Self-Testing Options in the Era of Primary HPV Screening for Cervical Cancer: the STEP Trial
Phase: NA
Conditions: Uterine Cervical Neoplasm, Uterine Neoplasms, Genital Neoplasms, Female, Urogenital Neoplasms, Neoplasms by Site, Neoplasms, Uterine Cervical Diseases, Uterine Diseases, Cervical Cancer, Cervical Dysplasia, Human Papilloma Virus, HPV-Related Cervical Carcinoma, HPV Infection, HPV-Related Malignancy
Sponsor: Kaiser Permanente

Version: August 16, 2021 
 
Page 1 of 18 
ClinicalTrials.gov Identifier:  
 
OFFICIAL TITLE: Self-Testing Options in the era of Primary HPV screening for cervical cancer: the STEP 
trial 
 
SHORT TITLE: STEP Study 
 
Coordinating Center: 
Kaiser Permanente Health Research Institute 
 
Principal Investigators: 
Diana S.M. Buist (7/2019-2/2022) 
Kaiser Permanente Washington Health Research Institute 
Seattle, Washington, U.S.A. 
 
Beverly B. Green (2/2022-Present) 
Kaiser Permanente Washington Health Research Institute 
Seattle, Washington, U.S.A. 
 
 
Rachel L. Winer (7/2019-Present) 
Department of Epidemiology 
School of Public Health 
University of Washington 
Seattle, Washington, U.S.A. 
 
 
Study Coordinator: 
 
Kris Hansen 
Kaiser Permanente Washington Health Research Institute 
Seattle, Washington, U.S.A. 
 
Study Exempt from IDE requirements 
On 12/16 /2019 (Study Determination request Q191276/S001) the FDA determined the intervention 
is a nonsignificant risk (NSR) device as it does not meet the definition of a significant risk (SR) device 
under §812.3(m) of the investigational device exemptions (IDE) regulation (21 CFR 812). 
 
 
NCI Award Number: R01 CA240375 
 
ClinicalTrials.gov: NCT04679675 
 
Final Protocol Date: 
8/16/2021 
 
Protocol Revision Dates: 
 
 
Initial Protocol Date: 
11/17/2020 
 
 

Version: August 16, 2021 
 
Page 2 of 18 
Summary of Changes – Protocol 
 
# 
Date 
Change 
1. 
12/29/2020 
Expand date range of patient history primary objective variables to be 
captured: 
- Change cervical cancer screening history interval from 12 months pre-
randomization, to most recent screen pre-randomization screen or date 
of health care system enrollment 
- Preventative services history from 10 years pre-randomization to 16 
years pre-randomization 
- Add COVID testing/history  
2. 
8/16/2021 
Addition of sub-study of optimized and age-tailored educational 
brochures. 
3. 
 
 
4. 
 
 
5. 
 
 
 
 
 
 

Version: August 16, 2021 
 
Page 3 of 18 
TABLE OF CONTENTS 
Summary of Changes – Protocol .................................................................................................................. 2 
1. 
BACKGROUND ................................................................................................................................. 4 
1.1 
Study Disease(s) ................................................................................................................. 4 
1.2 
Rationale ............................................................................................................................ 4 
2. 
OBJECTIVES ..................................................................................................................................... 4 
2.1 
Primary Objective .............................................................................................................. 4 
2.2 
Secondary Objectives ......................................................................................................... 5 
Schema FIGURE 1: Self-Testing Options in the era of Primary HPV screening for cervical 
cancer ................................................................................................................................ 6 
3. 
PATIENT SELECTION ........................................................................................................................ 6 
3.1 
Eligibility Criteria ................................................................................................................ 6 
3.2 
Exclusion Criteria ............................................................................................................... 6 
3.3 
Inclusion of Women and Minorities .................................................................................. 6 
3.4 
Inclusion of Children .......................................................................................................... 7 
4. 
STUDY PROCEDURES ....................................................................................................................... 7 
4.1 
Subject Recruitment and Screening ................................................................................... 7 
FIGURE 2: STEP Mid-study Educational Brochure allocation for embedded sub-study – 
optimized and age-targeted .............................................................................................. 8 
4.2 
Procedures ......................................................................................................................... 9 
4.3 
Early Termination ............................................................................................................. 10 
5. 
STATISTICAL CONSIDERATIONS ..................................................................................................... 10 
5.1 
Sample Size ...................................................................................................................... 10 
FIGURE 3: STEP randomization allocation by screening history ................................................... 11 
5.2 
Planned Enrollment ......................................................................................................... 12 
5.3 
Analysis Plans ................................................................................................................... 12 
6. 
ADVERSE EVENTS: REPORTING REQUIREMENTS .......................................................................... 15 
6.1 
Determination of Study Risk ............................................................................................ 15 
6.2 
Reporting Adverse Events ................................................................................................ 15 
6.3 
Reporting the Intensity of an Adverse Event ................................................................... 16 
6.4 
Reporting the Relationship of an Adverse Event to intervention .................................... 16 
7. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY REQUIREMENTS .............................. 16 
7.1 
Protocol Review ............................................................................................................... 16 
7.2 
Informed Consent ............................................................................................................ 16 
7.3 
Changes to Protocol ......................................................................................................... 17 
7.4 
Data and Safety Monitoring Plan ..................................................................................... 17 
8. 
REFERENCES .................................................................................................................................. 17 
 
 

Version: August 16, 2021 
 
Page 4 of 18 
1. 
BACKGROUND 
1.1 
Study Disease(s) 
In August 2018, the US Preventive Services Task Force (USPSTF) released updated cervical cancer 
screening guidelines that include human papillomavirus (HPV) testing alone (i.e., primary HPV screening) 
as a newly recommended strategy for people with a cervix aged 30-65 years.1 With primary HPV 
screening, home-based screening is an emerging option, because HPV tests (unlike Pap tests) can be 
performed on clinician- or self-collected samples. Self-collected samples are as sensitive as clinician-
collected samples for detecting HPV and mailing HPV self-sampling kits increases screening 
participation.2-6 Australia and the Netherlands—the first countries to implement primary HPV 
screening—have HPV self-sampling options.3-7 As US healthcare systems prepare to implement primary 
HPV screening, they will need to consider a variety of strategies 
 
Our recent pragmatic trial at Kaiser Permanente Washington (KPWA) found that mailing HPV self-
sampling kits to overdue individuals increased screening uptake by 50% compared to usual care. 
Nonetheless, screening remained low in both arms, 30% of HPV-positive individuals did not attend 
follow-up, and we noted gaps in patient understanding of HPV testing.8,9 With the USPSTF guideline 
update,1 we have a timely opportunity to optimize how health systems offer HPV self-sampling outreach 
to Overdue individuals and test HPV self-sampling outreach approaches among non-Overdue individuals 
(i.e., those who have successfully screened in the past and are now due). To date, HPV self-sampling 
randomized clinical trials (RCTs) in the US have included only Overdue individuals4; no study has 
evaluated uptake of HPV self-sampling kits as an alternative to in-clinic screening in a screening-
adherent population. Evaluating the cost-effectiveness of different approaches to offering HPV self-
sampling kits (e.g., directly mailing kits to all vs. informing individuals about kit availability so they can 
Opt-In and request the kit) to different health system populations is also an important component of 
optimizing this strategy. 
 
1.2 
Rationale 
Pap screening has reduced cervical cancer incidence and mortality by >50% over the last 40 years.10 
Nearly all cervical cancer can be prevented by identifying and removing precancers caused by high-risk 
HPV. However, US adherence to guideline-recommended screening intervals has declined from a high of 
82% in 2003 to 74% in 2016.11,12 Increasing screening coverage is a top national priority for cervical 
cancer prevention.1,13 Well-documented barriers include sociodemographic factors (e.g., race and 
ethnicity and insurance), knowledge about HPV and cervical cancer, beliefs about importance of regular 
screening, discomfort/embarrassment with the Pap procedure, and scheduling/time barriers.13-18 
Individuals who never or rarely screen are a clear intervention priority, as >50% of the 12,000 cervical 
cancers diagnosed annually are in people who have not been recently screened.10,19-21 At the same time, 
keeping people engaged in routine screening is critical; in 2017, only 48% of KPWA individuals who were 
up-to-date with Pap testing attended screening within 6 months after their next due date. HPV 
vaccinations will not end the need for cervical cancer screening,22 since current vaccines do not protect 
against all cancer-associated HPV types.23 Identifying new, patient-centered options that motivate 
continued screening initiation and completion is essential now and in the future.  
 
2. 
OBJECTIVES 
2.1 
Primary Objective 
To compare cervical cancer screening completion within six months after randomization among 
individuals randomized to different outreach approaches, stratified by three categories of prior 
screening behavior:  
 

Version: August 16, 2021 
 
Page 5 of 18 
A) Screening-adherent and coming due:  
Outreach #1: Usual care 
Outreach #2: Usual care + Education (hereafter referred to as “Education”)  
Outreach #3: Usual Care + Education + Opt-In to request an HPV self-sampling kit (hereafter 
referred to as “Opt-In”)  
Outreach #4: Usual Care + Education + Direct Mail HPV self-sampling kit (hereafter referred 
to as “Direct Mail”) 
B) Screen Overdue:  
Outreach #1: Usual care 
Outreach #2: Education  
Outreach #4: Direct Mail  
C) Unknown Prior Screening Behavior:  
Outreach #1: Usual care 
Outreach #2: Education  
Outreach #3: Opt-In 
 
Primary outcome 
• 
Screening completion (returning the HPV self-sampling kit and attending the recommended 
in-clinic follow-up screen (if applicable); or receiving in-clinic screening) within 6 months of 
randomization  
Secondary outcomes  
• 
Screening initiation (returning the HPV self-sampling kit or receiving in-clinic screening) 
within 6 months of randomization  
• 
Time from randomization to screening  completion 
• 
Completion of recommended follow-up after a positive HPV self-sampling kit result (per 
current guidelines, in-clinic Pap after other-HR HPV positive; or colposcopy after HPV 
16/18+) 
• 
Initial screening method (none, HPV self-sampling kit, in-clinic) 
 
The main analysis of primary and secondary outcomes will assess differences between Education, Direct 
Mail and Opt-In, depending on prior screening behavior. Secondary analyses will assess the benefit of 
education materials alone, by directly comparing Education to Usual Care. 
 
2.2 
Secondary Objectives 
2.2.1. Evaluate the incremental cost-effectiveness by outreach approach and by prior screening 
behavior. The outcome will be the incremental cost effectiveness ratio, which will be defined for 
each outreach approach compared to Education. 
 
2.2.2. Identify patient preference for, and satisfaction with, in-home HPV screening and barriers to 
follow-up of abnormal screening results (1:1 qualitative interviews and focus groups). 

Version: August 16, 2021 
 
Page 6 of 18 
Schema FIGURE 1: Self-Testing Options in the era of Primary HPV screening for cervical cancer 
 
 
3. 
PATIENT SELECTION 
3.1 
Eligibility Criteria  
• 
Currently enrolled at Kaiser Permanente Washington  
• 
Female sex 
• 
30 years to 64 years of age  
• 
Intact cervix 
• 
Have a primary care provider at Kaiser Permanente Washington 
• 
Due for cervical cancer screening  
 
3.2 
Exclusion Criteria 
• 
Flagged by the delivery system as being on a non-routine screening schedule 
• 
Previously randomized to the intervention arm of the HOME trial24 or invited to the PATH 
study (P50 CA244432) (participants from the PATH study and individuals randomized to the 
intervention arm in the HOME trial are excluded from STEP because their prior inclusion in a 
cervical cancer-related research study could influence their screening uptake and affect the 
outcome of this trial.) 
• 
On "do not contact list" for research studies 
• 
Currently pregnant or had a pregnancy-related procedure within prior 3 months 
• 
Language interpreter needed 
 
3.3 
Inclusion of Women and Minorities 
The primary goal of the proposed research is to study whether a programmatic in-home HPV screening 
outreach strategy improves cervical cancer screening uptake. Because cervical cancer only affects 
people with a uterine cervix, our entire study population will be composed of female sex individuals. 
Race and ethnicity are not eligibility requirements for participation in our study. All Kaiser Permanente 
Washington members who meet our study eligibility requirements will be eligible for random selection 

Version: August 16, 2021 
 
Page 7 of 18 
into the study. The ethnic/racial composition of our study population will therefore largely reflect the 
ethnic/racial composition of Kaiser Permanente Washington female members. The projected 
proportions of participants from different ethnic/racial backgrounds are based on the composition of 
Kaiser Permanente Washington members (See Planned Enrollment Report table in Section 5.1). 
 
For the secondary objective (2.2.2) focus groups, we will oversample across non-white race categories to 
prioritize having at least 60-80% non-white participants overall if possible. For the secondary objective 
(2.2.2) qualitative interviews, the number of eligible (HPV self-sampling kit positive) individuals is 
expected to be insufficient to oversample based on race and/or ethnicity. As such, the ethnic/racial 
composition will largely reflect the ethnic/racial composition of Kaiser Permanente Washington female 
members.  
 
3.4 
Inclusion of Children 
We are not enrolling individuals younger than age 30. As of 2020, USPSTF cervical cancer screening 
guideline recommendations1 include primary HPV screening only for individuals ages 30 years and older. 
USPSTF guidelines recommend Pap alone for screening individuals ages 21 to 29. Thus, no participants 
under age 30 and no children will be included in the study. 
 
4. 
STUDY PROCEDURES 
4.1 
Subject Recruitment and Screening 
4.1.1 
Primary objective (2.1), and secondary objective (2.2.1) 
Under a waiver of consent and HIPAA authorization, the study programmer will use electronic medical 
record data from KPWA to identify individuals who are due for cervical cancer screening based on 
previous screening history:  
 
1) Screening-adherent and coming due (previously screened and due for screening within three months);  
2) Overdue (never screened; or HPV and Pap co-test >5.25 years ago [or Pap alone >3.25 years ago]; or 
no past Pap and continuously enrolled at KPWA for ≥3.25 years)*; and 
3) Unknown Prior Screening (enrolled ≥6 months and <3.25 years, with no recorded screening history).  
 
*Individuals with due dates falling between March 2020-August 2020 will have randomization delayed 
for 12 months (March 2021-August 2021), because KPWA halted routine cervical cancer screening 
during these months of the COVID-19 pandemic. A 12-month delay in randomization of these individuals 
will (1) allow time for the delivery system to catch-up on the 6-month back log of screening visits, and 
(2) avoid potential misclassification of individuals as overdue solely due to their temporary inability to 
screen during the halted screening or due to their potential likely difficulty to schedule a screening visit 
during the expected surge in catch-up visits. 
 
Clinical outreach provided by KPWA includes sending individuals a reminder letter that they are coming 
due approximately 60 days before their screening due date (for screening-adherent individuals), or 
repeat reminders every 60 days for individuals who are overdue (known to be overdue, or with an 
unknown screening history). The study programmer will use these clinical system outreach letters to 
identify eligible individuals. Each week, we will identify individuals who meet eligibility criteria and are 
mailed a clinical outreach letter. Eligible individuals will be identified, and a random sample will be 
randomized to intervention groups, stratified by screening history, as described below. Randomization 
will occur weekly over a 14-month recruitment period, and eligible individuals will be enrolled under a 
waiver of consent. 
 

Version: August 16, 2021 
 
Page 8 of 18 
The study programmer will use SAS software built in simple random sample procedure to randomly 
select study participants from all eligible individuals, and then randomly allocate participants into Usual 
Care, Education, or 1 of 2 intervention arms based on prior screening history (See Figure 1). Screening-
adherent individuals will be randomized to one of 4 arms: Usual Care, Education, Opt-In or Direct Mail. 
Overdue individuals will be randomized to Usual Care, Education, or Direct Mail. Unknown individuals 
will be randomized to Usual Care, Education, or Opt-In. Target sample size estimates are detailed in 
section 5.1. During study enrollment and follow-up, the electronic randomization sequence will be 
concealed from all researchers by the study programmer, and allocation will only be revealed as 
minimally necessary to investigators directly involved in data collection and/or safety monitoring.  
 
In March 2021, investigators decided to embed a sub-study to investigate the impact of age-tailored 
educational materials on screening uptake. The initial wave/week 1-42 educational materials were 
reviewed and edited via supplemental PATH study grant funding (P50 CA244432). The materials were 
studied via focus groups conducted by the PATH research group, results were reviewed and brochures 
edited by the PATH and STEP study teams, and new non-age-specific "optimized"/edited and age-
tailored (≤45 and >45 years of age) educational brochures were produced. The sub-study will be 
implemented from wave/week 43 onward. Individuals randomized to study intervention arms will be 
stratified by ≤45 versus >45 years of age, and then randomly allocated 1:1 to either age-tailored or non-
age-tailored educational materials (see Figure 2). The study programmer will use the same 
randomization and concealment procedures for the sub-study stratification and allocation.  
 
FIGURE 2: STEP mid-study educational brochure allocation for embedded sub-study – optimized and 
age-targeted 
 
 
 
4.1.2 
Secondary objective two (2.2.2): Qualitative Interviews 
We will conduct a series of in-depth semi-structured 1:1 interviews among participants randomized to 
the intervention arms of the main study who returned an HPV self-sampling kit that tested HPV positive. 
We expect to invite approximately 100 – 150 participants and anticipate enrolling up to 50 for 
interviews. Each week, the study programmer will identify eligible individuals. Participants will be 
contacted by telephone and those interested in participating will be administered verbal informed 

Version: August 16, 2021 
 
Page 9 of 18 
consent under an IRB approved waiver of written consent. 
 
4.1.3 
Secondary objective two (2.2.2): Focus groups  
We will conduct a series of focus groups among individuals randomized to the intervention arms of the 
main study who either did not request/return a kit or returned a kit that tested HPV negative. Each 
week, the study programmer will identify eligible individuals for recruitment.  The programmer will 
oversample from the study population across non-white race categories to prioritize having at least 60-
80% non-white participants overall if possible. Participants will be contacted by telephone and those 
interested in participating will be administered verbal informed consent under an IRB approved waiver 
of written consent. We will conduct up to eight focus groups of up to 10 people per group to learn about 
study participant experiences with the educational materials and the HPV self-sampling kits.  
 
4.2 
Procedures 
 
4.2.1 
Mailings 
Individuals randomized to the Usual Care only arm will receive no study materials. Individuals in all other 
arms will receive the following after randomization: 
1. 
Introduction letter: The letter describes the collaboration between our research team and 
delivery system. For individuals randomized to the Education arm, the letter describes that we 
are trying to learn how health education materials may help people understand why cervical 
cancer screening is important. For individuals randomized to the Opt-In or Direct Mail arms, 
the letter describes that we are trying to learn more about the best ways to offer an in-home 
cervical cancer screening option as an alternative to screening in a clinic. 
2. 
Study information sheet: The study information sheet contains study procedures, potential 
risks and benefits, measures to protect privacy and confidentiality, and HIPAA compliance. 
Individuals are informed their participation is voluntary and that they may call a telephone 
number to “opt-out” of having their individual data included in the research. 
3. 
Educational Brochure: Individuals randomized to intervention arms in waves/weeks 1-42 will 
receive an educational brochure on HPV and cervical cancer that includes information about 
why screening for cervical cancer is important, key information about HPV and its role in 
cervical cancer, and different strategies for cervical cancer screening. For the embedded sub-
study (wave/week 43 onward), individuals randomized to intervention arms will be stratified 
by age (≤45 versus >45 years) and then randomly allocated 1:1 to either age-tailored or non-
age-tailored educational materials (see Figure 2).  
4. 
Opt-In or Direct Mail Inserts: Individuals randomized to the kit arms will receive an 
informational insert that describes the in-home cervical cancer screening option. Inserts for 
Opt-In arm participants will additionally include language on how to order a kit.  
 
4.2.2 
HPV self-sampling kits 
Individuals in the Direct Mail arm will receive their HPV self-sampling kit one week after receiving the 
above materials. Individuals in the Opt-In arm will receive their HPV self-sampling kit with instructions 
within a week of requesting a kit. The kit will include a single use COPAN FLOQswab 552C tube with an 
affixed pre-printed specimen label; biohazard bag with absorbent material; and a postage paid return 
mailing box. HPV self-sampling kit testing and resulting will follow KPWA’s standard HPV sample 
processes. 
 

Version: August 16, 2021 
 
Page 10 of 18 
4.2.3 
Medical records data 
We will obtain data from subject electronic medical records including cervical cancer 
screening/diagnostic/treatment, medical information related to cervical cancer risk factors, health care 
use (including preventive services), comorbidities and demographic information.  
 
4.2.4 
1:1 Qualitative Interviews  
The 1:1 telephone interviews will focus on experiences with follow-up procedures for HPV self-sampling 
kit intervention arm participants whose results were HPV positive. The 30-minute interview will be 
recorded and transcribed for coding and thematic analyses. Participants will receive $50 incentive for 
their participation. 
 
4.2.5 
Focus Groups 
Focus group discussions will assess participant experiences with the educational material, preferences 
and satisfaction with the HPV self-sampling kit and barriers to diagnostic testing for those who did not 
use the kit. A trained facilitator will ask closed-ended items and open-ended questions exploring feelings 
about self-collection, communication with providers about screenings, and how aspects of the screening 
process could be more patient-centered. The focus groups will be audio recorded and transcribed for 
thematic analysis and participants will receive $75 incentive for participation.  
 
4.3 
Early Termination 
Subjects will not be terminated from the study by the study investigators; however, subjects may 
choose to decline some or all study procedures. Participants in all arms, except Usual Care only, will be 
provided a toll-free number that they can call to withdraw consent. All subject withdrawals will be 
documented in the study database. 
 
5. 
STATISTICAL CONSIDERATIONS 
5.1 
Sample Size 
Our sample size calculations are based on pairwise comparisons of screening rates and used preliminary 
data from the KPWA electronic medical record and observed data from the prior HOME trial.24 Using 
2019 KPWA cervical cancer screening data, we estimate 37.1% of screening-adherent, 30.8% of 
Overdue, and 27.8% of individuals with Unknown screening histories will be screened within 6 months 
of randomization in the Education arm. Calculations assume a two-sided level 0.05 test, for differences 
in two proportions.  
 
Our sample size was selected for adequate power to detect meaningful differences in cervical cancer 
screening rates between outreach strategies within each of the 3 target populations. Meaningful 
differences were selected based on estimates from the literature4,25,26 and observed data from the 
HOME trial.22 Small improvements in screening uptake are important, particularly if cost-effective and 
patient-centered; thus, the study is powered to detect relatively small differences between groups. 
Based on prior studies,4,25,26 we anticipate the Direct Mail strategy will have a greater impact on 
screening uptake than the Opt-In approach compared to Education; therefore, we have powered the 
study for a larger minimal detectable difference for the Direct Mail effect. 
 
We estimated the sample size necessary to have 80% power to detect a 3% difference between Opt-In 
and Education and a 5% difference in screening completion between Direct Mail and Education. We 
anticipate that the Direct Mail strategy will have a larger impact on screening outcomes than the Opt-In 
approach, therefore we selected a larger detectable difference (and thus a smaller sample size needed) 

Version: August 16, 2021 
 
Page 11 of 18 
for the Direct Mail group. However, in the screening-adherent population, we computed the sample 
sizes needed for the 3% and 5% detectable differences respectively, and based the Education arm on the 
sample size necessary for the Education versus Opt-In comparison, which was larger than necessary for 
the Education versus Direct Mail comparison. Thus, we will have 80% power to detect a 4.1% difference 
for the Education vs. Direct Mail screening completion comparison. We selected sample size in the Usual 
Care group to detect a difference of 3.0% in screening completion between Usual Care and Education 
for the Screening-Adherent and Unknown populations. Given the smaller sample sizes in the 
intervention groups for the Overdue population, we were unable to achieve a least detectable 
difference (LDD) of 3.0% between Usual Care and Education.  With a sample size of N=1398 in the 
Education group (based on an LDD of 3% for Education vs Direct Mail), we computed the detectable 
difference for a variety of sample sizes for the Usual Care group. We selected a sample size of N=5592 (4 
Usual Care participants for each Education participant), because further increasing the Usual Care group 
led to diminishing improvements in LDD. This sample size yields a least detectable difference of 3.8%.  
 
FIGURE 3: STEP randomization allocation by screening history 
 
 
Target sample sizes for each group, stratified by screening history, are shown in Figure 3, and will 
include randomizing a total of 13,735 Screening-Adherent (3879 Usual Care, 4171 Education, 4171 Opt-
In, and 1514 Direct Mail); 8388 Overdue (5592 Usual Care, 1398 Education, and 1398 Direct mail); and 
10,500 Unknown (3128 Usual Care, 3686 Education, and 3686 Opt-In).  
 
Study enrollment will occur over a 14-month recruitment period. For all three study populations 
(Screening-Adherent, Overdue, and Unknown), the number of eligible individuals is estimated to exceed 
the number needed for the study. Therefore, to reach target sample size over the recruitment period, 
we will randomly select 231 Screening-Adherent, 142 Overdue, and 1777 Unknown individuals from the 
pool of all eligible individuals each week, for inclusion in the study. We will allocate each weekly sample 
to randomization groups as follows: Screening-Adherent (65 Usual Care, 70 Education, 70 Opt-In, and 26 
Direct Mail), Overdue (94 Usual Care, 24 Education, and 24 Direct Mail), and Unknown (53 Usual Care, 
62 Education, and 62 Opt-In). This sampling strategy maintains a consistent distribution across 
randomization arms over time, minimizing any potential impacts of temporal trends on group 
comparisons. If the number of eligible individuals in any given week is lower than the weekly target, the 
shortfall will be added to the target recruitment sample for the following week.  
 
Beginning with wave 43, each randomization group (except Usual Care) will be further stratified by £45 
years and >45 years age groups, and then 1:1 randomized to receive age-targeted or non-age-targeted 
optimized Education brochure as part of their intervention materials (see Figure 2). 
 

Version: August 16, 2021 
 
Page 12 of 18 
Our sample size estimates were based on data from 2019, before the COVID-19 pandemic which has 
impacted in-person cervical cancer screening. The sample size and recruitment plan described above is 
our a priori sampling strategy to achieve target sample size over the 14-month recruitment period. 
However, since the number of eligible individuals will vary with each data pull, and may be impacted by 
changes to care delivery, we will closely monitor recruitment and make necessary changes to ensure 
target sample sizes are met. Potential changes include the following: 
1) If the number of eligible individuals is consistently below the weekly target sample size, we will 
consider randomizing all eligible individuals rather than a sample, during weeks where there are 
more eligible individuals than the weekly target. The allocation fractions to randomization 
groups would remain the same as the original recruitment plan.  
2) Since our comparison between Usual Care and Education is an exploratory aim, if the number of 
eligible individuals is considerably lower than anticipated, we will consider reducing the sample 
size allocated to Usual Care, to ensure target sample sizes in the Education, Opt-In, and Direct 
Mail groups are met. 
 
5.2 
Planned Enrollment 
 
ANTICIPATED/PLANNED ENROLLMENT for ENTIRE STUDY: 
Number of Participants (must provide exact numbers. i.e. no range) 
 
Ethnic Categories 
 
 
 
Sex/Gender 
 
Females 
Males 
Total 
Hispanic or Latino 
1,957 
0 
1,957 
Not Hispanic or Latino 
30,666 
0 
30,666 
Ethnic Categories: Total of All Participants 
32,623 
0 
32,623 
Racial Categories 
American Indian/Alaska Native 
391 
0 
391 
Asian 
3,720 
0 
3,720 
Native Hawaiian or Other Pacific Islander 
391 
0 
391 
Black or African American 
2,120 
0 
2,120 
White 
23,717 
0 
23,717 
More Than One Race 
2,283 
 
2,283 
Racial Categories: Total of All Participants  
32,623 
0 
32,623 
 
5.3 
Analysis Plans 
5.3.1 
Analysis plan relevant to primary objectives 2.1 and secondary objective 2.2.1 
Figure 1 provides an overview of how our outcomes will be defined by randomization arm.  
 
We define screening completion as follows: 
Direct Mail or Opt-In: 
a) Receive in-clinic screening; or 
b) Return kit and complete reflex cytology if recommended per USPSTF primary HPV 
guidelines. 
Usual care or Education: 
a) Receiving in-clinic screening. 
 

Version: August 16, 2021 
 
Page 13 of 18 
Screening completion is our primary outcome because of the importance of ensuring individuals follow 
through with a complete screening episode. One potential disadvantage of a self-collected test is the 
estimated 8% of individuals who have an other-HR HPV positive or unsatisfactory result27 who will need 
to have an in-clinic Pap to determine whether any additional diagnostic evaluation is needed (whereas 
with in-clinic primary HPV screening, the same sample is used for both HPV testing and reflex cervical 
cytology).  
 
Screening initiation is a secondary outcome. We define screening initiation as either receiving in-clinic 
cervical cancer screening or returning an HPV self-sampling kit (without the requirement to complete 
reflex cytology when warranted). Screening initiation is an important indicator of the success or failure 
of self-collection, since returning an HPV self-sampling kit will count towards cervical cancer screening 
for Healthcare Effectiveness Data and Information Set quality metrics.11 If there is a large difference 
between initiation and completion, it will be informative for implementation efforts (e.g., additional 
resources may be needed to ensure that individuals with other-HR HPV positive or unsatisfactory kit 
results complete in-clinic reflex cytology).  
 
All analyses will be stratified by screening history population (Adherent, Overdue, and Unknown). All 
analyses will be based on the intention to treat principle, with individuals analyzed by the outreach 
approach arm to which they were randomly assigned. We will first conduct an overall chi-square test to 
assess differences in observed screening rates among randomization groups. The primary analysis will 
use a modified Poisson regression modeling approach to estimate the relative risk of screening 
completion associated with Direct Mail, and Opt-In strategies relative to Education (as appropriate by 
screening history population). A binary indicator for screening completion within 6 months (yes/no), as 
defined above, will be the dependent variable. Models will be fit using generalized estimating equations 
with an independent working correlation structure and robust standard error estimation to account for 
correlation between participants paneled to the same primary care provider. Models will adjust for 
baseline characteristics that differ by randomization arm. Models for Overdue participants will also be 
adjusted for overdue duration (<3 years and ≥3 years). The analysis for the outcome of screening 
initiation will use the same methods. The primary analysis will not include the Usual Care group, but 
secondary analyses will include this group, and will estimate the relative risk of screening outcomes for 
Education, relative to Usual Care. 
 
Delays in screening impact time in compliance with screening recommendations and can also impact 
cancer outcomes. Thus, our analysis will also assess the time it takes to complete screening, defined as 
the number of days between randomization and screening completion, as a secondary outcome. We will 
use Kaplan-Meier log-rank tests to compare time to screening completion by randomization arm, with 
follow-up time censored at 6 months for non-completers. Analyses will be stratified by screening history 
population (Adherent, Overdue, and Unknown).  
 
Given the importance of in-clinic follow-up after a positive self-sampling result, data on implementation 
outcomes will be critical for informing sustainability and translation to other health care systems. We 
will report the proportion of participants who complete necessary in-clinic follow-up after an abnormal 
kit result (e.g., reflex cytology after kit result other-HR HPV positive, or diagnostic colposcopy after kit 
result HPV16/18+) within 6 months after randomization.  We will summarize these proportions 
separately by randomization group (Direct Mail vs. Opt-In) and by prior screening behavior (Adherent, 
Overdue, and Unknown). 
 

Version: August 16, 2021 
 
Page 14 of 18 
Screening method choice is another important secondary outcome among participants randomized to 
Opt-In and Direct Mail. We will report the proportion of participants choosing no screening, in-clinic 
screening, or HPV self-sampling kit. We will summarize these proportions separately by randomization 
group (Direct Mail vs. Opt-In) and by prior screening behavior (Adherent, Overdue, and Unknown).  
 
Differences in rates of missing data across groups can result in biased estimates of intervention effects. 
We expect missingness to be minimal since outcome data on screening completion will be defined from 
automated databases. All randomized participants will be included in the primary analysis, regardless of 
duration of enrollment in the 6-month follow-up period. In this age group and because outcome 
assessment is based on only 6 months of post-randomization follow-up, loss to follow-up is expected to 
be minimal. We do not anticipate any effect of assigned treatment arm on health plan disenrollment. 
However, we will report the rate of disenrollment by arm. The primary analysis will be unweighted, but 
if disenrollment rates are high (>10%), we will also perform sensitivity analyses using follow-up duration 
as an offset parameter in the Poisson regression models. The offset parameter allows estimation of the 
screening completion rate for censored data where participants had varying lengths of follow-up time.  
 
To protect against multiple comparisons for analyses among the screening-adherent population (which 
has 3 intervention groups in the primary analysis), we will use the Fisher protected least-significant 
difference approach, which requires that pairwise group comparisons are made only if the overall 
omnibus test of any differences between group is statistically significant. The referent group for all 
analyses will be Education. When evaluating Opt-In and Direct Mail, the primary interest is in the impact 
of the mailed-kit interventions. The educational materials may also impact screening rates, but by using 
Education as the referent group for comparisons, the estimated group differences will be the effect 
related to the mailed kit.  
 
The secondary analysis comparison between Education and Usual Care will allow estimation of the 
effect of the educational materials alone. 
 
Starting with recruitment wave 43, the original educational brochure was replaced with new brochures, 
revised based on focus group feedback.  A new non-age-specific brochure, plus age-tailored (≤45 and 
>45 years of age) educational brochures were produced, and study participants, stratified by age group, 
were randomized to receive the non-age-specific or age-tailored materials.  Using data from this 
embedded sub-study, we will investigate the effects of the revised education materials compared to 
usual care, and the effects of age-tailored materials compared to non-age-specific materials, on 
screening completion.  This analysis will be limited to individuals randomized to the Usual Care or 
Education arms, starting with wave 43.  We will use a generalized linear model approach, with log link 
function and Poisson error distribution to estimate the difference in screening completion rates.  
Indicators for usual care, non-age-specific materials, or age-tailored materials will be the exposure 
variables, and the binary outcome of screening completion (yes/no) will be the outcome.  For the 
primary analysis, we will assume a constant effect of the revised education materials, and of age-
tailoring, across all individuals, and the model will be fit using data from individuals in all screening 
history groups (Adherent, Overdue, and Unknown), and all ages.  In secondary analyses, we will explore 
whether the effect of the non-age-specific and age-tailored materials differ by screening history or age 
(≤45 and >45) by adding indicator variables for these characteristics and interaction terms between 
these variables and the primary exposure variables.   
 
Further analytic details of the above analyses, and additional secondary and exploratory analyses are 
provided in the study’s Statistical Analysis Plan (SAP). 

Version: August 16, 2021 
 
Page 15 of 18 
 
5.3.2 
Analysis plans relevant to secondary objective one (2.2.1) 
We will conduct a cost-effectiveness analysis of the outreach approaches for in-home HPV self-sampling 
kits with the incremental cost-effectiveness ratio (ICER) defined as the incremental cost per incremental 
increase in number of individuals who successfully achieve cervical cancer screening completion as 
defined by our primary study outcome, which includes appropriate follow-up of other-HR HPV positive 
HPV self-sampling kit results. The primary economic outcome will be an ICER. For screening-adherent 
individuals, ICERs will reflect comparisons between a) Opt-In and Education, b) Direct Mail and 
Education, and c) Direct Mail and Opt-In with Opt-In as the reference strategy. For Overdue individuals, 
the ICER will compare Direct Mail to Education. For individuals with Unknown screening histories, the 
ICER will compare Opt-In to Education. Within each screening status group, we will also be able to 
generate an ICER for Education compared to Usual Care. The study design precludes a comprehensive 
ICER comparing a single strategy (or set of strategies) to Education or Usual Care across all participants. 
Costs and screening outcomes will be varied in univariate, multivariable, and/or probabilistic sensitivity 
analyses as appropriate in Excel-based and Stata-based programs. Discounting and inflation adjustments 
will not be applied to costs or outcomes because of the 6-month assessment period. The STEP study will 
allow us to inform the delivery system with screening uptake projections, screening strategy selection, 
and the relative cost implications of switching from in-clinic to in-home testing, which may differ by 
prior screening behavior. 
 
5.3.3 
Analysis plans relevant to secondary objective two (2.2.2)  
We will use data from the interviews and focus groups to evaluate participants’ preferences for, and 
satisfaction with, in-home HPV screening and barriers to follow-up of abnormal screening results. 
Surveys administered during the interviews and embedded in focus groups discussions will measure 
knowledge, perceived risk, efficacy beliefs about in-home HPV screening, trust in kit, self-efficacy, kit 
experience, reasons for not returning kit, screening test preference, future screening intentions, and 
patient-centered communication around screening.  
 
6. 
ADVERSE EVENTS: REPORTING REQUIREMENTS  
6.1 
Determination of Study Risk 
This is a minimal risk study where the medical intervention has similar potential adverse events as 
individuals undergoing standard clinical procedures such as Pap, HPV or other sexually transmitted 
infection testing.  
 
6.2 
Reporting Adverse Events 
Based on our own previous and ongoing studies and numerous other prior studies involving self-
collected vaginal swabs, we expect adverse events will be rare and minor in severity. The study focus 
groups and 1:1 qualitative interviews also present minimal risk to subjects as they do not address highly 
sensitive information. As such, the Principal Investigators and medical monitor will continuously monitor 
adverse events as they are reported to the study hotline and through individuals’ primary care teams. 
The reviewing institutional review board for this study (Kaiser Permanente Washington) has ruled in 
agreement with this assessment. 
 
Discomfort and light bleeding are the expected adverse events (AEs). In our previous HOME study of in-
home HPV testing, light bleeding was reported by a small minority of subjects who used HPV self-
sampling kits (less frequent than bleeding from standard Pap testing). We have no plan for stopping 
rules due to bleeding because we are only capturing AEs through self-report to the study hotline or 
primary care teams, and do not expect that the number of reports of bleeding would exceed the 

Version: August 16, 2021 
 
Page 16 of 18 
frequency of bleeding from standard Pap testing. All adverse events will be continuously monitored by 
the Principal Investigators. 
 
All adverse events reported to the study hotline, regardless of causality, will be documented in the 
electronic adverse event (AE) case report form (CRF). Adverse events will be assessed using the NCI 
Common Toxicity Criteria for Adverse Events v5.0 (CTCAE). A copy can be downloaded from the CTEP 
home page: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm  
The Principal Investigators will designate a medical monitor that will be responsible for following serious 
adverse events (SAEs). The patient should be followed until the event resolves or stabilizes. Frequency 
of follow-up is at the discretion of the medical monitor. Serious AEs ongoing at the end of the study 
period must be followed up to resolution. 
 
6.3 
Reporting the Intensity of an Adverse Event 
Adverse events intensity will be described and graded per NCI Common Terminology Criteria for Adverse 
Events CTC AE v5.0: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Referenc
e_8.5x11.pdf 
 
6.4 
Reporting the Relationship of an Adverse Event to intervention 
The medical monitor will assess the causal relationship of the event to study intervention using the 
following guidelines: 
Definite: The event is clearly related to the intervention. 
Possible: The event is possibly related to the intervention. 
Not related: The event is clearly NOT related to the intervention. 
All adverse events, regardless of severity, will be classified as expected or unexpected and reported to 
the Kaiser Permanente Washington Human Subjects Review Committee, per Kaiser Permanente 
Washington Human Subjects Review Committee Incident Guidelines, as loaded in IRBNet. 
 
7. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY REQUIREMENTS 
7.1 
Protocol Review 
The protocol and informed consent forms for this study will be reviewed and approved in writing by the 
Kaiser Permanente Washington Institutional Review Board before any individual is enrolled in this study. 
 
7.2 
Informed Consent 
7.2.1 
Primary objectives and secondary objective one  
All consent will be conducted in compliance with Code of Federal Regulations, Title 45, Part 46 (45 CFR 
part 46). To reduce participation bias, eligible individuals will be identified and randomized into the 
study under a waiver of consent. Informed consent of Education, Opt-In, and Direct Mail participants 
will be per a waiver of documentation of consent. These individuals will be notified they have been 
enrolled in a study and will be provided with the ability to opt-out of having their individual-level 
medical record data used in the research, but passive consent will be used which will significantly 
enhance the generalizability of the findings. We will request a waiver of informed consent and a waiver 
of HIPAA Authorization to identify, enroll and collect data for individuals randomized to Usual Care.  
 
7.2.2 
Secondary objective two (2.2.2) (focus groups with participants in Opt-In and Direct Mail arms) 
In compliance with 45 CFR part 46, informed consent will be obtained from all participants via verbal 
consent under a waiver of documentation of consent.  

Version: August 16, 2021 
 
Page 17 of 18 
 
7.3 
Changes to Protocol 
Any protocol modifications will be approved by the Principal Investigators and approved by the IRB 
before the revision or amendment may be implemented. The only circumstance in which the 
amendment may be initiated without regulatory approval is for a change necessary to eliminate an 
apparent and immediate hazard to the participant. In that event, the investigators will notify the IRB in 
writing per current IRB rules. 
 
7.4 
Data and Safety Monitoring Plan 
This is a minimal risk study where the medical intervention has similar potential adverse events as 
individuals undergoing standard clinical procedures such as Pap, HPV or other sexually transmitted 
infection testing. There is no data safety and monitoring committee for this study. However, the 
Principal Investigators will be continuously monitoring adverse events (see Section 6) as they are 
reported to the study hotline and as reported to the study team by individuals’ primary care teams. 
 
Study staff involved in interim data activities will not be involved in any scientific decisions about 
modifications to the study protocol, but may consult with the scientific leadership team with potential 
concerns. The scientific leadership team, comprised of the co-Principal Investigators, project senior 
biostatistician, and one additional co-investigator not involved in data activities, will be blinded to all 
primary and secondary outcomes review or analyses until 6 months after the last subject is enrolled. 
 
8. 
REFERENCES 
1. 
U. S. Preventive Services Task Force, Curry SJ, Krist AH, et al. Screening for Cervical Cancer: US 
Preventive Services Task Force Recommendation Statement. JAMA. 2018;320(7):674-686. 
2. 
Winer RL, Feng Q, Hughes JP, et al. Concordance of self-collected and clinician-collected swab 
samples for detecting human papillomavirus DNA in women 18 to 32 years of age. Sex Transm 
Dis. 2007;34(6):371-377. 
3. 
Arbyn M, Castle PE. Offering Self-Sampling Kits for HPV Testing to Reach Women Who Do Not 
Attend in the Regular Cervical Cancer Screening Program. Cancer Epidemiol Biomarkers Prev. 
2015;24(5):769-772. 
4. 
Verdoodt F, Jentschke M, Hillemanns P, Racey CS, Snijders PJ, Arbyn M. Reaching women who do 
not participate in the regular cervical cancer screening programme by offering self-sampling kits: 
a systematic review and meta-analysis of randomised trials. Eur J Cancer. 2015;51(16):2375-2385. 
5. 
Arbyn M, Verdoodt F, Snijders PJ, et al. Accuracy of human papillomavirus testing on self-collected 
versus clinician-collected samples: a meta-analysis. Lancet Oncol. 2014;15(2):172-183. 
6. 
Leinonen MK, Nieminen P, Lonnberg S, et al. Detection rates of precancerous and cancerous 
cervical lesions within one screening round of primary human papillomavirus DNA testing: 
prospective randomised trial in Finland. BMJ. 2012;345:e7789. 
7. 
Smith M, Lew JB, Simms K, Canfell K. Impact of HPV sample self-collection for underscreened 
women in the renewed Cervical Screening Program. Med J Aust. 2016;204(5):1941e-1947. 
8. 
Winer RL, Tiro J, Miglioretti D. Can home-based HPV self-sampling improve cervical cancer 
screening adherence in underscreened women? Results from the HOME pragmatic randomized 
trial. In. ASPO Abstracts. 
9. 
Winer RL, Tiro J, Gao H. Home-based HPV self-sampling to increase cervical cancer screening 
participation: A pragmatic randomized trial in a U.S. Healthcare delivery system (Abstract FC 08-
05). In. 
10. 
Noone AM, Howlader N, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2015. Bethesda, 
MD: National Cancer Institute. 

Version: August 16, 2021 
 
Page 18 of 18 
11. 
National 
Committee 
for 
Quality 
Assurance. 
Cervical 
Cancer 
Screening 
(CCS). 
https://www.ncqa.org/hedis/measures/cervical-cancer-screening/. 
Published 
Published 
September 7, 2018. Accessed October 19, 2020. 
12. 
National Committee for Quality Assurance. Non-Recommended Cervical Cancer Screening in 
Adolescent Females (NCS). https://www.ncqa.org/hedis/measures/non-recommended-cervical-
cancer-screening-in-adolescent-females/. Published Published September 15, 2018. Accessed 
October 19, 2020. 
13. 
Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for 
Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening 
guidelines for the prevention and early detection of cervical cancer. Am J Clin Pathol. 
2012;137(4):516-542. 
14. 
White A, Thompson TD, White MC, et al. Cancer Screening Test Use - United States, 2015. MMWR 
Morbidity and mortality weekly report. 2017;66(8):201-206. 
15. 
Limmer K, LoBiondo-Wood G, Dains J. Predictors of cervical cancer screening adherence in the 
United States: a systematic review. J Adv Pract Oncol. 2014;5(1):31-41. 
16. 
Zapka J, Taplin SH, Price RA, Cranos C, Yabroff R. Factors in quality care--the case of follow-up to 
abnormal cancer screening tests--problems in the steps and interfaces of care. J Natl Cancer Inst 
Monogr. 2010;2010(40):58-71. 
17. 
Crawford A, Benard V, King J, Thomas CC. Understanding Barriers to Cervical Cancer Screening in 
Women With Access to Care, Behavioral Risk Factor Surveillance System, 2014. Preventing chronic 
disease. 2016;13:E154. 
18. 
Akinlotan M, Bolin JN, Helduser J, Ojinnaka C, Lichorad A, McClellan D. Cervical Cancer Screening 
Barriers and Risk Factor Knowledge Among Uninsured Women. J Community Health. 
2017;42(4):770-778. 
19. 
Janerich DT, Hadjimichael O, Schwartz PE, et al. The screening histories of women with invasive 
cervical cancer, Connecticut. Am J Public Health. 1995;85(6):791-794. 
20. 
Kinney W, Sung HY, Kearney KA, Miller M, Sawaya G, Hiatt RA. Missed opportunities for cervical 
cancer screening of HMO members developing invasive cervical cancer (ICC). Gynecol Oncol. 
1998;71(3):428-430. 
21. 
Leyden WA, Manos MM, Geiger AM, et al. Cervical cancer in women with comprehensive health 
care access: attributable factors in the screening process. J Natl Cancer Inst. 2005;97(9):675-683. 
22. 
Moyer VA, U. S. Preventive Services Task Force. Screening for cervical cancer: U.S. Preventive 
Services Task Force recommendation statement. Ann Intern Med. 2012;156(12):880-891, W312. 
23. 
Markowitz LE. HPV vaccines prophylactic, not therapeutic. JAMA. 2007;298(7):805-806. 
24. 
Winer RL, Tiro JA, Miglioretti DL, et al. Rationale and design of the HOME trial: A pragmatic 
randomized controlled trial of home-based human papillomavirus (HPV) self-sampling for 
increasing cervical cancer screening uptake and effectiveness in a U.S. healthcare system. 
Contemp Clin Trials. 2018;64:77-87. 
25. 
Kellen E, Benoy I, Vanden Broeck D, et al. A randomized, controlled trial of two strategies of 
offering the home-based HPV self-sampling test to non- participants in the Flemish cervical cancer 
screening program. Int J Cancer. 2018;143(4):861-868. 
26. 
Tranberg M, Bech BH, Blaakaer J, Jensen JS, Svanholm H, Andersen B. Preventing cervical cancer 
using HPV self-sampling: direct mailing of test-kits increases screening participation more than 
timely opt-in procedures - a randomized controlled trial. BMC Cancer. 2018;18(1):273. 
27. 
Winer RL, Lin J, Tiro JA, et al. Effect of Mailed Human Papillomavirus Test Kits vs Usual Care 
Reminders on Cervical Cancer Screening Uptake, Precancer Detection, and Treatment: A 
Randomized Clinical Trial. JAMA Netw Open. 2019;2(11):e1914729.