Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT03369600 |
| Other study ID # |
Protocol # 20170872-01H |
| Secondary ID |
|
| Status |
Enrolling by invitation |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
August 17, 2018 |
| Est. completion date |
July 31, 2025 |
Study information
| Verified date |
May 2023 |
| Source |
University of Ottawa |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Uterine fibroids (leiomyomas, myomas, fibroids) are benign tumors of the uterus that can
cause heavy menstrual bleeding, pain, and/or infertility. Fibroids can be managed with
medication, surgery, or interventional radiology. While conservative methods that avoid
surgical risks and complications are becoming more common, there are limitations to medical
therapies including side effects, short durations of use, and incomplete response to
treatment. To optimize patient outcomes, it is imperative clinicians and researchers better
understand which patients may benefit from medical therapies and which may not. Fibroids with
less blood supply can degenerate and take on a variety of histological characteristics (e.g.
cystic, red, fatty, calcific) which may decrease response to medical management. These
histological characteristics in degenerated fibroids correspond to altered mechanical
properties, ranging from very soft to very hard. There is currently no guidance on how to
predict medical responsiveness based on such fibroid characteristics. As a result, physicians
treat patients empirically with medications, without the ability to counsel on effectiveness
or failure rates. Our research goal is to understand if and how uterine fibroid tissue
stiffness can predict response to medical therapies. To achieve this, the investigators will
use a new ultrasound technology, called shear wave elastography (SWE), that non-invasively
measures tissue stiffness and is currently used in practice for staging of chronic liver
diseases; however, given that this technology is very new, evidence of its clinical
application in gynecology is limited. Through implementing an innovative and
multidisciplinary approach, the investigators will (1) systematically establish SWE as a
feasible and reliable tool for measuring non-neoplastic myometrial and uterine fibroid tissue
stiffness, and (2) use SWE to classify and monitor fibroid tissue properties in
pre-menopausal women undergoing medical intervention for symptomatic uterine fibroids.
Understanding the connection between pathological tissue properties and the success of
medical therapies is essential to streamline assessment and intervention planning and improve
overall patient outcomes for the many Canadian women who suffer from uterine fibroids.
Description:
Aims and Objectives The goal of this project is to understand if and how uterine fibroid
tissue stiffness, measured by SWE, can be used to predict and monitor response to medical
therapy in patients with symptomatic uterine fibroids.
Aim 1: To assess the feasibility of using SWE for measuring stiffness of non-neoplastic
myometrium and uterine fibroid tissue in pre-menopausal women Objective 1.1: Assess the
inter- and intra-session reliability of measuring uterine tissue stiffness with SWE in 60
women with uterine fibroids and 60 healthy matched control participants.
Objective 1.2: Using data acquired from the 60 women with uterine fibroids, the validity of
SWE will be assessed by comparing in vivo uterine tissue stiffness measured by SWE to the
stiffness of surgically excised uterine tissue samples measured ex vivo by a mechanical
tester.
Objective 1.3: To assess the confounding effect of age, parity, contraceptive use, and
presence of fibroids on myometrial stiffness measured by SWE in 60 women with uterine
fibroids and 60 healthy matched control participants.
Aim 2: To assess the clinical applicability of using tissue stiffness measured by SWE for the
classification and monitoring of uterine fibroids in pre-menopausal women.
Objective 2.1: Determine if SWE is sensitive enough to identify differences in tissue
stiffness between non-degenerative and degenerative fibroids, as validated by histology from
surgically excised tissue samples of 60 women.
Objective 2.2: Determine if SWE is sensitive enough to identify differences in fibroid tissue
stiffness in 60 women with uterine fibroids before and after two 3-month courses of SPRM
therapy and evaluate if medical responsiveness (i.e. symptom relief) is related to baseline
SWE measures.
Study Design: This will be a prospective case-control study that will used a mixed model
(within and between subject) study design (Figure 1). Women with uterine fibroids and healthy
matched control participants will be recruited and attend two or three US imaging sessions
(depending on group assignment). Participants with fibroids will have both their myometrium
and fibroid stiffness measured using SWE. Healthy matched controls will have their myometrium
measured only. Participants with fibroids receiving surgical intervention will undergo a
hysterectomy or myomectomy and tissue samples will be harvested and tested in a jig that
measures stiffness under mechanical tension. Participants with fibroids seeking medical
management will have an US imaging session before and after two 3-month courses of ulipristal
acetate (UPA; an SPRM prescribed in Canada20).
Participants: Three groups of 60 premenopausal women over the age of 18 will be recruited:
1. Patients seeking surgical management for uterine fibroids (FIB-Sx) will be recruited
from a list of patients consented for surgery (hysterectomy or myomectomy with primary
indication of fibroids) by a member of The Ottawa Hospital Minimally Invasive Gynecology
Group (led by Nominated Principal Applicant, S. Singh). FIB-Sx will be excluded if they
have >5 fibroids identified on US or suspicion of leiomyosarcoma based on clinical,
surgical, or gross pathological examination.
2. Patients seeking medical management for uterine fibroids (FIB-Mx) will be screened from
a list of referrals to the Shirley E. Greenberg Women's Health Center (SEGWHC) at The
Ottawa Hospital and recruited at the time of consult if they have been prescribed a
course of UPA by their attending physician. FIB-Mx will be excluded if they have >5
fibroids identified on US or previous course of SPRM/GnRH analogues within 3 months of
recruitment.
3. Healthy control participants (CON) (matched to FIB in age, parity, and BMI) will be
recruited from the Ottawa community through advertisement posters, word of mouth, and
social media. CON will be excluded is they have a history of uterine pathology (e.g.
adenomyosis, hyperplasia, endometriosis), have irregular menstrual cycles, are currently
pregnant or have been pregnant within the last six months prior to recruitment.
Initial assessment: Consented women in the control (CON) and surgical (FIB-Sx) streams will
attend two evaluations. Consented women in the medical stream (FIB-Mx) will attend one visit
at their earliest convenience after recruitment, another at three months after treatment
initiation, and third visit at 6 months after treatment initiaition. At each visit, women
will undergo shear wave elastography (SWE) and 3D US (Supersonic UltrafastTM Aixplorer®,
Apexium Medical, Canada) assessments of their uterus as a whole, at 10 healthy sites and at
up to 5 fibroid sites. SWE and volumes will be recorded in series of 10 frame clips.
Morphologic measurements of the uterus and selected fibroids will be made and fibroids will
be given identification numbers based on a 3D size and location map. SWE will be used to take
relevant measures of tissue stiffness at all sites of interest. Three repetitions of each
measurement will be performed. Women in the CON and FIB-Sx streams will receive a second
identical imaging session during their first visit and a single imaging session during the
second visit. Participants in the FIB-Mx stream will receive a single imaging session at each
visit.
Surgical Intervention: the surgical approach (abdominal vs laparoscopic) will be recorded as
well as secondary outcomes including operating time, blood loss, surgical technique
conversions, failed/incomplete excisions, and additional procedures performed. These data
will be used for descriptive purposes and contribute to the development of a database for our
long-term research goal.
Tissue Sampling: For participants in the FIB-Sx stream, the surgical approach (myomectomy or
hysterectomy + abdominal or laparoscopic), course of resection and secondary outcomes
including operating time, blood loss, surgical technique, failed/incomplete excisions, intra-
or post-operative complication and additional procedures will be recorded for descriptive
purposes. Morcellated tissue specimens will be excluded. All surgically excised tissue will
be sent to pathology for gross inspection and processing following standard procedures. For
hysterectomy cases, a pathology assistant (trained and under the supervision of collaborator
S. Strickland) will excise five 1cm3 samples of non-neoplastic tissue from myometrial
sites-of interest and 1cm3 sections from each fibroid of interest. For myomectomy cases, 1cm3
sections from each fibroid of interest will similarly be excised. In surgical cases with >3
fibroids excised, the participating surgeon will include the study specific fibroid
identification number given at the US imaging session in the pathology requisition. A member
of the research team will meet the pathology assistant at the time of dissection to ensure
each sample is placed in individual bottles with isotonic saline and labelled with its unique
study identification number. Samples will be transported to M. Labrosse's (collaborator)
laboratory at the Ottawa Heart Institute for mechanical testing.
Medical Intervention: Medical treatment will be recorded as well as secondary outcomes
relating to patient symptoms and quality of life.These data will be used for descriptive
purposes and contribute to the development of a database for our long-term research goal.
Mechanical Testing: All samples will be stored in saline and tested within 24 hours of
excision. Samples will be further dissected into 2x10mm slices and loaded into a mechanical
jig (Biotester, CellScale, Waterloo, Canada) at collaborator M. Labrosse's laboratory and
tested at 37°C, cyclically in tension (1Hz, 2-3% strain) following procedures developed in
the literature for mechanical testing on uterine tissue. The modulus of elasticity (E, kPa),
analogous to stiffness, and stiffness contrast ratio (E_fibroid/E_myometrium ) will be
calculated three times for each sample and averaged. The mechanical testing protocol will
take approximately 2 hours to complete. Mechanical loading will be under displacement control
(2-3% strain) to eliminate the risk damaging tissues, allowing for repeated measurements and
histological analysis. All samples will be placed in 10% neutral buffered formalin
immediately after testing and returned to pathology for definitive diagnosis. Pathology
reports and slides will be retrospectively reviewed to extract descriptive fibroid
characteristics. Members of the research team acquiring subsequent SWE measurements,
mechanical stiffness measurements, and reviewing pathology reports will be blinded to results
of initial SWE measurement.
Statistical analyses:All data will be tested for normality and equivalent non-parametric
tests to those described below will be used as appropriate. All tests will be performed using
SPSS statistical software (v25, IMB Corp., Armonk, USA) and significance will be accepted as
p<0.05. Appropriate post-hoc comparisons will be performed. Dependent variables of SWE peak
and mean stiffness are assumed to be interrelated.
Objective 1.1: Two-way (3x2) multivariate analyses of variance (MANOVAs) will test for
significant differences in mean and peak stiffness (kPa) as they relate to the independent
variable of test time (repetition and session) for each measurement site. One-way analyses of
variance (ANOVAs) and dependent t-tests will be used for post-hoc Bonferroni corrected
evaluation of significant main effects. Dependent t-tests will determine if measurement plane
significantly affects SWE stiffness measures. Intra-class correlation coefficients and
standard error of measurements will evaluate intra- and inter-session, and between-plane
reliability of SWE stiffness measurements.
Objective 1.2: Univariate linear regressions will map the relationship between SWE mean and
peak stiffness and the complex modulus of elasticity, with the complex modulus of elasticity
considered the criterion standard. For non-linear relationships, appropriate transformations
will be made.
Objective 1.3: Two-way multivariate analyses of covariance will test the effect of site
(cervical junction, isthmus, fundus) and group (FIB vs CON) on peak and mean myometrial
stiffness and the confounding effects of age, parity and contraceptive use on the adjusted
group mean difference. Independent t-tests will be used for post-hoc evaluation if a
significant main effect/interaction is observed. Logistic regressions will map the
relationship of age, parity, and contraceptive use to myometrial stiffness at each
measurement site. Acceptable regressions will explain >80% of the variance in the data. For
non-linear relationships, appropriate transformations will be made.
Objective 2.1: Based on the pathology report, fibroids will be classified as either
non-degenerative (i.e. normal) or degenerative (inclusive of all variations in presentation).
One-way MANOVAs will evaluate between group differences in fibroid type (non-degenerative vs
degenerative) and uterine tissue peak and mean stiffness measured with SWE, while post-hoc
evaluation of significant main effects will involve independent t-tests using appropriate
Bonferroni corrections.
Objective 2.2: SWE measurements will be ensemble averaged across intra-session repetitions
for each site. Two-way MANOVAs will evaluate site and time (pre, post-course 1, post-course
2) differences in mean and peak stiffness measured with SWE One-way ANOVAs and dependant
t-tests will be used for post-hoc Bonferroni corrected evaluation of significant main
effects.
