Clinical trial NCT02206048
Conditions: Cervix Carcinoma
Keywords: Cervix Carcinoma Cervical adenocarcinoma in situ AIS Cervical intraepithelial neoplasia CIN microinvasive carcinoma of the cervix cold knife cone of the cervix CKC High-Resolution Microendoscopy HRME Proflavine
Sponsor: M.D. Anderson Cancer Center
Start date: 2015-10-02; Completion date: 2021-04-21
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if it is possible to get high-resolution microendoscopy (HRME) images of AIS tissue and/or tissue from microinvasive carcinoma right before a biopsy of the cervix. Researchers also want to learn if HRME images can show the difference between cancerous tissue and normal cervical tissue.

Detailed description:
If you agree to take part in this study, after you are in the operating room and under general anesthesia, proflavine hemisulfate solution (contrast dye) will be applied to the cervix. Images will be collected with the probe from the HRME device. The HRME probe is a long thin tube with a camera at the tip. This probe will be applied to the cervix and images obtained. These images will be used for research. This should add about 10 minutes to the total time you are in the operating room.

There will be no change to the planned standard-of-care colposcopy and biopsy.

Follow-Up:

A member of the research team will call you within 30 days after the procedure to ask how you are feeling and if you are having any symptoms. This call should last about 5 minutes.

Length of Study:

Your active participation in this study will be over after the biopsy.

This is an investigational study. The goal of this clinical research study is to learn if it is possible to get high-resolution microendoscopy (HRME) images of AIS tissue and/or tissue from microinvasive carcinoma right before a biopsy of the cervix. Researchers also want to learn if HRME images can show the difference between cancerous tissue and normal cervical tissue.

Arms: arm 1: Before participant's cold knife cone biopsy (CKC), topical application of 0.01% proflavine solution applied to cervix. HRME probe applied to cervix and high-resolution images obtained. Participant undergoes cervical biopsies of any abnormal areas noted with colposcopy and/or HRME. Immediately following the CKC, the removed surgical specimen evaluated. Proflavine reapplied to surgical specimen and repeat evaluation with HRME performed and high-resolution images obtained.
Interventions: intervention 1: Proflavine intervention 2: High-Resolution Microendoscopy (HRME) Imaging
Intervention descriptions: intervention 1: 0.01% proflavine solution topically applied to cervix before high-resolution microendoscopy (HRME) imaging. intervention 2: in-vivo high-resolution microendoscopy (HRME) images of cervical adenocarcinoma in situ (AIS) performed immediately prior to conization.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Protocol 2013-0885 
 
 
July 12, 2019 
 
 
1 
Use of high-resolution microendoscopy (HRME) in patients with 
adenocarcinoma in-situ (AIS) of the cervix  
 
 
Principal Investigator: 
Kathleen M. Schmeler, MD 
Department of Gynecologic Oncology & Reproductive Medicine, MDACC 
 
 
Co-Principal Investigators: 
Rebecca Richards-Kortum, PhD 
Department of Bioengineering, Rice University 
 
Andrea Milbourne, MD 
Department of Gynecologic Oncology & Reproductive Medicine, MDACC 
 
 
Collaborators: 
 
Preetha Ramalingam, MD 
Department of Pathology, MDACC 
 
Pedro T. Ramirez, MD 
Department of Gynecologic Oncology & Reproductive Medicine, MDACC 
 
Nicole Fleming, MD 
Department of Gynecologic Oncology & Reproductive Medicine, MDACC 
 
 
 
 
 


 
 
Protocol 2013-0885 
 
 
July 12, 2019 
 
 
2 
1.0 Objectives 
 
1. To determine the feasibility of acquiring in-vivo high-resolution microendoscopy (HRME) 
images of cervical adenocarcinoma in situ (AIS) immediately prior to conization. 
 
2. To determine accuracy of HRME images in distinguishing AIS from normal cervical tissue. 
 
 
2.0 Background 
 
Cervical adenocarcinoma in situ (AIS): 
Cervical AIS is a precursor to invasive cervical adenocarcinoma, which accounts for 
approximately 25% of cervical cancers in the United States (1). While the incidence of squamous 
cell carcinoma of the cervix has been on the decline in the U.S. due to widespread screening, 
detection, and treatment of precancerous lesions, the incidence of both AIS and invasive cervical 
adenocarcinoma has been rising for unclear reasons (2). Similar to squamous cervical 
intraepithelial neoplasia (CIN) and squamous cell carcinoma, cervical AIS and invasive 
adenocarcinoma are caused by persistent cervical infections by carcinogenic or high-risk human 
papillomavirus (HPV). AIS is histologically characterized by atypical columnar epithelial cells 
with no invasion present. Unlike squamous CIN lesions, 10 to 13% of patients with AIS have 
multifocal disease, with foci of AIS separated by at least 2 mm of normal mucosa (“skip” lesions) 
(1,3-5). 
 
The majority of patients are asymptomatic and the diagnosis of AIS is usually made following an 
abnormal Pap test. There are no clearly distinguishable clinical, cytological or colposcopic 
features of AIS. The lesion is usually located at the transformation zone with contiguous 
involvement of the endocervical canal (1,6). Cervical cytology and colposcopy-directed biopsy 
can miss up to 60% of AIS cases, however, the addition of endocervical curettage (ECC) 
significantly improves the detection rate (7).  Cervical conization is usually required to make the 
diagnosis of AIS. Cold knife conization is preferred over loop electrosurgical excision procedure 
(LEEP) as it minimizes the risk of thermal artifact and allows the pathologist to determine the 
presence of invasive disease and margin status (8-10).   
 
AIS is difficult to manage conservatively for several reasons. The lesion may be located high in 
the endocervical canal or be multicentric with “skip” lesions present. The sensitivity of cervical 
cytology and ECC is therefore only approximately 50%, making it difficult to adequately monitor 
women with AIS managed conservatively (4,11). In addition, the incidence of residual AIS or 
invasive adenocarcinoma following conization for AIS is high (3-5, 9, 12-14). Given these 
challenges, the standard treatment of AIS in women who have completed childbearing is simple 
hysterectomy. However, if the cervical cone margins are positive, a repeat cervical conization is 
performed prior to proceeding to simple hysterectomy to confirm negative margins and rule out 
an invasive occult cancer that could require different treatment. For women who desire future 
fertility, conservative management with cervical cone is an alternative provided the conization 
margins and ECC sample are negative. In women with a positive margin or ECC, repeat 
conization to remove the entire lesion and exclude the presence of invasive disease is 
recommended.   
 
 


 
 
Protocol 2013-0885 
 
 
July 12, 2019 
 
 
3 
 
 
 
 
High-Resolution Microendoscopy (HRME) Imaging: 
The HRME imaging system is a low-cost, innovative cervical visualization technique to evaluate 
epithelial cell morphology in situ. Proflavine, 
a topical contrast agent is applied to the 
cervix in a manner similar to the application 
of acetic acid at the time of colposcopy. The 
tip of a small fiber-optic probe is then placed 
directly onto the cervix, and the fluorescence 
from the proflavine-stained epithelium is 
immediately transmitted back to the HRME 
unit and displayed on a laptop computer, 
tablet or cell phone screen (Fig. 1). 
Morphologic features typically evaluated by 
pathologists including nuclear crowding, 
pleomorphism, and nuclear-to-cytoplasm 
(N/C) ratio are assessed in vivo in real-time. 
Image analysis software is then used to 
quantify nuclear morphology parameters 
and calculate N/C ratio. This approach 
allows for real-time, point-of-care detection 
of high-grade precancerous cervical lesions without a biopsy being performed. The technique 
has been shown to be effective in the evaluation of squamous lesions and is being studied as 
part of a “See & Treat” approach in limited resource settings where patients can be screened 
and treated at the same visit with cryotherapy or LEEP. 
 
3.0 Preliminary Data and Rationale 
 
Cervical adenocarcinoma in-situ (AIS): 
Our group recently performed a large, retrospective study evaluating the outcomes of 188 
patients with AIS (15). The mean age at diagnosis was 33.8 years (range 17.6-76.1), with many 
women of childbearing age. One hundred and seventy-two of the 180 women had at least one 
cone biopsy performed, with 110 (64.0%) undergoing a cold knife cone (CKC), and 62 (36.0%) 
undergoing a LEEP as their initial method of treatment.  Positive margins were noted in 35.0% 
of patients undergoing CKC compared with 55.6% undergoing LEEP (p=0.017). Seventy-one 
patients ultimately underwent hysterectomy with residual disease noted in 10 patients (14.1%), 
8 patients (11.3%) with residual AIS and 2 patients (2.8%) with invasive carcinoma. Of the 101 
patients who did not undergo hysterectomy, 2 patients (2.0%) developed recurrent AIS at a 
median of 27.5 months (range 18- 37 months) from the last cone, and none developed invasive 
carcinoma. However, 28.6% of patients required more than one conization to achieve negative 
margins. The study concluded that conservative, fertility-sparing management of AIS with CKC 
alone is feasible but that two or more CKCs may be required to obtain negative margins. 
 
High-Resolution Microendoscopy (HRME) Imaging: 
A pilot study evaluating HRME imaging for pre-invasive cervical neoplasia was recently 
 
Fig. 1 (a) HRME system; (b) Proflavine is applied; (c) fiber optic 
probe; (d) high-resolution image is displayed on a laptop computer 
in real-time; (e) colposcopic view of lesion at 5:00, and (f) resulting 
HRME image. Histologic diagnosis was normal, consistent with the 
HRME image showing small, evenly spaced nuclei. (g) Colposcopic 
view of lesion at 1:00, and (f) resulting HRME image. Histologic 
diagnosis of this site was CIN3, consistent with the HRME image 
showing large, crowded, pleomorphic nuclei.   


 
 
Protocol 2013-0885 
 
 
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4 
performed in 174 women in rural China (16). All patients underwent HPV testing, VIA, 
colposcopy and HRME imaging. Of the 69 women noted to have abnormalities on colposcopy, 
only 12 (17%) showed high-grade disease on biopsy. However, HRME imaging correctly 
classified all 12 high-grade areas (100%) as abnormal, and correctly classified 38 of the 
remaining 57 (67%) as normal. Furthermore, when patients were stratified based on a positive 
high-risk HPV DNA test, HRME imaging correctly identified 100% of the patients with CIN2 or 
greater. Of the 30 patients with a positive high-risk HPV DNA test but no histologic evidence of 
disease, only 6 patients (20%) were incorrectly identified as abnormal on HRME imaging. These 
preliminary data suggest that HRME has improved specificity over VIA and colposcopy, 
potentially leading to more accurate identification of patients needing treatment as part of a See 
& Treat protocol. Our collaborative group also recently completed a pilot study comparing HRME 
to colposcopy and biopsy in 60 patients with cervical dysplasia at Barretos Cancer Hospital in 
Brazil with final data analysis pending.  
 
Our group is also evaluating HRME for use in conservative, fertility-sparing surgery for women 
with endometrial cancer. We are evaluating if HRME can help distinguish tumor margins in 
women undergoing resection of the endometrial tumor without hysterectomy. We recently 
completed a prospective pilot study evaluating the use of HRME in patients with endometrial 
cancer. Following hysterectomy, the uterus was examined ex-vivo to identify whether HRME 
could distinguish between tumor and normal endometrium following the application of proflavine. 
Preliminary results show a 74% concordance rate between HRME and final pathology, which is 
significantly higher than the 59% concordance rate between gross evaluation and final 
pathology. A prospective trial evaluating HRME in-vivo in women with endometrial cancer was 
recently approved and accrual will begin in the near future. 
 
Rationale: 
Cervical AIS is a significant pre-invasive disease that affects women of childbearing age. For 
women who desire future fertility, conservative management with cervical conization is 
considered a feasible option. However, the treatment is challenging as lesions are often located 
high in the endocervical canal, and are multicentric with “skip” lesions present. Repeat 
conizations must therefore be performed until negative margins are obtained. Given the 
microscopic nature of the disease, the surgeon typically cannot visually distinguish AIS from 
normal tissue in order to obtain negative margins. Furthermore, frozen section is difficult and 
inaccurate in assessing AIS margins. This lack of accurate intraoperative assessment results in 
25-30% of patients undergoing one or more repeated conizations to obtain negative margins. In 
addition, an unnecessarily large specimen is sometimes removed in an attempt to be certain of 
obtaining negative margins. These large and repeat cervical conizations are known to be 
associated with adverse obstetrical outcomes, including preterm delivery and very low birth 
weight infants (17-19).  
 
In order to overcome these challenges associated with the conservative management of AIS, 
we are proposing to use HRME, a novel cervical visualization technique, to evaluate epithelial 
cell morphology in situ in order to distinguish AIS from normal cervical tissue. Our overall goal 
is to eventually use HRME to guide resection margins at the time of cervical conization for AIS. 
Our primary objective is to determine the feasibility of acquiring in-vivo high-resolution 
microendoscopy (HRME) images of cervical adenocarcinoma in situ (AIS) immediately prior to 
conization.  Our secondary objective is to determine accuracy of HRME images in distinguishing 
AIS from normal cervical tissue. 


 
 
Protocol 2013-0885 
 
 
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5 
 
4.0 Eligibility Criteria 
 
Inclusion Criteria: 
1.  Any woman with a confirmed preoperative diagnosis of cervical AIS, including co-existing 
squamous CIN and/or microinvasive cancer 
2.  Women undergoing cold knife cone (CKC) of the cervix at MD Anderson 
3.  Negative pregnancy test for women of child-bearing potential 
4.  Women who are >/= 21 years of age and < 65 years of age 
5. Ability to understand and the willingness to provide informed consent and sign a written 
Informed Consent Document (ICD) 
 
Exclusion Criteria: 
1.  Women < 21 years of age and >/= 65 years of age 
2.  Women with a known allergy to proflavine or acriflavine 
3.  Women who are pregnant or nursing 
4. Patients unable or unwilling to provide informed consent or sign a written Informed Consent 
Document (ICD)  
 
 
5.0 Pretreatment Evaluation/Obtaining Informed Consent: 
 
Patients will be screened for the study prior to surgery in the MD Anderson Cancer Center 
Colposcopy and Gynecologic Oncology clinics. All eligible patients will be approached by the PI 
or designee and offered participation in the study. Written informed consent will be obtained. 
The patient will be registered in the Clinical Oncology Research System (CORe). All patients will 
have their surgery performed at MD Anderson.  Patients who are of child-bearing potential will 
have a pre-treatment pregnancy test (within 7 days) prior to surgery performed as part of their 
standard of care.  
 
 
6.0 Research Plan and Methods 
 
Treatment Plan: 
The patient will be taken to the operating room and per standard practice, prior to converting the 
surgical area to a sterile field, an exam under anesthesia will be performed. Five percent acetic 
acid will be applied to the cervix. Routine colposcopy with visual inspection of the cervix for 
aceto-whitening will be performed and the findings noted. This will be followed by the topical 
application of 0.01% proflavine solution to the cervix. The HRME probe will then be applied to 
areas of the cervix that appear to be both normal and abnormal.  High-resolution images will be 
obtained and the findings noted. Lugol’s solution may then be applied to the cervix per standard 
practice and the findings noted. This may be followed by re-application of 0.01% proflavine 
solution to the cervix. The HRME probe will then be applied to areas of the cervix that appear to 
be both normal and abnormal.  High-resolution images will be obtained and the findings noted. 
 
The patient and surgical area will then be prepped in the typical sterile fashion.  A cold knife 
cone biopsy will then be performed per standard practice. The investigational procedures are 
anticipated to add approximately 10 minutes to the patient’s time in the operating room. 
 


 
 
Protocol 2013-0885 
 
 
July 12, 2019 
 
 
6 
Immediately following the CKC, the removed surgical specimen will be evaluated. Proflavine will 
be reapplied to the surgical specimen and repeat evaluation with HRME performed and high-
resolution images obtained. Small ink dots will be placed on the tissue surface at each area that 
was noted to be abnormal as well as normal areas, to enable co-registration of image sites with 
subsequent histopathology sections. The specimen will then be submitted to pathology for the 
usual pathological analysis.   
 
A member of the research team will contact each participant within 30 days of the procedure to 
ask how they are feeling and if they are experiencing any of the symptoms mentioned under the 
risks and side effects section of the informed consent. 
 
 
Proflavine: 
Proflavine powder will be purchased from Sigma-Aldrich and the solution will be prepared by the 
MD Anderson Investigational Pharmacy Services using specified instructions. 
Data: 
The protocol specific data collected will be stored in the Research Electronic Data Capture 
(REDCap) System/CORe.  
Data collected will include the following, as well as all other protocol specific data: 
• 
Age at diagnosis 
• 
Histology 
• 
Date of diagnosis 
• 
Date of surgery 
• 
Operative time 
• 
Duration of time for intraoperative HRME imaging 
• 
HRME imaging findings 
• 
Final pathologic findings 
 
7.0 Potential Side Effects 
 
The HRME imaging system will be used prior to the standard CKC procedure. The standard 
CKC procedure itself has potential risks including, but not limited to, bleeding, infection and 
damage to rectum and bladder. These risks will be reviewed with the patient and standard 
informed consent obtained for the surgical procedure in addition to the study informed consent. 
There are no known risks associated with the imaging device used in this study.   
 
However, there is the rare possibility of a severe allergic reaction to proflavine, the contrast dye 
used in imaging. Proflavine may be combustible at high temperatures. Proflavine is the principal 
component of acriflavine and has been used for fluorescent imaging in the European, Asian, and 
Australian gastrointestinal literature without any adverse effects noted. Proflavine has been 
clinically used as an antibacterial agent.  In neonatal care, Triple dye, a combination of brilliant 
green, proflavine hemisulfate, and gentian violet is routinely used as a topical antibacterial agent 
on the umbilical stump of newborn babies (21), with a recent review of the practice categorizing 
toxicity as rare (22).  We propose the use of proflavine solution at concentrations lower than that 
of the proflavine component in commercial triple dye, 0.11% (w/v) (Kerr Triple Dye, 
VistaPharm).  We have currently done several patients with Barrett’s esophagus under an 
existing protocol and IND and no complications or adverse events have been reported. The 


 
 
Protocol 2013-0885 
 
 
July 12, 2019 
 
 
7 
quantity of solution used for diagnostic imaging is likely to be no greater than that used in 
neonatal care (0.65 ml per single-use swab).  Investigational in vivo human studies of confocal 
microscopy for gastrointestinal cancer currently use topical acriflavine at 0.05% concentration 
(23).   
 
The additional exposure to light which will occur during imaging can also be compared to that 
received by newborn babies undergoing phototherapy for jaundice.  The high-resolution fiber-
optic microendoscope proposed for use here delivers 0.5 mW of 455 nm light to the tissue 
through a 0.8 mm diameter fiber-optic bundle, corresponding to an irradiance level of 
100 mW/cm2.  The American Academy of Pediatrics defines intensive phototherapy as a 
spectral irradiance of at least 30 mW/cm2 per nanometer over the 430-490 nm spectral band, 
equivalent to a total irradiance of 1.8 mW/cm2 (24).  Although the irradiance level is over 50-
times higher with the fiber microendoscope system, a typical imaging session of 30 minutes 
(including imaging for routine care) is approximately 50-times shorter than a typical 24 hour 
(1440 minutes) phototherapy incubation, leading to an equivalent light dose in each scenario.  
  
The imaging procedure will add approximately 10 minutes to the patient’s time in the operating 
room. There is the rare possibility that there may be additional risks from the added time of 
additional sedation. 
 
 
8.0 Criteria for Removal from Study: 
 
1.  Any patient who is consented for the study but prior to surgery declines to participate in the 
study. 
2.  Any patient in whom the surgery is scheduled but not performed. 
3.  Any patient who withdraws consent for any reason. 
 
 
9.0 Patient Confidentiality 
 
All pathology specimens, evaluations forms, reports and other patient records will be identified 
in a manner designed to maintain patient confidentiality. All data and specimens will be entered 
into REDCap/CORe. Clinical information will not be released without the written permission of 
the patient or the patient’s guardian, except as necessary for monitoring by the MD Anderson 
IND office or its representative, regulatory authorities, or the IRB.  
 
Study data will be collected and managed using REDCap (Research Electronic Data Capture) 
electronic data capture tools hosted at MD Anderson. [24] REDCap (www.project-redcap.org) is 
a secure, web-based application with controlled access designed to support data capture for 
research studies, providing: 1) an intuitive interface for validated data entry; 2) audit trails for 
tracking data manipulation and export procedures; 3) automated export procedures for seamless 
downloads to common statistical packages; and 4) procedures for importing data from external 
sources. In the case of multi-center studies REDCap uses Data Access Groups (DAGs) to 
ensure that personnel at each institution are blinded to the data from other institutions. REDCap 
(https://redcap.mdanderson.org) is hosted on a secure server by MD Anderson Cancer Center's 
Department of Research Information Systems & Technology Services. REDCap has undergone 
a Governance Risk & Compliance Assessment (05/14/14) by MD Anderson's Information 


 
 
Protocol 2013-0885 
 
 
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8 
Security Office and found to be compliant with HIPAA, Texas Administrative Codes 202-203, 
University of Texas Policy 165, federal regulations outlined in 21CFR Part 11, and UTMDACC 
Institutional Policy #ADM0335. Those having access to the data file include the study PI and 
research team personnel. All protected health information (PHI) will be removed from the data 
when it is exported from REDCap for analysis or review by the study collaborators at Rice 
University. All dates for a given patient will be shifted by a randomly generated number between 
0 and 364, thus preserving the distance between dates. Dates for each patient will be shifted by 
a different randomly generated number. 
 
The investigators and all employees and co-workers involved with this study shall not disclose 
or use for any purpose, other than performance of the study, any data, records or other 
unpublished, confidential information disclosed to those individuals for the purpose of the study. 
No patient identifiers will be used when analyzing the data or reporting the results.  
 
For this protocol we will only capture adverse events that are determined by the PI to be definitely 
related to the proflavine and/or HRME imaging. Adverse events and serious adverse events 
related to the standard of care CKC will not be captured as part of the protocol data 
 
 
10.0 Statistical Evaluation 
 
We will enroll 20 patients in this exploratory study. We will first examine data from 5 patients to 
work out the logistical issues in the use of the imaging technology with the surgery as well as 
evaluation of safety.  We will then examine data from the remaining patients in cohorts of 5. 
After each cohort of 5 patients we will review the logistics of the imaging technology and make 
adjustments deemed necessary to improve the surgical procedure.  We will also evaluate 
safety.  
 
Our primary objective is to determine the feasibility of acquiring in-vivo high-resolution 
microendoscopy (HRME) images of cervical adenocarcinoma in-situ (AIS) immediately prior to 
conization. We will use descriptive statistics to summarize the demographic and clinical 
characteristics of patients. We will estimate the proportion of patients for whom we can 
successfully acquire in-vivo HRME images of AIS immediately prior to conization with a 90% 
credible interval, assuming a beta(1.8, 0.2) prior distribution. This prior distribution is based on 
an anticipated success rate of 90%. If we complete the study with 18 patients for whom we can 
successfully acquire in-vivo HRME images of AIS, then our 90% credible interval will be 0.78 
to 0.98.  If we are able to successfully acquire in-vivo HRME images of at least 18 of the 20 
patients enrolled in the study, then we will determine that the methodology is feasible. 
 
Our secondary objective is to determine the accuracy of HRME images in distinguishing AIS 
from normal cervical tissue. We will tabulate AIS finding by the CKC specimen results as 
determined by pathology, and we will estimate the concordance of HRME images taken ex-vivo 
(as described in section 6.0) with pathology findings with a 90% credible, assuming a beta (1.8, 
0.2) prior distribution for the concordance. 
 
11.0 
Serious Adverse Event Reporting (SAE) for MD Anderson-Sponsored IND Protocols  
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 


 
 
Protocol 2013-0885 
 
 
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9 
 
• Death 
• A life-threatening adverse drug experience - any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it occurred 
in a more severe form, might have caused death.  
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
 
Important medical events as defined above, may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate by 
the Principal Investigator or the IND Sponsor, IND Office. 
 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must 
be reported to the IRB in accordance with the timeframes and procedures outlined in “The 
University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Unanticipated Adverse Events for Drugs and Devices”.  Unless stated 
otherwise in the protocol, all SAEs, expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the event). 
 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must have 
a written report submitted within 24 hours (next working day) of knowledge of the event to the 
Safety Project Manager in the IND Office.   
 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety reporting 
to the IND Office and MDACC IRB. Serious adverse events will be captured from the time of the 
first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical recovery is complete 
and laboratory tests have returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event. 
 
Additionally, any serious adverse events that occur after the 30 day time period that are related 
to the study treatment must be reported to the IND Office. This may include the development of 
a secondary malignancy. 
 
All adverse events encountered during the study will be evaluated according to the NCI 
Common Toxicity Criteria (CTCAE) version 4.03. 


 
 
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The investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events and assigning attribution of all events for subjects 
enrolled. 
 
Reporting to FDA: 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
12.0 Unanticipated Adverse Device Effect (UADE) Reporting for M. D. Anderson-
Sponsored IDE Protocols 
 
Unanticipated Adverse Device Effect 
 
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death was not previously identified in 
nature, severity, or degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious problem associated with 
a device that relates to the rights, safety, or welfare of subjects” (21 CFR 812.3(s)). 
 
Events that are related to the surgery will not be reported or recorded in the case report form. 
 
All UADE will be reported to the IRB in accordance with the timeframes and procedures 
outlined in “The University of Texas M. D. Anderson Cancer Center Institutional Review Board 
Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs and Devices”. 
 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and IRB. Unanticipated Adverse Device Effects will be forwarded to 
FDA by the IND Sponsor (Safety Project Manager IND Office) according to 21 CFR 812.150. 
 
It is the responsibility of the PI and the research team to ensure unanticipated adverse 
device effects are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional Review 
Board policy. 
 
Device failure 
 
Device failures which occur at the time of participant evaluation and which may prevent a 
participant from receiving therapy on trial will be kept on a log and will be reported as part of 
the annual report. Device failures at this point are not expected to affect patient safety, as 
participants may still receive appropriate therapy as determined by their attending physician. 
 


 
 
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13.0 References 
 
1. 
Lee KR, Flynn CE. Early invasive adenocarcinoma of the cervix. Cancer. 2000 Sep 1;89(5):1048-
55. 
2. 
Wang SS, Sherman ME, Hildesheim A, Lacey JV, Jr., Devesa S. Cervical adenocarcinoma and 
squamous cell carcinoma incidence trends among white women and black women in the United States 
for 1976-2000. Cancer. 2004 Mar 1;100(5):1035-44. 
3. 
Ostor AG, Duncan A, Quinn M, Rome R. Adenocarcinoma in situ of the uterine cervix: an 
experience with 100 cases. Gynecol Oncol. 2000 Nov;79(2):207-10. 
4. 
Wolf JK, Levenback C, Malpica A, Morris M, Burke T, Mitchell MF. Adenocarcinoma in situ of the 
cervix: significance of cone biopsy margins. Obstet Gynecol. 1996 Jul;88(1):82-6. 
5. 
Poynor EA, Barakat RR, Hoskins WJ. Management and follow-up of patients with 
adenocarcinoma in situ of the uterine cervix. Gynecol Oncol. 1995 May;57(2):158-64. 
6. 
Bertrand M, Lickrish GM, Colgan TJ. The anatomic distribution of cervical adenocarcinoma in situ: 
implications for treatment. Am J Obstet Gynecol. 1987 Jul;157(1):21-5. 
7. 
Shin CH, Schorge JO, Lee KR, Sheets EE. Cytologic and biopsy findings leading to conization in 
adenocarcinoma in situ of the cervix. Obstet Gynecol. 2002 Aug;100(2):271-6. 
8. 
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Bull-Phelps SL, Garner EI, Walsh CS, Gehrig PA, Miller DS, Schorge JO. Fertility-sparing surgery 
in 101 women with adenocarcinoma in situ of the cervix. Gynecol Oncol. 2007 Nov;107(2):316-9. 
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adenocarcinoma in situ: a systematic review of therapeutic options and predictors of persistent or 
recurrent disease. Obstet Gynecol Surv. 2001 Sep;56(9):567-75. 
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Kennedy AW, Biscotti CV. Further study of the management of cervical adenocarcinoma in situ. 
Gynecol Oncol. 2002 Sep;86(3):361-4. 
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Im DD, Duska LR, Rosenshein NB. Adequacy of conization margins in adenocarcinoma in situ of 
the cervix as a predictor of residual disease. Gynecol Oncol. 1995 Nov;59(2):179-82. 
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McHale MT, Le TD, Burger RA, Gu M, Rutgers JL, Monk BJ. Fertility sparing treatment for in situ 
and early invasive adenocarcinoma of the cervix. Obstet Gynecol. 2001 Nov;98(5 Pt 1):726-31. 
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Shin CH, Schorge JO, Lee KR, Sheets EE. Conservative management of adenocarcinoma in situ 
of the cervix. Gynecol Oncol. 2000 Oct;79(1):6-10. 
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Costales A, Milbourne A, Rhodes H, Munsell M, Wallbillich J, Brown J, Frumovitz M, Ramondetta 
L, Schmeler K. Risk of residual disease and invasive carcinoma in women treated for adenocarcinoma 
in situ of the cervix. Gynecol Oncol 129(3):513-6, 6/2013. 
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Pierce MC, Guan Y, Quinn MK, Zhang X, Zhang WH, Qiao YL, et al. A pilot study of low-cost, 
high-resolution microendoscopy as a tool for identifying women with cervical precancer. Cancer Prev Res 
2012;5:1273–9. 
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Kyrgiou, M., et al., Obstetric outcomes after conservative treatment for intraepithelial or early 
invasive cervical lesions: systematic review and meta-analysis. Lancet, 2006. 367(9509): p. 489-98. 
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Albrechtsen, S., et al., Pregnancy outcome in women before and after cervical conisation: 
population based cohort study. BMJ, 2008. 337: p. a1343. 
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Arbyn, M., et al., Perinatal mortality and other severe adverse pregnancy outcomes associated 
with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ, 2008. 337: p. a1284.  
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Janssen, P.A., et al., To dye or not to dye: a randomized, clinical trial of a triple dye/alcohol regime 
versus dry cord care. Pediatrics, 2003. 111(1): p. 15-20. 
21.       McConnell, T., et al., Trends in Umbilical Cord Care: Scientific Evidence for Practice. Newborn 
and Infant Nursing Reviews, 2004. 4: p. 211-222. 
22.       Polglase, A.L., et al., A fluorescence confocal endomicroscope for in vivo microscopy of the upper- 
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23.       Maisels, M.J. and A.F. McDonagh, Phototherapy for neonatal jaundice. The New England journal 
of medicine, 2008. 358(9): p. 920-8. 


 
 
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24.     Paul A. Harris, Robert Taylor, Robert Thielke, Jonathon Payne, Nathaniel Gonzalez, Jose G. 
Conde. Research electronic data capture (REDCap) - A metadata-driven methodology and workflow 
process for providing translational research informatics support. J Biomed Inform, 2009. 42(2):377-81. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Appendix A – Flammability 
 
 
 
 
 


 
 
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