The Effectiveness of High Resolution Microendoscopy (HRME) in High Grade Intraepithelial Lesions (HSIL) Diagnosis for People Living With HIV
Phase: PHASE1
Conditions: Anal High Grade Squamous Intraepithelial Lesion
Sponsor: Baylor College of Medicine

Cover Page 
Official Study 
Title 
THE EFFECTIVENESS OF HIGH RESOLUTION MICROENDOSCOPY 
(HRME) IN HIGH GRADE INTRAEPITHELIAL LESIONS (HSIL) 
DIAGNOSIS FOR PEOPLE LIVING WITH HIV 
NCT Number 
04563754 
Document/Version 
Date 
24 March 2023 
 

 
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THE EFFECTIVENESS OF HIGH RESOLUTION MICROENDOSCOPY (HRME) IN 
HIGH GRADE INTRAEPITHELIAL LESIONS (HSIL) DIAGNOSIS FOR PEOPLE 
LIVING WITH HIV 
 
Principal Investigator:   
Sharmila Anandasabapathy, MD, Professor of Medicine  
Baylor College of Medicine (Study Contact PI) 
Elizabeth Chiao, MD, MPH, Professor of Medicine 
MD Anderson Cancer Center (Study Co-PI) 
Supported by:  
The National Institutes of Health (NIH) 
GRANT - 12622467 
 
Study Intervention Provided by:  
RICE UNIVERSITY 
 
Sponsor of IND:  
Proflavine Hemisulfate  
Dr. Sharmila Anandasabapathy 
IND # 102217 
 
 

 
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Tool Revision History 
Version Number: 1.2 
Version Date: 2023 Mar 24 
Summary of Revisions Made:  
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TABLE OF CONTENTS 
Page 
Clinical Study Protocol Template ............................................................................................... 1 
Tool Revision History ................................................................................................................. 3 
TABLE OF CONTENTS ............................................................................................................. 4 
STUDY TEAM ROSTER........................................................................................................... 7 
PARTICIPATING STUDY SITES ............................................................................................ 9 
PRÉCIS ..................................................................................................................................... 10 
1. STUDY OBJECTIVES ........................................................................................................... 10 
1.1 
Primary Objective ......................................................................................................... 10 
1.2 
Secondary Objectives.................................................................................................... 10 
2. BACKGROUND AND RATIONALE .................................................................................. 11 
2.1 
Background ................................................................................................................... 11 
2.2 
Study Rationale ............................................................................................................. 12 
3. STUDY DESIGN ..................................................................................................................... 14 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS .............................................. 14 
4.1 
Inclusion Criteria .......................................................................................................... 14 
4.2 
Exclusion Criteria ......................................................................................................... 14 
4.3 
Study Enrollment Procedures ....................................................................................... 14 
5. STUDY INTERVENTIONS .................................................................................................. 15 
5.1 
Interventions, Administration, and Duration ................................................................ 15 
5.2 
Handling of Study Interventions ................................................................................... 15 
5.3 
Concomitant Interventions ............................................................................................ 15 
5.4 
Adherence Assessment ................................................................................................. 15 
6. STUDY PROCEDURES ........................................................................................................ 16 
6.1 
Schedule of Evaluations ................................................................................................ 16 
6.2 
Description of Evaluations ............................................................................................ 17 
6.2.1 Screening Evaluation ................................................................................................ 17 
6.2.2 Enrollment, Baseline, and/or Randomization ........................................................... 17 
6.2.3 Blinding..................................................................................................................... 18 
6.2.4 Follow-Up Visits ....................................................................................................... 18 
6.2.5 Completion/Final Evaluation .................................................................................... 18 

 
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7. SAFETY ASSESSMENTS ..................................................................................................... 18 
7.1 
Specification of Safety Parameters ............................................................................... 18 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters .... 18 
7.3 
Adverse Events and Serious Adverse Events ............................................................... 19 
7.4 
Reporting Procedures .................................................................................................... 20 
7.6 
Safety Monitoring ......................................................................................................... 20 
8. INTERVENTION DISCONTINUATION ........................................................................... 20 
9. STATISTICAL CONSIDERATIONS .................................................................................. 20 
9.1 
General Design Issues ................................................................................................... 20 
9.2 
Sample Size and Randomization .................................................................................. 21 
Treatment Assignment Procedures ....................................................................................... 21 
9.3  
Definition of Populations .............................................................................................. 21 
9.4 
Interim Analyses and Stopping Rules ........................................................................... 22 
9.5 
Outcomes ...................................................................................................................... 22 
9.5.1 Primary Outcome ...................................................................................................... 22 
9.5.2 Secondary Outcomes ................................................................................................ 22 
9.6 
Data Analyses ............................................................................................................... 22 
10. DATA COLLECTION AND QUALITY ASSURANCE .................................................. 23 
10.1 
Data Collection Forms .................................................................................................. 23 
10.2 
Data Management ......................................................................................................... 23 
10.3 
Quality Assurance ......................................................................................................... 24 
10.3.1 
Training ................................................................................................................. 24 
10.3.3 
Metrics .................................................................................................................. 24 
10.3.4 
Protocol Deviations ............................................................................................... 24 
10.3.5 
Monitoring ............................................................................................................ 25 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY ................................................... 25 
11.1 
Institutional Review Board (IRB) Review .................................................................... 25 
11.2 
Informed Consent Forms .............................................................................................. 26 
11.3 
Participant Confidentiality ............................................................................................ 27 
11.4 
Study Discontinuation ................................................................................................... 27 
12. COMMITTEES..................................................................................................................... 27 
13. PUBLICATION OF RESEARCH FINDINGS .................................................................. 27 
14. REFERENCES ...................................................................................................................... 27 

 
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15. SUPPLEMENTS/APPENDICES ........................................................................................ 35 
I. Manual of Operations  
II. Study Calendar  

 
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STUDY TEAM ROSTER  
     Name:   
ELIZABETH CHIAO 
 
 
 
     Phone:   
 
     Id:   
            Non-Baylor 
     Department:   MD Anderson Cancer Center 
     Email:    
eychiao@mdanderson.org  
     Address:   
 
  
     Name:    
ADRIANNA OLGA MALIGA 
 
     Phone:   
713-798-5987 
     Email:    
maliga@bcm.edu 
     Mail Stn:   
BCM271 
 
 
     Name:   
SHARMILA ANANDASABAPATHY  
 
     Phone:   
713-798-8105 
     Department:   MEDICINE: GASTROENTEROLOGY  
     Email:    
anandasa@bcm.edu 
     Mail Stn:    
BCM271  
 
     Name:             REBECCA RICHARDS-KORTUM   
     Phone:   
713-348-3823 
     Institution:      Rice University  
 
     Email:    
rkortum@rice.edu 
     Address:    
6100 Main Street, MS 142  
 
 
  
     Name:   
MAXIMILIAN GAISA  
     Phone:   
212-241-3150 
     Id:   
            Non-Baylor  
 
Institution:      Icahn School of Medicine at Mount Sinai  
 
     Email:    
michael.gaisa@mssm.edu 
     Address:    
One Gustave L. Levy Place   
 
 
     Name:   
YUXIN LIU   
     Phone:   
212-241-5283 
     Id:   
            Non-Baylor  
     Institution:      Icahn School of Medicine at Mount Sinai  
 
     Email:    
yuxin.liu@mountsinai.org 
     Address:    
One Gustave L. Levy Place   
 
 
     Name:   
KEITH SIGEL  
 
     Phone:   
212-824-7558 

 
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     Id:   
            Non-Baylor   
     Institution:      Icahn School of Medicine at Mount Sinai  
 
     Email:    
keith.sigel@mssm.edu 
     Address:    
One Gustave L. Levy Place   
 
 
     Name:   
TERESA DARRAGH  
 
     Phone:   
415-353-7861 
     Id:          
Non-Baylor   
     Institution:      University of California San Francisco  
 
     Email:    
Teresa.Darragh@ucsf.edu 
     Address:    
3333 California Street  
 
 
  
     Name:   
ASHISH DESHMUKH  
 
     Phone:   
713-500-9180 
     Id:          
Non-Baylor   
     Institution:      Medical University of South Carolina  
 
     Email:    
adeshmukha@musc.edu  
 
Address:    
E-329, 1200 Pressler Street, Houston, TX  
 
 
      
    Name:   
JOHN WINTERS  
 
     Id:   
            Non-Baylor   
     Institution:      Icahn School of Medicine at Mount Sinai  
 
     Email:    
john.winters@mssm.edu 
    Address:    
One Gustave L. Levy Place   
 
 
     Name:   
 IVY COHEN  
  Institution:       Icahn School of Medicine at Mount Sinai  
 
    Address:    
One Gustave L. Levy Place   
 
 
     Name:   
RICHARD SILVERA  
 
 
     Id:   
            Non-Baylor   
 
 
Institution:       Icahn School of Medicine at Mount Sinai  
 
     
 
 

 
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PARTICIPATING STUDY SITES 
List the name and address of each study site investigator, including telephone and fax numbers 
and e-mail address.  
ELIZABETH CHIAO (MD Anderson Study Co-PI) 
 
 
Email:   eychiao@mdanderson.org 
      
 SHARMILA ANANDASABAPATHY (BCM Study PI) 
 
 Phone:  713-798-8105 
 Department:   MEDICINE: GASTROENTEROLOGY  
 Email:  anandasa@bcm.edu 
 
 
REBECCA RICHARDS-KORTUM (Rice University Co-PI) 
 
Phone:  713-348-3823 
Email:   rkortum@rice.edu  
 Address:   6100 Main Street, MS 142 
 
MAXIMILIAN GAISA (Mount Sinai Site PI) 
Phone:   212-241-3150 
Institution:   Icahn School of Medicine at Mount Sinai  
 
Email:   michael.gaisa@mssm.edu  
Address:   One Gustave L. Levy Place 
      
 KEITH SIGEL (Mount Sinai Site Co-PI) 
 
 Phone:     212-824-7558 
 Institution:   Icahn School of Medicine at Mount Sinai  
 Email:   keith.sigel@mssm.edu   
 Address:   One Gustave L. Levy Place 
 
 YUXIN LIU (Mount Sinai Site Co-PI) 
 
  Phone:  212-241-5283 
                Id:   Non-Baylor  
  Institution:   Icahn School of Medicine at Mount Sinai  
 
  Email:   yuxin.liu@mountsinai.org  
  Address:   One Gustave L. Levy Place 
      
 TERESA DARRAGH (University of California Site PI) 
 
 Phone:       415-353-7861 
 Institution:   University of California San Francisco  
 
 Email:   Teresa.Darragh@ucsf.edu  
 
ASHISH DESHMUKH (Medical University of South Carolina Site PI) 
Phone:  713-500-9180 
Email:   deshmukha@musc.edu  

 
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PRÉCIS  
Squamous cell cancer of the anus (SCCA) is one of the most common cancers among aging HIV-
infected individuals in the United States. HIV-infected persons are at 40-80-times higher risk for 
SCCA than the general population, and recent cohort studies report that the incidence of SCCA 
among HIV-infected men is between 49-144/100,000 person-years, which is substantially higher 
than the incidence of cervical cancer prior to widespread screening with cervical cytology. The 
alarming increase in anal precancer and cancer in HIV- infected individuals has led to an increased 
emphasis on prevention. Current HIV primary care Guidelines (NY state HIV primary care 
guidelines, HIV Medical Association, and Infectious Diseases Society of America) both 
recommend annual anal cytology screening, with triage to high resolution anoscopy (HRA)-guided 
biopsy for histologic confirmation of anal high grade intraepithelial lesions (HSIL) among HIV-
infected men who have sex with men (MSM), and certain HIV-infected women. However, HRA-
guided histologic diagnosis of HSIL is resource intensive, and has several drawbacks, including: 
extensive clinician expertise/training; pathology cost, availability, interpretation expertise; 
separate patient visits for diagnosis and treatment; and patient discomfort associated with 
unnecessary, non-neoplastic biopsies, given the low specificity of HRA-based visual HSIL 
identification. Our group has developed a portable, battery-operated, high-resolution 
microendoscope (mHRME) that provides subcellular images of the anal epithelium, delineating 
the cellular and morphologic changes associated with neoplasia. Our central hypothesis is that this 
'optical' approach will increase the efficiency, clinical impact, and cost-effectiveness of the current 
standard of HRA-guided biopsy. In a recent pilot trial, the mHRME demonstrated a high sensitivity 
and specificity of anal HSIL diagnosis (94% and 92% respectively) compared to anal biopsy. 
Based on our significant preliminary data, we now propose to optimize and validate 3D imaging 
and HRME with a software interface that provides real- time image interpretation assistance, thus 
facilitating usage by less-experienced clinicians in community-based or low-resource settings. To 
validate this, we will conduct a study to determine the efficiency and diagnostic characteristics of 
an mHRME 'optical biopsy' approach versus the current standard of HRA-based tissue biopsy. In 
addition, we will construct, refine and analyze a disease model of HRA-based screening with 
mHRME to determine the cost- effectiveness of incorporating HRME into HRA-based HSIL 
diagnosis. Successful results will allow for improved efficacy and resource utilization for cancer 
screening in HIV-infected individuals for anal cancer and other epithelial cancers including the 
cervix, oral cavity, bladder, and GI tract. 
1. STUDY OBJECTIVES 
1.1 
Primary Objective  
To compare the diagnostic performance and efficiency of the optimized mHRME 
during HRA to standard of care HRA-guided anal biopsies. Using the optimized 
mHRME during HRA, we will evaluate the diagnostic performance (sensitivity, 
specificity, positive predictive value, negative predictive value) of mHRME optical 
diagnosis compared to paired anal tissue histology. 
1.2 
Secondary Objectives 
a) To compare the diagnostic performance and efficiency of the optimized mHRME 
during HRA to standard of care HRA-guided anal biopsies. Using the optimized 

 
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mHRME during HRA, we will evaluate the efficiency (number of potential biopsies 
averted, reduction in procedure time) 
 
b) To develop and optimize i) a mobile high-resolution microendoscope (mHRME) and 
3D image mapping for anal HSIL diagnosis and ii) image-analysis software during 
HRA. To facilitate rapid interpretation and biopsy correlation in community-based 
settings, we will develop and test two innovative features: mHRME enhanced 3D-
mapping, as well as anal HSIL automated image-analysis software for correlation of 
anoscopic and mHRME images to allow clinicians to identify areas of HSIL in real 
time in feasibility study. 
2. BACKGROUND AND RATIONALE 
2.1 
Background  
The alarming increase in anal precancerous and cancerous lesions among HIV-infected 
individuals, has led to an increasing emphasis on anal cancer prevention.6 The 2015 New York 
State HIV Primary Care Guidelines recommend annual anal cytology screening, with triage to high 
resolution anoscopy (HRA)-guided biopsy for histologic confirmation of anal high-grade 
intraepithelial lesions (HSIL) among HIV-infected men who have sex with men (MSM), and 
certain HIV-infected women.7 However, HRA-guided histologic diagnosis of HSIL is resource 
intensive, and has several drawbacks, including: extensive clinician expertise/training; pathology 
cost; separate patient visits for diagnosis and treatment; and patient discomfort associated with 
biopsies which are often negative or low grade.8,9 These drawbacks, in part, have led to limited 
adoption of anal cancer screening as evidenced by the fact that only 11% of HIV-infected MSM 
reported receiving screening in the preceding 6-12 months.10 Identifying novel, low cost, biopsy-
free approaches which offer an accurate, real-time “optical biopsy” diagnosis could transform the 
current standard of practice by decreasing the numbers of procedures, reducing loss to follow up, 
and facilitating a “see and treat” approach. 
 
Mobile High-Resolution MicroEndoscopy (mHRME) provides subcellular resolutionof epithelial 
images, (up to transverse resolution of 4 microns) which delineates cellular and morphologic 
features (nuclear size, and pleomorphism) of epithelial neoplasia. Using this technology assisted 
by visual 3D mapping of the anal canal during anoscopy, clinicians will be able to localize all 
potential HSIL lesions and obtain “optical biopsies” of each documented lesion. Thus, this novel 
technology will allow for comprehensive documentation and accurate diagnoses of anal HSIL, 
thereby decreasing patient discomfort and procedure cost. The mHRME has already been shown 
to have high sensitivity and specificity with histologic diagnoses in other pre-cancer screening 
studies, including cervical 11 and esophageal squamous neoplasia.12 Furthermore, in preliminary 
data, HRME was shown to have a sensitivity of 93% and a specificity of 87% for anal HSIL 
detection.13 We propose to: 1) optimize the diagnostic performance of mHRME with 3D image 
maps for anal HSIL detection, followed by determiningthe of anal mHRME compared to the gold 
standard of HRA-guided biopsy. Our hypothesis is that mHRME plus 3D mapping will improve 
the accuracy andefficiency of HSIL diagnoses. 

 
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2.2 
Study Rationale 
Squamous cell anal cancer (SCCA) rates in HIV-infected individuals have continued to 
increase over the past decade despite the widespread use of cART.14-16 The availability of 
combined antiretroviral therapy (cART) has dramatically prolonged survival among HIV-infected 
individuals with life expectancy now approaching that of uninfected individuals.17-19 Driven by the 
aging HIV-infected population, and the fact that the incidence of SCCA has continued to increase 
in the cART era, 20 SCCA has become one of the most common HIV-associated cancers.21 The 
highest risks appear to be among HIV-infected men who have sex with men (MSM) who have an 
increased SCCA risk of approximately 40-80 times greater than the general population, and an 
incidence of approximately 89/100,000 HIV-infected men. Women are also at increased risk for 
anal cancer (8-14 times greater than the general population), with a current incidence rate of 
approximately 18-30 per 100,000 person-years.4,20,22 The incidence of SCCA among HIV-infected 
MSM over the age of 60 is approximately 131/100,000 person-years, and the 10-year cumulative 
incidence of SCCA among men who have sex with men (MSM) over age 30 is approximately 
1%.1,4,23-25  
 
Furthermore, SCCA leads to significant morbid effects in HIV-infected persons, who develop the 
disease at much younger ages (approximately 10 years younger) than uninfected persons 26 and 
have higher rates of colostomy placement (in eventually >30% of cases),26 higher rates of treatment 
failure,27-30 increased disease recurrence,31 and thus lower progression-free survival.32 These poor 
outcomes highlight the need to implement screening strategies for earlier detection. 
 
HIV-infected individuals have a high prevalence of anal high-risk (HR) HPV infection and 
anal HSIL, leading to recommendations for anal dysplasia screening. HPV has been detected 
in 99% of cervical cancers and 80 to 90% of anal cancers, with HPV types 16 or 18 detected in 
about 70% of cervical and 80% of anal cancers.33 Persistent anal HPV infection, in conjunction 
with other factors (smoking, history of advanced AIDS, and longer time period of detectable HIV 
viremia)34 leads to the development of anal intraepithelial neoplasia grade 2 and 3 (AIN 2 and 3) 
also called anal high-grade squamous intraepithelial lesions (HSIL), a likely precursor to anal 
cancer. 35,36 In meta-analyses and recent reviews, the prevalence of HR-HPV infection and HSIL 
in HIV-infected MSM been shown to be 73.5% (48.9%-94.4%) and 29.1% (20.8%- 42.9%), 
respectively.37 Among HIV-infected women, the prevalence of HR-HPV infection are somewhat 
lower at 43% (16%-85%),37 but anal HSIL rates have been reported as high as a26% in another 
recent study.38,39 The rate of progression from anal dysplasia to invasive SCCA is also high;40,41 
with estimates of HSIL progression to anal cancer in HIV-infected individuals ranging from 
approximately 1 in 263 to 377 cases per year.37,42,43 In a recent study of HIV-infected MSMs, 7% 
of 156 individuals with HSIL developed invasive anal cancer over a median period of 8.6 months.44 
Screening for anal cancer precursors is feasible and has been shown to be cost-effective.45,46 
Several research and practice groups have recommended anal cancer prevention strategies 
focusing on anal cytology followed by anal colposcopy for both HIV-infected men and women 
because of the high rates of progression from anal dysplasia to invasive SCCA, and because SCCA 
shares many biologic properties with cervical cancer.47  Currently, consensus on specific screening 
and treatment strategies are lacking, thus the development of optimal screening strategies based 
are critical. This proposal will provide a novel alternative surveillance tool that would substantially 
improve HSIL screening and surveillance strategies.  
 

 
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Current Screening for HSIL and Its Limitations:  
The New York State guidelines for primary care of HIV-infected individuals recommend 
screening HIV-infected MSM and women with a history of CIN and condyloma yearly with anal 
Pap tests.7 If the cytology is normal, then the patient returns for routine screening again in one 
year. Because the specificity of anal pap smears is relatively low (ranging from 32%-59%), experts 
recommend performing anal colposcopy or high resolution anoscopy (HRA), a procedure similar 
to cervical colposcopy with acetic acid and Lugol’s Iodine augmentation to identify high grade 
squamous intraepithelial lesions (HSIL), as the gold standard diagnostic test for any cytologic 
abnormality which includes: squamous cells of uncertain significance (ASCUS), low grade 
squamous intraepithelial lesions (LSIL), or high grade squamous intraepithelial lesions (HSIL).49 
At this time, current expert-guided anal dysplasia guidelines suggest either surveillance, ablative 
therapy (electrocautery, etc.) or topical treatment of anal HSIL because of the high rates of 
progression to invasive anal cancer among HIV-infected individuals.50 Thus, with the current 
screening algorithm, patients need to return to the clinic at least three times from initiation of 
screening to HSIL treatment. Novel optimal imaging techniques, such as mobile high resolution 
microendoscopy (mHRME) to identify histologic HSIL could substantially simplify screening and 
surveillance algorithms.  
 
In addition to the multiple visits needed for current anal dysplasia screening algorithms, the 
HRA procedure requires substantial training and expertise among practitioners. 
Anecdotally, the original group of researchers who brought HRA to the United States note a high 
degree of dexterity and technical prowess required to effectively visualize the entire anal canal and 
obtain reliable biopsy specimens.51 One study demonstrated that new HRA practitioners needed 
approximately 200 cases before demonstrating no missed high grade lesions found on follow-up.52 
This substantial learning curve and the lack of practitioners trained formally in residency or 
fellowship has led to a scarcity of providers able to provide HRA. Due to both the low numbers of 
trained HRA practitioners, and the amount of health care resources needed to initiate an anal 
dysplasia screening program, anal cancer screening rates in HIV-infected individuals remain 
extremely low. For example, the CDC reported that only 11% (95% CI 9%-13%) of a nationally-
representative cohort of HIV-positive MSM (highest risk individuals) had an anal cytology test in 
the preceding year.10 Furthermore, a recent study found that among those who are screened, 35% 
of patients are lost to follow-up between HRA and biopsy and treatment.53 Currently, there are 
several ongoing studies evaluating biomarkers for screening, and a large clinical trial called the 
ANal Cancer Outcomes Research (ANCHOR) evaluating the effectiveness of HSIL treatment on 
the incidence of invasive anal cancer. However, research focused on improving the visualization 
and diagnosis of HSIL through novel imaging technology are lacking. 
 
Need for Low-Cost, High-Resolution Imaging: As HSIL treatment recommendations evolve, 
simplifying HSIL and/or early anal cancer screening, detection and surveillance will radically 
improve the access, cost and efficiency of anal cancer prevention. A robust, low-cost method of 
identifying HSIL or minimally invasive SCCA without need for biopsy would markedly improve 
existing HRA and histology-based diagnostic strategies. By offering an in vivo diagnosis, more 
selective biopsies can be performed. Additionally, the ability to delineate normal from neoplastic 
mucosa in real-time may reduce the number of patients lost to follow-up and facilitate “see and 
treat” approaches using minimally-invasive  ablative therapies.54-56 We anticipate that the 
mHRME may enhance the efficiency and cost-effectiveness of current practice by preventing 

 
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unnecessary biopsies, repeat procedures, and loss of patients to follow-up. Successful results can 
easily be translated to other epithelial cancers: colon, cervix, stomach, etc.  
3. STUDY DESIGN 
This is a Device, Phase II, Multicenter, Cross-sectional Research Study with the following 
objectives: 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS  
4.1 
Inclusion Criteria 
For all objectives: 
• Consentable patients with documented HIV disease, and either previously 
documented HSIL or abnormal anal cytology within the past 2 years  
• Ages 18 years and older  
• Seen at the Baylor-affiliated Thomas Street Clinic (TSC), Mount Sinai Hospital and 
affiliated clinics 
4.2 
Exclusion Criteria 
For all objectives: 
• Patients with a platelet count less than 75,000 cells/mm3 and an absolute neutrophil 
count less than 1000 cells/mm3 
• A known permanent or irreversible bleeding disorder that, in the opinion of the 
principal investigator (PI), would contraindicate any biopsy of the anal canal; current 
or prior history of anal cancer 
• Allergy or prior reaction to the fluorescent contrast agent Proflavine or Iodine 
• Patients who are unable to give informed consent. 
• Patients who are pregnant  
4.3 
Study Enrollment Procedures  
This study involves recruitment of 200 HIV infected men and women with evidence of anal 
dysplasia from the Anal Dysplasia Clinics. This study will be available for enrollment at 
Thomas Street Clinic (TSC), Baylor College of Medicine and at the Mount Sinai Anal 
Dysplasia Clinic. In order to recruit these subjects, we will distribute information to both 
clinics and also physicians and their clinical staff who are in charge of the care of the subjects. 
The subjects will talk with their own physician who will describe the study, and arrange for 
an appointment. After their questions have been addressed, women who remain interested will 
sign the informed consent form. Potential participants will be approached by a trained research 
assistant (RA) to determine eligibility. Patients who participate in the study and are identified 
with anal disease will have access to appropriate ongoing care after study completion and will 
be offered remuneration for travel and inconvenience. 
 
Potential subjects will read the informed consent. The consenting clinician will answer all 
their questions. The subject will be given a copy of the signed consent. The signed consent 

 
15 of 41 
will be kept in a locked cabinet at the clinical site. We will explain all the procedures that will 
be performed, possible risks, benefits and alternatives. 
 
Once the patient is enrolled, their information will be entered in the OnCore™ Database 
System, which is a collection of interrelated tables that contain information on various aspects 
of enrollment activities. Information about human subjects will only be available to the research 
clinicians of the originating site. There is a potential loss of confidentiality at these gatherings, so 
participants will be counseled regarding the loss of confidentiality and this risk will be documented 
in the informed consent form. 
 5. STUDY INTERVENTIONS  
5.1 
Interventions, Administration, and Duration  
Study Drug – Proflavine Hemisulfate 
Proflavine was used under FDA IND #102217; the HRME itself is an IDE-exempt 
device by the FDA. The contrast agent, proflavine, used in this study is the principal 
component of acriflavine and has been used for fluorescent imaging in the European, 
Asian and Australian gastrointestinal literature without any adverse events. 
 
Study Intervention - mobile High Resolution Microendoscope (mHRME) 
Patients will have mHRME images taken of Lugol’s negative (abnormal) areas and 
subsequent standard-of-care HRA biopsies at each image site. In addition, there will be 
at least one extra image and biopsy taken at a Lugol’s positive (normal) site. Each 
patient will likely have ≥ 2 biopsies. We plan to enroll 200 patients, which will yield 
225-300 images. 
 
Our approach uses topical contrast (proflavine) that directly highlights cell nuclei 
change, the most important pathologic marker of squamous cell intraepithelial 
neoplasia.  In addition, we will implement image-analysis software to highlight these 
changes in real time, enabling less experienced practitioners to accurately recognize 
the hallmarks of neoplasia. The high- resolution fiber-optic microendoscope (mHRME) 
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 100mW/cm2.  
5.2 
Handling of Study Interventions  
See Manual of Operations (Appendix 1) for detailed instructions of HRME 
intervention. 
5.3 
Concomitant Interventions  
N/A 
5.4 
Adherence Assessment  
N/A 

 
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6. STUDY PROCEDURES  
6.1 
Schedule of Evaluations  
See Appendix 2 for Study Calendar 

 
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6.2 
Description of Evaluations  
See Manual of Operations (Appendix 1) for a detailed description of the Evaluations 
6.2.1 Screening Evaluation 
All patients scheduled for HRA will be screened for eligibility for the study at 
each clinic date. 
Consenting Procedure 
The research population will be identified from patients at Thomas Street Clinic 
and the Anal Dysplasia clinic at the Mount Sinai Medical Center (Dr. Gaisa) in 
New York City. The patient will be given information regarding the study and will 
be given the appropriate amount of time to carefully weigh the risks and benefits of 
the study. If the patient agrees to consent to participating in the study, the 
patient/participant will be counseled regarding all alternatives to study enrollment 
and regarding the right to withdraw consent at any time. In addition, the participant 
will be reassured that participation in the clinical trial will not in any way affect the 
future medical care received. The only document linking the participant and the 
research will be the consent form which will be filed in the subject's medical record. 
Screening 
The screening will be performed through secure electronic medical record system. 
The study investigators and study staff will make sure that personal information is 
kept confidential. All participant information will be stored securely in locked file 
cabinets in areas with access limited to study staff. All reports, study data 
collection, and administrative forms will be identified only by a coded number to 
maintain participant confidentiality. All local databases will be secured with 
password-protected access systems. Forms, lists, logbooks, appointments books, 
and any other listings that link participant ID numbers to other identifying 
information will be stored in a separate, locked file in an area with limited access. 
 
Since Dr. Chiao is a medical provider at TSHC, this temporary access to patients' 
PHI to determine eligibility does not constitute more than minimal risk and will not 
adversely affect the privacy rights and welfare of the individuals who are covered 
by the waiver. Since Dr. Gaisa is a medical provider at MSSM, this temporary 
access to patients' PHI to determine eligibility does not constitute more than 
minimal risk and will not adversely affect the privacy rights and welfare of the 
individuals who are covered by the waiver. 
6.2.2 Enrollment, Baseline, and/or Randomization 
Enrollment 
Patients who are then found to be eligible and enroll in the study would provide 
written consent to do so. The patients covered by the waiver (those who are 
screened for the study but who are found to be ineligible will have no information 
recorded about them. Patients who refuse enrollment will only have their name and 

 
18 of 41 
demographic information recorded so that the research coordinators will not re-
contact them. 
Baseline Assessments 
See Manual of Operations (Appendix 1) for a detailed description of the Baseline 
Assessments 
Randomization 
There is no randomization for any of the objectives in this protocol.    
6.2.3 Blinding 
NA 
6.2.4 Follow-Up Visits 
There will be no Follow-up Visits. See Manual of Operations (Appendix 1) for 
a detailed description of the Follow-up phone Calls. 
 
6.2.5 Completion/Final Evaluation 
The study is a single visit study. Patients will be contacted by phone at 1 year 
and 2 years for follow up evaluation. See MOP for the phone contact details. 
7. SAFETY ASSESSMENTS  
7.1 
Specification of Safety Parameters 
We will use Common Terminology Criteria for AE v5.0. Serious adverse events 
will count as Grade 3 (Severe or Medically Significant, but not Immediately Life 
Threatening: Hospitalization or Prolongation of Hospitalization Indicated; 
Disabling; Limiting Self Care ADL), Grade 4 (Life-threatening consequences; 
urgent intervention indicated) or Grade 5 (Death related to AE). 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
Upon completion of the study imaging, subjects will be contacted to screen for 
adverse events after a period of 2 and 30 days from procedure. Patients with 
abnormal clinical findings will be followed until the condition resolves or 
stabilizes. Adverse events or serious adverse events that occur during the follow-
up period will be recorded regardless of relatedness to the study procedure. The 
safety follow-up may be conducted by a phone visit or a clinic visit; if clinically 
indicated, a clinic visit should be performed along with relevant lab work. 
 
Patients will be contacted by phone at 1 and 2 years for follow up evaluation. See 
MOP for details.  
 
We anticipate most AE/SAEs will be related to anoscopy (pain, bleeding). 
Proflavine has been administered to >1000 patients for use with HRME imaging 

 
19 of 41 
under Dr. Anandasabapathy’s studies and we have had 0 related adverse events or 
serious adverse events. 
7.3 
Adverse Events and Serious Adverse Events  
Possible risks associated with the study procedures are listed below. There may also 
be risks that are not known. 
Allergic reaction 
There is the possibility of an allergic reaction to the Proflavine contrast dye in 
which participant may have local irritation. The participant can receive anti-
histamines and other anti-allergy medications if this happens. 
Specimen Imaging Probe 
There are no known risks from the use of the imaging probe. 
Anal biopsies 
The risk for anal biopsies are pain, bleeding, and infection. The biopsies are part 
of the standard of care procedure and would be obtained regardless of study 
enrollment. It is important that the participant tell the study staff about any side 
effects that he/she may have had even if he/she does not think it is related to the 
procedure. Because these patients will all have abnormal anal cytology, the HRA 
is a standard-of-care procedure. 
Pregnancy 
Insufficient information is available on the use of Proflavine in pregnancy. Drugs 
can have harmful effects on the fetus at any stage of pregnancy. 
Loss of Privacy 
Subjects will be consented on the day of their procedure. Subjects will be taken to 
a private area where the study information will be discussed. No additional sensitive 
information will be requested from the subjects beyond what is required to perform 
a standard study.. Subjects will be given an ID number for all forms, images, and 
communications. All data will be coded. Source documents will be redacted of all 
PHI before being sent from outside sites for data monitoring/data entry in the 
database. All PHI collected on BCM subjects will be stored in locked cabinets or 
password-protected files/computers where only the PI and study coordinator can 
see the names. All case report forms will use the assigned subject ID. Since the 
subject participation is only for one visit, there will be limited opportunity for 
privacy interests to arise between study recruitment and end of the study. The only 
extra intrusion of privacy will be an additional phone call at 2 and 30 days after the 
procedure to ensure that the subject has not suffered any adverse events. During the 
follow-up, only the study coordinator and/or the PI will have contact with the 
subject. Information pertaining to the study will only be discussed with the subject 
and messages containing identifiers of the subject's participation will not be left on 
voice-mail messages 

 
20 of 41 
7.4 
Reporting Procedures 
PI will inform local and IRB of record within 5 days of SAE reporting. AEs will be reported 
to the IRB annually at renewal. Any event that is reportable to IRB will also be reported to 
the DLDCCC Data Review Committee (DRC) via the Patient Safety Officer at dldcc-
pso@bcm.edu.  
 
Any event that is reportable to the BCM IRB must also be reported by the BCM PI to the 
FDA via safety reports and in the annual report. Unexpected fatal or life-threatening 
adverse drug experiences will be reported within 7 calendar days. Serious and unexpected 
adverse drug experiences will be reported within 15 calendar days. 
 
7.5 
Follow up for Adverse Events 
Upon completion of the study imaging, subjects will be contacted to screen for adverse 
events after a period of 2 and 30 days from procedure. Patients with abnormal laboratory 
or clinical findings will be followed until the condition resolves or stabilizes, or until the 
laboratory values are no longer considered clinically significant. Adverse events or serious 
adverse events that occur during the follow-up period will be recorded regardless of 
relatedness to the study procedure. The safety follow-up may be conducted by a phone call 
or a clinic visit; if clinically indicated, a clinic visit should be performed along with relevant 
lab work. 
 
Patients will be contacted via phone at 1- and 2-years post-appointment for follow up 
evaluation. See MOP for further details.  
7.6 
Safety Monitoring  
100% of serious adverse events will be monitored by the PI and study team.  Because this 
is a low risk study there is no Data Safety Monitoring Board. Adverse events will be 
reviewed annually by the IRB. Serious adverse events will be reported within 5 days by 
the PI to IRB. Any event that is reportable to the IRB will also be reported to the DRC and 
FDA in accordance with their polices. 
8. INTERVENTION DISCONTINUATION  
N/A 
9. STATISTICAL CONSIDERATIONS  
9.1 
General Design Issues  
The primary outcome of this cross- sectional study is to measure the operating 
characteristics including SN, SP, PPV and NPV comparing the physician- and algorithm- 
guided HRME-based image compared to the Lugol’s- guided physician diagnosis of HSIL 
during HRA.  

 
21 of 41 
9.2 
Sample Size and Randomization 
The study will primarily be powered to determine the precision around the operating 
characteristics of mHRME imaging. We estimate that because the median number of 
lesions per patient is approximately 1.5-2, and HSIL prevalence of 30%, approximately 
150 patients (225-300) lesions will be needed to estimate the confidence intervals around 
SN and SP estimates see Table 1 below. In order for 150 patients to complete study 
procedures, we will target a total enrollment of 200, because we will also be improving 
the technology as a secondary objective and assume that up to 30% of patients may not 
have evaluable optimized HRME images. 
 
Precision calculation 
 
The damage to precision due to within-subject correlation is mitigated by the fact that 
the average number of per-patient slides is at most 2. Correlation = 0.5 is a high 
estimate, but the table below shows precision values close to the original independence-
assumption based ones. 
 
SN/SP estimate ½ width CI for 225 slides ½ width CI for 300 slides 
 
indep 
corr = 0.5 
indep 
corr = 0.5 
10% 
4.66% 
6.99% 
3.94% 
5.91% 
15% 
5.28% 
7.93% 
4.50% 
6.75% 
20% 
5.74% 
8.61% 
4.91% 
7.37% 
25% 
6.07% 
9.10% 
5.21% 
7.82% 
30% 
6.30% 
9.46% 
5.43% 
8.14% 
35% 
6.46% 
9.69% 
5.57% 
8.35% 
40% 
6.54% 
9.81% 
5.65% 
8.47% 
45% 
6.55% 
9.82% 
5.67% 
8.50% 
50% 
6.50% 
9.74% 
5.63% 
8.45% 
55% 
6.55% 
9.82% 
5.67% 
8.50% 
60% 
6.54% 
9.81% 
5.65% 
8.47% 
65% 
6.46% 
9.69% 
5.57% 
8.35% 
70% 
6.30% 
9.46% 
5.43% 
8.14% 
75% 
6.07% 
9.10% 
5.21% 
7.82% 
80% 
5.74% 
8.61% 
4.91% 
7.37% 
85% 
5.28% 
7.93% 
4.50% 
6.75% 
 
Treatment Assignment Procedures 
All participants will undergo HRME-imaging prior to biopsy 
9.3  
Definition of Populations 
HIV infected men and women with either previously documented HSIL or abnormal anal 
cytology within the past 2 years. 
 

 
22 of 41 
Please see section 4.1 and 4.2 for inclusion and exclusion criteria description 
9.4 
Interim Analyses and Stopping Rules 
N/A 
9.5 
Outcomes  
9.5.1 Primary Outcome   
The primary outcome are the performance characteristics: SN, SP, PPV, NPV 
 
9.5.2 Secondary Outcomes   
The first secondary outcome is efficiency (number of potential biopsies averted, 
reduction in procedure time). 
 
The second secondary outcome is to develop and optimize i) a mobile high-
resolution microendoscope (mHRME) and 3D image mapping for anal HSIL 
diagnosis and ii) image-analysis software during HRA. 
 
 
 
9.6 
Data Analyses  
Objective 1. We will determine the performance characteristics of mHRME for the 
prediction of anal HSIL in flat mucosa and mucosal lesions using histopathology as the 
gold standard. Our hypothesis is that the sensitivity (SN) specificity (SP), positive 
predictive value (PPV) and negative predictive value (NPV), as well as the receiver 
operating curve for the identification of neoplasia on a per biopsy and per patient basis will 
be high. We will first compare the HRA-directed biopsy (as the gold standard) to the results 
of the mHRME HSIL diagnosis. The SN of mHRME diagnosis in detection of HSIL will 
be estimated with the binomial proportion of study participants who are positive for HSIL 
on HRA-guided biopsy at two thresholds of histology thresholds which are: 1) AIN 2+ 
threshold, and 2) AIN3+ threshold. SP will be estimated as the proportion of study 
participants who are negative for HSIL on HRA-guided biopsy at both thresholds. Positive 
and negative predictive values will be estimated using the binomial proportion and its 95% 
CI. In addition, the Cohens kappa statistic, and receiver operator characteristic curves will 
be generated if patient characteristics such as low CD4 count, cART utilization, or high 
HIV viral load impact the determination of SN and SP. The lab information will be 
collected and placed in the source document and entered in Oncore. SN and SP of 
mHRME-based HSIL diagnosis will be estimated on a per lesion and per patient basis with 
95% confidence intervals and compared by McNemar's test. A generalized linear model 
for logistic regression with multiple correlated outcomes will compare SN and SP of each 
method on a per biopsy and per patient basis. For Device optimization: No Data Analyses 
are planned.  
 
Objective 2a. Determine clinical efficiency of mHRME + HRA for the diagnosis of HSIL. 
Clinical efficiency is defined as: `Diagnostic Yield: Percent of HRME diagnosed HSIL 
lesions that were classified as non-HSIL by clinician. `Biopsies averted: Percent of HRA-
visualized lesions that the clinician originally categorized as potentially needing a biopsy 

 
23 of 41 
but on mHRME were appropriately down-graded, averting an unnecessary biopsy. 
Procedure time: Total procedure time (mHRME and HRA). For Diagnostic Yield and 
Biopsies Averted, we will estimate 95% confidence intervals. Total procedure time will be 
recorded. mHRME Procedure time will measured separately once mHRME is initiated. 
Median and standard deviation of procedure times and mHRME procedure times will be 
calculated. 
 
Objective 2b. Images collected from the 50 patients will be compared to biopsies. 
Preliminary Sensitivity, Specificity, positive predictive value (PPV) and negative 
predictive values (NPV) will be estimated and precision of interval width calculations will 
be done. 
10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 
Data Collection Forms  
Study data will be collected at all clinical sites on paper CRFs identifiable by subject ID 
number. The electronic CRFs in OnCore are the official study documents. Local CRCs will 
enter data for their site (Mt. Sinai CRC will enter Mt. Sinai data, BCM CRC will enter 
BCM data) into OnCore. The CRCs will enter data on both paper and OnCore. CRF scans 
will be stored electronically in BCM-approved platform Box. 
10.2 
Data Management  
Data will be stored securely at the Coordinating Center. Data and safety monitoring will 
be performed by the study statistician and external research coordinator (BCM Global 
Health). Data will be entered into the web application by authorized research personnel via 
secure HTTPS connections. De-identified data will be shared with the Co-investigators at 
Baylor, Mount Sinai, UC San Francisco, Medical University of South Carolina, and Rice 
University. 
 
Only deidentified images (microscopic images) will be analyzed at Rice University, by the 
bioengineers who developed the devices and are collaborating on the project. The Rice 
team will not be responsible for other data analyses, interim/final or DRC report. The 
device being used in this study (the HRME) is manufactured in Dr. Richards-Kortum's lab 
at Rice University. The images collected from the clinical trial are used to build software 
that will work to automatically analyze data. While images are de-identified, some PHI 
will be transmitted (Date of Service only). A data use agreement will be issued stating this.  
 
De-identified histopathologic slides will be shared with and read by a consensus 
pathologist at UCSF. All histopathologic slides and optical images will be labeled with the 
subjects study ID number and will be presented to the pathologist who will read them in a 
blinded fashion. The subjects' clinical research forms with the associated optical biopsy 
read(s) are similarly labeled with the subjects study ID number. There is no PHI shared 
with the slides. Material transfer agreements between BCM-UCSF & Mt. Sinai-UCSF and 
will be issued. 

 
24 of 41 
10.3 
Quality Assurance  
10.3.1 Training 
All study staff have undergone their institutions’ human subjects research and good 
clinical practice training. They will undergo OnCore training, training on CRF 
completion and data quality assurance. In addition, during the study start-up visit, 
all study staff will undergo training in HRME care, disinfection, and technical 
support. 
10.3.3 Metrics 
Device qualification: Each mHRME and smart ring camera will undergo full quality 
control at the manufacturing facility prior to clinical use. Metrics to be evaluated include: 
illumination power & uniformity, spatial resolution, camera response, signal/noise ratio, 
accuracy of N/C area ratio and mean feature area as measured from standardized test 
targets. Illumination uniformity and camera response will be measured using a high-
resolution imaging standard (e.g., 1951 USAF Hi-Resolution Target, Edmund Optics). 
Accuracy of N/C area ratio and mean feature area measurements will be evaluated using a 
test standard with a uniform standardized spatial pattern (e.g., 2285-26N image analysis 
standard slide, Ted Pella, Inc, or equivalent). Performance metrics will be required to be 
within 10% of target values prior to distribution to clinical sites. 
 
Site performance: Initial visits to both sites will ensure proper training on the optimized 
mHRME, as well as allow for provider feedback on the modifications. Annual visits to the 
New York sites and weekly review of ALL video images from every patient accrued in the 
pilot trial provides assurance that the devices are performing consistently and uniformly.  
To insure further uniform performance, imaging test standards and training (described 
above) will be provided to technical personnel. Site technicians will be trained in device 
use, disinfection/sterilization, realignment and basic repairs; spare parts (LED modules, 
probes, cameras) will be available at all sites. Devices that cannot be repaired will be 
returned to Rice or Baylor for repair. An additional trip will be made at study initiation to 
ensure that the enhanced mHRME systems and image-assist software are standardized and 
functioning and at least annually thereafter.  
 
The gold standard histologic diagnosis will be based on a consensus pathology review. 
After the result for the local pathologist is documented, the slides will be reviewed by 
another pathologist (who is blinded to the original review). If the two reads differ, then the 
histopathology slide will be adjudicated by a third pathologist. The final read will ensure 
consensus by 2 pathologists. 
 
10.3.4 Protocol Deviations 
All protocol deviations will be reported to IRB and DRC in accordance with their policies.  
 
In the event of an emergency, the sponsor and the reviewing IRB and DRC will be notified of any 
deviation from the protocol to protect the life or physical well-being of a subject. Such notice shall 
be given no later than 5 working days after the emergency occurred. 
 

 
25 of 41 
Otherwise, the quality monitoring processes by which deviations were identified, and process 
changes to prevent unintended variances will be reported to the IRB and DRC at continuing review. 
 
10.3.5 Monitoring 
All the study data (including Mt. Sinai and Houston data) will be monitored regularly by 
the Data Review Committee (DRC) of the Dan L Duncan Comprehensive Cancer Center, 
at a frequency of at least once per year, in accordance with the DLDCCC Data and Safety 
Monitoring Plan. The DRC will monitor the study for progress and enrollment, toxicities, 
adverse events, and soundness of data. Additionally, an independent research coordinator 
from BCM will monitor and review 25% of the data for accuracy  
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 
Institutional Review Board (IRB) Review  
This project will comply with the National Institutes of Health (NIH) Policy on the Use of 
a Single Institutional Review Board (sIRB) of Record for Multi-Site Research. The 
proposed project will use the same protocol to conduct non-exempt human subjects 
research at four locations, and will not initiate human subjects research prior to obtaining 
sIRB approval. 
 
sIRB – Institutional Review Board for Baylor College of Medicine and Affiliated 
Hospitals (BCM IRB), Houston, TX. All project sites (the Icahn School of Medicine at  
Mount  Sinai,  University  of  Florida, University of California, San Francisco and Rice  
University) have agreed to allow the BCM IRB to serve as the sIRB for this project. The 
BCM IRB will conduct the ethical review required by the Department of Health and Human 
Services regulations for the Protection of Human Subjects at 45 CFR Part 46 for all project 
sites. The BCM IRB also will serve as a Privacy Board to fulfill the requirements of the 
HIPAA Privacy Rule for use or disclosure of protected health information for research 
purposes. 
 
The BCM IRB operates under the BCM Federal Wide Assurance No. 00000286, as well 
as those of hospitals and institutions affiliated with the College. 
 
Should the project add any new sites after award, those sites also will rely on the BCM IRB 
as the sIRB of record. 
 
Participating Sites – All participating sites will adhere to the sIRB Policy and will rely on 
BCM IRB to carry out the functions that are required for institutional compliance with IRB 
review set forth in the HHS regulations at 45 CFR 46. Participating sites will be responsible 
for meeting other regulatory obligations, such as obtaining informed consent, overseeing 
the implementation of the approved protocol, and reporting unanticipated problems and 
study progress to BCM IRB. 
 
Participating sites will communicate relevant information necessary for the BCM IRB to 
consider local context issues and state/local regulatory requirements during its 

 
26 of 41 
deliberations. Participating sites are expected to rely on the BCM IRB to satisfy the 
regulatory requirements relevant to the ethical review. The investigators and local sites 
understand that although IRB ethical review at the local site level would be counter to the 
intent and goal of this policy, the policy does not prohibit any participating site from 
duplicating the sIRB. However, the PIs understand that if this approach is taken, NIH funds 
may not be used to pay for the cost of the duplicate review. 
 
All participating sites will, prior to initiating the study, sign an authorization/reliance 
agreement that will clarify the roles and responsibilities of the BCM IRB and the 
participating sites. The BCM IRB will maintain records of the authorization/reliance 
agreements and of the communication plan. 
 
Communications Between Participating Sites BCM IRB – BCM IRB will collaborate 
with the BCM PI to establish a mechanism for communication between BCM PI and the 
participating sites. The proposed plan is as follows: 
 
1) The 
BCM 
uses 
the 
SMART 
IRB 
platform 
to 
initiate 
and 
establish 
authorization/reliance agreements and prior to any site initiating the research, each site 
will sign an authorization/reliance agreement that will clarify the roles and 
responsibilities of the BCM IRB and participating sites. These reliance agreements will 
be maintained at the BCM IRB office as well as with each participating site. 
2) The BCM PI, with assistance from the BCM IRB office, will collect local context 
issues and federal/state/local regulatory requirements for each participating site. 
3) The BCM PI will develop master study specific templates for Informed Consent Form 
(ICF), as well as HIPAA authorization, which will include local context for all 
participating sites and submit a single protocol to the BCM IRB that will be reviewed, 
approved, and used at all participating sites. 
4) After BCM IRB reviews and grants final approval, the BCM PI will provide the 
participating sites with the IRB-approved versions of all study documents. 
5) The BCM PI will be responsible for preparing and submitting IRB applications on 
behalf of all sites, including initial reviews, local amendments, personnel updates, local 
reportable events, and study wide information for continuing review. 
6) The BCM PI will be responsible for communicating all IRB actions and determinations 
to all participating sites as well as maintaining the documentation of all required 
communications with participating sites under this plan. 
11.2 
Informed Consent Forms 
The Baylor PI will develop master study specific templates for Informed Consent Form 
(ICF), as well as HIPAA authorization, which will include local context for all 
participating sites and submit a single protocol to the BCM IRB that will be reviewed, 
approved, and used at all participating sites. The BCM PI will be responsible for 
preparing and submitting IRB applications on behalf of all sites, including initial 
reviews, local amendments, personnel updates, local reportable events, and study wide 
information for continuing review.  
 

 
27 of 41 
All participating sites will adhere to the sIRB Policy and will rely on BCM IRB to carry 
out the functions that are required for institutional compliance with IRB review set 
forth in the HHS regulations at 45 CFR 46. Participating sites will be responsible for 
meeting other regulatory obligations, such as obtaining informed consent, overseeing 
the implementation of the approved protocol, and reporting unanticipated problems and 
study progress to BCM IRB. 
11.3 
Participant Confidentiality  
Participation in research may involve loss of privacy. Research records will be handled 
as confidentially as possible within the law. All records linking patient identifiers with 
unique study identifiers will be coded and kept in password protected files, so that only 
the study investigators have access to them. All data and information will be stored in 
files that are stripped of identifiers. No individual identities will be used in any reports 
or publications resulting from this study. The subject records may be reviewed by the 
research staff, and the study site Institutional Review Board, the National Institutes of 
Health (NIH), the Office for Human Research Protections (OHRP), and their designees. 
 
We plan to obtain a Certificate of Confidentiality from the National Institutes of Health. 
With this Certificate, the researchers cannot be forced to disclose information that may 
identify the subject, even by a court subpoena, in any federal, state, or local civil, 
criminal, administrative, legislative, or other proceedings. The researchers will use the 
Certificate to resist any demands for information that would identify the subject, except 
as explained below. The Certificate cannot be used to resist a demand for information 
from personnel of the United States Government that is used for auditing or evaluation 
of federally funded projects or for information that must be disclosed in order to meet 
the requirements of the federal Food and Drug Administration (FDA). 
11.4 
Study Discontinuation  
The study may be discontinued at any time by the IRB, the DLDCCC DRC, the NIH, 
the OHRP, the FDA, or other government agencies as part of their duties to ensure that 
research participants are protected. The participant has the right to withdraw from the 
study at any time. 
12. COMMITTEES 
N/A 
13. PUBLICATION OF RESEARCH FINDINGS  
Publications will be reviewed by the co-PIs and the co-Is of the study 
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Bower M, Powles T, Newsom-Davis T, et al. HIV-associated anal cancer: has highly active 
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Colon-Lopez V, Shiels MS, Machin M, et al. Anal Cancer Risk Among People With HIV 
Infection in the United States. J Clin Oncol. 2017:JCO2017749291. 
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Piketty C, Selinger-Leneman H, Bouvier AM, et al. Incidence of HIV-related anal cancer 
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Ong JJ, Fairley CK, Carroll S, et al. Cost-effectiveness of screening for anal cancer using 
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7. 
New York State Department of Health AIDS Institute. Clinical Guidelines: 
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Pineda CE, Berry JM, Jay N, Palefsky JM, Welton ML. High-resolution anoscopy targeted 
surgical destruction of anal high-grade squamous intraepithelial lesions: a ten-year experience. 
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Pineda CE, Welton ML. Controversies in the management of anal high-grade squamous 
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Freedman M, Weiser J, Beer LR, RL S. Anal cancer screening in men who have sex with 
men in care for HIV infection, United States, 2009-2012. In. IDWeek 2016, October 26-30: 
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Grant BD, Fregnani JH, Possati Resende JC, et al. High-resolution microendoscopy: a 
point-of-care diagnostic for cervical dysplasia in low-resource settings. Eur J Cancer Prev. 
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Protano MA, Xu H, Wang G, et al. Low-Cost High-Resolution Microendoscopy for the 
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Varela B, Shin D, Perl D, et al. High-Resolution Microendoscopy (HRME) in the Detection 
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Crum-Cianflone NF, Hullsiek KH, Marconi VC, et al. Anal cancers among HIV-infected 
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15. SUPPLEMENTS/APPENDICES 
Appendix 1: Manual of Operations 
 
MOP - HRME at Thomas Street Clinic 
H-44616: THE EFFECTIVENESS OF HIGH RESOLUTION MICROENDOSCOPY 
(HRME) IN HIGH GRADE INTRAEPITHELIAL LESIONS (HSIL) DIAGNOSIS FOR 
PEOPLE LIVING WITH HIV 
Supplies to take: 
• Proflavine (dispensed from Investigational Pharmacy) 
• Pen 
• Staple remover  
• Stapler 
• Research charts (Consent Forms, CRF, Questionnaires, Proflavine Order form)  
• Watch/phone 
 
4 Weeks Prior to Clinic: 
 
1. Patient is identified either by looking at clinic schedule or in clinic by Physician. Physician 
notifies CRC (via email or phone) to provide consent form for patient’s review.  
 
2. Physician discusses procedure with patient and answers questions. Physician adds note in Epic 
that procedure was discussed (using templates below).  If patient is interested and agrees to 
enroll, use Epic Note Template #1 and continue to Step 3. If patient wants to keep consent 
form and further review, use Epic Note Template #2 and instruct patient not to sign consent. 
If patient is not interested, use Epic Note Template #3 so they are not approached again.  
   
Epic Note Templates 
 
#1: If patient wants to enroll 
“I discussed study H-44616 with the patient, including study procedures. Patient was enrolled on 
[date].  Study procedure is being scheduled.”  
 
 #2: If patient wants to further review 
“I discussed study H-44616 with the patient, including study procedures. A copy of the consent 
form was given to the patient for his/her review, with instructions not to sign the consent until they 
returned to clinic. The patient can contact clinical research coordinator to follow-up regarding 
questions and interest in participating.” 
 
#3: If patient is not interested 
“I discussed study H-44616 with the patient, including study procedures. Patient was not interested 
in study and should not be approached again.” 
 
3. The CRC should sign and date the consent form after the patient has signed. If a translator 
and foreign language consent form were used, the translator will sign and date on translator 
line.  The original consent form(s) will remain in the research chart. Make two copies of the 
signed consent form(s). Place one copy of all languages used in the medical chart for scanning 

 
36 of 41 
into Epic by the nurse and give a copy/copies to the subject. The subject’s copy should have 
CRC’s contact info written on it (or business card) so the subject can contact our office with 
any questions or concerns. 
 
4. Take the patient ID stickers from the medical chart. Place a sticker on each page of the consent 
form. If a foreign language consent form is used, place stickers on each page of both consent 
forms.  
 
5. CRC completes pages 1-2 of the CRF and questionnaire packet at time of consent in English 
or in Spanish (HRME Sexual Behaviors and Sexual History for men and women, EQ-5D-5L).  
 
6. Procedure is scheduled (by research scheduler). 
 
7. CRC verifies the appointments have been scheduled by reviewing Epic and confirms with 
patient over the phone.  
 
8. CRC registers patient in OnCore and assigns patient study ID based on OnCore ID.  
 
7 Days Prior to Clinic: 
9. CRC completes the Proflavine order form for study by providing, name, DOB, MRN, and 
study ID (or placing patient sticker with above information). CRC verifies patient allergies in 
Epic (Iodine, Proflavine).  
 
10. Send the completed Proflavine order form to Investigational Drug Service to prepare the 
Proflavine batch. Place confirmation (email/fax confirmation) and original Proflavine order 
form in the research chart. 
 
11. CRC will inform HRME operator of the date and time of HRME clinic, and the anticipated 
number of HRME study patients. 
 
2 Days Prior to Clinic: 
12. CRC will send reminder email to physician and HRME operator to remind them of clinic 
schedule. 
 
13. CRC prepares research charts for n+1 (extra) patients scheduled for that clinic. Research 
charts should include the following: consent form (English, Spanish), CRF, questionnaires, 
and Proflavine order form. Research charts will be stored in CRC’s locked office file cabinet.  
Day of Clinic: CRC will coordinate with the physician’s clinic staff to block off appropriate 
number of slots. 
 
14. CRC arrives at clinic 30 minutes before scheduled clinic appointment to set up. CRC picks 
up Proflavine from Investigational Drug Service. 
 

 
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15. Once a patient is checked in, CRC leads them back to research office or procedure room to 
complete any unfinished questionnaires and baseline symptoms screen. 
 
16. Complete pages 2-10 of the CRF with the subject, using the translation services if necessary. 
The baseline symptoms form should be completed the day of the procedure. 
 
17. Record the Proflavine lot number and expiration date from the syringe packaging in CRF. 
 
18. Give Proflavine to nurse in procedure room to administer during procedure and log into Epic. 
 
19. During the procedure, complete the CRF (pages 11-20).  
 
a. Record scope in time, HRA start time (page 12) 
b. Record first abnormal area as Biopsy 1 (page 13)  
i. Describe lesion, mark location, take anoscopy image  
ii. Record clinician HRA read, plan (standard of care)  
c. Go onto second abnormal area as Biopsy 2 (page 14)   
i. Describe lesion, mark location, take anoscopy image  
ii. Record clinician HRA read, plan (standard of care)  
d. Repeat above steps for each abnormal area using extra biopsy pages if necessary 
e. Record HRA end time. Apply Proflavine, insert HRME. Record HRME start time.  
f. Proceed to first abnormal area (Biopsy 1)  
i. Once feed is in focus, freeze HRME  
ii. Record clinician read and plan based on HRME image 
iii. Analyze image. Record image number and score. 
iv. Ask clinician if they are happy with this image or if they would like to take 
another. Take as many images as needed, using extra biopsy pages if 
necessary 
v. Select best image of site (most representative)  
g. Go onto Biopsy 2.  
i. Once feed is in focus, freeze HRME  
ii. Record clinician read and plan based on HRME image 
iii. Analyze image. Record image number and score. 
iv. Ask clinician if they are happy with this image or if they would like to take 
another. Take as many images as needed, using extra biopsy pages if 
necessary 
v. Select best image of site (most representative) 
h. Repeat above steps for each Biopsy using extra biopsy pages if necessary 
i. Record end HRME time. Remove HRME attachment and insert biopsy forceps. 
Record biopsy start time.  
j. Proceed to Biopsy 1, biopsy area. Place sample in labeled specimen container. 
Record specimen label.  
k. Repeat for each biopsy.  

 
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l. Record biopsy end time.  
m. Record scope out time.  
Within 2 Days of the Clinic: 
20. Within 2 days of the procedure, CRC calls the study participant and complete the Follow Up 
Symptoms form. Be sure to provide the study participant with CRC and PI phone number 
(business card/consent form) in case of any adverse events. Any adverse events or serious 
adverse events reported during the phone call should be reported to PI within 24 hours of 
being reported. If applicable, the CRC and PI will complete the Serious Adverse Event form. 
The PI will inform the local and IRB of record if needed within 5 days. 
Within 30 Days of the Clinic: 
21. Within 30 days of the procedure, CRC calls the study participant and complete the Follow Up 
Symptoms form. Be sure to provide the study participant with CRC and PI phone number 
(business card/consent form) in case of any adverse events. Any adverse events or serious 
adverse events reported during the phone call should be reported to PI within 24 hours of 
being reported. If applicable, the CRC and PI will complete the Serious Adverse Event form. 
The PI will inform the local and IRB of record if needed within 5 days.  
 
22. CRC obtains the HRA procedure report, local pathology diagnosis from Epic. Place them in 
study participant’s research chart. Record the local pathology diagnosis for each biopsy in 
CRF. 
 
23. Request images from HRME operator. 
 
24.  CRC reviews chart, source documents, consent form, and Epic record for each local subject. 
 
25. After completion of all study requirements, CRC and site PI will sign and date the Study 
Completion Form. 
 
26. CRC scans the de-identified CRF and HRA procedure report, collects HRME images, and 
uploads into Box. 
 
27. Paper copy of the original CRF and print out of pathology report, along with consent form 
and print out of HRA procedure report, are filed in CRC’s office. Research charts should be 
stored in locked file cabinet when not in use. Secure workstation (Epic, computer, charts) if 
away from desk. 
 
28. CRC will complete data entry in OnCore. 
 
29. Data entered into OnCore will be monitored by Project Manager at Baylor College of 
Medicine including 100% of adverse events and ICFs and 25% of all charts at both sites. 
 

 
39 of 41 
30. The BCM IRB will annually review all adverse events. SAEs will be reported and reviewed 
within 5 days. Any event that is reportable to the BCM IRB will also be reported to the 
DLDCCC DRC and FDA in accordance with their policies. 
Follow Up Evaluation:  
At 1 year and 2 years post-enrollment, patients will be contacted via phone to assess rates of disease 
progression and recurrence. Patients will be contacted 3 times within 3 months of follow up time 
point. If they are unable to be reached, they will be designated “lost to follow up”.  
 
Adverse Event/Serious Adverse Event Definition  
Serious adverse events will count as Grade 3 (Severe or Medically Significant, but not Immediately 
Life Threatening: Hospitalization or Prolongation of Hospitalization Indicated; Disabling; 
Limiting Self Care ADL), Grade 4 (Life-threatening consequences; urgent intervention indicated) 
or Grade 5 (Death related to AE).  
 
Data Safety Monitoring  
We will follow the Cancer Therapy Evaluation Program (CTEP) guidelines for reporting of 
adverse events. All expedited adverse event reports are required to be submitted to the local 
Institutional Review Board (IRB) of the reporting institution. Baylor College of Medicine has a 
standardized system for data and safety monitoring used by all investigators conducting NIH-
funded research on patients. This includes a preliminary evaluation by the Dan L. Duncan Cancer 
Center (DLDCC) PRMC during the scientific review process, and an Institutional Review Board 
(IRB) review of serious and unexpected adverse events. Additionally, an independent research 
coordinator from BCM will monitor and review 25% of the data for accuracy , and 25% of all 
charts at both sites. 100% of adverse events will be monitored by the PI and study team. On site 
audits will be conducted every 6 months. Madeleine Allman (Research Coordinator) and Dr. 
Anandasabapathy will handle all reporting to the FDA for IND for proflavine. 
 
All the study data (including Mt. Sinai and Houston data) will be monitored regularly by the 
DLDCCC DRC Data Review Committee (DRC) of the Dan L Duncan Comprehensive Cancer 
Center, at a frequency of at least once per year, in accordance with the DLDCCC Data and Safety 
Monitoring Plan. The DRC will monitor the study for progress and enrollment, toxicities, adverse 
events, and soundness of data. Each site will plan to have weekly meetings. At each weekly 
meeting, the Project Coordinator will provide the following information: number of participants 
entering the study, status with respect to meeting recruitment targets, percentage of patients 
assessed who enter the study, number of drop-outs, reasons for drop-out, percentage of patients at 
each stage of the project, and percentage of assessments completed at each assessment point. 
Information about any adverse events (including IRB reporting of short- and long-term remedies) 
also will be presented. By examining this information, the data and safety monitoring team will 
keep abreast of critical issues regarding recruitment and data integrity. Study staff also will notify 
at least one supervisor immediately if at any point a patient shows the need for urgent treatment 
(e.g. diagnosis of cancer). A written report containing the current status the trial monitored while 
the IND is active, and when appropriate, any toxicity and outcome data, are sent to DRC members 
at a frequency specified by the DRC Charter, which is usually annually. 
 
 
 
 

 
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Helpful phone numbers: 
Harris Health Translation Services 
Thomas Street Translator: 713-873-9782 
 
Investigational Drug Service (IDS): Celia Fenceroy, Pharmacist 
Email: INVdrugs@harrishealth.org 
Fax: 713 873-4455 
Office: (713) 873-4457 
Pager: (281) 963-0802 
 
HRME Operator: Yubo Tang  
Email: ytang@rice.edu 
 
Cell: (281) 908-9364 
 
Consent forms – who signs, who gets a copy?  
Using translated short form: 
 
Short form 
English long form 
Subject 
Signs, gets a copy 
Gets a copy 
Witness/translator 
Signs 
Signs 
PI/designee 
- 
Signs 
 
Using Spanish long form: 
 
Spanish long form 
English long form  
Subject 
Signs, gets a copy 
Gets a copy 
Witness/translator 
Signs 
Signs 
PI/designee 
Signs 
Signs 
**If designee is fluent in Spanish, he/she can sign as translator but must have a witness fluent in 
both languages to sign as the witness 
 
 
 
 
 
 

 
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Appendix 2: Study Calendar  
 
Form 
Day 0 (Procedure Day) 
Day 2 
Day 30 
Year 1 Year 2 
Procedure Form  
 
 
 
 
 
Symptoms  
X 
X 
X 
 
 
HRA Assessment  
X 
 
 
 
 
Procedure Time  
X 
 
 
 
 
HRME and Biopsy  
X 
 
 
 
 
Pathology  
X 
 
 
 
 
Medical History Form 
 
 
 
 
 
Medical History  
X 
 
 
 
 
Physical Exam 
X 
 
 
 
 
Cyto/Pathology Review  
X 
 
 
 
 
Post Procedure Form 
 
 
 
 
 
Post Procedure Questionnaire  
X 
 
 
 
 
Follow Up Evaluation  
 
 
 
X 
X