kingdom (two sites), and The Netherlands (four sites). The protocol was approved by the Ethics Committees of the respective institutions as well as by the Federal Commission for Protection against Health Risks (COFEPRIS) in Mexico. All enrolled patients provided written informed consent for treatment with the VizAblate System prior to enrollment. The study overview was published on ClinicalTrials.gov (identifier—NCT01226290) and conducted in accordance with Standard ISO 14155 (Clinical investigation of medical devices for human subjects—Good clinical practice) of the International Organization for Standardization (ISO), the Helsinki Declaration of 1975, as revised in 2008, and in accordance with the ethical standards of applicable national regulations and institutional research policies and procedures governing human experimentation.
Women were eligible for inclusion if they were 28 years of age or older and not pregnant, with regular predictable menstrual cycles and abnormal uterine bleeding for at least 3 months associated with one to five uterine fibroids measuring between 1 and 5 cm in maximum diameter. Fibroids were counted in this total if they had an edge within the inner half of the myometrium; these were termed “target fibroids,” as they are believed to be more likely associated with heavy menstrual bleeding than myomata that are distant from the endometrial cavity. Target fibroids, which therefore were the only fibroids to be ablated, consisted of fibroids of FIGO types 1, 2, 3, 4, and 2–5 (“transmural”). At least one fibroid was required to indent the endometrium, as determined via hysterosonography and/or hysteroscopy and corroborated via contrast-enhanced MRI. All MRI studies were forwarded to a core laboratory (MedQIA, 924 Westwood Blvd., Suite 650, Los Angeles, CA 90024, USA) for quality control and interpretation to reduce variability in the measurements; the core laboratory also developed standardized imaging protocols for use at the individual study sites, credentialed the sites, and trained MRI technologists at each study site. A Menstrual Pictogram score ≥120 was required for inclusion along with a baseline UFS-QOL SSS score ≥20. The Menstrual Pictogram is a variant of the Pictorial Blood Loss Assessment Chart (PBAC) that patients complete to provide a visual assessment of menstrual blood loss during a single cycle [14, 15]. Unlike the original PBAC described by Higham and colleagues, the Menstrual Pictogram includes a greater range of icons representing different saturations of sanitary products, clots and losses in a toilet, and also distinguishes different absorbency levels of sanitary napkins and tampons [16].
Patients were willing to maintain the use or non-use of hormonal contraception from 3 months prior to the study through the 12-month follow-up period. Exclusions included a desire for future fertility, the presence of one or more type 0 myomata, cervical dysplasia, endometrial hyperplasia, active pelvic infection, clinically significant adenomyosis (>10 % of the junctional zone measuring more than 10 mm in thickness as measured by MRI), and the presence of one or more treatable fibroids that were significantly calcified (defined as <75 % fibroid enhancement by volume on contrast-enhanced MRI). Each patient underwent screening that included transvaginal sonography, hysteroscopy or hysterosonography, contrast-enhanced MRI, endometrial biopsy, and a pregnancy test.
Patients were assigned a unique identification number at the time that they provided informed consent for study screening. Patients were considered “enrolled” in the study once adherence with all inclusion and exclusion criteria had been verified and documented. All records were de-identified and only the range of each patient’s age was documented, as per clinical trial requirements in The Netherlands. Women were followed at 7–14 days, 30 days, 3 months, 6 months, and at 12 months post-treatment.
The primary study endpoint was the percentage change in target fibroid perfused volume as assessed by contrast-enhanced MRI at baseline and again at 3 months. The patient success criterion was >30 % reduction in mean target fibroid perfused volume at 3 months in at least 50 % of patients.
Additional endpoints, reached at 6 months, included safety, percentage reductions in the Menstrual Pictogram (MP) score and the Symptom Severity Score (SSS) subscale of the Uterine Fibroid Symptom-Quality of Life questionnaire (UFS-QOL), the rate of surgical reintervention for abnormal uterine bleeding, and the mean number of days to return to normal activity. While there is no absolute level below which the SSS would be considered as “within normal limits,” a population of 29 healthy women without uterine fibroids was demonstrated by Spies and colleagues to have an average SSS of 22.5 ± 22.1 [17]. Additional assessments included the Health-Related Quality of Life (HRQOL) subscale of the UFS-QOL, medical reintervention for menorrhagia, and procedure times (as recorded from the start of transvaginal sonography to the end of RF ablation). Lower scores on the SSS subscale are desirable; conversely, higher scores on the HRQOL subscale are preferable. For the SSS, a 10-point reduction in the score is generally considered clinically significant [17–19].
Statistical analysis
The null hypothesis for this study endpoint is H0: probability of success <50 % versus the alternative Ha: probability of success ≥50 %. Thus, the lower bound of the two-sided 95 % confidence interval on the observed probability of success must be greater than or equal to 50 %. We anticipated that at least 90 % of the patients would remain in the set of patients who were not excluded from analysis, and that the true probability of success for included patients would be 72.0 %. If this is the case, a sample of 40 patients is sufficient to detect this difference of 22 % in probability of success with a power of 82 % using a one-group chi-square test with a 0.05 two-sided significance level. Allowing for an expected dropout rate of 20 % at the 12-month follow-up visit, the minimum recommended sample size for the initial study protocol was 48. The primary study endpoint success criterion was achievement of >30 % reduction in mean target fibroid perfused volume in at least 50 % of patients. The primary endpoint analysis is performed on a per-fibroid basis, rather than using a subjective “dominant fibroid” in a given patient who could have multiple similar fibroids that were ablated.
The Full Analysis dataset includes all patients enrolled under the protocol who provided a baseline fibroid volume assessment and received treatment with the VizAblate System. The Per-Protocol dataset includes all patients enrolled under the protocol who received treatment with the VizAblate System and provided both a baseline fibroid volume assessment and a 3-month assessment and/or who received a surgical reintervention. Patients who received a surgical reintervention were considered treatment failures. Any patients with major protocol deviations that were considered to influence a treatment evaluation were excluded (e.g., pregnancy, concomitant procedures, medical reintervention). The Per-Protocol dataset was used as the primary analysis set for the primary endpoint analysis.
All statistical analyses were performed with SAS 9.3 (SAS, Cary, NC). Values were considered significant at the level of α = 0.05. The Wilcoxon signed-rank test was used to test if a change was significantly different from 0. Missing data were not imputed for patients included in this Per-Protocol analysis.
Procedure
The VizAblate System consists of a reusable intrauterine ultrasound (IUUS) probe and a single-use, disposable articulating RF handpiece that are combined into a single treatment device (Fig. 1). Other integrated components of the VizAblate System include an RF generator and an ultrasound system with a custom graphical user interface. This graphical user interface provides the gynecologist with an image-guided treatment system that indicates the borders of the thermal ablation as well as the border beyond which thermal heating is not present (Fig. 2).
Pregnancy was excluded before the procedure by utilizing a urine pregnancy test. Anesthesia was chosen by each investigator in consultation with an anesthesiologist; options included general inhalational anesthesia, regional anesthesia, and conscious sedation with or without paracervical blockade. Two dispersive electrode pads were placed, one on each anterior thigh; the dispersive electrodes contain thermocouples positioned at each leading edge for skin temperature monitoring. Just before insertion of the VizAblate Handpiece, transvaginal sonography was employed at the discretion of each investigator to confirm the presence, location, and size of each fibroid.
Transvaginal sonography, if desired for fibroid mapping before insertion of the VizAblate Handpiece, was performed with a transvaginal ultrasound probe as provided with the VizAblate System. After achieving cervical dilatation to 8 mm, the integrated VizAblate Handpiece (containing the RF electrode array and the intrauterine ultrasound probe) was inserted transcervically into the uterus. A small volume (generally 10–15 mL) of hypotonic fluid such as sterile water or 1.5 % glycine was infused through the device for acoustic coupling. Leiomyomata were then visualized with IUUS and mapped in a systematic fashion within the uterus.
After articulating the ultrasound probe, the investigators used the graphical overlay to simulate various ablation widths, angles, and locations of the intended ablation. In this fashion, before introducing the RF electrodes into a fibroid, the investigator planned and optimized the ablation. Once the size, angle, and location of the ablation were established, the investigator advanced a trocar-tipped introducer into the fibroid under intrauterine ultrasound visualization. The investigator aligned the graphical overlay with the introducer tip and then rotated the VizAblate Handpiece about the introducer to assess the position of the Ablation Zone and Thermal Safety Border relative to the uterine serosa, as displayed on the graphical user interface, adjusting the size and/or position of the desired ablation if necessary. Depending on the width of the ablation, the distance from the Ablation Zone to the uterine serosal margin will vary from 6.0 to 9.5 mm. When properly positioned, the introducer is located within the fibroid while the serosa is maintained tangent to or beyond the Thermal Safety Border. The investigator then deployed the electrodes, again rotating to ascertain the position of the Thermal Safety Border relative to the serosa. Once the Thermal Safety Border was confirmed to be within the uterine serosal margin in all adjacent ultrasound planes, RF energy was used to accomplish the ablation. Treated fibroids each received one or more ellipsoidal ablations, ranging from 1 to 4 cm in width and 2–5 cm in length. The number of ablations, along with their sizes, was at the discretion of the investigator. While usually only one ablation may sufficiently ablate up to a 5-cm myoma, two smaller ablations might be needed rather than one larger one, in order to ablate a greater aggregate volume when a fibroid is close to the serosa or where there is additional constraint on ablation volume and position (e.g., the cornu).
The VizAblate System delivers up to 150 W of RF energy for a preset duration. The RF generator controls energy delivery to maintain a constant temperature of 105 °C at the needle electrodes. Upon completion of RF treatment, the needle electrodes were retracted along with the introducer, the ultrasound articulation angle was reset to 0°, and the device was withdrawn.
Throughout this study, the investigator was asked to treat fibroids to maximize the ablated volume of each treated fibroid while maintaining the thermal safety border within the uterine serosal margin. In doing so, the investigator determined the best ablation size and location for each individual fibroid, and whether one or more ablations should be performed. The intent was to ablate all target fibroids (up to the eligibility limit of 5) present within a given patient. At each center, only a single physician would perform each procedure in the interests of consistency and quality.