Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01464775 |
| Other study ID # |
MMC-2011-57 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 2011 |
| Est. completion date |
December 2014 |
Study information
| Verified date |
April 2020 |
| Source |
Mercy Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Endometriosis is a relatively common chronic gynecological condition that affects
approximately 10% of all women of reproductive age. It is a pelvic inflammatory disease that
is characterized by the presence of endometrial glands and stroma outside of the uterine
cavity. Typical symptoms of endometriosis include dysmenorrhea, pelvic pain, and infertility;
the severity of pain associated with this disease often leads to a considerable decrease in
quality of life.
The standard treatment for severe pelvic pain and infertility is to surgically remove
endometriotic areas. Identifying all endometriotic lesions is paramount to "optimal
endometriosis debulking." The inability to see all endometriosis lesions has been thought to
be a factor for patients with little or no relief following surgery. Using the Narrow Band
Imaging (NBI) method has the potential to improve visualization of endometriosis lesions,
assist in debulking and thus, result in improved clinical outcomes.
NBI is a technique that uses a specific narrow wavelength of light to change the normal color
contrasts of the endoscopic image and improve detection of neovascularization, which is the
pathological feature of endometriosis for both superficial and deeper vascularization. This
type of imaging has the potential to offer improved discrimination of lesions, increasing
diagnostic yield as well as resulting in more complete debulking.
This study is designed to determine the degree to which NBI improves the detection and
diagnosis of endometriosis lesions. Data collected during the study will be used to test the
hypothesis that the use of NBI will improve the detection and diagnosis of endometriotic
lesions at the time of laparoscopy compared to standard visible white light examination.
Furthermore, this study will also determine the impact of the use of NBI compared to use of
white light examination on reported severity of pain at 6-weeks, 3-months, and 6 months
following surgery.
Hypotheses:
The use of NBI in addition to white light examination will improve the diagnostic yield of
endometriotic lesions at the time of laparoscopy compared to only using white light
examination.
The use of NBI in addition to white light examination will improve the sensitivity of
detecting endometriotic lesions and reduce false positives at laparoscopy compared to only
using white light examination.
Secondarily, the use of NBI will be associated with a greater reduction in pain at the
6-week, 3-month, and 6-month follow-up compared to the use of white light examination alone
because of improved lesion identification and debulking.
Description:
Introduction:
Endometriosis is a relatively common chronic gynecological condition that affects
approximately 10% of all women of reproductive age. It is a pelvic inflammatory disease that
is characterized by the presence of endometrial glands and stroma outside of the uterine
cavity. Typical symptoms of endometriosis include dysmenorrhea, pelvic pain, and infertility;
the severity of pain associated with this disease often leads to a considerable decrease in
quality of life.
The standard treatment for severe pelvic pain and infertility is to surgically remove
endometriotic areas. Identifying all endometriotic lesions is paramount to "optimal
endometriosis debulking." The inability to see all endometriosis lesions has been thought to
be a factor for patients with little or no relief following surgery. Using the Narrow Band
Imaging (NBI) method has the potential to improve visualization of endometriosis lesions,
assist in debulking and thus, result in improved clinical outcomes.
NBI is a technique that uses a specific narrow wavelength of light to change the normal color
contrasts of the endoscopic image and improve detection of neovascularization, which is the
pathological feature of endometriosis for both superficial and deeper vascularization. This
type of imaging has the potential to offer improved discrimination of lesions, increasing
diagnostic yield as well as resulting in more complete debulking.
The results of a pilot study of 21 patients conducted at Mercy Medical Center demonstrated
that use of NBI resulted in the diagnosis of pathologically-proven endometriosis among 4
patients whose lesions were missed with visible white light only examination. In addition,
the number of confirmed endometriosis lesions increased with the use of NBI in addition to
white light. The study also suggested that NBI may assist in discriminating endometriosis
from other lesions, thus reducing false positives: one patient had no lesions detected with
NBI and the lesions biopsied based on visible white light examination were not endometriosis
at pathologic examination.
Lesion discrimination under white light examination based on lesion color has been previously
described in the literature. Red (also known as clear and/or pink) lesions are considered to
be active and early lesions on endometriosis. White lesions may indicate areas of fibrosis
and may be latent or dormant lesion of endometriosis. The red and white lesions are also
known as the "subtle" lesions of endometriosis. Black (also known as brown, chocolate green,
purple or blue) represent a more severe stage of the disease. Black lesions are also known as
"gunshot" or "powder-burn" lesions and are considered the "typical" lesions of endometriosis.
Mixed color lesions can include a mixture of any color. It has been speculated that the
subtle lesions of endometriosis are more likely to be positive lesions and to be missed under
white light examination. The red lesions are also considered to have more vessels of smaller
diameter and may also include peritoneal microlesions and therefore may be more easily
detected under NBI.
The investigators will conduct a multi-center study with the following primary aims to
determine the degree to which NBI improves the detection and diagnosis of endometriosis
lesions.
1. Determine the degree to which NBI improves the diagnosis of endometriosis (diagnostic
yield) of laparoscopic examinations compared to use of visible white light-only
laparoscopy.
2. Determine if NBI improves sensitivity in the detection of potential endometriosis
lesions and reduces false positives compared to visible white light.
Secondary aim:
Determine the impact of the use of NBI, and presumed more complete removal of endometriotic
lesions, compared to use of white light examination on reported severity of pain at 6-weeks,
3-months, and 6 months following surgery.
The results of this study would significantly advance the state of art for the diagnosis and
treatment of endometriosis. Improved detection and treatment of endometrial lesions should
translate to a significant health benefit to women suffering from endometriosis. Potential
health benefits include improved diagnosis of the etiology of pelvic pain, therefore guiding
appropriate treatment management for women with pelvic pain due to endometriosis and improved
debulking of lesions.
The proposed study design is a multisite randomized controlled device trial conducted in two
clinical centers. Women will be randomized to have laparoscopic examination with white light
followed by NBI (white light/NBI) examination or white light followed by repeat white light
examination (white light/white light). Women of reproductive age (<50 years of age)
undergoing diagnostic laparoscopy for pelvic pain, suspected endometriosis, or infertility
will be eligible. A systematic examination covering the four quadrants of the pelvis will be
conducted using white light followed by either NBI or white light to identify and document
endometriotic lesions.
Study Aims
Hypotheses:
The use of NBI in addition to white light examination will improve the diagnostic yield of
endometriotic lesions at the time of laparoscopy compared to only using white light
examination.
The use of NBI in addition to white light examination will improve the sensitivity of
detecting endometriotic lesions and reduce false positives at laparoscopy compared to only
using white light examination.
Secondarily, the use of NBI will be associated with a greater reduction in pain at the
6-week, 3-month, and 6-month follow-up compared to the use of white light examination alone
because of improved lesion identification and debulking.
Pass/Fail Criteria for Primary Aims. In this randomized clinical trial, failure is defined as
no statistically significant difference in the primary outcomes of diagnostic yield or
sensitivity between the white only examination arm and the white light followed by NBI
examination arm.
Study Design and Methods The investigators will test the hypotheses by conducting a
multicenter device trial. Participants will be randomized to either white light/NBI or white
light/white light at a 3:1 ratio. In both study groups, each of the quadrants of the pelvis
will first be examined by white light.
Once a full exam is performed using the white light with lesion location documented with
photographs, a randomization envelope will be opened to reveal the patient's second modality
(NBI or white light). Each area will then be inspected by this second modality with
photographs taken for each quadrant, documenting lesion location. All identified lesions in
areas amenable to resection will then be resected, labeled by method of detection, and sent
for pathologic examination.
Study Outcomes:
The primary outcomes are the comparison of the diagnostic yield, sensitivity, and false
positive rate of visible white light (white light/white light) versus NBI (white light/NBI)
based on pathology gold standard.
Methods:
Investigator Training:
The investigators will be trained on the visualization of endometriosis under NBI
- Viewing WL and NBI images of potential endometrial lesions of various types
- The procedural use of NBI
- Completion of study forms to ensure data integrity
The participating surgeons and assistants from each site will be trained on the procedural
use of NBI by Olympus and the coordinating center. A minimum of three cases of patients
suspected to be positive for endometriosis will be watched by surgeons and coordinators from
remaining sites. The training surgeon will perform the sweep through the quadrants of the
pelvis. Each area will be viewed under white light. The training surgeon will ask the
surgeons to identify suspicious areas that they would biopsy. Then the training surgeon will
switch to NBI and once again ask the training surgeons to identify suspicious areas that they
would biopsy. This will be done to ensure that all participating surgeons are able to
identify suspicious areas under both imaging modalities to learn what potential endometrial
lesions look like under NBI.
Olympus will visit each site prior to the first procedure and train the assistant(s) on the
completion of the study case report forms. Olympus will also monitor adherence to the
protocol and the completion of the first study case report forms during the time of study
start (first patient enrollment) to ensure the surgeon is performing the procedure according
to the protocol and that the assistant is accurately capturing all of the required
information.
Study Population:
The population will include women of reproductive age undergoing diagnostic laparoscopy for
suspected endometriosis. The study population may include:
- Patients undergoing initial diagnostic laparoscopy for pelvic pain, suspected
endometriosis or infertility
- Patients previously evaluated with laparoscopy undergoing repeat laparoscopy for
suspected recurrence or onset of endometriosis
Recruitment:
Women will be recruited through the gynecologic practices of the participating physicians. At
the pre-surgery visit, patients will be informed of the purpose of the study as well as the
risks and benefits of the procedure and will be asked to sign an informed consent.
After signing the informed consent, women will be asked to complete a baseline questionnaire
to obtain information on demographic characteristics, medication history, and symptoms. A
10-centimeter (cm) visual analog scale and a validated endometriosis symptom questionnaire
[the Endometriosis Health Profile-30 (EHP-30)] will also be administered to assess pain. The
EHP-30 is an instrument specifically designed to measure pain and quality of life among women
diagnosed with endometriosis. The EHP-30 consists of a core questionnaire with 30 items and
five scales and six modular parts consisting of 23 questions. The EHP-30 has demonstrated
both high reliability and validity.
Equipment:
- OLYMPUS HD EndoEYE Video Telescope (Models WA50011A, WA50013A, WA50013L, WA50013T,
WA50015L) or OLYMPUS HD EndoEYE Laparo-Thoraco Videoscope LTF-VHOLYMPUS CLV-180 EVIS
EXERA II Xenon Light Source OLYMPUS CV-180 EVIS EXERA II Video System Center OLYMPUS HD
LCD Surgical Monitor
- SONY HD recorder PDW-70MD
- Printers OEP-4
Examination Procedures:
The laparoscopic examination will be conducted in a standardized fashion with visible white
light (standard), followed by an additional sweep with either white light (control) or NBI.
The second look examination will be determined by random assignment after completion of the
first examination with white light.
The examination will include visualizing each quadrant of the pelvis (Right Anterior, Right
Posterior, Left Posterior, Left Anterior).
Each area will first be viewed and photographed under white light. The absence or presence of
suspected endometrial lesions will be noted. If suspected lesions are seen, the number of
lesions, the extent of the lesions and the surgeon's confidence in the lesion being
endometriosis will be recorded. Photographs will be labeled by quadrant and all lesions will
be circled and numbered. Clinicians will record their degree of confidence on a 5 point
likert scale that the lesion to be excised is a lesion of endometriosis.
Following visualization, photographic identification and documentation of the quadrants under
white light has been completed, the study coordinator will open the randomization envelope
and reveal the second modality to be used. The physician will then repeat the exam and
photographs with either white light (control) or under NBI (switching on NBI).
Again, under the second modality, the absence or presence of suspected endometrial lesions
will be noted. If suspected lesions are seen, the number of lesions, the extent of the
lesions, the lesion color and the surgeon's confidence in the lesion being endometriosis will
be recorded. A photograph will be taken, labeled and all lesions will be circled and
numbered. Clinicians will record their degree of confidence on a 5 point likert scale that
the lesion to be excised is a lesion of endometriosis. The surgeon will record if the lesion
was also visualized under the 1st imaging modality or under only one of the modalities.
The order at which the areas are examined through the sweep will be at the surgeon's
discretion. Examination by both sweeps will be photographed. Photos of all areas and detected
lesions will be printed, labeled and lesions will be circled and numbered.
All suspected endometrial lesions will be included in the analysis, even lesions that may be
latent or healed (otherwise known as white lesions).
Once both exams are complete, additional areas of the abdomen can be evaluated at the
surgeon's discretion; those randomized to white light only will continue with only white
light examination.
All lesions detected by either method that are amenable to resection will be numbered and
biopsied. Data collected will include location, method of detection and clinical diagnosis
confidence score. Pathologists will be masked to method of detection (NBI versus white
light).
Lesions will be recorded according as falling within three categories: visible white
light-detected only; NBI-detected only; or both NBI- and visible white light-detected.
Pathology will be performed at each center following a standardized protocol for the
diagnosis of endometriosis. Pathologists at each institution will be masked to the method of
examination used to identify the specimen. All discordant lesions (visualized under only one
imaging modality), a random 10% sample of specimens and a random 10% of images from each
center will be re-reviewed by a central independent reviewer at the coordinating center.
Lesions that are not amendable to resection will be photographed only and will not be
included in the data analysis.
Data Collection:
1. Patient baseline questionnaire: symptoms, medication history, demographic information,
pain measurement (including 10-cm visual analog scale and EHP-30)
2. Photo documentation of each light examination
3. Case report forms:
- Recording of location of lesion by method of examination
- Notation of lesion color
- Clinical impression of detected lesions - degree of confidence on a scale of 1 to 5
that the lesions observed are endometriosis
- Notation of lesions excised
- Photographic documentation of lesions
- Change in surgical treatment (larger excision/smaller excision/organ removal) based
on results of visualization under the different imaging modalities.
4. Pathology reports
5. Medical record review
6. Provider questionnaire: planned follow-up treatment after surgery
7. Follow-up questionnaires for pain at 6-weeks, 3-months and 6-months; follow-up surveys
will include both the 10-cm visual analog scale and the EHP-30
Quality Control:
Quality control will be maintained by standardizing the protocols across the centers. As
stated above, in each patient, the locations of all lesions suspected to be endometriosis
detected with each modality will be documented with photographs. All discordant lesions (seen
under only one imaging modality) and a random 10% sample of the images and specimen samples
from each center will be re-reviewed by a central independent reviewer at the coordinating
center. The results between the site physician and the central reviewer will be compared. If
the site and central reviewer have disagreement on the photographed lesion or pathology,
adjudication will be performed between the site and the central reviewer. If a consensus
still cannot be reached, a third party (surgeon and/or pathologist (from the remaining site)
will be used as the tie breaker.
Randomization Procedure Subjects will be assigned to one of two groups in a stratified
randomized design. All subjects will undergo a white light examination followed by either a
second examination with white light or an examination using NBI. Investigators will be
blinded to second look imaging method until after the initial white light examination is
complete. Randomization to either white light/NBI or white light/white light will occur at a
3:1 ratio. Each site is treated as independent and subjects will be combined across sites for
analyses.
A randomization table will be generated using Microsoft Excel at the beginning of study
recruitment. The randomization number will be a three digit number and will form the last 3
digits of the study ID. Sealed envelopes will be provided to each site by the coordinating
center to be opened after the initial white light examination.
Sample size
Sample size in the original protocol for this study was calculated as described in section
12.1 below. Because data from a third site of this multicenter trial (Atlanta Northside) will
not be used, the total sample size goal (N = 170) in the original protocol will not be
reached. Mercy was approved by the IRB in September 2012 to enroll 100 patients total; the
Chicago site is approved to enroll 57 patients. Thus, the total sample size goal has been
revised to 157; minimal detectable differences under the conditions of 90% power are
described in section 12.2 below.
Sample size calculations from original protocol, dated 5/14/2010
Sample size calculations were based on the primary outcomes of diagnostic yield and
sensitivity as well as the secondary outcome of impact on pain symptoms. The sample size is
largely driven by the primary outcome of diagnostic yield. A sample size of 170 will provide
90% power to detect an improvement in diagnostic yield of 20% (95% CIs 72%-85% white light
and 95%-100% NBI), based on a randomization scheme of 3:1 for white light/NBI versus white
light/white light examination. This sample size takes into consideration a 25% drop out/not
evaluable rate for the following reasons: incomplete visualization of the pelvis, loss to
follow-up for pain assessment or patients not evaluable for pain assessment (a subset of
infertility patient who may not have pain as a presenting symptom).
This sample size provides 90% power to detect an average increase of one additional
endometriosis lesion with the NBI examination (white light/NBI group) compared to white light
only examination (white light/white light group). To note, this power calculation was based
on data from the pilot study that showed an average of 2 lesions (per patient) found using
white light and 3 lesions (per patient) detected using NBI; the calculation assumes a common
standard deviation of 1.
Data used for sample size calculations:
Diagnostic yield: The calculations for sample size were based on information obtained from a
pilot study that examined patients using white light followed by NBI during diagnostic
laparoscopy. In that study, 4 additional patients were diagnosed with endometriosis with the
addition of NBI to white light examination for an absolute improvement of 27% (4/15 patients
with endometriosis were found with NBI examination only) (Barrueto and Audlin, 2008). Using
these data, sample size calculations were conducted using nQuery 6.01 (Elashoff, 2005) for a
two group chi-square test with unequal Ns (3:1 ratio). A two group chi-square test with a
0.05 two-sided significance level will have 90% power to detect the difference between a
Group 1 (white light/white light) diagnostic yield of 0.79 and a Group 2 (white light/NBI)
diagnostic yield of 0.99 when the sample sizes in each group are 34 and 101, respectively (a
total sample size of 135).
Sensitivity and false positive rate:
In the pilot study, 15 of 20 patients examined were diagnosed with endometriosis on
histology. All 15 patients were detected with NBI and white light. Four patients were
diagnosed by lesions that were detected only with NBI. Based on these data, the estimated
sensitivities of white light and NBI are 73% and 100% respectively. Given these sensitivities
and the small total sample size, 95% confidence intervals are wide (48%-90% white light and
80%-100% NBI). At the lesion level, pilot data have shown an average of 2 lesions seen under
white light compared to an average of 3 lesions using NBI. Using a common standard deviation
of 1, the current sample size has at least 90% power to detect an average difference of at
least one additional lesion.
Pain difference:
The study will also consider pain reduction as a clinically relevant outcome. A recently
published study by Abbott et al (2003) reported that participants undergoing laparoscopy for
potential endometriosis on average rated non-menstrual pelvic pain prior to surgery as 6 on a
10-point visual analogue scale, with 10 being the worst pain. In the Abbott et al (2003) and
other similar studies, laparoscopic surgery using white light was shown to be associated with
a 30% reduction in pain at 6 month follow up and 50%-75% at 12 month follow up with
increasing variance (Abbott et al., 2004, Jarrell et al., 2005). An RCT from Jarrell et al.
(2005) showed a reduction in pain score of 1.9 (SD 0.5) at 6 month follow up and 2.6 (SD 0.5)
at 12 month follow up, although the sample size of this study was small (N=16 overall, N=7
for laparoscopy arm). This study will test the hypothesis that NBI will result in an
additional 20% decrease in pain compared to what has been observed in these previously
published studies examining the reduction in pain using white light laparoscopy.
Using the unbalanced randomization design with 1 patient randomized to white light/white
light for every 3 patients randomized to white light/NBI , a two group t-test with a 0.050
two-sided significance level will have 90% power to detect the difference in pain change with
a Group 1 (white light/white light) mean change of 1.9 and a Group 2 (white light/NBI) mean
of 2.28, a difference in means of 0.38 with a common SD of 0.5, when the sample sizes in the
two groups are 25 and 75, respectively (a total sample size of 100). We project that the
majority of patients enrolled (over 70%) will be symptomatic with pelvic pain despite the
indication for surgery (i.e. pelvic pain or infertility). Only 1 of the 2 study center sites
has a significant population of women undergoing laparoscopy for evaluation and treatment of
infertility.
Amended sample size The sample size of the study has been adjusted downward to 157 due to the
loss of one of the study centers for accrual. The revised sample size considers the outcomes
of diagnostic yield and sensitivity of clinical determination of identified lesions at the
time of surgery, by modality. A review of the first 69 patients enrolled and assigned to the
combined white light/NBI arm shows an average detection rate for any lesion to be 4.2 per
patient using NBI versus 2.9 per patient with white light. The minimal detectable difference
in diagnostic yield and sensitivity was determined using nQuery 6.01 (Elashoff, 2005). With
the current projected sample size of 157 patients, the minimal detectable difference between
the two modalities, with 90% power, in diagnostic yield proportions and sensitivity estimates
is 12.2%. Thus, the power of the study remains sufficient to detect a clinically meaningful
difference in detection of endometriosis by white light and NBI.
Data Analysis The investigators hypothesize that NBI will improve detection of endometriosis
lesions thus improving the diagnosis of endometriosis. For the primary outcome of diagnostic
yield, the reference standard will be the pathologic confirmation of excised lesions where
any one lesion within an individual detected by either method will confirm the diagnosis of
endometriosis. The investigators will address the detection of endometriosis by comparing the
diagnostic yield of the white light/white light group versus the white light/NBI group. The
investigators will use a McNemar's test for the proportion comparison, which accounts for the
pairing of assessment within a participant and makes no assumptions about the distribution of
samples. At the lesion level, the investigators will assess the average change in the number
of lesions detected between the white light/white light group to the white light/NBI group
using independent samples t-test. The investigators will also calculate and compare the
sensitivities and false positive rates for the white light/white light group and the white
light/NBI group. Pain across the study period will be assessed by comparing average change in
pain score (using both the VAS and the EHP-30 scores) between the two groups. The difference
in average pain change scores will be assessed using an independent samples t-test.
Differences in average pain between baseline and follow-up will be assessed using paired
t-tests.
Data Management A copy of the consent form will be sent to the Data Coordinating Center
(DCC). Report forms will be sent by fax or electronically (secured/encrypted) to the DCC data
entry. The data will be checked for consistency by using selected double entry where 1/10th
of the entered data will be re-entered and checked for errors. Data cleaning procedures will
be done using SAS with extensive program files to ensure the correctness of skip patterns and
responses. After baseline information is collected and entered, an analysis will be done to
confirm comparable baseline characteristics across the two groups.
Confidentiality:
Hard copies of questionnaires and interview records will be locked in file cabinet with
limited keyed access to research personnel. Computer data files are also kept on the Mercy
Medical Center Intranet in a password protected file that is accessible only by research
staff.
Any results from this study will be published using data from the group as a whole. No
individual will be identified in any reports.
Risks/Benefits Assessment
Risks/Discomforts:
White light examination is the current standard of care. NBI itself does not incur any
additional risk. However, the use of NBI may result in the identification of additional
lesions and thus incur the risk of additional resection at the time of laparoscopy.
Additional sites identified for biopsy using NBI have no additional risks for removal as
compared to white light. Lesions identified which are associated with higher risk structures
such as the bowel and the diaphragm will not be removed.
Benefits:
It is uncertain to what extent participants may benefit clinically and this will be clearly
stated in the consent form. If diagnosis of endometriosis is improved, then patients may
benefit from improved medical management. If additional lesions are identified and resected,
patients may benefit from an improved clinical outcome.
Withdrawal from protocol All participants are informed that taking part in this study is
completely voluntary and they have the right to not participate. If they do not want to join
the study, or if they wish to withdraw from the study, they will still receive the same
quality of medical care.
Modifications to the Protocol Any modifications to the protocol will be sent to the IRB for
approval.
Protocol Deviations The IRB (and other review boards as required for this study) will be
notified of any protocol deviations.
Reporting of Serious Adverse Events and Unanticipated Problems The protocol has minimal
additional risks beyond the usual risks associated with diagnostic laparoscopy. Should any
unanticipated problems develop, the investigators will attend to/address the problem and
notify institutional IRBs and the sponsor.
