Cervical Cancer Screening Among HIV-infected Women in Western Kenya: Evaluation of the Safety, Acceptability, and Efficacy of an Alternative Ablation Method for Treatment of Precancerous Lesions
Phase: NA
Conditions: Human Immunodeficiency Virus, HPV Infection, CIN 2/3
Sponsor: University of California, San Francisco

Proprietary and Confidential
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by federal 
and state laws. Persons to whom this information is disclosed should be informed that this information is privileged 
and confidential and that it should not be further disclosed.
Cervical cancer screening among HIV-infected women in 
Western Kenya:  Evaluation of the safety, acceptability, and 
efficacy of an alternative ablation method for treatment of 
precancerous lesions
Protocol Number:  CC # 19405
Study Intervention:  Thermocoagulation
Version Number:  1.3
Version Date:  07-25-2019
Principal Investigator (Sponsor-Investigator)
Chemtai Mungo, MD, MPH 
University of California San Francisco
Statistician
Li Zhang, PhD
Revision History
Version 1.0 
01-01-2019
Version 1.1
04-15-2019
Version 1.2
06-06-2019
Version 1.3
07-25-2019
NCT# 04191967

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Protocol Signature Page
Protocol No.: 19405
Version Date: 07-25-2019
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee
(PRC), Institutional Review Board (IRB), and Data and Safety Monitoring Committee
(DSMC).
2.
I will conduct the study in accordance with Good Clinical Practices (ICH-GCP) and the
applicable IRB, ethical, federal, state, and local regulatory requirements.
3.
I certify that I, and the study staff, have received the required training to conduct this
research protocol.
4.
I agree to maintain adequate and accurate records in accordance with IRB policies, federal,
state and local laws and regulations.
UCSF Principal Investigator 
Printed Name
Signature
Date

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Protocol Signature Page – Participating Site
Protocol No.: 19405
Version Date: 07-25-2019
Participating Site
Principal Investigator Name: 
Cirillus Ogollah
Institution Name:
Kenya Medical Research Institute, 
Kisumu, Kenya
Address:  
Kisumu, Kenya
Telephone: 
 
E-mail:  
I have read this protocol and agree to conduct the protocol in accordance with Good Clinical 
Practices (ICH-GCP) and the applicable IRB, ethical, federal, state, and local regulatory 
requirements.  
Principal Investigator
Site
Printed Name
Institution Name
Signature
Date

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Abstract
Title
Cervical cancer screening among HIV-infected women in Western 
Kenya:  Evaluation of the safety, acceptability, and efficacy of an 
alternative ablation method for treatment of precancerous lesions
Study Description
The purpose of this study is to evaluate the safety, acceptability, and 
efficacy of Thermocoagulation for treatment of precancerous lesions 
among HIV-positive women in a screen-and-treat program in Western 
Kenya. Thermocoagulation is endorsed as an alternative to 
Cryotherapy for treatment of Visual Inspection with Acetic Acid (VIA) 
or Human Papillomavirus (HPV)-positive women by the 2018 Kenya 
national cancer guidelines.32 Data primary from Western countries 
demonstrate similar efficacy for the treatment of precancerous lesions 
between Cryotherapy and Thermocoagulation. Data on safety, 
acceptability, and efficacy, particularly linked to gold-standard 
pathology, among HIV-positive women in low-resource settings are 
scare. Given the demonstrated benefits over cryotherapy including 
increased portability and availability hence easier implementation, use 
of thermal coagulation for the treatment of precancerous lesions in low 
resource settings could significantly improve access to treatment 
compared with cryotherapy. This study seeks to fill a critical data gap 
by evaluating the efficacy of thermocoagulation among HIV-positive 
positive women using gold-standard biopsy for disease verification at 
baseline and follow-up, as indicated. We will also assess the safety 
and acceptability of this treatment modality among patients and 
providers. 
Study Intervention
Thermocoagulation
Study population
HIV-infected women age 30 – 65 years old enrolled in care at the 
FACES- supported HIV clinics in Kisumu County in Kenya.

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Objectives
Primary Objective: 
To evaluate the efficacy of thermal coagulation for the treatment of 
HIV-positive, HPV-positive women by assessing the rate of HPV 
persistence and CIN2/3 rate at 12 months after treatment.
Secondary Objectives: 
To evaluate the safety of thermal coagulation for the treatment of 
abnormal cervical lesions within a screen-and-treat program among 
HIV-positive women in Western Kenya.
To evaluate patient satisfaction with thermal coagulation for the 
treatment of abnormal cervical lesions within a screen-and-treat 
program among HIV-positive women in Western Kenya. 
Exploratory Objective: 
To evaluate provider acceptability of thermal coagulation for the 
treatment of precancerous cervical lesion within a screen-and-treat 
program in Western Kenya.
Sample Size
400 HIV-positive participants
We seek to enroll 400 participants in order to obtain sufficient numbers 
of women who have CIN2/3, our outcome of interest. Based on prior 
studies in this population, we anticipate approximately 35% of HPV-
positive women (N ~ 140) will have biopsy-proven CIN2/3

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List of Abbreviations
LMIC
Low- and middle-Income countries 
VIA
Visual inspection with acetic acid
VAT
Visual assessment for treatment
HPV
Human papillomavirus 
HR-HPV
High-risk human papillomavirus 
HIV
Human Immunodeficiency Virus 
WHO
World Health Organization
CIN2
Cervical intraepithelial neoplasia grade II 
CIN2/3
Cervical intraepithelial neoplasia grade II or III
SCJ
Squamo-columnar junction
IARC
International Agency for Research on Cancer
JOOTRH
Jaramogi Oginga Odinga Teaching and Referral Hospital
FACES
Family AIDS Care and Education Services 
LEEP              Loop excisional electrosurgical procedure 
UCSF
University of California, San Francisco 
KEMRI
Kenya Medical Research Institute 
AE
Adverse Events
MOH
Ministry of Health
DNA
Deoxyribonucleic Acid
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
NCI
National Cancer Institute

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Table of Contents
Protocol Signature Page ............................................................................................................2
Protocol Signature Page – Participating Site .............................................................................3
Abstract
4
List of Abbreviations...................................................................................................................6
Table of Contents.......................................................................................................................7
1
Introduction.....................................................................................................................9
1.1
Abstract......................................................................................................9
1.2
Background................................................................................................9
1.3
Literature Review ....................................................................................10
1.4
Study Rationale........................................................................................11
1.5
Anticipated Application of Study Results ...............................................12
2
Study Objectives ..........................................................................................................12
2.1
Hypothesis ...............................................................................................12
2.2
Primary Objective....................................................................................12
2.3
Secondary Objectives ..............................................................................12
2.4
Exploratory Objective..............................................................................13
3
Study Design................................................................................................................13
3.1
Characteristics..........................................................................................13
3.2
Study Population......................................................................................13
3.3
Sample Size and Power Calculation........................................................13
3.4
Study Site.................................................................................................14
3.5
Risks and Benefits ...................................................................................14
3.5.1
Potential Risks ..............................................................................................14
3.5.2
Protection Against Risks...............................................................................15
3.5.3
Potential Benefits..........................................................................................15
4.1
Eligibility Criteria....................................................................................16
4.1.1
Inclusion Criteria ..........................................................................................16
4.1.2
Exclusion Criteria .........................................................................................16
4.2
Recruitment and Enrollment....................................................................16
5
Study Procedures and Assessments ...........................................................................17
5.1
HPV Self-Testing.....................................................................................17
5.2
Pelvic Exam.............................................................................................17
5.3
Visual Inspection with Acetic Acid.........................................................18
5.4
Baseline Colposcopy and Cervical Biopsy..............................................18
5.5
Thermocoagulation..................................................................................18
5.6
Post-treatment Pain Assessment..............................................................19
5.7
4-6 Week Follow-up................................................................................19
5.7.1
Adverse Events Evaluation...........................................................................19
5.7.2
Provider Acceptibility Evaluation.................................................................19
5.8
12 Month Follow-up Exam......................................................................20
5.9
Medical Record Data Collection..............................................................20

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Table of Contents
6
Data Quality and Management.....................................................................................20
6.1
Staff Training...........................................................................................20
6.2
Secure Data Storage and Study Files.......................................................20
7
Statistical Analysis Plans..............................................................................................21
7.1
Primary Objective....................................................................................21
7.2
Secondary Objectives ..............................................................................22
7.3
Exploratory Objective..............................................................................22
8
Study Management ......................................................................................................22
8.1
Pre-study Documentation ........................................................................22
8.2
Institutional Review Board Approval......................................................23
8.3
Informed Consent ....................................................................................23
8.4
Changes in the Protocol...........................................................................23
8.5
Oversight and Monitoring Plan................................................................23
8.5.1
Data and Safety Monitoring Plan and Procedures ........................................23
8.5.2
Adverse Event Monitoring............................................................................24
8.5.3
Review of Adverse Event Rates ...................................................................25
8.5.4
Management of Risks to Subjects.................................................................25
8.5.5
Interim Data Analysis for Safety and Acceptability.....................................25
8.6
Record Keeping and Record Retention ...................................................26
8.7
Duration of the Study/Project ..................................................................27
9
References...................................................................................................................28

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1
Introduction
1.1
Abstract
Although cervical cancer is preventable, in 2018, an estimated 570,000 new cases will be 
diagnosed, 90 percent in low- and middle-income countries (LMICs).1 Women infected with the 
Human Immunodeficiency Virus (HIV) are at increased risk of cervical cancer due to increased 
incidence and persistence of the human papillomavirus (HPV) infection, the causative agent.2 
Low-income countries have been unable to implement cytology-based screening programs used 
in high-income countries due to significant infrastructure and human resource requirements not 
feasible in these settings.3 In 2013, the World Health Organization (WHO) recommended 
cervical cancer screening using Visual Inspection with Acetic Acid (VIA) or HPV testing in 
LMICs, followed by immediate treatment with cryotherapy without histologic diagnosis.4 This 
screen-and-treat strategy decreases loss-to-follow-up, and is associated with a reduction in 
cervical intraepithelial neoplasia grade 2 and 3 (CIN2/3) and mortality from cervical cancer.5,8 
However, impact on disease burden will not occur until women who screen positive are 
effectively linked to and receive treatment and appropriate follow-up. Currently, widespread 
implementation of cryotherapy programs has proven to be difficult given the need for bulky 
equipment that limits mobility in the field, and need for an ongoing supply of refrigerant gas 
which is expensive and of unrealizable quality.6 Recent data primarily among HIV-negative 
women suggests that thermal coagulation, an alternative treatment method, may be more 
feasible for implementation in LMICs, with similar efficacy compared to cryotherapy.6,7 If 
supported by more research, population-level implementation of thermal coagulation for the 
treatment of precancerous lesions within LMICs may result in increased access to treatment 
and hence secondary prevention of cervical cancer. 
1.2
Background 
Despite being a preventable disease through screening and vaccination, cervical cancer is a 
leading cause of death of women in Sub-Saharan Africa, where 90 percent of the 311,000 
deaths in 2018 will occur.1 In Kenya, cervical cancer accounts for 70-80% of cancers of the 
genital tract, and is the most common cause of cancer-related death for women, with an 
estimated 1700 yearly deaths.8  Cervical cancer is an AIDS-defining malignancy and women 
infected with the Human Immunodeficiency Virus (HIV) are at increased risk due to increased 
incidence and persistence of the human papillomavirus (HPV) infection, the causative agent.2 
Compared to HIV-negative women, women with HIV develop precancerous lesions at younger 
age and have faster progression to cervical cancer, making prevention efforts among this group 
particularly urgent.9  While access to the HPV vaccine may play the most significant role in 
cervical cancer control and elimination, access is currently limited in Sub-Saharan Africa, and its 
impact on cervical cancer will not be evident for at least twenty years.10 Therefore, effective 
cervical cancer screening remains a priority for cancer control in the current generation. 
African countries have been unable to implement widespread cytology-based screening 
programs due to high infrastructure requirements and the need for multiple visits, leading to 
loss-to-follow-up.11 In 2013, following significant evidence, the World Health Organization 
(WHO) recommended cervical cancer screening using Visual Inspection with Acetic Acid (VIA) 
or high-risk Human Papillomavirus (HR-HPV) testing in low resource settings, followed by 
immediate treatment with cryotherapy without histopathologic verification.4 This single-visit 
strategy decreases loss-to-follow-up in settings where women often overcome significant 
barriers to reach clinics and is associated with a reduction in CIN2/3 and mortality from cervical 

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cancer.4 Studies confirm that the benefit far outweighing the harms of overtreatment.4 However, 
while screen-and-treat with cryotherapy has demonstrated high cure rates – 88 percent for 
CIN1/2, and 77 percent for CIN3, and low rate of adverse events (2.1% with mild pain or 
cramping, 1.6% with malodorous excessive vaginal discharge, 0.7% with mild bleeding or 
spotting, and no severe adverse events noted)12,  there are significant barriers to widespread 
implementation, leading to a need for alternative treatment methods. 6,13 Challenges associated 
with cryotherapy include bulky equipment limiting mobility, as well as the need for an ongoing 
supply of refrigerant gas which is expensive and of unrealizable quality in rural areas.6 An 
evaluation of 25 health facilities with cryotherapy services in Uganda showed that almost half of 
them were not operationally owing to lack of gas.6 In Malawi, over a 5-year period, only 43.3% 
of women who screened VIA-positive accessed treatment owing to challenges with delivering 
cryotherapy.14 This has led to a search of alternative, more easily implementable methods of 
treatment of cervical pre-cancer in low resource settings.  
1.3
Literature Review
Thermal coagulation is an alternative ablative treatment method has increasingly been 
investigated for use in low resource settings. Thermocoagulation uses heat instead of cold to 
ablate cervical tissue - the superficial epithelium sloughs off after treatment, and the underlying 
stroma and glandular crypts are destroyed by desiccation.15 Similar to cryotherapy, studies 
support tolerability of thermocoagulation without the use of anesthesia, and the equipment 
supports self-sterilization.6,13,16 Compared to cryotherapy, thermal coagulation has several 
advantages for remote areas. Newer generation battery-powered devices are light and highly 
portable, weighing only 4.6 kilograms compared to 15-20 kilograms for each cryotherapy gas 
cylinder.6 Thermal coagulation also allows for faster treatment – a single application lasting 20 - 
40 seconds, compared with the 3-min freeze, 5-min thaw, 3-min freeze cycle for cryotherapy, 
enabling treatment for more women.6,16 Widely accepted criteria for eligibility for treatment with 
thermocoagulation is similar to that for cryotherapy.6 
Thermal coagulation has been used for treating CIN3 for 3-4 decades, primarily in the United 
Kingdom.6 In a systematic review of thirteen primarily European studies on the efficacy of 
thermal coagulation for treatment of CIN1-3 among 4569 patients, Dolman et al. report a 96% 
(95% CI 92 – 99%) cure rate for CIN1 and 95% (CI 92-98%) for CIN2/3 disease, comparable to 
published rates for cryotherapy.16 
In the last few years, several small studies in LMIC have similarly reported comparable results 
with the use of thermal coagulation for the treatment of precancerous lesions. In Brazil, Naud et 
al. investigated the acceptability, safety and efficacy of thermocoagulation for the treatment of 
histologically proved CIN2-3.16  Among 52 women included in the study, 44 (85%) had no 
evidence of disease one year after thermocoagulation. The rate of no disease at follow-up was 
similar for women with CIN2 (17/20), 85% and those with CIN3 (27/32), 84%. At follow-up, 
disease status was evaluated by VIA and cytology, with colposcopy and biopsy as needed.17 
Their study also reported no serious adverse effects following treatment with thermocoagulation.  
In Malawi, Campbell et al. report that 85% of approximately 300 VIA-positive women treated 
with thermocoagulation had negative VIA at 12-month follow-up, although they had no 
histological disease verification either at baseline or at follow-up.18 In Cameroon, Tran et al. 
evaluated the efficacy of thermocoagulation for treatment of biopsy-proven CIN2/3 among 
women age 30-49 years.13 Although limited by a small sample size, at 12-months follow-up, 
using cytology and biopsy to evaluate cure, 70.6% of women had no evidence of disease, 
comparable to the efficacy rates of cryotherapy within a similar population.6,19 

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In a 2019 updated metanalysis of the efficacy of thermocoagulation for precancerous lesions 
including 7 studies from LMICs, Randall et al report a pooled estimate of 93.8% (95% CI 90.4 – 
95.1).20 The authors examined the effect of potential modifying factors on the cure rates for 
thermal ablation for treatment of biopsy-proven CIN2+. Studies restricted to countries in LMICs 
had a cure rate of 83.6% ((95% CI 78.2 – 88.2%).20 
Data on safety and efficacy of thermocoagulation among HIV-positive women in low resources 
settings are limited. A 2016 Nigerian study among VIA-positive, HIV-positive women treated 
with thermocoagulation reported a cure rate of 81.7% (95% CI 74.7 – 88.6%), with cure defined 
as negative VIA at 12-month follow-up,.21 In a metanalysis of LMIC studies including 155 HIV-
positive women, 120 (84% - confidence interval not reported) were without evidence of 
dysplasia at follow-up, the majority assessed by VIA.20 
While limited, current data suggests that thermocoagulation is comparable to cryotherapy for 
treatment of precancerous lesions in HIV-positive women. The 2018 Kenya National Cancer 
Guidelines recommend the use of either Cryotherapy or Thermocoagulation for treatment of 
precancerous lesions among both HIV-positive and HIV-negative women.22 The WHO has 
convened a Guideline Development Group to review the evidence for thermocoagulation and is 
expected to make a recommendation.20 
1.4
Study Rationale 
Despite significant progress in developing feasible and context-appropriate cervical cancer 
screening tools for low resource settings, impact on disease burden will not occur until all 
women who screen positive for precancerous cervical lesions are linked to treatment.6 Despite 
cryotherapy being WHO-recommended for use in screen-and-treat programs in LMICs, wide-
scale implementation has proven challenging. Given the demonstrated benefits over 
cryotherapy, use of thermal coagulation for the treatment of precancerous lesions in low 
resource settings could significantly increase access to treatment compared with cryotherapy, 
potentially closing this important effectiveness gap in screening programs in low-resource 
settings.  
Data on the safety, acceptability, and efficacy of thermocoagulation for treatment of 
precancerous lesions is limited, however, particularly among HIV-positive women who face 
disproportional burden of cervical cancer.  From this study, we will provide crucial data on the 
safety, acceptability, and efficacy of thermocoagulation for treatment of CIN2/3 among HIV-
positive women by supporting gold-standard biopsy verification at baseline and at 12-months 
follow-up after treatment. We will also evaluate provider acceptability of this new treatment 
method, a crucial aspect of widespread uptake. This data will inform national cervical cancer 
programs as well as inform policy and guideline development within the national government 
and the World Health Organization for this high-risk group of women in urgent need of 
prevention strategies.
We seek to investigate the safety, acceptability, and effectiveness of thermal coagulation for the 
treatment of biopsy-proven CIN2/3 among HIV-positive women in Western Kenya. We also seek 
to evaluate provider acceptability of thermocoagulation as a treatment method for precancerous 
lesions. 

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1.5
Anticipated Application of Study Results
The results from this study will we will provide crucial data on the safety, acceptability, and 
efficacy of thermocoagulation for treatment of CIN2/3 among HIV-positive women by supporting 
gold-standard biopsy verification at 12-months after treatment. If proven safe and efficacious, 
given the benefits over cryotherapy, there is potential for widespread adoption of thermal 
coagulation within screen-and-treat programs which may vastly improve access to treatment of 
precancerous lesions within Kenya and other LMICs, and support the goal of prevention, and 
elimination, of cervical cancer. This data will inform national cervical cancer programs as well as 
inform policy and guideline development within the national government and the World Health 
Organization for this high-risk group of women in urgent need of prevention strategies.
2
Study Objectives
2.1
Hypothesis
We hypothesize that the efficacy of thermal coagulation for the treatment of CIN2/3 among HIV-
infected women will be similar to reported rates of cryotherapy among this population.
2.2
Primary Objective 
To evaluate the efficacy of thermal coagulation for the treatment of HIV-positive, HPV-
positive women by assessing rates of HPV persistence and CIN2/3 rate at 12 months 
after treatment

Endpoints: 
o
Proportion of women with no evidence of cervical dysplasia at 12-month follow-
up based on colposcopy and biopsy.  
o
Proportion of women with persistent HPV at 12-month follow-up 
2.3
Secondary Objectives
To evaluate patient safety of thermal coagulation for the treatment of abnormal cervical 
lesions within a screen-and-treat program among HIV-positive women in Western Kenya.

Endpoints:  
o
Average pain score immediately after treatment 
o
The rate of AEs reported at 4-6 week follow-up 
To evaluate patient satisfaction with thermal coagulation for the treatment of abnormal 
cervical lesions within a screen-and-treat program among HIV-positive women in 
Western Kenya. 

Endpoint: Proportion of participants who answer ‘yes’ to satisfaction questions  at 4-6 
week follow-up.

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2.4
Exploratory Objective 
To evaluate provider acceptability of thermal coagulation for the treatment of 
precancerous cervical lesion within a screen-and-treat program in Western Kenya. 

Endpoint: Healthcare providers satisfaction scores on a validated Usability Likert Scale 
administered via a questionnaire.
3
Study Design
3.1
Characteristics
We will prospectively enroll four hundred HIV-positive women to undergo cervical cancer 
screening at FACES-supported MOH clinics in Kisumu County. After informed consent, clinical 
and demographic information will be collected, and participants will undergo cervical cancer 
screening using HPV testing. Women who previously screened positive for HPV (within the last 
3 months) but have not undergone treatment will also be eligible for recruitment. Women with a 
positive HPV test will be evaluated for treatment with thermal coagulation, per WHO standards 
of ablative treatment. Per the WHO and Kenya Ministry of Health guidelines, women who will be 
candidates for thermal coagulation if the squamocolumnar junction is fully visualized, the 
cervical lesion covers less than 75% of the cervix, and there is no endocervical component or 
suspicion of cancer.8 Women who are not candidates for ablation will be referred to nearby a 
referral facility.  All participants with a positive HPV test will undergo directed biopsy just prior to 
treatment for disease ascertainment but proceed to have same-day treatment, according to the 
WHO guidelines for screen & treat. 
At 12-months after treatment, all participants treated at baseline will undergo repeat colposcopy, 
directed biopsy for those with cervical abnormalities or those with CIN2/3 at baseline, as well as 
provider collected HPV testing for persistence. Twenty-five percent of women with normal 
colposcopy will have a random biopsy at 6 or 12-O'Clock to confirm the absence of disease. 
Pain will be assessed immediately following treatment using a visual analog scale (VAS). The 
presence and severity of AEs will be assessed 4-6 weeks following treatment via a phone call, 
or in person visit, if warranted. Healthcare providers offering thermal ablation for the treatment 
of precancerous lesions will be surveyed at 4-6 week follow-up to evaluate provider acceptability 
and satisfaction with this treatment method.
3.2
Study Population
HIV-infected women age 30 – 65 years old enrolled in care at the FACES- supported HIV clinics 
in Kisumu County in Kenya.
3.3
Sample Size and Power Calculation
The study sample size is calculated based on the primary objective. 
We seek to enroll 400 participants in order to obtain sufficient numbers of women who have 
CIN2/3, our outcome of interest. Based on prior studies in this population, we anticipate 
approximately 35% of HPV-positive women (N ~ 140) will have biopsy-proven CIN2/3.24  The 
study design is a non-inferiority trial using results from the only study using standard 
cryotherapy in a similar population19 to establish the non-inferiority boundary.  We 

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will compare the efficacy rate in our study using thermocoagulation to the non-inferiority 
boundary established using the efficacy rate and lower 95% confidence bound from this 
cryotherapy treatment publication from a similar population.19
The efficacy results of cryotherapy in the De Vuyst paper were 77.2% (95% CI: 66.4-
85.9%).19  Using 77.2% with a non-inferiority margin of 10% which is at the limit of the 
confidence bound and is closest to the null effect.24 Using this margin, the new treatment 
method is hypothesized to be at least as good as cryotherapy. Based on this non-inferiority 
margin, a sample size of 140 women with CIN2/3 achieves 90% power in using a one-sided test 
with a significance level of 0.025.  Based on this sample size, power of 90%, and significance of 
0.025, the minimal detectable effect size (the actual difference between cryotherapy and 
thermocoagulation) is 0.0102.
We will leverage the robust HIV-care infrastructure at FACES in which patients are seen at 
every one to three months, and the presence of an established patient tracing system (including 
home visits) to reduce loss-to-follow-up. Assuming a 14% loss to follow-up, which would result 
in a sample size of 120, we are still be powered for our non-inferiority margin of 10% with a 
minimal detectable effect size of 0.0184, with 80% power and an alpha of 0.025. Sample size 
and non-inferiority calculations used NCSS PASS software and G-Power software.
3.4
Study Site
This study will take place at the Family AIDS Care & Education Services (FACES)-supported 
Ministry of Health (MOH) clinics in Kisumu County in Kenya. At FACES, cervical cancer 
screening using VIA or HPV testing is offered to sexually active women enrolled in care 
between 18 and 65 years of age, according to the Kenya Ministry of Health guidelines. Women 
who screen positive are offered treatment onsite when available or referred to a nearby tertiary 
center. 
3.5
Risks and Benefits
3.5.1 Potential Risks
We anticipate that the potential risks to participants in the study will be minimal.  Study subjects 
may feel discomfort or embarrassment during the pelvic exam. There may be minimal 
discomfort during self-collection of HPV specimens. Participants may be at risk for psychological 
or emotional discomfort at different stages of the study if they have a diagnosis of CIN2/3 and 
learn about the potential risk of cervical cancer. Participants may risk some discomfort and mild 
spotting after the colposcopy and biopsy.  We anticipate that this will be minimal, as exams will 
be performed by trained clinicians, and thermal coagulation would ablate the biopsied area with 
the tissue desiccation, hence stopping any bleeding. Other mechanisms to achieve hemostasis 
at bleeding sites including use of Silver Nitrate sticks will be available to study clinicians. 
Women who are not eligible for thermocoagulation due to large lesions will be referred to a 
nearby tertiary facility for further care, per clinic protocol. Following treatment for abnormal 
screening, women will have vaginal discharge for a few days for which they will be provided 
anticipatory guidance. During the 12-month follow-up visit, all treated women will have repeat 
screening with colposcopy and biopsy as needed, as well as repeat HPV-testing with provider 
collection. Twenty-five percent of women who have normal colposcopy results will have a 
random biopsy for ascertainment of cure after treatment. This may not have been performed in 
a routine clinical visit and may be associated with slight discomfort, but the risk to the patient will 

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be minimized by adequate training of clinicians, and anticipatory guidance provided to the 
patient. We believe that the benefit of reducing verification bias in performing these biopsies will 
strengthen the study results and prove a strong case for implementing this treatment method on 
a large scale. 
3.5.2 Protection Against Risks
To reduce the likelihood of participants experiencing psychological discomfort, we will make 
every effort to create a secure and trustworthy environment.  Study staff that counsel 
participants and carry out examinations will undergo training on culturally sensitive ways to 
reduce discomfort and embarrassment during the pelvic exam, including providing a private 
area for women to undress for pelvic exams, providing a clean sheet to cover the woman during 
exams and obtaining verbal consent prior to each step of the procedure. To assist participants 
who may experience psychological discomfort when learning of a diagnosis of cervical 
dysplasia, we will ensure access to experienced counselors who work at FACES. When 
diagnosed with early-stage cervical cancer during this study will be navigated through the 
referral process to ensure adequate care by a gynecologist oncologist at the referral facility. All 
study staff will be thoroughly trained in the study protocol, study procedures, good clinical 
practices and protection of human subjects prior to starting the study.  All exams will be 
performed gently and, in a way that most minimizes discomfort, bleeding or anxiety in the 
participants.
3.5.3 Potential Benefits
The research question in the Primary Objective will directly benefit study participants by 
identifying women with abnormal cervical cancer screening results and offering treatment to 
prevent progression to cancer. Previously, women who screened positive for precancerous 
lesions were referred for care, some of whom are lost to follow-up in navigating the referral 
process. In enrolling in the study, all eligible women will access immediate treatment in the clinic 
instead of referral. During screening, some women with potential early-stage cancer may be 
identified and will be referred for appropriate evaluation and treatment to a gynecologist 
oncologist at the referral site. Study staff will support these participants through the referral 
process to ensure they are seen by a Gynecologist Oncologist. The research questions in the 
Secondary Objectives will not directly benefit individual patients but will contribute to the 
knowledge of safety and acceptability of this method of treatment for precancerous lesions that 
may enable widespread adoption of this technique if proved safe and effective. The Exploratory 
Objective will evaluate provider acceptability of Thermocoagulation thereby providing crucial 
insights into potential limitations for widespread provider acceptability of this treatment method. 
All participants may also gain knowledge about cervical cancer screening and prevention from 
spending more time with study staff and study clinicians.  According to KEMRI regulations, 
participants will only be reimbursed for their transportation expenses related to participation in 
the study. Hence, for study-specific visits, women will be reimbursed a rate set by KEMRI. 
Women participating in the study during a scheduled visit will be reimbursed a meal voucher 
only. 

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4
Participant Eligibility, Recruitment, and Enrollment
4.1
Eligibility Criteria
4.1.1 Inclusion Criteria
1.
Age 30-65 years.
2.
Enrolled in HIV care at FACES-supported clinics in Kisumu County.
3.
Able to understand a written informed consent document, and willing to sign it.
4.
Speaks a language that the consent form and data collection instruments are written in.
4.1.2
Exclusion Criteria
1.
Has a history of cervical cancer.
2.
Has received any treatment for cervical precancer after screening positive for precancer.
3.
Has evidence of cervical infection.
4.
Pregnant women are excluded from this study. 
4.2
Recruitment and Enrollment
Women receiving care at FACES-supported HIV- clinics will be considered for recruitment into 
the study. At these clinics, patients are introduced to cervical cancer screening as part of an HIV 
education session when they enroll in care. Information about cervical cancer and the 
opportunity for screening is reinforced as part of a general daily health talk given while patients 
are waiting to be seen for their routine HIV care, and then reinforced through individualized 
counseling during their clinical visit. Women willing to undergo cervical cancer screening will be 
screened consecutively for their study eligibility and asked about their willingness to participate 
in the study. 
Screening and informed consent for participation in the study will take place in a private 
gynecologic exam room prior to a pelvic exam. Women who previously screened positive for 
HPV (within the last 3 months) but have not undergone treatment will also be eligible for 
recruitment. Those who screen positive and are eligible for thermal ablation will be offered 
treatment and will form the study group
Participant Registration
A written, signed, informed consent form (ICF) must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record.  The original will be kept on file with the study records.  
All participants consented to the study will be registered in OnCore®, the UCSF Helen Diller 
Family Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The system 
is password protected.

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5
Study Procedures and Assessments
5.1
HPV Self-Testing
In this study, cervical cancer screening will be done using HPV testing via self-sampling.
HPV testing at baseline will be performed using patient self-collected samples. After providing 
informed consent, participants will be provided with visual and verbal instructions for HPV self-
collection and offered a private area to perform self-collection before returning the kit to the 
health provider. During self-collection, women will be instructed to proceed to a designated 
private area with the collection brush and tube. While inside the collection area, she will undress 
from the waist down. She will then open the cap of the collection tube and lay both the tube and 
the cap aside on a flat surface. Next, they will open the case of the collecting brush, holding it 
from the plastic end that is the handle. She will then squat or stand in a comfortable position 
with her legs and thighs wide open. With one hand holding the plastic handle of the collection 
brush, she will use the other hand to open the outside of her vagina and gently insert the tip of 
the brush into her vagina. While holding the brush steady, she will gently advance the brush, 
with a slight left or right rotation for easy penetration until she feels resistance (at the cervix). At 
this point, she will turn the brush left or right five times to collect cells from the cervix. She will 
then remove the brush from her vagina and insert it into the collection tube until it reaches the 
bottom of the container. While holding the tube firmly with one hand, she will break off the 
handle of the brush with her other hand at the scored line against the mouth of the tube. She will 
then replace the lid of the collection tube and dispose of the brush handle in a rubbish container. 
A sanitizer for cleaning hands will be available for use before and after collection.  
We will use the CareHPVTM system which tests for DNA of 14 high risk HPV types (16, 18, 31, 
33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68).25 The self-collected samples will be placed in a 
cool area within the FACES laboratory and tests will be run in batches of 90, per the 
manufacturer’s instructions, by a trained laboratory technician. Women who screen positive for 
HR-HPV will be offered a pelvic exam and treatment per the WHO recommendation.4 Visual 
inspection with acetic acid will be performed at the time of the pelvic exam to determine 
eligibility for thermal ablation based on the size of the lesion and other characteristics, as 
recommended by the WHO and Ministry of Health.4 A HPV-positive woman will be considered a 
candidate for thermal coagulation if the squamocolumnar junction is fully visualized, the cervical 
lesions takes up less than 75% of the cervix, there is no endocervical component of the lesion, 
and the lesion is not suspicious for cancer. Women who do not meet these criteria will be 
referred to a tertiary facility for appropriate care.  
5.2
Pelvic Exam
Study examinations will take place in a private room equipped with a gynecologic exam bed in 
the FACES clinic. Participants will be placed in a dorsal lithotomy position. The external 
genitalia will be examined to look for any evidence of infection or genital ulcer disease. After 
introduction of a sterile speculum, the clinician will use a swab to wipe away cervical mucus or 
blood and assess for evidence of cervicitis.26 In the case of concern for cervical infection, 
routine testing and treatment will be performed and screening deferred until treatment is 
complete.8 

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5.3
Visual Inspection with Acetic Acid
In this study, VIA will be performed on all HPV positive women to assess for eligibility for 
ablative treatment in a process referred to visual assessment for treatment (VAT).6 After 
identification of the cervical anatomy, including the squamocolumnar junction, the clinician will 
apply 5% acetic acid to the cervix. After one minute, the clinician will examine the cervix again 
to interpret results of the VIA according to the following criteria:  
VIA will be defined as negative if the following findings are present:26 
1.
Circumferential identification of the squamocolumnar junction (SCJ)
2.
No aceto-white or faint, ill-defined white lesions at the SCJ or aceto-white lesions far 
away from the SCJ
VIA will be defined as positive if the following findings are present, as established by the 
International Agency for Research on Cancer (IARC):8,26 
1.
Raised, thickened, a well-defined, opaque aceto-white lesion at or close to the SCJ
2.
Large circumferential aceto-white lesions covering the external os
3.
Pre-existing condyloma or leukoplakia which turns intensely white after application of 
acetic acid
The WHO criteria for cryotherapy will be used to assess for eligibility for thermal coagulation – 
namely, if the squamocolumnar junction is fully visualized, the cervical lesion covers less than 
75% of the cervix, and there is no endocervical component or suspicion of cancer.4 These 
criteria for the use of thermal coagulation widely accepted and is used in other studies and 
clinical settings.
5.4
Baseline Colposcopy and Cervical Biopsy
All women with a positive HPV screening test will undergo a colposcopy exam followed by a 
directed biopsy of abnormal areas using a punch biopsy forceps. If there are no abnormal 
areas, a random biopsy will be performed at 6 or 12 O'clock. Colposcopy exam will be done in 
accordance with the International Federation for Cervical Pathology and Colposcopy (IFCPC) 
guidelines, including sequential evaluation using a green filter and acetic acid.27 During the 
cervical biopsy, the study clinician will use a biopsy forceps to obtain a rice-grain-sized cervical 
specimen, either at the site of abnormality or at random quadrants. The specimen(s) will be 
placed in a container with formalin, labeled and stored while awaiting transportation to 
pathology.   
5.5
Thermocoagulation
Treatment of positive screening results will be performed using the Liger Thermocoagulator 
device.28 Eligibility for ablative treatment with the thermal coagulator is similar to the WHO-
recommended criteria for cryotherapy, as described above.4,13 The Liger thermocoagulator 
device is a second-generation, hand-held, battery powered, rechargeable device that was 
developed by Liger Medical in Utah USA specifically for use in low resource settings. Previous 
generations of this device have been used for treatment of precancerous lesions in multiple 
studies both in Sub-Saharan Africa and in Europe.6,7,13,17,18,29

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 The cordless, rechargeable device has two components, the detachable probe that comes in 
different sizes to match lesion size, and is heated once in contact with the cervix, and the hand-
held portion that contains the battery and control mechanism with automated timing. Once 
activated, the tip of the probe, in contact with the cervix heats up to 100 ºC over approximately 
four seconds. Once at this temperature, an inbuilt timer starts for a recommended treatment 
length of 20 seconds. If the lesion is larger than the probe, or the transformation zone is not fully 
covered by the probe, several overlapping applications are performed to cover the entire 
lesion.17 
This temperature and length of treatment induce tissue necrosis to a depth of just over 5 mm, 
which is necessary to destroy close to 100% of CIN3 lesions.6 While there is no consensus in 
the literature about the optimal thermoablation temperature and application time, Prendiville et 
al. compared the depth of tissue damage produced by the Liger thermocoagulator applied for 
20, 30, or 45 seconds at 90 ºC, 100 ºC, and 120 ºC on a tissue model.30 They found that a 
depth of more than 5 mm was achieved for all application durations at both 100 ºC and 120 ºC, 
supporting the choice of 100 ºC for 20 seconds setting.30 
This setting has been used for treatment of precancerous lesions in many studies including a 
recent study in Brazil among women with biopsy-proven CIN2/3, in which 85% (17/20) of those 
with CIN2 and 84% (27/32) with CIN3 had no evidence of disease at 12-month follow-up.17 
Studies on thermocoagulation so far confirm patient tolerability with no local anesthesia or 
analgesics, similar to cryotherapy.6,13,17,18,31 
Once treatment is complete, for sterilization, the manufacturer recommends one of two 
methods. The detachable probe can be rinsed with mild detergent and water, and then soaked 
for 20-60 minutes with ~ 2.5% glutaraldehyde solution (Cydex) or 0.5% Chlorine solution.28 
Alternatively, the probe can be decontaminated with alcohol and re-heated to 100 ºC for 
sterilization before reuse, as viral proteins are denatured at temperatures above 60 ºC.15,17,28 
5.6
Post-treatment Pain Assessment 
Pain will be assessed using a visual analog scale (VAS) immediately following treatment.
5.7
4-6 Week Follow-up 
5.7.1 Adverse Events Evaluation 
Adverse events will be evaluated at 4-6 weeks following treatment with a follow-up phone call or 
in-person visit (based on patient preference, distance from the clinic, and symptom severity) at 
which time a woman’s subjective assessment of symptoms and duration will be obtained and 
recorded in a study questionnaire. Adverse events will be graded using the Division of AIDS 
Table for Grading Severity of female genital symptoms in which Grade 0 is normal, 1 is mild, 2 
is moderate and 3 is severe symptoms. Women who elect a phone-call evaluation and report 
grade 2 or 3 symptoms will be asked to present for an in-person evaluation. Transport 
reimbursement will be provided for all study visits. 
5.7.2 Provider Acceptibility Evaluation
At 4-6 week follow up, providers will be surveyed using a Provider Acceptability survey, modified 
from the System Usability Scale to evaluate provider acceptability and satisfaction with the use 
of thermal coagulation for treatment of precancerous lesions.32 

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5.8
12 Month Follow-up Exam
At approximately 12-months after treatment, all participants treated at baseline will undergo 
repeat colposcopy, biopsy for those with CIN2/3 at baseline or those with suspicious lesions on 
colposcopy, as well as provider collected HPV-collection for persistence. Twenty-five percent of 
women with normal colposcopy will have a random biopsy at 6 or 12-O’Clock for ascertainment 
and avoidance of verification bias. 
5.9
Medical Record Data Collection
Individual participant data, including demographic and clinical information, will be collected from 
paper and electronic medical record at FACES and recorded into study-specific data collection 
forms. Participants will be enrolled in FACES for HIV-care and have regular laboratory 
monitoring of CD4+ counts and viral loads. 
Predictor demographic variables will include participant age, gravidity, parity, history of cervical 
cancer screening, marital status, and the number of current and previous sexual partners. 
Clinical variables include current WHO status, CD4+ count levels, previous sexually transmitted 
infections, contraceptive use, and ongoing use of antiretroviral therapy.  
6
Data Quality and Management
6.1
Staff Training
Study exams will be carried out by clinical officers and nurses who have undergone training in 
HPV testing, speculum exam, VIA, specimen collection, colposcopy, and biopsy. The training 
will be based on the International Agency for Research on Cancer (IARC), Kenya Ministry of 
Health (MOH) and WHO curricula and will contain didactic lectures, discussions, review of 
cervical photographs, and hands-on experience. 33,8,34,35 
Several providers at FACES have already undergone training for cervical cancer screening and 
treatment based on cryotherapy and thermocoagulation. Additional, specific training and 
demonstration regarding the use of the Liger thermocoagulator will be performed by the 
Principal Investigator, a U.S trained Gynecologist, using instructional material, including 
demonstration videos, from the manufacturer. All providers will be observed performing several 
treatment cases to ensure competency. All study staff will undergo training in Good Clinical 
Practices, informed consent, participant confidentiality, and study-specific procedures. 
After satisfactory completion of training, including an examination and proctored procedures, 
staff will receive certification. Periodic training and assessment sessions will be done throughout 
the study.  Lab technicians will be oriented in the proper handling, storage, and transport of 
laboratory specimens.
6.2
Secure Data Storage and Study Files
The study will be conducted within existing clinic settings at the FACES clinics in Nyanza 
Province. Participant data will be collected from the participant's electronic and paper records 
into study-specific forms. Study-specific forms will be stored in locked file cabinets within the 
clinic. Data from study-specific forms will be entered into a web-based, secure data storage 

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platform (ODK or RedCap), with labeling by unique study ID only. A file correlating study ID and 
medical file number will be kept in a separate password-protected excel computer file and 
accessible only to the core research team. Additionally, all study computers are password 
protected and kept in locked offices within the clinics. 
The PI is responsible for ensuring the accurate capture of study data.  The information collected 
on study-specific forms shall be identical to that appearing in original source documents.  
Source documents will be found in the participant’s medical records maintained by study 
personnel. All source documentation should be kept in separate research files for each 
participant. All source documentation and CTMS data will be available for review/monitoring by 
the UCSF DSMC and regulatory agencies.
7
Statistical Analysis Plans
Statistical analysis for all study objectives will be carried out using STATA and SPSS software.
7.1
Primary Objective
To evaluate the efficacy of thermal coagulation for the treatment of HIV-positive, HPV-
positive women by assessing rates of HPV persistence and CIN2/3 at 12 months after 
treatment
Four hundred HIV-positive women with positive HPV testing will undergo colposcopy-directed 
biopsy for disease ascertainment prior to same-day treatment with thermal coagulation. At 12-
months after treatment, all participants will undergo repeat HPV testing for persistence, and 
those who are HPV-positive will undergo repeat colposcopy, and biopsy as indicated for 
abnormal results, or random biopsy for 25% of those with normal colposcopy. We will define 
cure as a normal biopsy result or normal colposcopy among those who do not receive a biopsy. 
Statistical Analysis: We will report the proportion of women with no evidence of cervical 
dysplasia at 12-months (primary outcome) follow-up, including 95% confidence intervals. We 
will extrapolate the rate of disease among those with normal colposcopy based on the rate of 
disease among the 25% in this group who will receive biopsy, and this will be incorporated in 
calculating persistence. We will perform a logistic regression to examine predictors of treatment 
success, using clinical and demographic variables as predictor variables. We will also report the 
rate of persistence of HPV at follow-up and compare with rates reported in the literature in this 
same population. We will compare efficacy rates for clearance of CIN2/3 to historical results 
following cryotherapy treatment in similar settings. A one-sample exact test will be used to 
compare the obtained efficacy proportion to that of historical controls. 
We will leverage the robust infrastructure of the FACES in which patients are seen every one-to 
three months, and there is an established patient tracing system (including home visits) to 
reduce loss-to-follow-up. With a loss-to-follow-up rate of 10%, we will still be powered to answer 
this objective. Prior studies at this clinic have been able to achieve > 90% follow-up rate.36 While 
limited by the lack of randomization to cryotherapy versus thermocoagulation, this study will 
provide pilot results that may enable a future randomized study evaluation of these two 
treatment methods.

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7.2
Secondary Objectives
To evaluate the safety of thermal coagulation for the treatment of abnormal cervical 
lesions within a screen-and-treat program among HIV-positive women in Western Kenya.
Statistical Analysis: We will calculate the average pain score immediately after treatment, as 
reported using the visual analog scale with confidence intervals. We will determine the 
proportion of women who experience grade 2 and 3 AEs, and severe adverse events (SAEs) 
during follow-up and calculate confidence intervals. Rates of AEs and SAEs will be compared to 
published rates for cryotherapy amongst this population (2.1% with mild pain or cramping, 1.6% 
with malodorous excessive vaginal discharge, 0.7% with mild bleeding or spotting, and no 
severe adverse events).12 We will use one sample proportion test to compare proportions. 
To evaluate patient satisfaction with thermal coagulation for the treatment of abnormal 
cervical lesions within a screen-and-treat program among HIV-positive women in 
Western Kenya. 
Statistical Analysis: We will evaluate patient satisfaction with thermocoagulation by determining 
the proportion of participants answering yes to satisfaction questions at the 4-6 week follow-up. 
7.3
Exploratory Objective
To evaluate provider acceptability of thermal coagulation for the treatment of 
precancerous lesions within a screen-and-treat program in Western Kenya. 
Statistical Analysis: Healthcare providers offering thermocoagulation for treatment of 
precancerous lesions will be surveyed to evaluate provider acceptability and satisfaction with 
this treatment method using a modified System Usability Scale. The System Usability Scale is a 
widely used measure of product usability, using a Likert scale, rated from 1-5 in order of 
agreement with statements related to usability, acceptability, and satisfaction.32 A one-way 
frequency table will be used to describe and summarize responses to questions on acceptability 
and satisfaction based on a Likert scale. Higher ratings will signify higher acceptability and 
satisfaction. Descriptive statements of challenges associated with this treatment method or 
safety concerns will also be elicited and reported in summary form.
8
Study Management
8.1
Pre-study Documentation
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements.
Before initiating this trial, the PI will have written and dated approval from the Institutional 
Review Board for the protocol, written informed consent form, subject recruitment materials, and 
any other written information to be provided to participants before any protocol-related 
procedures are performed on any participants.  
The Principal Investigator must comply with GCP/ICH guidelines and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements.

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8.2
Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant-facing materials 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF IRB.  Prior to obtaining IRB approval, the protocol must be approved by 
the Helen Diller Family Comprehensive Cancer Center Site Committee and by the Protocol 
Review Committee (PRC).  The initial protocol and all protocol amendments must be approved 
by the IRB prior to implementation.  
We will ensure that all procedures conform to US, Kenyan and international ethical standards 
regarding research involving human subjects. 
8.3
Informed Consent
To participate in any study activities, women must be willing and able to participate, be able to 
sign or mark a consent form, and speak one of the languages into which the consent form and 
data collection instruments have been translated, including English, D’Luo, and Kiswahili. All 
participants must be provided a consent form describing the study with sufficient information for 
each participant to make an informed decision regarding their participation.  Participants must 
sign the IRB -approved informed consent form prior to participation in any study-specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  
The original signed copy of the consent document must be retained in the medical record or 
research file.
8.4
Changes in the Protocol
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the PI and 
approved by the IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to participants, an 
amendment may be implemented prior to IRB approval.  In this circumstance, however, the PI 
must then notify the IRB according to institutional requirements.  
8.5
Oversight and Monitoring Plan
Oversight of the trial is provided by the Principal Investigator (PI), Dr. Chemtai Mungo and 
principal co-investigators Dr. Jackton Omoto and Cirilus Ogollah. 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) will be responsible for monitoring data quality and patient safety 
for this study. 
8.5.1 Data and Safety Monitoring Plan and Procedures 
As this trial is categorized as low-risk based on the study design, per the risk-based algorithm in 
the DSMC, twenty percent of all enrolled subjects and all regulatory documents will be audited 
remotely once per year as per the HDFCCC National Cancer Institute (NCI)-approved Data and 
Safety Monitoring Plan (DSMP).  The subject data will be remotely audited by the HDFCCC 
DSMC via the use of a HIPAA compliant system and will be source document verified with the 
data entered in Red Cap and OnCore.

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The Principal Investigator, Dr. Chemtai Mungo will assure that informed consent will be obtained 
before performing any research procedures, that all subjects meet eligibility criteria, and that the 
study is conducted according to the IRB-approved research plan.   
Study data will be accessible at all times for the Principal Investigator and co-investigators to 
review. The Principal Investigator and co-investigators will review study conduct - accrual, 
dropouts, and protocol deviations - on a weekly basis.  The Principal Investigator and co-
investigators will review AEs individually and in aggregate on a weekly basis.  The Principal and 
Investigator and co-investigators will review serious adverse events (SAEs), in real-time. The 
Principal Investigator will ensure all protocol deviations, adverse events (AEs), and SAEs are 
reported to the DSMC and IRB according to the applicable regulatory requirements. 
Investigators will conduct a continuous review of data and patient safety at the monthly 
Gynecologic Oncology Site Committee meetings
8.5.2 Adverse Event Monitoring 
All clinically significant AEs and all SAEs, whether or not considered to be expected or 
unexpected and whether or not considered to be associated with the use of an investigational 
product or study procedure, will be entered into OnCore®, UCSF’s Clinical Trial Management 
System.
All AEs will be reported according to the Maseno University Ethics Review Committee (MUERC) 
and UCSF IRB Committee in accordance with AE reporting guidelines. 
Adverse events are graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) as developed and revised by the Common Therapy Evaluation Program 
(CTEP) of the National Cancer Institute.  Adverse events are further given an assignment of 
attribution or relationship to the investigational device or study procedure.  Attribution categories 
are:

Definite – The adverse event is clearly related to the investigational device(s) or study 
procedure.

Probable – The adverse event is likely related to the investigational device(s) or study 
procedure.

Possible – The adverse event may be related to the investigational device(s) or study 
procedure.

Unlikely – The adverse event is doubtfully related to the investigational device(s) or 
study procedure.

Unrelated – the adverse event is clearly not related to the investigational device(s) or 
study procedure.
All clinically significant adverse events entered into OnCore® will be reviewed on a monthly 
basis at the Site Committee meetings.
8.5.2.1 Serious Adverse Event Reporting

An adverse event is defined as a serious adverse event (SAE) according to the following 
criteria:

Death.

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
Life-threatening (i.e., results in immediate risk of death).

Requires inpatient hospitalization 

Permanent or significant disability/incapacity.

An event that changes the risk/benefit ratio of a study.

Any other event the Principal Investigator judges to be serious or which would suggest a 
significant hazard, contraindication, side effect, or precaution.
SAEs are reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing 
basis and discussed at DSMC meetings, which take place every six (6) weeks.  The date the 
SAE was sent to all required reporting agencies will be documented in OnCore®.
If a death occurs during the treatment phase of the study or within 30 days after the last study 
intervention and is determined to be possibly, probably, or definitely related either to the 
investigational agent or any research related procedure, the Principal Investigator or his/her 
designee must notify the DSMC Chair or Vice-Chair within 1 business day.  The reporting 
procedure is by communication via phone or in person with written documentation of the one-
on-one communication via e-mail, with a copy of the e-mail to the DSMC Manager.
8.5.3 Review of Adverse Event Rates
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert) is noted in the study, the Principal Investigator will 
notify the DSMC at the time the increased rate is identified.  The report will indicate if the 
incidence of adverse events observed in the study is above the range stated in the Investigator 
Brochure or package insert.
If at any time the Investigator stops enrollment or stops the study due to safety issues, the 
DSMC Chair and DSMC Manager must be notified within 1 business day and the IRB must be 
notified within 10 business days.
8.5.4 Management of Risks to Subjects
Expected AEs
Expected AEs associated with the Thermocoagulation include:  

Mild discomfort associated with biopsy collection and treatment

Mild vaginal discharge for a few days to weeks following treatment 
AE Management
-
Concerning symptoms will be evaluated in person by a trained clinician, and treatment 
offered where appropriate 
-
AEs will be evaluated for whether or not they are attributable to the treatment and 
reported as such
-
All AEs will be followed to conclusion 
8.5.5 Interim Data Analysis for Safety and Acceptability 
For the safety and acceptability objective, we will perform an interim analysis after enrolling 1/3 
of the expected number of women planned (n=133). 

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We will evaluate the proportion of grade 3 or higher adverse events associated with 
Thermocoagulation (as graded by the Scale above) with 95% Confidence Intervals. We will 
compare this proportion of grade 3 or above adverse events to the published literature on  
cryotherapy in similar settings. The results of the interim analysis will be submitted to the 
HDFCCC DSMC for review at the next scheduled DSMC meeting.
8.6
Record Keeping and Record Retention
The PI is required to prepare and maintain adequate and accurate case histories that record all 
observations and other data pertinent to the investigation on each participant enrolled in the 
study. Case histories include the case report forms and supporting data including, for example, 
signed and dated consent forms and medical records including, for example, progress notes of 
the physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study.
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol 
and amendments, IRB correspondence and approval, signed participant consent forms).
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study.
Compliance of regulatory documents and study data accuracy and completeness will be 
maintained through an internal study team quality assurance process. The quality assurance 
process used by the study team must be reviewed and approved by the HDFCCC DSMC.
Confidentiality throughout the trial is maintained by ensuring all study staff have undergone 
training in Good Clinical Practices, informed consent, participant confidentiality, and study-
specific procedures. Study-specific forms will be stored in locked file cabinets within the clinic. 
Data from study-specific forms will be entered into a web-based, secure data storage platform 
(ODK or RedCap), with labeling by unique study ID only. A file correlating study ID and medical 
file number will be kept in a separate password-protected excel computer file and accessible 
only to the core research team.
Data and Safety Monitoring Committee Contacts:
 
 
 (DSMC Chair)
 
Box 1705
UCSF HDFCCC
San Francisco, CA 94158
 
DSMC Monitors 
Box 0128
UCSF HDFCCC
San Francisco, CA 
94143

Version date: 07-25-2019
Protocol CC#:19405 
Thermocoagulation in Kenya
 Page 27 of 30
8.7
Duration of the Study/Project
March
2019
April-
June
2019
Jul-
Sep
2019
Oct-
Dec
2019
Jan-
March
2020
April-
June
2020
Jul-
Sep
2020
Oct-
Dec 
2020
Hire and train project 
coordinator
X
Develop SOPs, Study Manual, 
Database
X
X
Train clinic and lab staff in 
protocols
X
X
Participant Enrollment and
Specimen Collection
X
X
X
X
X
Specimen Processing and 
Evaluation
X
X
X
X
12-month follow-up study visits
X
X
Analyze data
X
X
X
Present data at regional, 
national, or international 
meetings
X
X
Write and submit manuscript
X
X

Version date: 07-25-2019
Protocol CC#:19405 
Thermocoagulation in Kenya
 Page 28 of 30
9
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