An Evaluation of a Doppler-Guided Uterine Artery Occlusion Device (D-UAO) as Treatment for the Reduction of Fibroid-Associated Symptoms

Background:Uterine fibroids are the most common solid pelvic tumor in women,
estimated to occur in 77% of women of reproductive age1.  Patients with
fibroids commonly present with menorrhagia2-4 and pelvic pressure symptoms. 
The physical, emotional, and social lives of fibroid patients are negatively
affected.Vascular Control Systems (VCS) developed and manufactured the
Doppler-Guided Uterine Artery Occlusion Device  (D-UAO) and conducted the
initial clinical studies as discussed in later in this section. ETHICON CDMA is
the sponsor for this study. Alternative Treatments:Hysterectomy:  Historically,
hysterectomy has been performed as the definitive treatment for symptomatic
fibroids symptoms providing complete and effective relief of symptoms.  Using
Center for Disease Control and Prevention data5 and a cohort study6 would
predict 234,000 hysterectomies for fibroids in 2002.  Symptom relief following
hysterectomy has been associated with a marked improvement in quality of
life.6,7   This surgical procedure does present many risks with complications
including death, transfusions, deep vein thrombosis, intra-abdominal abscess,
surgical wound abscess, sepsis, bowel or bladder trauma requiring repair,
pulmonary embolism/infarct, myocardial infarction or cardiac and/or respiratory
arrest.8  Hysterectomy is also associated with lengthy hospital stays and
longer recovery.  Myomectomy: Myomectomy has become a surgical alternative to
hysterectomy for conservation of the uterus for reproductive or
non-reproductive reasons.  Although not a global uterine treatment, myomectomy
typically removes more than one fibroid and provides symptom reduction.9,10 
Myomectomy is plagued with high fibroid recurrence rates9,10 and with small
bowel adhesions.11,12   Thus, myomectomy successfully relieves the symptoms of
fibroids, but it does not affect the underlying process.13Drug Therapy: Drug
therapy with gonadotropin-releasing hormone (GnRH) agonist therapy has been
used to shrink uterine fibroids prior to myomectomy by suppressing estrogen and
progesterone production and by the direct effect of GnRH agonist on fibroid
tissue.  Even though GnRH agonists can temporarily shrink fibroids, the
suppression of ovarian production of estrogen and progesterone causes patients
treated with GnRH agonists to experience the unpleasant symptoms of menopause. 
Letterie et al14 reported the rate of GnRH agonist related side-effects
including hot flashes (78%), vaginal dryness (32%) and transient frontal
headaches (55%).  Despite a significant decrease in uterine and fibroid volume
and decrease in menorrhagia while on therapy, fibroid and uterine volumes
rapidly return to pre-treatment sizes and menorrhagia recurs in all patients
within one or two months after discontinuing GnRH agonist therapy.  GnRH
agonists, thus, only provide temporary relief from fibroid symptoms.  Uterine
Artery Embolization: Bilateral uterine artery embolisation (UAE) is an
angiographic, uterine sparing procedure designed to stop blood flow to the
uterus.  This procedure, performed by interventional radiologists, involves
catheterization of both uterine arteries under fluoroscopic (x-ray)
visualization, and injection of either polyvinyl alcohol (PVA) particles or
acrylic co-polymer (trisacryl) cross-linked with gelatin.  Three-month data on
538 women from the Ontario Uterine Fibroid Embolisation Trial showed
significant improvements in fibroid-related symptoms including menorrhagia.15 
Many publications have reported complications from particles flowing to organs
and tissues other than fibroids.  For example, embolic particles intended to
reach the uterus instead reached the buttocks resulting in gluteal muscle
pain16 and ischemia17 as well as necrosis.18  Ryu et al19 reported complete
loss of detectable ovarian arterial circulation in the majority of patients
undergoing UAE. When the plastic particles are on target, embolization has also
resulted in serious adverse events relating to diffuse uterine necrosis
requiring hysterectomy.20  Patient deaths have also been reported as a result



of uterine artery embolization.21-25  These studies suggest that UAE of the
uterine arteries is a successful treatment option for symptomatic uterine
fibroids, but the adverse events are numerous, widespread, and can be
fatal.ExAblate® 2000: The ExAblate 2000 employs a focused ultrasound beam that
heats and destroys the uterine fibroid tissue using high-frequency, high-energy
sound waves.  This system, operated by a radiologist, uses magnetic resonance
imaging (MRI) and a thermal mapping system to visualize patient anatomy, map
the volume of fibroid tissue to be treated, and monitor the temperature of the
uterine tissue after heating. This device is not recommended for fibroids near
sensitive organs such as the bowel or bladder.  Initial results show a mean
fibroid shrinkage rate of 13.5% at 6 months with a 79.3% reduction in the
symptoms.26  Total uterine volume results were not reported.  Adverse events
described with the ExAblate 2000 system included nerve injury/leg pain, bowel
symptoms, bladder symptoms and skin injury. Effects on the composition and
strength of the uterine tissue are not completely understood.27Previous
Clinical Experience:The following discussion describes clinical experience in
human subjects with the Transvaginal Doppler Clamp design.  One feasibility
study and two clinical studies have been conducted with the 510(k) cleared
Transvaginal Doppler Clamp in Canada and the U.S. under a Research Ethics Board
or Institutional Review Board approval, respectively.  Review Board
requirements have been followed.  Informed consent was received from all
enrolled subjects.  Health Canada approval was obtained for the Canadian
studies.  In all three studies, the subject population consisted of women with
symptomatic uterine fibroids seeking treatment.  Changes in bleeding symptoms
and general quality of life were assessed by the (Ruta) Menorrhagia Severity
Scale28 and the SF-12, respectively.  VCS026 Clinical Evaluation (St. Joseph*s
Health Care in London, Ontario, Canada)Seventeen (17) subjects ranged in age
from 32 to 51 years (mean 43.2 years) with uterine fibroids, menorrhagia,
pelvic pressure/pain, dysmenorrhea, and bladder and bowel dysfunction present. 
The ability to locate and occlude the uterine arteries was achieved in all 17
subjects by loss of audible Doppler signal.  Procedural success occurred in 16
of 17 (94%) subjects; average clamp time of the 17 subjects was 5.8 hours
(range 0.7 to 7.0 hours).  One subject experienced a reaction to the anesthesia
and did not complete the procedure; review of this case necessitated a change
in the anesthesia type for the procedure.  Inspection of the vaginal tissue
following clamp removal indicated no damage to the surrounding tissue in a
majority of the subjects (75% or 12 of 16); the remaining subjects had light
bruising or vaginal edema.  The majority of subjects (59% or 10 of 17) in the
feasibility study did not experience any adverse events.  The remaining 7
subjects had 9 events.  Onset of seven events occurred within 2 weeks
post-procedure.  Prophylactic medications were not prescribed at this site.  In
addition to the anesthesia reaction discussed above, events included two
urinary tract infections (resolved 13 and 25 days after onset), back pain
(resolved 11 days after onset), and suprapubic pressure and urgency secondary
to fibroid ischemia (resolved 74 days after onset).  Thirty days after the
procedure, one subject developed pain with menses (resolved 63 days after
onset).  Finally, one subject first noted worsened bulk effects at the 6-month
follow-up visit; no further information on resolution is available.Two events
of hydronephrosis occurred in two subjects.  Subject 007 developed left
hydronephrosis post-procedurally; a renal ultrasound 47 days later indicated
spontaneous resolution.  (Note: This subject also had pre-existing right
hydronephrosis.  As the hydronephrosis remained unchanged after the procedure,
it is not considered an adverse event.)  Subject 001 developed hydronephrosis
on the day of the procedure that was not confirmed as r



esolved until 200 days later.  One month after the procedure, all symptoms had
subsided.  At 53 days, the clinician and radiologist consult did not
recommended further follow-up based upon an essentially normal renal
ultrasound.  A Sponsor-recommended renal ultrasound confirmed resolution at 200
days.  Subject 001 did not have any clinical complaints of the hydronephrosis
during this time.Efficacy analyses results are initially stated for the overall
study population mean of individual subject changes from the baseline to
6-month follow-up period.  Results then classify *Responders* (subjects with
individual changes of 5% or greater). Six-month follow-up on 14 of 16
feasibility study subjects indicated encouraging changes.  Bleeding symptoms
were assessed by the Menorrhagia Severity Scale.  Overall, the mean change was
a 41% symptom reduction. Responders (11 of 14 subjects or 79%) experienced a
54% mean symptom reduction (range -78% to -18%). The study population
demonstrated substantial mean point improvement in general health over
gender-matched norms. The SF-12 Physical Component Summary mean increased from
1.6 points at baseline to 4.5 points at 6 months. The SF-12 Mental Component
Summary mean increased from 0.1 point at baseline to 4.3 points at 6
months.Objective measures included transvaginal ultrasound and MRI.  On
transvaginal ultrasound, dominant fibroid volume decreased 24%.  Responders (8
of 13 subjects or 62%) experienced 56% mean volume shrinkage (range -90% to
-7%).  Uterine volume decreased 12%.  Responders (8 of 14 subjects or 57%)
experienced 32% mean volume shrinkage (range -74% to -6%). Final efficacy
evaluation of the feasibility study was completed on MRI examination of 12
subjects.  A post 6-month follow-up MRI was performed at a mean of 10.3 months
(range 8.3 to 12.1 months).  Overall, dominant fibroid volume decreased 24%. 
Responders (9 of 12 subjects or 75%) experienced 36% mean volume shrinkage
(range -84% to -9%).  Uterine volume decreased 3%.  Responders (6 of 12
subjects or 50%) experienced 22% mean volume shrinkage (range -44% to -5%).
VCS030 Clinical Evaluation (St. Joseph*s Health Care in London, Ontario,
Canada)Thirteen (13) subjects ranged in age from 35 to 49 years (mean 42.9
years) with uterine fibroids, menorrhagia, pelvic pressure/pain, pain during
periods, and cramps.  The ability to locate and occlude the uterine arteries
was achieved in all 13 subjects by loss of audible Doppler signal.  Procedural
success occurred in all 13 subjects; average clamp time was 7.1 hours (range
6.0 to 9.0 hours).  Inspection of the vaginal tissue following clamp removal
indicated no damage to the surrounding tissue in all of the subjects.
Thirty-eight percent (5 subjects) did not experience any adverse events.  The
remaining 8 subjects had 18 events.  Onset of 11 of the 18 events occurred
within 2 weeks post-procedure.  Prophylactic medications were not prescribed at
this site.  Subject 004 experienced half of all the events including (in
temporal occurrence from procedure) urinary retention that resolved with
medication 5 days after onset, left hydronephrosis that resolved spontaneously
6 days after onset, right hydronephrosis (discussed below), edema of the thighs
and labia that resolved 7 days after onset, two lower urinary tract infections
that resolved with medications 10 and 11 days after onset, back pain, flank
pain and difficulty voiding (discussed below).  Other subject events included
right hydronephrosis and flank pain (discussed below), bloating (resolved 2
days after onset), pinkish discharge (resolved 14 days after onset), cystitis
(resolved 12 days after onset), mild discomfort and heavy bleeding (resolved 7
days after onset), urinary leakage/mild dysuria (resolved 30 days after onset),
bloating (resolved 1 day after onset), and cramping (resolved 31 days after
onset).Subjects 004 and 010 developed hydronephrosis post-procedurally that
required further intervention.  Repeat renal ultrasounds indicated worsening
progression.  Cystoscopy, right retrograde pyelogram and ureteral sten



t insertion was performed on both subjects.  Both stents were removed and the
subjects reassessed.   Subject 010 had complete resolution of the
hydronephrosis and associated flank pain after the stent removal.  For Subject
004, the hydronephrosis and associated flank pain, back pain, and difficulty
voiding continued after stent removal:  A right ureteroscopy, laser
endoureterotomy, and second ureteral stent placement were completed.  Six
months after the procedure, all events for Subject 004 had resolved.Six-month
follow-up was obtained on all 13 subjects.  All subjects were Responders with a
Menorrhagia Severity score change of 42% bleeding symptom reduction (range -81%
to -13%). On transvaginal ultrasound, dominant fibroid volume decreased 20%. 
Responders (9 of 13 subjects or 69%) experienced 44% volume shrinkage (range
-82% to -11%).  Overall, uterine volume decreased 21%.  Responders (10 of 13
subjects or 77%) experienced 34% volume shrinkage (range -64% to -8%).  On MRI,
dominant fibroid volume decreased 29%.  Responders (10 of 13 subjects or 77%)
experienced 45% volume shrinkage (range -100% to -13%).  Overall MRI uterine
volume decreased 16%.  Responders (10 of 13 subjects or 77%) experienced 24%
volume shrinkage (range -39% to -12%).  VCS025 Clinical Evaluation (Holy Cross
Medical Group in Fort Lauderdale, Florida)  Ten (10) subjects ranged in age
from 34 to 49 years (mean 39.8 years) with uterine fibroids, menorrhagia,
prolapse, pelvic pressure/pain, bloating and urinary tenesmus, and irregular
menses.  The ability to locate and occlude the uterine arteries was achieved in
all 10 subjects by loss of audible Doppler signal.  Procedural success occurred
in all 10 subjects; average clamp time was 6.2 hours (range 6.0 to 6.7 hours). 
Inspection of the vaginal tissue following clamp removal indicated no damage to
the surrounding tissue in all of the subjects.  The majority (7) of subjects
(70%) did not experience any adverse events.  The remaining 3 subjects had 3
events.  Onset of all events occurred within 2 weeks post-procedure.  Events
including a spinal headache from the anesthesia (resolved the same day), left
hydronephrosis (resolved 42 days after onset), and vaginal discharge (resolved
2 days after onset). Six-month follow-up was obtained on five subjects. 
Overall, the Menorrhagia Severity score reflected a 55% bleeding symptom
reduction.  Responders (4 of 5 subjects or 80%) experienced a 70% symptom
reduction (range -88% to -63%). The study population demonstrated mean point
improvement in general health over gender matched norms. The SF-12 Physical
Component Summary mean increased from -0.3 points at baseline to 6.0 points at
6 months. The SF-12 Mental Component Summary mean increased from -4.4 points at
baseline to 0.9 points at 6 months.Transvaginal ultrasounds results were
available on only two subjects.  Both subjects were Responders.  Overall
dominant fibroid volume decreased 10% and uterine volume decreased 15%.   No
post-procedure MRIs were completed for VCS-025.The Canadian Investigator
informed the sponsor that two subjects in the feasibility study sought
alternative treatment after the conclusion of the 6-month follow-up visits. The
choice of alternative treatment was unrelated to safety or efficacy outcomes
from the use of the Transvaginal Doppler clamp. One subject underwent a
hysterectomy; the second a uterine artery embolization. Additionally, one
subject within the Florida clinical study withdrew from the study prior to the
1-month visit and completed a myomectomy. No reports of complications as a
result of the earlier Clamp treatment were indicated.

The primary objective of this study is to evaluate the safety and effectiveness
of Doppler guided Uterine Artery Occlusion (D-UAO) as treatment for the
reduction of fibroid-associated symptoms. 

This is a multicentre, prospective, single-arm study conducted at approximately
12 to 16 investigational sites in Europe. Endpoint analyses will be based upon
12-month data however there will be a 24-month follow-up visit to report
re-intervention and safety data. Two interim analyses will be performed: 1) To
review the safety data on the first 60 patients receiving ureteric flow
evaluation (colour Doppler ultrasound and/or cystoscopy); 2) An interim
descriptive analysis will be performed on 6-month data. Safety and
effectiveness will be summarised using data from a minimum of 60 patients and
peri-operative data from all available patients. The primary effectiveness
variable will not be evaluated.The anaesthesia administration for the study
procedure will be either epidural or local anaesthesia. Patients will not be
randomised to anaesthesia type, as this will be determined by the site's
anaesthesia capabilities and the most appropriate anaesthesia for the
patient.All subjects will have their bilateral ureteric flow evaluated by
colour Doppler ultrasound or cystoscopy both before and immediately after
bilateral uterine artery occlusion. Subjects with no flow visualized prior to
clamping will be considered screening failures and will not undergo the
procedure. If after bilateral artery occlusion, no ureteral flow is visualized,
the clamb should be removed and the subject recorded as a treatment failure.
The subject will be followed up for one month for safety evaluation.Any subject
who requires unplanned intervention including placement of a ureteral stent due
to hydronephrosis that is thought to be associated with the study procedure
will be deemed to have clinically significant hydronephrosis. This category
would not include subjects with hydronephrosis that spontaneously resolves
without medical or procedural intervention.If the total number of cases with
clinically significant hydronephrosis exceeds 5 cumulatively, sites will be
notified to suspend subject enrolment and the events will be reviewed by an
Independent Data Safety Monitoring Board (DSMB) composed of at least 3
individuals including at least 2 clinicians with experience in managing
hydronephrosis and 1 graduate statistician. These individuals may not be
employees of the sponsor and may not otherwise be involved in this clinical
study.The recommendation of the DSMB will be used to arrive at a plan to halt
or re-start the study. Regulatory Authorities and ethics committees in all
study site countries will be provided with the sponsors plan following the DSMB
review..

Doppler Guided Uterine Artery Occlusion, Bilateral

Potential Benefits of Doppler Guided Uterine Artery Occlusion:The Doppler
guided, mechanical device is intended for bilateral occlusion of the uterine
arteries.  Through a transvaginal approach, gynecologists can offer a treatment
option with the following possible benefits and advantages.1.Reduces uterine
fibroid symptoms.a.Reduces fibroid associated bleeding.b.Improves health
related quality of life.c.Reduces fibroid bulk and associated bulk
symptoms.2.Offers a minimally invasive, incision-less, and uterine-sparing
treatment.3.Presents a minimal number and degree of observed adverse events
from prior clinical experience.4.Does not prevent future treatments as no heat,
particles, or energy are used to treat the patient and no portion of the device
remains after the procedure.  5.Provides an alternative treatment option for
gynecologists and their patients.  Gynecologists are the primary physicians in
the medical care of women with symptomatic fibroids.  Potential Risks of
Doppler Guided Uterine Artery Occlusion:Gynecological procedures for the
treatment of uterine fibroids are associated with certain risks.  These risks
are outlined in section 10 of the protocol.  Additionally, there are potential
risks that may be directly associated with the device.  These risks are as
follows:1.Hydronephrosis and associated symptoms are possible with device
placement.  In 4 of the 6 prior cases with hydronephrosis discussed above, the
event was mild in degree, resolved spontaneously and the subject did not
experience any symptoms.  In the 2 remaining cases, a ureteral stent was
necessary for resolution.  To further reduce this risk, procedural mitigations
and safety evaluations are present in this study. Procedural mitigations
include retrograde bladder filling to displace ureters, restriction of
excessive Clamp movement during placement and appropriate device size
selection. Safety evaluations include ureter flow assessments and renal
ultrasounds.2.Deep vein thrombosis (DVT) is possible due to the 6-hour
anaesthesia usage, however, this event has not been observed in prior studies.
Safety mitigations of pneumatic compression devices are present in this study
to reduce this risk.3.Local tissue injury. Vaginal and cervical lacerations
have occurred with the placement of the tenaculum and clamp devices. They have
been insignificant, have healed well and are to be expected with the use of
such mechanical devices.4.Urinary Tract Infection (UTI). Insertion of a
catheter and clamp placement is associated with an increased risk of urinary
tract infection. Patients may not be enrolled with active UTI. If the condition
develops, it is typically managed with antibiotics.5.Clinical symptoms
associated with uterine fibroid degeneration (e.g. diffuse abdominal pain,
generalized malaise, anorexia, nausea, vomiting, low-grade fever, and
leukocytosis and/or low back pain may occur).  Some submucous fibroids that
undergo degeneration following Doppler guided uterine artery occlusion
treatment may spontaneously pass from the body per vagina or require removal by
a gynecologist.Conclusion:Early clinical experience has demonstrated promising
results.  Subjects indicated a reduction in uterine fibroid symptoms and an
improved quality of life.  Dominant fibroid volumes decreased.  A minimal
number and degree of adverse events have been observed. Despite the potential
risks mentioned above, the possible benefits warrant the need for further
evaluation of this device.  This investigation aims to evaluate the device in a
controlled subset of subjects.  The current design should be sufficient to
support the study*s objectives.