Repeat Surgery for Patients With Post-operative Trachomatous Trichiasis Trial
Phase: NA
Conditions: Trichiasis, Surgery
Sponsor: University of North Carolina, Chapel Hill

 
 
Repeat Surgery for Patients with 
Post-Operative Trichiasis (PTT) Trial 
Protocol 
 
NCT number NCT03886519 
Document Date 05/08/2020 
 

 
Version 4.0 
Repeat Surgery for Patients with Post-Operative Trichiasis Trial 
8 May 2020 
 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
 
 
 
 
 
Repeat Surgery for Patients with  
Post-Operative Trichiasis (PTT) Trial 
Protocol 
 
 
 
 
Randomized Controlled Trial 
NCT03886519 
 
 
A Collaborative Operational Research Project between SNNPR, Oromia and 
Amhara Regional Health Bureau, Orbis International Ethiopia, Fred Hellows 
Foundation, The Carter Center and University of North Carolina (UNC)  
 
 
Version Number: 4.0 
8 May 2020   
 

 
 
i 
 
STATEMENT OF COMPLIANCE 
The study will be conducted in accordance with the International Conference on 
Harmonisation guidelines for Good Clinical Practice (ICH E6), the Code of Federal 
Regulations on the Protection of Human Subjects (45 CFR Part 46), and the NIDCR 
Clinical Terms of Award. All personnel involved in the conduct of this study have 
completed human subjects protection training. 
 
This protocol is modeled in part based on NIDCR Clinical Trial (Interventional) Protocol 
Template v4.0 - 20140103 
 

 
 
ii 
 
 

 
 
iii 
TABLE OF CONTENTS 
PAGE 
STATEMENT OF COMPLIANCE ................................................................................................. I 
TABLE OF CONTENTS ............................................................................................................. III 
LIST OF ABBREVIATIONS AND ACRONYMS .......................................................................... V 
PROTOCOL SUMMARY ............................................................................................................. 1 
STUDY DESIGN SCHEMATIC: .................................................................................................. 3 
1.1 
Timeline and Feasibility of Adhering to Study Schedule ..................................................... 0 
2. 
KEY ROLES AND CONTACT INFORMATION ................................................................... 1 
3. 
INTRODUCTION ................................................................................................................ 4 
3.1 
MTSS Trial ......................................................................................................................... 4 
3.2 
Background and Rationale ................................................................................................. 4 
3.3 
Potential Risks and Benefits ............................................................................................... 5 
3.4 
Study Objectives ................................................................................................................ 6 
3.5 
Study Endpoints ................................................................................................................. 6 
4. 
STUDY DESIGN ................................................................................................................ 8 
4.1 
Overall Design .................................................................................................................... 8 
4.2 
Scientific Rationale for Study Design .................................................................................. 8 
4.3 
End of Study Definition ....................................................................................................... 8 
4.4 
Data Collection and Management ...................................................................................... 8 
5. 
STUDY POPULATION ..................................................................................................... 10 
5.1 
Subject Inclusion Criteria .................................................................................................. 10 
5.2 
Subject Exclusion Criteria ................................................................................................. 10 
5.3 
Strategies for Recruitment and Retention ......................................................................... 10 
6. 
STUDY INTERVENTION .................................................................................................. 12 
6.1 
Study Intervention Description .......................................................................................... 12 
 
Trabut........................................................................................................ 12 
 
BRAP ........................................................................................................ 12 
6.2 
Randomization Procedures .............................................................................................. 14 
 
Masking Procedures .................................................................................. 15 
6.3 
Assessment of Clinician and/or Subject Compliance with Study Procedural 
Intervention ............................................................................................................................... 15 
6.4 
Procedures for Training of Clinicians on Procedural Intervention ...................................... 15 
6.5 
Procedures for Ensuring BRAP Surgery is Performed According to Study 
Procedure ................................................................................................................................. 16 
6.6 
Study Procedural Intervention Description ........................................................................ 16 
7. 
STUDY DISCONTINUATION, PARTICIPANT DISCONTINUATION OR WITHDRAWAL . 17 
7.1 
Subject Withdrawal ........................................................................................................... 17 
7.2 
Lost to Follow-Up ............................................................................................................. 17 
8. 
STUDY ASSESSMENT PROCEDURES .......................................................................... 18 
8.1 
Efficacy Assessment ........................................................................................................ 18 
9. 
STATISTICAL CONSIDERATIONS .................................................................................. 19 
9.1 
Study Hypotheses ............................................................................................................ 19 

 
 
iv 
9.2 
Sample Size Considerations ............................................................................................ 19 
9.3 
Analysis Plan .................................................................................................................... 20 
10. 
STUDY ASSESSMENT PROCEDURES .......................................................................... 23 
10.1 Eligibility Screening, Eye Exam, and Consent .................................................................. 23 
10.2 Enrollment and Surgery .................................................................................................... 24 
10.3 Follow up Visits ................................................................................................................ 24 
10.4 Unscheduled Visit ............................................................................................................. 24 
11. 
PROVISIONS FOR MONITORING STUDY PROGRESS ................................................. 25 
11.1 Data and Safety Monitoring Board .................................................................................... 25 
12. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............. 26 
12.1 Regulatory, Ethical, and Study Oversight Considerations ................................................. 26 
 Informed Consent Process ........................................................................ 26 
 Subject Confidentiality ............................................................................... 26 
 Ethical Standards ...................................................................................... 27 
 Institutional Review Board ......................................................................... 27 
 Exclusion of Women, Minorities, and Children (Special Populations) ........ 27 
 Quality Assurance and Quality Control ...................................................... 27 
13. 
PUBLICATION/DATA SHARING POLICY ........................................................................ 30 
14. 
CONFLICT OF INTEREST ............................................................................................... 31 
15. 
REFERENCES ................................................................................................................. 32 
 

 
 
v 
List of Abbreviations and Acronyms 
 
Abbreviation and Acronyms 
Name 
BLTR 
Bilamellar Tarsal Rotation 
BRAP 
Bevel/rotate/advance procedure 
CHW 
Community Health Worker 
DSMC 
Data Safety and Monitoring Committee 
ECA 
Eyelid Contour Abnormality 
FMHACA 
Food Medicine and Health Care Administration and Control 
Authority 
FTP 
File Transfer Protocol (method for securely transferring data 
electronically) 
IRB 
Institutional Review Board 
JHU 
John Hopkins University 
MTSS 
Maximizing Trichiasis Surgery Success (clinical trial) 
MTSS-PTT 
Maximizing Trichiasis Surgery Success – Post-operative 
Trachomatous Trichiasis (clinical trial) 
NEI 
National Eye Institute 
NIH 
National Institutes of Health 
PTT 
Post-operative Trachomatous Trichiasis 
SNNPR 
Southern Nations Nationalities and Peoples Region 
TT 
Trachomatous Trichiasis 
UNC 
University of North Carolina 
WHO 
World Health Organization 

 
 
1 
PROTOCOL SUMMARY 
Title: 
Randomized Control Trial of Repeat Surgery for Patients with Post-
Operative Trichiasis 
Précis: 
In this trial we will randomize 936 individuals with post-
operative trichiasis on a 1:1 basis to standard Trabut surgery 
or the recently developed bevel/rotate/advance procedure 
(BRAP).  Participants will receive trichiasis surgery and will be 
followed at 1 day, 2 weeks, 3-6 months and 12 months after 
surgery.  The primary outcome is development of post-
operative trachomatous trichiasis (PTT) within 12 months after 
surgery.  Logistic regression analyses will be performed to 
compare the rates of PTT between the two procedures, 
controlling for demographic characteristics and pre-operative 
trichiasis severity.     
Objectives: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endpoints 
 
Primary objective:  
1) To determine whether the rate of post-operative 
trichiasis (PTT) differs significantly at 12 months after 
repeat surgery with the Trabut procedure compared to 
surgery with a recently developed procedure, the 
bevel/rotate/advance procedure (BRAP). 
Secondary objectives:  
1) To determine whether the frequency of moderate/severe 
eyelid contour abnormalities 12 months after surgery 
differs between the two procedures. 
2) To determine whether the frequency of pyogenic 
granulomas within 12 months after surgery differs 
between the two procedures. 
3) To determine whether the frequency of PTT differs 
between the two procedures at 3-6 months after 
surgery. 
 
The primary endpoint for this study is presence of one or more 
eyelashes touching the globe or signs of epilation after repeat 
trichiasis surgery. 
 
Population: 
Participants will be recruited from three regions in Ethiopia:  
Southern Nations Nationalities and Peoples Regional State 
(SNNPR), Oromia, and Amhara. Some participants will be 

 
 
2 
recruited from within the US National Eye Institute (NEI) 
funded clinical trial of incident trichiasis surgeries, the 
Maximizing Trichiasis Surgery Success (MTSS) Trial, currently 
taking place in SNNPR. Other non MTSS post-operative 
trichiasis (PTT) cases from the 3 regions will also be recruited. 
All individuals with PTT in at least one eye, aged >18 years, 
and living in the area will be eligible to participate. We aim to 
enroll  936 individuals during the 2019-2020 surgical 
campaigns being supervised by Orbis International, The Carter 
Center and the Fred Hollows Foundation.  
 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
 
Recruitment will take place at rural health centers and health 
posts in the SNNPR, Amhara, and Oromia Regions of Ethiopia.  
Description of  
Intervention: 
A new surgical procedure, the bevel/rotate/advance procedure 
(BRAP), for the correction of post-operative trichiasis (PTT) will 
be compared against Trabut surgery (posterior lamellar tarsal 
rotation) 
Study Duration: 
1.5 years 
Subject 
Participation 
Duration: 
12 months 
Estimated Time to 
Complete 
Enrollment: 
Recruitment is scheduled for April 2019 through December 
2020.  

 
 
3 
 STUDY DESIGN SCHEMATIC: 
 
Prior to  
Enrollment 
 
 
 
 
 
 
 
 
 
 
Visit 1 
Surgery 
 
 
 
 
Visit 2 
One-Day Exam 
  
 
 
Visit 3 
2-weeks post  
surgery  
 
 
Visit 4 
3-6 month 
Exam 
 
 
 
 
Visit 5 
12-month Exam 
 
 
 
 
 
Screen potential subjects by inclusion and exclusion criteria; Obtain informed 
consent. Total N to enroll: 936 
Randomize patients; Perform study surgery and record surgical details on 
Surgical Evaluation Form. Before surgery, take photographs to confirm patient 
identity and severity of TT. 
  (Study intervention to be administered during surgery). 
Ocular exam to evaluate presence of trichiasis, eyelid contour abnormalities and 
granuloma formation. Record results on 3-6 month Ocular Exam form.  
Randomize 
Arm 2: Trabut 
N = 468 
Arm 1:BRAP  
N = 468 
Complete 2-week visit form to assess eyelid characteristics. 
Final assessment of participants. Ocular exam to evaluate presence of trichiasis, 
eyelid contour abnormalities and granuloma formation. Record results on 12-
month Ocular Exam form.  
Remove bandages and complete 1-day visit form to assess eyelid characteristics. 

 
 
0 
1.1 
Timeline and Feasibility of Adhering to Study Schedule 
The study recruitment and follow up schedule is outlined in the table below. 
 
Year 1  
(Sept 2018 – Aug 2019) 
Year 2  
(Sept 2019 – August 2020) 
Year 3 
(September 2020-August 
2021) 
Year 4 
(September 2021-August 
2022) 
Activity 
Q1 
(Sept-
Nov) 
Q2   
(Dec-
Feb) 
Q3   
(Mar- 
May) 
Q4   
(Ju-
Aug) 
Q1     
(Sep- 
Nov) 
Q2     
(Dec-
Feb) 
Q3   
(Mar- 
May) 
Q4   
(Jun-
Aug) 
Q1     
(Sep- 
Nov) 
Q2     
(Dec-
Feb) 
Q3   
(Mar- 
May) 
Q4   
(Jun-
Aug) 
Q1     
(Sep- 
Nov) 
Q2     
(Dec-
Feb) 
Q3   
(Mar- 
May) 
Q4   
(Jun-
Aug) 
Ethics Applications  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Case identification 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
 
Randomization, 
Surgery,  
1-day follow up visits 
 
 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
 
2-week follow up visits 
 
 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
 
3-6-month follow up 
visits 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
12-month follow up 
visits 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Data cleaning and 
analyses 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dissemination of 
Study Findings 
(manuscripts and 
presentations) 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 

 
 
1 
2. KEY ROLES AND CONTACT INFORMATION 
 
Principal 
Investigator:   
Emily W. Gower, PhD 
Gillings School of Global Public Health 
University of North Carolina at Chapel Hill 
Chapel Hill, North Carolina 
egower@email.unc.edu  
 
 
 
 
Clinical Site 
Investigators: 
Alemayehu Sisay, MD; Orbis International 
 
Institutions: 
 
 
Orbis International 
Rebecca Building 
Addis Ababa, Ethiopia 
 
University of Maryland School of Medicine 
Baltimore, Maryland 
 
Fred Hollows Foundation 
Addis Ababa, Ethiopia 
 
The Carter Center 
Addis Ababa, Ethiopia 
   
Other Key 
Personnel: 
 
 
 
 
 
 
Shannath L. Merbs, MD PhD (University of Maryland School of 
Medicine site PI) 
Belay Bayissasse, MPH (Project Director, Orbis International) 
Scott Nash, PhD (Carter Center PI) 
 
 
 
 
 

 
 
2 
 
Personnel 
Job Title 
Affiliation 
IRB of 
Record 
Study 
Responsibilities 
Emily Gower  
Associate 
Professor, 
Overall study PI 
and coordinating 
center director 
(Coordinating 
Center is 
housed at UNC) 
UNC 
UNC 
Assume primary 
leadership for the 
study; manage 
budget; liaise 
between other 
organizations; lead 
manuscripts; 
report to DSMC 
and UNC IRB. 
Alemayehu 
Sisay 
Country 
Director, Orbis 
PI for this Study 
Orbis 
International 
UNC 
Assume primary 
responsibility for 
Orbis team.  
Manage Orbis 
budget.  Assist in 
manuscript 
preparations.  
Occasionally 
observe field team 
activities to ensure 
protocols are 
being followed. 
 
Belay 
Bayissasse 
Project Director 
Orbis 
International 
UNC 
Oversee field-
based study team; 
oversee on-site 
day-to-day 
operations; Field 
team will perform 
the screening of 
study participants; 
establish their 
eligibility and 
consent them; 
follow participants 
after surgery; 
report adverse 
events to the 
Coordinating 
Center;   send 
accumulating data 
to Coordinating 
Center. 
 

 
 
3 
Shannath Merbs 
Professor 
University of 
Maryland School 
of Medicine 
University of 
Maryland 
School of 
Medicine 
Perform surgeries 
in Ethiopia; train 
another 
oculoplastic 
surgeon to perform 
surgeries in 
Ethiopia;  
Report to 
University of 
Maryland IRB; 
assist with 
manuscript 
preparations 
Demissie 
Tadesse 
Ophthalmologist; 
Independent 
consultant 
Independent 
consultant 
UNC  
Observe subset of 
surgeries to 
ensure they are 
being performed in 
a consistent 
fashion across 
surgeons; observe 
other field 
activities on a 
periodic basis.  
Scott Nash 
Epidemiologist 
The Carter 
Center 
Emory 
Will provide 
technical and 
scientific support 
to the study staff in 
Amhara for the 
duration of the 
study as needed 
 

 
 
4 
3. INTRODUCTION  
3.1 
MTSS Trial  
The Maximizing Trichiasis Surgery Success Trial (MTSS Trial) is an ongoing US 
National Eye Institute (NEI) clinical trial evaluating 3 methods for performing incident 
trichiasis surgery in Ethiopia.  The study is enrolling roughly 5000 individuals with 
previously unoperated trichiasis and following them for 1 year.  We anticipate that 15-
20% of these individuals will develop trichiasis again during the course of the MTSS trial 
and these will need repeat surgery.  We plan to investigate ways to perform repeat 
surgery.   
3.2 
Background and Rationale 
The World Health Organization (WHO) has set 2020 as the year by which programs 
should eliminate trachoma as a public health problem.  Many countries are rapidly 
scaling up trichiasis surgery programs to meet this goal.  Significant progress has been 
made, yet much remains to be done, and trichiasis surgery will likely be needed for at 
least another decade.  Post-operative trichiasis (PTT), or the presence of trichiasis after 
surgery, is a problem that plagues most national programs.  In some regions, rates of 
PTT as high as 50% have been reported1–7.  However, consensus has not been 
reached on how these patients should be managed.   
Repeat surgical management of these cases is more challenging than primary surgery 
because of increased scarring resulting from the first round of surgery plus continued 
disease progression, both of which cause the tarsus to become thicker and more 
irregular.  In most settings where repeat surgery is performed, patients are operated 
with the same procedure that they received for their initial surgery.  Research indicates 
that second surgeries using currently available procedures have higher rates of poor 
outcomes than initial surgeries, with over 40% of patients having repeat PTT within 6 
months after surgery and 45% experiencing an eyelid contour abnormality (unpublished 
data).   
Recent WHO guidelines indicate that repeat TT surgery should be performed by the 
most highly skilled health workers available.  Furthermore, at the 2017 annual meeting 
of the Alliance for the Global Elimination of Trachoma by 2020 (GET 2020), significant 
discussion focused around the need for identifying an appropriate method for 
management of PTT cases.  It has been proposed that a regional training session 
should be held to train higher cadres of medical staff on how to perform repeat surgery.  
Before that time, however, it is critical that the best possible method for addressing 
these cases is determined.  To that end, a clinical trial investigating approaches to 
improving repeat trichiasis surgery outcomes is urgently needed.  Here, we propose to 
conduct a clinical trial comparing a recently developed procedure, the 
bevel/rotate/advance procedure (BRAP), to the current standard of care used to treat 
PTT patients.   
Surgical Procedure Comparison 

 
 
5 
The Trabut procedure is the WHO-recommended standard procedure used for initial 
trichiasis surgeries and is also widely used for PTT8. The bevel/rotate/advance 
procedure (BRAP) is a procedure developed by Dr. Shannath Merbs and colleagues in 
Colombia. They worked together to develop the BRAP by combining steps from existing 
procedures in order to address multiple challenges associated with conducting repeat 
trichiasis surgery utilizing current TT surgical procedures.  Specifically, in the typical 
upper eyelid with PTT, the tarsus is thick and scarred, especially near the previous 
incision.  Additionally, the tarsus thickness can be quite variable across the width of the 
eyelid.  These factors make a repeat Trabut or Bilamellar Tarsal Rotation (BLTR) 
procedure9 more challenging to perform successfully because it is more difficult to make 
a uniform incision across these eyelids and the variability of the thickness makes it 
challenging to stably rotate the inturned eyelashes.  
To address these challenges, BRAP employs a beveled full-thickness incision at a 
location, slightly different from the incision of the original surgery, and utilizes a different 
approach for repositioning the inturned eyelashes.  BRAP was first evaluated in Mitu, 
Colombia (see letter from Columbian MOH).  Then, following training by Dr. Merbs, 
Ethiopian surgeons performed BRAP procedures in SNNPR, Ethiopia.  Specifically, 23 
patients were operated with BRAP.  Among these, 31 eyelids were assessed 3-6 
months post-surgery. These surgeries were performed through the Orbis program to 
provide care for these patients, not as part of a research project.  Of these eyelids, 16% 
had PTT, and 84% had no evidence of trichiasis at follow up.  Of those with PTT, 2 had 
central trichiatic eyelashes (1 with 1 lash and 1 had 3 lashes). Comparatively, among 4 
eyelids operated with Trabut during the same period, only 50% had no evidence of 
trichiasis at follow up.  These initial surgeries suggest that this procedure is likely to 
have a lower rate of second post-operative trichiasis. We believe this procedure may 
have more success than currently available TT surgery procedures because of the 
incision location and orientation and the manner in which the eyelashes are 
repositioned during the procedure.   
 
3.3 
Potential Risks and Benefits 
Potential Risks 
The risks associated with this study are minimal.  Repeat surgery to treat post-operative 
trichiasis is a standard practice commonly performed in many countries, and all subjects 
enrolled in this study would be offered repeat surgery regardless of whether they 
participate in the clinical trial. Theoretically, a newly-developed procedure utilizing a new 
method for repositioning lashes could ultimately be found to have higher rates of post-
operative trichiasis or eyelid contour abnormalities. Preliminary data suggest that this 
new procedure is not associated with an increased risk of eyelid contour abnormalities 
or of higher post-operative TT rates.  However, it is important to be aware of this 
possible risk.  
Potential Benefits 

 
 
6 
Participants enrolled in this study will not benefit directly from this study.  The team will 
give patients surgery even if they decide not to participate in the study.  In the study, we 
will evaluate patients at 3-6 months and 12 months after surgery.  Participants may view 
this as a benefit.  
 
OBJECTIVES AND ENDPOINTS 
3.4 
Study Objectives 
This study has one primary objective: 
1) To determine whether the rate of post-operative trichiasis (PTT) differs 
significantly at 12 months after repeat surgery with the Trabut procedure 
compared to surgery performed with a recently developed procedure, the 
bevel/rotate/advance procedure (BRAP). 
This study has three secondary objectives:  
1) Determine whether the frequency of moderate/severe eyelid contour 
abnormalities at 12 months after surgery differs between the two procedures. 
2) Determine whether the frequency of pyogenic granulomas within 12 months after 
surgery differs between the two procedures. 
3) Determine whether the frequency of PTT differs between the two procedures at 
3-6 months after surgery. 
 
 
3.5 
Study Endpoints 
Post-operative Trichiasis 
We will evaluate post-operative trichiasis at two time points after surgery: 3-6 months 
and 12 months. A patient examiner standardized against Dr. Shannath Merbs or Dr. 
Alemayehu Sisay will perform the assessments.  The assessment is made by looking at 
the eyelid with the eye in primary gaze.  Any eyelashes touching the eye with the eye in 
primary gaze are considered to be trichiatic. Presence of post-operative trichiasis 
(primary outcome) is defined as 1+ trichiatic eyelashes or evidence of recent epilation.  
If an eyelid has trichiasis at 2 weeks but not at 3-6 months or 12 months, the eyelid will 
be considered not to have post-operative trichiasis.  
Eyelid Contour Abnormalities 
We will evaluate eyelid contour abnormalities at each post-operative visit.   The 
examiner will grade the presence of abnormality using the definition provided below in 
the statistical considerations chapter.   Both field and photographic grades will be 
utilized. The field grade will serve as the primary grade for the primary study analyses; 
secondary analyses will utilize the photograph grade.  Examiners will be standardized at 

 
 
7 
the start of the 3-6 month visits. For primary analyses, the eyelid contour grade at 12 
months will be used. 
Pyogenic Granuloma 
Pyogenic granulomas occasionally develop after trichiasis surgery, and it is thought that 
these are a response to a foreign body, such as suture material or a jagged incision 
edge.  The patient examiners will evaluate presence of granulomas at 3-6 months and 
12 months.  All granulomas will be noted, regardless of size.  

 
 
8 
4. STUDY DESIGN 
4.1 
Overall Design 
This study is a randomized controlled trial comparing two surgical procedures for the 
management of post-operative trichiasis.  Individuals are eligible if they have at least 
one eye with post-operative trichiasis. Participants are identified either from the MTSS 
cohort at the MTSS 12 month visit or from screening patients for PTT using surgical 
logs from existing country programs throughout the three regions and/or conducting 
screenings during household visits.  Individuals will be consented and enrolled on the 
day they have surgery. We will enroll up to 936 individuals and randomize them on a 1:1 
basis to surgery with BRAP or surgery with Trabut.  They will be followed for 12 months 
to assess development of repeat post-operative trichiasis and eyelid contour 
abnormality. 
4.2 
Scientific Rationale for Study Design 
The BRAP has been used in two countries and initial study outcomes are excellent.  A 
larger, randomized study is required to determine whether BRAP is superior to Trabut.  
4.3 
End of Study Definition 
Each study participant reaches the end of the study at 12 months after surgery. 
 
4.4 
Data Collection and Management    
Data will be collected primarily electronically through customized Open Data Kit (ODK) 
forms on Motorola Moto X Pure Edition, Samsung S8, and Samsung A9 phones.  At the 
end of each day, data from the phones will be downloaded to a customized Access 
database. The Access database will be stored on a UNC approved, encrypted laptop.  
Both the laptop and the database will include password protection.   Each week, the 
project director will transfer accumulated data to the UNC Coordinating Center.  This 
transfer will be done via a secure File Transfer Protocol (FTP) connection.   
All data will be collected by trained staff members who have completed human subjects’ 
research training.   
Data will primarly be collected on encrypted mobile phones.  All devices will be 
encrypted and password protected.  They will be stored in locked offices each night.  
Adverse events (AE) will be monitored throughout the study.  At surgery, the data 
collection form will have specific questions regarding each of the possible adverse 
events that could happen during surgery (excess bleeding, division of the eyelid 
margin).  If an event is encountered, the project director will report it to FMHACA in 
writing, within 48 hours of occurrence of the event according to the authority guideline, 
and to the PI (Dr. Gower) within 72 hours.  This report will include measures taken to 
mitigate the event. At the 2-week and 3-6 month and 12 month visits, deaths and 

 
 
9 
hospitalizations will be proactively collected (the data collector will ask the participant if 
they have been hospitalized; death will be noted if a family member reports the 
participant has died).   Any AEs occurring at these visits will be reported to the 
Coordinating Center within 72 hours. At all visits, deaths will be noted and reported to 
the Coordinating Center within 72 hours. Whenever an AE is reported to the 
Coordinating Center, Dr. Gower will assume responsibility for sharing with the 
appropriate parties. If an event could possibly be related to the study treatment, she will 
share the details of the event with the study monitor, who will review the data in a 
masked fashion to determine whether it could be related to the study procedure. He 
also monitors all aspects of the study assuring Good Clinical Practice (GCP) of the trial.  
Therefore, he will have responsibilities with direct accountability to the sponsor with 
periodic monitoring, reporting the findings to the sponsor. We will follow the Data and 
Safety Monitoring Board’s guidelines on reporting these events to them.  
  

 
 
10 
5. STUDY POPULATION 
Participants will be recruited from three regions in Ethiopia:  SNNPR, Oromia and 
Amhara. Some participants will be recruited from within the US National Eye Institute 
(NEI) funded clinical trial of incident trichiasis surgeries, the Maximizing Trichiasis 
Surgery Success (MTSS) Trial, currently taking place in SNNPR. Other non-MTSS post-
operative trichiasis (PTT) cases from the 3 regions will also be recruited. All individuals 
with PTT in at least one eye, aged >18 years, and living in the area will be eligible to 
participate. We aim to enroll 936 individuals during the 2019-2020 surgical campaigns 
being supervised by Orbis International, The Carter Center and the Fred Hollows 
Foundation. The Carter Center will be responsible for the screening and identification of 
patients in Amhara, while the Fred Hollows Foundation will be responsible for 
conducting screening in Oromia. 
We will not exclude subjects based on race or gender.    
5.1 
Subject Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the 
following criteria: 
• Aged 18 or older 
• At least one eyelid with post-operative upper eyelid trichiasis needing surgery 
• Willing to comply with all study procedures and be available for the duration of 
the study  
5.2 
Subject Exclusion Criteria 
Any individual who is unable to provide informed consent will be excluded from 
participation in this study. 
5.3 
Strategies for Recruitment and Retention 
Subjects will be identified on the day that they present for their 12-month follow up visit 
for the MTSS Trial in the SNNPR region or from surgery logs from programs conducting 
village-based screening in all three regions. List of patients previously identified to have 
PTT during survey activities or programmatic follow-up activities may be consulted to 
determine potential study candidates. Trained case finders may also be used to conduct 
house-to-house visits to identify potential study candidates. Patients found to have post-
operative trichiasis in at least one upper eyelid that had surgery performed in the MTSS 
Trial will be eligible to have repeat surgery performed as part of the PTT trial. Patients 
suspected of having PTT (and thus may be eligible for the study) will be assessed by 
surgeons to confirm eligibility. Surgery will not be performed that day.  Instead, the team 
will schedule surgery days for that district after determining how many patients in the 
area have PTT of sufficient severity to warrant surgery. All recruitment and screening 
activities will be conducted by the coordinating partner in that region—The Carter 
Center in the Amhara Region, the Fred Hollows Foundation in Oromia, and Orbis in 
SNNPR.    

 
 
11 
On the day of surgery, an examiner will visit the patient and discuss the study as well as 
the opportunity to have repeat surgery.  If the patient agrees to repeat surgery s/he will 
be brought to the surgery site where she will meet with a consent specialist who will 
provide a full description of the study and will complete the consent process if the 
patient is eligible and interested.    
All repeat surgery trichiasis patients will receive surgery free of charge, regardless of 
participation in the trial.  If a patient has patient has bilateral post-operative trichiasis 
and elects to have surgery on both eyes, both eyes will be enrolled in the study. 
Patients that are not eligible for the study but are presenting with TT will be offered 
surgery at no cost by the program staff of the coordinating organization. 
Subjects will not receive compensation for participation.  Participant retention is 
maintained through contact with a local community health worker, who lives in the 
village with the participants and has a long-term relationship with them.  The project 
director will call community health workers approximately 2 weeks before upcoming 
study visits to remind them that they need to contact the subjects living in their village to 
bring them for the follow up visit. Also, during the surgery day and at each follow up, 
patients will receive reminder cards stating the date and location of the next follow up 
visit.  This approach has been extremely successful in our previous trials, with retention 
rates of over 95% of eligible subjects.  

 
 
12 
6. STUDY INTERVENTION 
6.1 
Study Intervention Description 
Participants will undergo either the Trabut procedure or the BRAP. Both procedures are 
performed under local anesthesia.  
 
 Trabut 
The Trabut procedure is the WHO-recommended standard surgical procedure used for 
initial trachoma trichiasis surgeries and is also widely used for PTT8,9. The eyelid is fixed 
on the Trabut plate and an incision 3 mm from the eyelid margin is made through the 
conjunctiva and tarsal plate, without cutting the orbicularis muscle. The muscle is 
dissected from the tarsal plate in both fragments, and the fragments are re-sutured so 
that the eyelid margin is rotated outwards and the eyelashes no longer touch the globe. 
For further details, refer to the WHO Yellow Manual.  
 
 BRAP 
 
Beveled Incision 
A Trabut plate is used to evert the upper eyelid in the standard fashion for Trabut surgery. (Fig. 
1A, and Fig. 22 and 23 in yellow manual).  A caliper is used to measure 3 mm (“C” in Fig. 2C) 
superior to the eyelash follicles on the conjunctiva across the width of the eyelid. The sharp 
point of the caliper or the scalpel blade can be used to make small scratches in the conjunctiva 
to delineate this position. This often corresponds to the scar or a portion of the scar from the 
original TT surgery (“scar” in Fig. 2B). A scalpel is used to make a tarsal incision along the 
marked position, beveled towards the eyelash follicles with care not to cut the follicles (the 
incision is the line between “B” and “D” in Fig. 2). Note that this beveled incision is in contrast to 
the typical Trabut incision that is made perpendicular to the plane of the upper eyelid tarsus. 
Upon completion of the tarsal incision, sharp dissection between the scarred orbicularis and the 
scarred and thickened proximal tarsus is performed (Fig. 2D).  White scar contributing to an 
eyelid contour abnormality is resected (Fig. 2E), and dissection is continued between the 
orbicularis and tarsus to the top of the tarsus (Fig. 2D). After dissection and release of the scar 
from the original TT surgery, the contour of both the beveled, distal fragment and the larger, 
proximal fragment should be normalized (Fig. 1B) The Trabut clamp and traction suture are 
removed.  
 
Rotation and Advancement 
The beveled fragment is then externally rotated (Fig. 2D), and the proximal tarsal fragment is 
advanced downward (Fig. 1C, Fig. 2E). The cut edge of the beveled distal fragment is 
positioned 1 mm above the cut edge of the proximal fragment (Fig. 2F).   
 
Suturing 

 
 
13 
If excess upper eyelid skin noted, a horizontal mattress suture (the “high” suture) is placed 
through the skin 10 mm above the lash line as the approximate position of the upper eyelid 
crease and through Muller’s muscle just above the top the upper tarsus using 5-0 polyglactin 
910 (Fig. 2F). Although, this suture is not tied until the end of the procedure, it is important to 
check that it is placed properly and does not undo the advancement when it is tightened. The 
relative position of the tarsal fragments is stabilized with horizontal mattress sutures as follows. 
Starting centrally, the suture is placed backhand from just above the lash line, through the distal 
fragment, and through the proximal tarsal fragment. The needle is repositioned in the standard 
forehand position, and the suture is advanced horizontally by 3 mm and is placed thorough the 
proximal tarsus, through the distal fragment, and exiting just above the lash line. At least 2 
additional sutures are placed in the same fashion, nasal and temporal to the central suture.  The 
3 sutures are tied. The 1 mm advancement should be uniform across the eyelid.  One or two 
additional sutures can be placed for optimum contour if necessary.  The “high” suture is then 
tied (Fig. 2F). 
 
A 
 
 
         B  
 
 
            C 
 
Figure 1. Initial steps of BRAP. A) Eversion of the upper eyelid with an eyelid contour 
abnormality over a Trabut plate. B) Upper eyelid after completion of the beveled incision, 
release and removal of the scar tissue, and normalization of the eyelid contour abnormality. C) 
Demonstration of ability to advance the proximal tarsal fragment, confirming adequate 
dissection. 

 
 
14 
 
 
 
Figure 2. BRAP.  A) Sagittal view of an upper eyelid immediately after Trabut surgery. B) 
Appearance of the upper eyelid after healing from Trabut surgery showing thickened tarsus in 
the region of the scar and recurrence of the entropion and post-operative trichiasis. C) A 
beveled incision through the tarsus is made along the line between B and D. The incision is 
continued superiorly between the orbicularis and tarsus to the top of the tarsus (arrow). D) Scar 
tissue in the region of the prior surgery (gray shading circled by dashed line) is identified and 
removed if needed. The distal fragment is externally rotated (large arrow). E) The larger 
proximal tarsal fragment in advanced downward and the smaller, rotated, distal fragment is 
recessed upwards. F) The cut edge of the beveled distal fragment is positioned 1 mm above the 
cut edge of the proximal fragment. The advancement is stabilized with three horizontal mattress 
sutures (lower suture) placed nasally, centrally and temporally. If needed, an additional 
horizontal mattress suture is placed centrally from the approximate upper eyelid crease (10 mm) 
to Mullers’ muscle (higher suture). 
 
We believe that BRAP may have more success than currently available TT surgery 
procedures because the margin fragment is recessed away from the eye creating more 
distance between the trichiatic lashes and the cornea. Additionally, the beveled incision 
creates a marginal fragment that is thinner and more uniform in thickness than the 
fragment created in an eyelid with PTT by the Trabut or BLTR procedures, making it 
easier to rotate, recess and stabilize during the healing period. 
6.2 
Randomization Procedures 
Participants will be randomized at the participant level on a 1:1 basis to one of two 
arms: 1) the BRAP procedure or 2) the Trabut procedure.  If both eyes need surgery, 
they both will have the same procedure performed.  Dr. Gower will oversee generation 
of the randomization assignments at UNC. We will utilize random, permuted blocks of 
varying sizes to ensure balance between arms on a frequent basis.   

 
 
15 
Randomization assignments will be prepared by UNC staff in Chapel Hill, in individual 
opaque envelopes with the patient ID number on both the outside of the envelope and 
on the internal papers indicating the arm assigned.  
Randomization will occur on the day of surgery in order minimize chances of 
randomizing an individual who does not present for surgery.  
The envelope will be opened in the surgery room by the surgical assistant. The surgeon 
and surgical assistant will both confirm verbally with one another the assigned surgical 
procedure at the start of the procedure. They will be required to indicate the assigned 
procedure on the surgical evaluation form as well as the procedure they ultimately 
perform.  
The randomization assignments will be developed at UNC. After each surgical outreach 
camp period, reported assigned surgical procedures will be compared against the 
master table to ensure the assigned procedure is consistently being reported for each 
participant. Details on monitoring are available in the quality assurance section. 
 Masking Procedures 
The study subject and the outcomes assessor will be masked to treatment assignment.  
However, the surgeon will not be masked to the treatment assignment, since s/he must 
know what procedure to perform.  
In order to ensure the outcomes assessor is masked, s/he will not be present at the 
surgical site, and s/he will not have access to data from the baseline and surgical visit.  
However, because one procedure involves a full-thickness incision and the other does 
not, we expect that the outcomes assessor will be able to determine which procedure 
many of the patients received through visual inspection. Thus, we will use photographs 
as a backup to verify the outcomes reported, by holding cardstock to cover the skin 
incision scar in the photographs so that evidence/lack of an incision is not visible.  
6.3 
Assessment of Clinician and/or Subject Compliance with Study 
Procedural Intervention 
The Project Director will regularly monitor surgical activities in-person to ensure that the 
surgeons are following the study procedures and are performing the correct procedure. 
After each surgical outreach period, the Coordinating Center (CC) will compare the 
assignment reported on the Surgical Evaluation form against the actual assignment.  
6.4 
 Procedures for Training of Clinicians on Procedural Intervention 
6.5 
Dr. Shannath Merbs will train up to two Ethiopian surgeons 
(ophthalmologist and IECW) in how to perform the BRAP procedure. 
Then Dr. Merbs and the Ethiopian surgeons will review/discuss the 
Trabut procedure steps to ensure that they both plan to perform the 
procedure in the same way. Dr. Merbs will monitor the surgeries to 

 
 
16 
ensure that all surgeons are performing the two procedures in the 
same way.Procedures for Ensuring BRAP Surgery is Performed 
According to Study Procedure 
1) We will provide the study surgeon with professional sketches of the surgery procedure, 
and Dr. Merbs will review these steps with him. The surgeon will take these sketches 
with him to the surgery site each time he performs the BRAP procedure. 
2) Dr. Merbs will be present for the first two surgery recruitment periods.  She will observe 
the study surgeon closely to ensure all steps of the procedure are understood and being 
followed.  Once he is performing all steps independently and consistently, she will 
periodically observe his surgery, but she will continue to examine each patient at the end 
of surgery to ensure that the surgery was performed according to the study procedure. 
3) After two surgical periods, if Dr. Merbs is comfortable with the study surgeon performing 
surgery in her absence, the surgeon may proceed to perform study surgeries 
independently.  At the start of each surgery period, he will review the surgical sketches 
to refresh his memory on the surgical approach and will be encouraged to have the 
project manager communicate with Dr. Merbs to address any questions or concerns.  
4) In Dr. Merbs absence, a second individual will be present at the surgery site to review 
completed surgeries and ensure the suture and incision placement follow the protocol. 
5) Each week that study surgeries are performed in Dr. Merbs’ absence, images of the 
eyelid immediately after surgery will be uploaded to the study’s secure shared folder.  
Dr. Merbs will review each image to ensure that there are no systematic differences from 
the study procedure.  
6) If systematic differences are noted, Dr. Merbs will contact the project manager and study 
surgeon to discuss and address them. 
 
6.6 
Study Procedural Intervention Description 
Surgeons will receive the surgical procedure assignment just prior to surgery for that 
participant.  Immediately before beginning surgery, the surgeon will confirm with the 
surgical assistant whether the procedure is BRAP or Trabut.    
 

 
 
17 
7. STUDY DISCONTINUATION, PARTICIPANT DISCONTINUATION OR 
WITHDRAWAL  
In this trial, all subjects will receive repeat trichiasis surgery using the BRAP or Trabut 
procedure.  The primary study intervention is surgical procedure, with either Trabut or 
the newly developed BRAP procedure being performed.   
7.1 
Subject Withdrawal 
Subjects may withdraw voluntarily from the study at any time. Because the intervention 
is a one-time intervention, the investigators should not have reason to withdraw a study 
subject for non-compliance. 
 
7.2 
Lost to Follow-Up 
If a participant misses a follow-up visit, the outcome examiner will make arrangements 
with the Community Health Worker for the two of them to visit the patient’s village and 
home together on one of the ‘mop up’ days.  
If evaluation for a required visit is not completed within the visit window, a Missed Visit 
form should be completed at the close of the window and submitted with the relevant 
blank follow up form.  At least three attempts should be made to find the participant 
within the relevant window before a Missed Visit form is completed.  If the participant 
has died, the form can be completed immediately. If the participant has relocated 
somewhere in the district, efforts should be made to track him/her at the new location. 
The participant is still eligible for any subsequent visits. 

 
 
18 
8. STUDY ASSESSMENT PROCEDURES  
8.1 
Efficacy Assessment 
This section lists the procedures and describes the general approach for data collection. 
Ocular Examination: The ocular exam will consist of a detailed evaluation of each 
eyelid. This information will be collected on the day of surgery.  At each follow up study 
visit, the study eye will be assessed for the presence of repeat post-operative trichiasis, 
eyelid contour abnormality and granuloma.   
Visual Acuity:  Visual acuity will be assessed monocularly at baseline and will be 
assessed again at the post-operative 3-6 months and 12 months visits; it will be 
assessed using an Early Treatment of Diabetic Retinopathy (ETDRS) tumbling “E” chart 
on a smartphone, using the PEEK acuity app.   
Trichiasis Surgery: All participants will receive trichiasis surgery with either the BRAP or 
Trabut procedure.  
Photographs: Photographs will be taken of the full face (headshot) and of each eyelid 
preoperatively, during surgery, immediately postoperatively, and at each follow up visit.  
 
 
 

 
 
19 
9. STATISTICAL CONSIDERATIONS 
9.1 
Study Hypotheses 
Primary Aim: 
Null hypothesis:  
1) Surgery performed using the Bevel/rotate/advance procedure (BRAP) will 
have the same rate of post-operative trichiasis as surgery performed using 
the Trabut procedure.   
Alternative hypothesis:   
1) Surgery performed using the BRAP procedure will result in a relative 30% 
reduction in the rate of post-operative trichiasis compared to surgery using 
the Trabut procedure.  
Secondary Aim: 
Null hypothesis:  
1) Eyelids operated with the bevel/rotate/advance procedure will have the 
same rate of moderate/severe eyelid contour abnormalities rate as eyes 
operated with the Trabut procedure.  
Alternative hypothesis:   
1) Eyelids operated with the bevel/rotate/advance procedure will have fewer 
moderate/severe eyelid contour abnormalities than eyelids operated with 
the Trabut procedure.  
 
9.2 
Sample Size Considerations 
The planned sample size for this trial is 700 participants.  This sample size will give 
sufficient power to detect a 30% relative difference in post-operative trichiasis rates 
between the BRAP and Trabut procedures. This estimate is based on the following 
assumptions: 
• 35% of eyelids in the Trabut group will develop post-operative trichiasis during 
the 12 months following surgery 
• Two-sided alpha error = 5% 
• Power = 80% 
• 10% loss to follow up 

 
 
20 
In the event that the number of participants is lower than anticipated, we are still 
adequately powered to detect a clinically significant difference (see table below).  
For instance, if only 600 participants enroll, we have 80% power to detect a relative 
difference of 32%.  
Power to Detect a Difference between Treatment Groups 
 
Relative Risk 
 
Number of 
Participants 
1.2 
1.3 
1.32 
1.4 
 
1.5 
560 
44% 
72% 
77% 
91% 
99% 
600 
47% 
75% 
80% 
93% 
99% 
640 
49% 
77% 
82% 
94% 
99% 
720 
53% 
82% 
86% 
96% 
99% 
800 
56% 
85% 
89% 
97% 
99% 
The subset of 186 participants who enrolled and received surgery prior to August 1, 
2019 will be excluded from the primary analysis because they were operated prior to 
precise standardization of the incision and suture placement. These individuals will 
continue to be followed and cared for in the same manner as all other study 
participants.   
9.3 
Analysis Plan 
We will follow these general analysis principles: 
• The primary analyses will be performed according to the participant’s assigned 
intervention (intention-to-treat).  
• All participants who complete randomization after August 1, 2019 and have 
surgery performed will be included in analyses. 
• All events following surgery will be counted.  
• All analyses will be conducted at the eye level, using the generalized estimating 
equations approach to correct standard errors (to account for the correlation 
between two eyes of a subject). 
We will use logistic regression analysis for each of the outcomes.  In previous trials, we 
have created time-to-PTT models using Cox proportional hazards with PTT as the 
outcome.  However, with the limited number of follow-up visits, Cox proportional 
hazards models do not provide much additional information.  Hence, we do not plan to 
conduct such modeling for this trial. 
 
Post-operative Trichiasis Analyses: 
The primary analysis will be based on the dichotomous outcome: presence or absence 
of post-operative trichiasis noted at any time point beginning with the 3-6 month visit 
and within 12 months following surgery (trichiasis noted at either the 3-6 month or 12 

 
 
21 
month visit will be considered as post-operative trichiasis, regardless of whether there is 
trichiasis at the final visit). Both unadjusted and adjusted analyses will be performed.  
Adjusted analyses will account for the severity baseline PTT, with severity defined 
based on the table below.  
 
Trichiasis Severity 
Classification 
Description 
Mild 
 
1-4 Eyelashes touching globe, no epilation  
 
OR 
 
< 1/3 of eyelid epilated, no lashes touching 
globe 
 
Moderate 
5-9 Eyelashes touching globe, no epilation  
 
OR 
 
1-4 lashes touching globe and < 1/3 of 
eyelid epilated  
 
Severe 
5-9 Eyelashes touching globe and 1-10 
eyelashes epilated  
 
OR 
 
10+ Eyelashes touching globe, regardless of 
epilation status  
 
OR 
 
>1/3 of eyelid epilated, regardless of lashes 
touching  
        (Gower et al. 2013. JAMA Ophthalmol.;131(3):294-301.) 
Multiple secondary analyses of post-operative trichiasis will be performed.  We will 
compare the severity of post-operative trichiasis between groups, with severity defined 
using the table above. Additionally, we will assess the frequency of overcorrection 
performed at the one-day visit. 
Eyelid Contour Abnormalities: 
Primary analysis of eyelid contour abnormalities will be based on a dichotomous 
variable: presence or absence of moderate/severe contour abnormality at the final study 

 
 
22 
visit (12 months) using the field grade, which will be based on the definitions below.  For 
the purposes of this analysis, mild will be combined with “no abnormality” and moderate 
and severe will be combined to form the “moderate/severe contour abnormality” group. 
We will adjust for first procedure performed (Trabut or BRAP) and severity of pre-
operative trichiasis.  
 
Abnormality 
Definition 
Mild 
Vertical deviation from the natural contour, 1 mm in 
height (less than half the pupil height in daylight) and 
affecting 1/3 of horizontal eyelid length 
 
Moderate 
Vertical deviation from the natural contour 1–2 mm in 
height (about the pupil height in daylight) or affecting 
1/3–2/3 of horizontal eyelid length 
 
Severe 
Vertical deviation from the natural contour 2 mm in 
height (more than the pupil height in daylight) or a 
defect >2/3 of the horizontal eyelid length  
 
       (Gower et al. 2012 PLoS Negl Trop Dis 6(6): e1713)  
 
Secondary analyses will explore the relationship between procedure and the full range 
of eyelid contour abnormalities, which will require use of the photographic grade that will 
be graded centrally.  
Treatment of Missing Data 
We have had great success in our trials to date, reporting over 95% follow up at 1 year 
after surgery in each of our prior trials. However, invariably, some participants will be 
lost to follow up.  To this end, we will conduct sensitivity analyses treating all missing 
data as success and then as failures.  Given that we collect limited external information 
on this population, it would be difficult to impute the values.  

 
 
23 
10. STUDY ASSESSMENT PROCEDURES  
Visit Type 
Timing 
Window 
Eligibility Screening  
Day 0 
N/A  
(potential subjects to be seen 
during MTSS 12-month visit or 
identified from programs’ surgical 
logs and screening activities) 
Eye Exam, Consent, 
Randomization and 
Surgery 
Within 3 months of 
eligibility screening 
0-3 months after eligibility 
screening. If surgery must take 
place more than 3 months after 
eligiblity screening, a new 
baseline exam will be done 
1 day post-operative 
visit 
1 day after surgery 
1 day after surgery 
2 week follow up 
2 weeks after surgery 
10 – 18 days after surgery 
3-6 month follow up 
3- 6 months after 
surgery 
12-30 weeks post-surgery 
12 month follow up 
12 months after 
surgery 
11 to 13 months post-surgery 
10.1 
Eligibility Screening, Eye Exam, and Consent 
Potential participants will be identified through review of the MTSS study data, 
examination of surgery logs, PTT patient lists from surveys, and through screening of 
patients from household visits.   
Patients will be screened for eligibility by a trained eye care worker acting as a case 
finder and confirmed by MTSS-PTT study team members. Patients will be required to 
have entropion, and/or lashes touching the cornea, and/or pain that leads them to 
request surgery.  These criteria are based on the definitions determined by a WHO 
expert panel held in Geneva on Nov 26-30, 2018.   If patients are deemed to meet TT 
severity inclusion criteria, they will be referred to a consent specialist. 
The consent specialists will meet with each PTT surgery patient to tell them about the 
study and then will assess eligibility using the Eligibility Review form.  If they are eligible 
and interested in participating, the consent specialist will proceed to obtain informed 
consent with one patient at a time.  The full process for obtaining informed consent is 
provided in the Manual of Procedures.   
Required Procedures/Data Collection: 

 
 
24 
• Complete Eligibility Screening form (Form 1) 
• Obtain informed consent 
• Confirm demographic and tracking information from MTSS patient list 
10.2 
Enrollment and Surgery 
When patients present for PTT surgery, a trichiasis surgeon or screener will screen 
them to confirm post-operative trichiasis and to confirm the patient’s identity using either 
a patient list generated from the MTSS Trial or the screening logs.  
After having pre-operative photographs taken to confirm patient identity and presence of 
post-operative trichiasis, the patient will receive PTT surgery.  
Required Data Collection: 
• Surgical Evaluation Form 
10.3 
Follow up Visits 
Follow up visits occur 1 day, 2 weeks, 3-6 months and 12 months following surgery.  At 
the 1-day visit, bandages are removed. At each follow-up visit the patient examiner 
evaluates each eyelid for the presence of trichiasis, eyelid contour abnormality and 
granuloma.  At the 1-day post-operative visit, the examiner checks the status of the 
surgery.  If eyelashes are touching the eye or if the eyelid is completely flipped (gross 
over-correction) then the surgeon should adjust the surgery to correct the eyelid.  
Required Procedures/Data Collection: 
• Follow up visit form (2 week, 3-6 month, 12 months form) 
• Adverse Event Form (if applicable) 
10.4 
Unscheduled Visit 
Between visits, the primary point of contact between subjects and the study team 
typically will be the Community Health Worker (CHW) living in their community.  
Subjects who experience problems between study visits will meet with the CHW who 
will assess the issue and determine whether a study team member should come to the 
village for an unscheduled study visit or whether the CHW can resolve the issue 
himself.  If such a visit is necessary, the study team member will visit the subject and 
will complete an Unscheduled Visit form to document the purpose of the visit and what 
procedures, if any, were performed.  If the CHW and study team member determine that 
a study visit is not required, the study team member simply needs to complete the 
CHW/Participant Call Log, indicating the date of the call, participant ID, reason for call 
and actions taken. 
Required Procedures/Data Collection: 
• CHW Participant Call Record 
• Unscheduled Visit Form 

 
 
25 
11. PROVISIONS FOR MONITORING STUDY PROGRESS 
Multiple levels of oversight have been built into the trial to ensure patient safety and 
data integrity.  These include: 
Internal Monitoring: 
• Weekly monitoring of accumulating data to ensure complete data collection 
• Periodic assessment of compliance with assignment of surgical procedure  
• Regular field monitoring by local and international team members 
• Active collection of adverse events during surgery and at each follow up visit 
In addition, we will follow UNCs guidelines for reporting all safety events. 
External Monitoring: 
• An NEI-designated Data and Safety Monitoring Board 
• Annual reports to the Institutional Review Boards at each institution and to the 
Ethiopian ethics board (National Health Research Ethics Review Committee, 
Ministry of Science and Technology).  
Detailed information on the managing guidelines and approaches for each of 
these is provided in the Manual of Procedures.   
11.1 
Data and Safety Monitoring Board 
With input from NIH, we have assembled a data and safety monitoring board (DSMB) to 
oversee the study.  The committee consists of a trialist, a statistician, and content 
experts, including someone with local cultural expertise.  We will plan for one DSMB 
meeting prior to study initiation, and then in-person meetings annually, with at least one 
scheduled teleconference between in-person meetings, and more as needed or desired 
by the DSMB.  We will prepare summary reports of accumulated data for each meeting. 
All members of the MTSS DSMB have agreed to serve on the MTSS-PTT DSMB. 
These members include, DSMB chair Maureen Maguire, PhD (biostatistician and 
clinical trialist), James Tielsch, PhD (epidemiologist and global health expert), Wondu 
Alemayehu, MD MPH (Ethiopian ophthalmologist and renowned trachoma expert) and 
Michael Kazim, MD (oculoplastic surgeon). We will plan for one DSMB meeting prior to 
study initiation, and then in-person meetings annually, with at least one scheduled 
teleconference between in-person meetings, and more as needed or desired by the 
DSMB.  We will prepare summary reports of accumulated data for each meeting. 
 

 
 
26 
12. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
12.1 
Regulatory, Ethical, and Study Oversight Considerations 
 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to 
participate in the study and continues throughout study participation.  Extensive 
discussion of risks and possible benefits of study participation will be provided to 
subjects and their families, if applicable.  A consent form written in the patient’s native 
language (Amharic and all necessary local languages, including Yem, Gamo, Afan 
Oromo, Gedioffa, Wolaitegna, Keffa, Konso, Hadiya, Amharic) and describing in detail 
the study procedures and risks will be given to the subject.  Consent forms will be IRB-
approved, and the subject is required to read and review the document or have the 
document read to him or her.  The investigator or designee will explain the research 
study to the subject and answer any questions that may arise.  The subject will sign 
(typically through providing a fingerprint) the informed consent document prior to any 
study-related assessments or procedures.  Subjects will be given the opportunity to 
discuss the study with their surrogates or think about it prior to agreeing to participate.  
They may withdraw consent at any time throughout the course of the study.  A copy of 
the signed informed consent document will be given to subjects for their records.  The 
rights and welfare of the subjects will be protected by emphasizing to them that the 
quality of their clinical care will not be adversely affected if they decline to participate in 
this study. 
The consent process will be documented in the research record.  
 Subject Confidentiality 
All patient data will be kept secure at all times.  Paper-based forms will be stored in 
locked file cabinets and access will be limited to those who have a specific need to 
review patient-level information.  All study computers will be encrypted following the 
UNC guidelines and will require passwords for logon to the computer, with a separate 
password to access the study database. When the team is travelling out of Hadiya zone 
and Yem special woreda where the project office is located, the team will establish a 
temporary office at the capital of the woreda where the surgical camp is taking place. All 
study data will be temporarily stored in this office until the field work at the area is 
completed and then all data will be stored at MTSS office located at Hossana, Hadiya.   
Safety Oversight 
An external monitor will be responsible for reviewing any adverse events related to 
surgery.  He will review photograph images and a written summary of events in a 
masked fashion. If it appears that the event may be related to the study procedure, he 
will be unmasked for that study participant to further complete his assessment.  The 
study PI will keep track of all adverse events and will report serious adverse events to 
the DSMB and regulatory boards in a timely manner.  If at any time it appears that the 

 
 
27 
frequency of adverse events is significantly higher in one study arm, the PI will convene 
a meeting of the DSMB to discuss the events and determine a course of action.  
 Ethical Standards 
The investigators will ensure that this study is conducted in full conformity with the 
principles set forth in the Declaration of Helsinki and The Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research, as drafted 
by the US National Commission for the Protection of Human Subjects of Biomedical and 
Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the ICH E6.  
The trial will also be conducted with full conformity with national GCP and CTA 
guidelines. 
 Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all subject materials 
will be submitted to University of North Carolina, University of Maryland, and Emory 
University IRBs as well as the National Health Research Ethics Review Committee, 
Ministry of Science and Technology (MoST) and Food, Medicine, Health Care 
Administration and Control Authority (FMHACA) of Ethiopia for review and approval.  
Approval of both the protocol and the consent form must be obtained before any subject 
is enrolled.  Any amendment to the protocol will require review and approval by the IRB 
and EFMHACA before the changes are implemented in the study.   
 Exclusion of Women, Minorities, and Children (Special Populations) 
We will not limit enrollment based on sex or racial/ethnic background.  Both sexes and 
all races are eligible for participation.   
Children will not be enrolled in the clinical trial because trichiasis is uncommon in this 
age range, and general anesthesia is required for trichiasis surgery on children.  
Children with trichiasis will be referred to the nearest location that can safely provide the 
necessary surgical services.  
 Quality Assurance and Quality Control 
We will ensure high quality data collection through the course of the trial by using only 
staff from MTSS who have already been trained in human subjects research, trial 
procedures, data collection methods, and their role in the trial. All staff must be certified 
in their respective roles by the project leaders before interacting with study participants 
and handling study-related data.  
12.1.6.1 Training 
Quality of data in a clinical trial is highly dependent on the competency of the personnel 
collecting the data and their ability to conduct their jobs.  To this end, as part of MTSS, 
all personnel have undergone extensive training to ensure consistency and accuracy in 
data-collection procedures. These same personnel will be responsible for data 

 
 
28 
collection in MTSS-PTT and are already trained in all of the necessary procedures for 
the proposed study.  Just prior to the start of MTSS-PTT data collection, we will host a 
training meeting for all study staff to provide an in-depth discussion of the MTSS-PTT 
trial. For those staff who are already part of MTSS, we will conduct a refresher ethics 
training session to review key aspects of conducting human subjects research. For any 
new staff hired for MTSS-PTT, we will conduct a full ethics training session, and ethics 
certification will be required from each staff member before the study begins. Next, we 
will conduct training on the MTSS-PTT procedures. We will explain what procedures are 
the same as in MTSS versus what procedures are different in MTSS-PTT and will 
review how to perform each of the procedures. Next we will work with each individual 
team member to observe them practicing their role in MTSS-PTT. Each person will be 
required to pass certification for their specific job responsibilities before initiating work 
for MTSS-PTT.  As with MTSS, we will require kappa agreement of 0.7 or greater for all 
key variables (specifically trichiasis grading) before staff can participate in study data 
collection.   
12.1.6.2 Quality Monitoring 
To ensure data integrity and study participants’ safety, our plan for data and safety 
monitoring involves several levels.  The first level is the extensive set of data-
management activities to help ensure data integrity.  These include daily field-based 
review of data collection to ensure completeness and accuracy, redundant systems to 
check randomization schemes, double data-entry practices, and continuous data-quality 
monitoring through generation of weekly reports. These reports are reviewed by the 
data manager to initiate data cleaning operations, and by the principal investigator, who 
will initiate re-training exercises or change supervisory practices as needed.  
 
The second level of monitoring includes regular site visits by our senior study team 
members.  Our team of experts will ensure all staff members are proficient in necessary 
procedures before the study begins.  During recruitment, Dr. Alemayehu will making 
monthly visits to the study team to monitor study activities.  At the start of 3-6 month and 
12 month visits, Dr. Merbs or Dr. Gower will return to Ethiopia to evaluate the outcomes 
assessor and ensure kappas are at least 0.7 for key outcomes (PTT and ECA). Dr. 
Gower also will visit Ethiopia at the start of the study and at least once during follow up 
data collection to provide refresher training to all study team members and to monitor 
data-collection procedures.    
Finally, with input from NIH, we will assemble a Data and Safety Monitoring Board 
(DSMB) to oversee the study.  The details of this committee are described above. 
12.1. Community Involvement Plan 
This project will be conducted in multiple regions within Ethiopia to ensure 
representativness.  These regions include SNNPR, Oromia and Amhara.  The project 

 
 
29 
will actively involve members of the community in several ways.  First, we will utilize 
community members such as trained community-based screeners (Eye Ambassadors) 
to identify potential trial participants.  Additionally, during the recruitment and surgery 
phase of the trial we will employ several individuals from Ethiopia and provide them with 
on-the-job training that will provide long-term skills development for them. Specific skill 
sets that we will develop in the staff are how to conduct clinical research, how to 
properly collect data, and how to utilize a computer for data entry and management 
(specifically MS Access).  Field staff will be taught how to evaluate trichiasis and how to 
be a surgical assistant (preparing equipment, recording data, etc).  
Community members with trichiasis may also benefit by taking part in the clinical trial 
(receiving PTT surgery) itself.  These individuals will be followed regularly in their 
communities, which should allow them to be able to be monitored closely and to quickly 
identify any additional trichiasis management needed.  
 
 
 
 
 

 
 
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13. PUBLICATION/DATA SHARING POLICY 
The Executive Committee will be responsible for developing publication procedures and 
resolving authorship issues.  At the start of the trial, the committee will outline the 
expected primary papers for the trial and will make initial assignments.  As additional 
papers are identified through the course of the trial, authorship will be discussed at the 
next Executive Committee meeting.  This procedure was followed in our most recent 
trial, and the investigative team (who comprise the majority of the current team) was 
happy with this approach. Because the scientific team is relatively small compared with 
other clinical trials, it is anticipated that all publications will follow traditional authorship 
instead of corporate or modified corporate authorship.   
EFMACA has the right to approve the primary results manuscript before submitting the 
manuscript for publication.  The study team will submit the manuscript to EFMACA and 
will await comments from the committee. If no response is received from EFMACA 
within 30 days, it will be assumed that the manuscript is acceptable for publication 
without further comment.  
This study will comply with the NIH Public Access Policy, which ensures that the public 
has access to the published results of NIH funded research. It requires scientists to 
submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital 
archive PubMed Central upon acceptance for publication. 
The International Committee of Medical Journal Editors (ICMJE) member journals have 
adopted a clinical trials registration policy as a condition for publication.  The ICMJE 
defines a clinical trial as any research project that prospectively assigns human subjects 
to intervention or concurrent comparison or control groups to study the cause-and-effect 
relationship between a medical intervention and a health outcome.  Medical 
interventions include drugs, surgical procedures, devices, behavioral treatments, 
process-of-care changes, and the like.  Health outcomes include any biomedical or 
health-related measures obtained in patients or participants, including pharmacokinetic 
measures and adverse events. The ICMJE policy requires that all clinical trials be 
registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the 
National Library of Medicine.  This study will be registered in ClinicalTrials.gov. 
The trial investigators fully support the dissemination of data from this clinical trial.  In 
accordance with NIH policies, we will prepare a de-identified dataset for public use.  The 
de-identified data, study protocol and annotated case report forms will be available 
through requests made to the University of North Carolina, and data release will 
coincide with publication of the primary and pre-planned secondary results.  
Photographic images of study eyelids will not be shared widely, as these cannot be 
completely de-identified. Hence, photographic images will be made available through 
formal requests from researchers to the University of North Carolina.  Researchers 
requesting these images will be required to sign a data use agreement adhering to the 
School’s and NIH’s requirements for maintaining strict confidentiality of all images. 

 
 
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14. CONFLICT OF INTEREST  
On a yearly basis, DSMB members and key study team members will be required to 
report any real or perceived conflicts of interest.  Additionally, study team members are 
required to complete UNC’s annual conflict of interest certification.  
 

 
 
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15. REFERENCES 
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Thanh TTK, Khandekar R, Luang VQ, Courtright P. One year recurrence of 
trachomatous trichiasis in routinely operated Cuenod Nataf procedures cases in 
Vietnam. Br J Ophthalmol. 2004;88(9):1114-1118. doi:10.1136/bjo.2003.039834 
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Gower EW, West SK, Harding JC, et al. Trachomatous trichiasis clamp vs 
standard bilamellar tarsal rotation instrumentation for trichiasis surgery: Results of 
a randomized clinical trial. JAMA Ophthalmol. 2013;131(3). 
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4.  
Rajak SN, Habtamu E, Weiss HA, et al. Absorbable versus silk sutures for 
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Rajak SN, Habtamu E, Weiss HA, et al. Surgery versus epilation for the treatment 
of minor trichiasis in Ethiopia: A randomised controlled noninferiority trial. 
Lewallen S, ed. PLoS Med. 2011;8(12):e1001136. 
doi:10.1371/journal.pmed.1001136 
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Burton MJ, Rajak SN, Ramadhani A, et al. Post-Operative Recurrent 
Trachomatous Trichiasis Is Associated with Increased Conjunctival Expression of 
S100A7 (Psoriasin). PLoS Negl Trop Dis. 2012;6(12). 
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Burton MJ, Kinteh F, Jallow O, et al. A randomised controlled trial of azithromycin 
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8.  
Habtamu E, Wondie T, Aweke S, et al. Posterior lamellar versus bilamellar tarsal 
rotation surgery for trachomatous trichiasis in Ethiopia: A randomised controlled 
trial. Lancet Glob Heal. 2016;4(3):e175-e184. doi:10.1016/S2214-109X(15)00299-
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Merbs S, Resnikoff S, Kello AB, Mariotti S, Greene G, West SK. Trichiasis 
surgery for trachoma. 2015:80. 
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Ahttp://apps.who.int/iris/bitstream/10665/155227/1/9789241549011_eng.pdf. 
 
 

 
 
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