Screening for Cervical Intraepithelial Neoplasia Using Self-collected Menstrual Blood
Conditions: HPV - Anogenital Human Papilloma Virus Infection
Sponsor: Stanford University

 
 
 
 
Screening for Cervical Intraepithelial Neoplasia Using Self-collected 
Menstrual Blood 
Study Protocol and Statistical Analysis Plan 
NCT03638427 
March 17, 2020 

TITLE:  Screening for Cervical Intraepithelial Neoplasia Using Self-Collected Menstrual Blood 
 
 
Coordinating Center 
Stanford Gynecology Clinic 
900 Blake Wilbur Drive 
Stanford, CA 94305 
 
Principal Investigator 
Dr. Paul Blumenthal 
300 Pasteur Drive 
 
Stanford, CA 94305 
T: 
 
F: 
 
  
 
Co-Investigators 
Sara Naseri 
300 Pasteur Drive 
 
Stanford, CA 94304 
T: 
 
F: 
 
 
 
Biostatistician 
, MPH 
300 Pasteur Drive 
 
Stanford, CA 94304 
T: 
 
F: 
 
 
 
Study Coordinator 
 
300 Pasteur Drive 
 
Stanford, CA 94304 
T: 
 
F: 
 
  
 
 
Version 4 / Version Date (03-17-2020) 
 
 
 
 

 
 
    
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TABLE OF CONTENTS 
1.0  
SPECIFIC STUDY AIMS 
3 
2.0  
BACKGROUND AND RATIONALE 
3 
3.0  
STUDY ENROLLMENT AND PARTICIPANT ELIGIBLITY 
4 
3.1 STUDY ENROLLMENT .......................................................................................................... 5 
3.2 PARTICIPANT CRITERIA....................................................................................................... 5 
3.3   ENROLLMENT ...................................................................................................................... 6 
4.0  
MATERIAL AND METHODS 
6 
5.0 
STATISTICAL CONSIDERATIONS 
7 
5.1 OUTCOME MEASUREMENTS ................................................................................................ 7 
5.2 ANALYSIS PLAN .................................................................................................................. 7 
5.3 SAMPLE SIZE ....................................................................................................................... 7 
6.0  
DATA MANAGEMENT CONSIDERATIONS 
7 
6.1 DATA MANAGEMENT .......................................................................................................... 7 
6.3 CONFIDENTIALITY .............................................................................................................. 8 
6.4 PROTOCOL REVIEW AND AMENDMENTS ............................................................................. 8 
REFERENCES 
9 
APPENDIX A: PARTICIPANT ELIGIBILITY CHECKLIST 
10 
APPENDIX B: PROTOCOL SUMMARY OF CHANGES 
12 
 
 

 
 
    
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1.0  
SPECIFIC STUDY AIMS  
Specific Aim #1: To compare the accuracy and percent analytic agreement of clinician- 
and self-collected cervico-vaginal brush samples with Q-pad-collected menstrual blood 
for HR-HPV detection in HR-HPV positive women and women with no previous history 
of HR-HPV.  
 
Specific Aim #2: 2.1: To assess the ability to detect oncoproteins in Q-pad collected 
menstrual blood samples from women with ASCUS+ to determine the utility in 
cervical cancer/precancer detection and 2.2: to test the utility of a low and high threshold 
HR-HPV reflex scheme to similarly increase the specificity of HR-HPV testing derived 
from menstrual blood. 
 
2.0  
BACKGROUND AND RATIONALE  
Cervical cancer (CaCx) is the fourth most common cancer among women worldwide, and 
the 2nd highest cause of cancer-related mortality among women1. Most cases of CaCx are 
preventable through the combination of screening and access to appropriate treatment of 
precancerous lesions2. Papanicolaou (Pap) cytology screening has been the most widely 
applied screening method for cervical cancer or precancer but has variable sensitivity and 
specificity and, globally, cytology is not effectively available to women in developing 
countries (where 80% or all cervical cancers occur)3. The combination of variable test 
qualities and limited access results in continued high incidence of fatal cancers in many 
settings.  
 
In recent years, tests to detect Human Papilloma Virus (HPV), particularly high-risk 
subtypes (HR-HPV) from cervical samples have been introduced in many settings and are 
poised to become a primary screening approach in the future. A known limitation to 
DNA-based HR-HPV testing is that it can only discriminate between presence or absence 
of an HPV specific DNA and cannot determine whether presence of the virus indicates 
mere infection or pre-cancer/cancer. Several studies have found that the molecular switch 
for the development of Cervical Intra-epithelial Neoplasia (dysplasia or CIN) and 
ultimately CaCx is the expression of the E6 and E7 onco-proteins resulting from infection 
with oncogenic HPV4. Results demonstrates that the specificity of HR-HPV E6/E7 
mRNA is higher than that of HR-HPV5-6 and that HR-HPV E6-E7 mRNA measured at 
baseline predicts future CIN2 or CIN3 development7. Finally, it has been shown that 
compared with HR-HPV testing alone, HR-HPV/E6-E7 mRNA testing could reduce half 
of the colposcopy referrals generated by current prevention rubrics4. Alternatively, 
changing the cycle threshold for a positive HR_HPV test from low (high sensitivity) to 
high (high specificity) as a serial “reflex” test could have the same effect.  In addition, the 
evolution to primary testing with HR-HPV has been accomplished in some settings using 
specimens obtained from patient self-collected swabs, obviating the need for the vast 
majority of women to undergo a gynecological exam, which is invasive, uncomfortable, 
and resource-intense.  
 
Detection of HR-HPV with E6/E7 via self-collected samples could improve access to 
screening, improve sensitivity, and increase objectivity of testing. A variety of self-
collection devices have been used to detect HPV including swabs, brushes, cervical 

 
 
    
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lavage devices, tampons, and urine.8 While most of these devices have comparable 
sensitivity for HR-HPV (compared to clinician collected samples)9, logistical challenges 
limit their utility. Most devices require instructions on proper insertion into the vagina 
(which can be culturally challenging in some settings), the specimens are difficult to 
transport, and often require storage in expensive, flammable fixative solution. A novel 
and innovative alternative involves the use of menstrual blood for the same diagnostic 
purpose. To this end, a specialized collection device integrated into an ordinary, 
inexpensive menstrual pad has been developed. Specifically, the “The Q-Pad” is a small, 
flexible, and easy-to-transport device involving dried paper – which essentially creates a 
Dried Blood Spot (DBS) specimen – embedded within a sanitary napkin. For purposes of 
CaCx screening, such a collection device does not require intra-vaginal manipulation of a 
brush/swab or lavage device and could improve participation in community screening 
efforts while also being easier to transport than urine or cervicovaginal samples. 
Menstrual blood has already been shown to corelate well with a number of commonly 
used serum tests such as Hemoglobin A1C and TSH10.  
 
Menstrual blood is composed of three distinct body fluids: whole blood, vaginal fluid, 
and endometrial cells shed from the endometrial lining. While menstrual blood has been 
presumed to be virtually identical to whole blood, important differences exist and have 
been understudied. Studies from the 1980s found that menstrual fluid lacks factor X, pro-
thrombin, and free thrombin15. Proteomic and small-scale HPV detection studies have 
been recently published on menstrual blood16, yet rigorous, larger-scale and 
implementation-level studies remain to be performed. In preliminary (unpublished) 
findings on HR-HPV screening with the Q-pad, we found that device detected HR-HPV 
using the GeneXpert POC test, and, anecdotally, women preferred this approach to self-
collected and clinician-collected samples. We found favorable participation in 
community-based screening. Additionally, in rural, low-resource settings, DBS is easier 
to transport than slides, urine, or liquid-based cervico-vaginal samples, requires no 
refrigeration, and can potentially provide a “woman’s physical” in a self-collected 
sample.  
 
Our proposed study would be the first to rigorously examine the utility and feasibility of 
using menstrual blood collected by women for detection of HR-HPV DNA and HPV 
E6/E7 mRNA, using the Q-pad. We hypothesize that using self-collected menstrual blood 
from the Q-pad may be a more convenient, comfortable and cost-effective method for 
HR-HPV and E6/E7 screening, compared to currently implemented approaches, with 
high correlation to conventional HR-HPV testing. Our approach to screening may also 
allow for improved access to screening for cancer and precancer in the areas with the 
highest burden of disease, including unscreened women in the US and worldwide. 
 
3.0  
STUDY ENROLLMENT AND PARTICIPANT ELIGIBLITY 
The participant population to be included in the study is menstruating women over the 
age of 18. There will be two groups: 1) menstruating women over the age of 18 who have 
a previous history of HR-HPV in the last 18 months and 2) menstruating women over the 
age of 18 who do not have a previous history of HR-HPV. We plan to recruit patients 
from Stanford research IT Starr cohort tool to identify patients who have had a positive 

 
 
    
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HR-HPV test in the past 18-months. In addition, we also plan to recruit women without 
previous history of HR-HPV, who present in clinic for a cervical cancer screening test as 
part of their standard of care well woman visit.   
  
3.1 
Study Enrollment 
For positive HR-HPV participants: 
We plan to recruit patients from Stanford research IT Starr cohort tool to identify patients 
who have had a positive HR-HPV test in the last 18-months. We will then contact their 
provider to get permission to include them in the study before their next in-person follow 
up. This follow-up visit can be any time after positive HR-HPV result up to 18-months. 
This follow-up visit can be for a repeat cervical cancer screening pap test, colposcopy, or 
loop electrosurgical excision procedure. Patients identified who are HR-HPV positive 
will be contacted by their provider to broach the possibility of research participation to 
the patient. If this patient expresses interest in the project, the provider will ask if the 
research staff can then contact the patient. If the patient agrees, then the research staff 
will contact the patient. In addition, patient’s with known positive HR-HPV results who 
present to the clinic for colposcopy or loop electrosurgical excision procedure will be 
approached by their provider during that clinic visit to see if the patient would be willing 
to participate in the project. If the patient agrees, then research staff will present the 
project in detail to the patient and obtain consent. Pre-procedure meetings (either in 
person or over the phone) will be performed with the subjects individually, where the 
process will be discussed and instructions on how to use the Q-pads and the vaginal 
swabs will be explained to ensure women fully understand the process. We will also hand 
out (or mail) instructions with pictures on paper to minimize any risk associated with 
using the devices. We do not anticipate any screen failures. Eligibility is based on 
standard of care testing. 
 
For participants with no prior HR-HPV history: 
We plan to recruit patients from Stanford Gynecology clinic. We will review the clinic 
schedule for patients presenting to the clinic for their routine well woman visit with 
cervical cancer screening. Their provider will approach the patient during that clinic visit 
to assess if the patient would be willing to participate in the project. If the patient agrees, 
then research staff will present the project in detail to the patient and obtain consent. At 
the time of the routine cervical cancer screening, additional study swabs will be collected. 
Prior to discharge, research staff will show the subject how to use the Q-pads and the 
vaginal swabs to ensure subjects fully understand the process. We do not anticipate any 
screen failures.  
 
3.2 
Participant Criteria  
The inclusion criteria are women older than 18 years, who regularly menstruate and have 
tested HR-HPV positive in the last 18-months. Further, we intend to include women older 
than 18 years who regularly menstruate and have not been tested HR-HPV positive in the 
last 18-months. The exclusion criteria are women younger than 18 years old or who are 
post-menopausal or not menstruating regularly.  
 

 
 
    
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3.3   
Enrollment 
The target number of subjects at our gynecology clinic is 250 patients with or without 
previous HR-HPV diagnoses. We expect to complete this study within 12 months. 
 
4.0  
MATERIAL AND METHODS  
 
Pre-procedure  
Pre-procedure meetings will be performed with the subjects individually where 
the process will be discussed and two designated menstrual pads (pad 1 and pad 2) 
and two pouches (pouch 1 and pouch 2) will be dispensed. We will instruct the subjects 
on how to use the pads and go through the consent form with them and answer any 
questions they might have.  
 
Self-Sample collection  
Participants will use the pads as close to their scheduled, standard of care appointment or 
follow-up appointment —either during the menstrual cycle before or after the 
appointment. When the woman has her period, she uses the pads following instructions 
given to her orally and in written format during the pre-procedure meetings.  
 
The Q-pad is used like any other menstrual pad. After usage you pull a small slip which 
removes a small paper-based collection strip. She will dispose the pad and put the 
collection strip into the provided envelope.  
 
The strip will be put in a pre-stamped envelope and into a mailbox and shipped to a CLIA 
waived and CAP certified laboratory for analysis. Results will be emailed back to the 
investigators in a coded fashion. DNA will not be extracted from the samples and the 
Stanford Tissue Bank will not be used for the banking of specimens. Samples will be 
disposed of after completion of the current study. 
 
Provider sample collection  
Participants will attend a scheduled, standard of care visit with their provider either for 
screening of HR-HPV or for follow-up within 18-months of the positive HR-HPV test for 
a repeat pap smear, colposcopy, or loop electrosurgical excision procedure. The provider 
will be asked to collect an additional sample for the study, which will be shipped to a 
laboratory for HR-HPV analysis. Additionally, at this time the participant will be asked 
to obtain two “self-swabs”. While in clinic, she will be administered swab device 
kits with verbal and written instructions.  
 
We are using a commercially available menstrual pad. The menstrual pad is made of 
organic cotton and is today commercially available in convenient stores such as CVS and 
Walgreens. The only difference to a normal product is a small strip that is embedded 
beneath the first cotton layer. The strip consists of medical grade materials manufactured 
according to the ISO 13495 standard for medical devices. The core material in the strip is 
a proprietary paper-based sample receiving material from GE, namely a Whatman 903 
collection paper. This is a commercially available product.  
 
 

 
 
    
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Follow-up  
After we have received the sample collected by the participant and the provider, the 
subject will receive compensation.  
 
 
5.0 
STATISTICAL CONSIDERATIONS 
 
5.1 
Outcome Measurements 
 
Primary outcome is to compare the accuracy and percent analytic agreement of clinician 
and self-collected cervico-vaginal brush samples with Q-pad-collected menstrual blood 
for HR-HPV detection in women with and without previous positive HR-HPV results. 
The secondary outcome is to assess the ability to detect oncoproteins in Q-pad collected 
menstrual blood samples from women with ASCUS+ to determine the utility in cervical 
cancer/precancer detection and to test the utility of a low and high threshold HR-HPV 
reflex scheme to similarly increase the specificity of HR-HPV testing derived from 
menstrual blood. Neither outcome measures relate to safety. 
 
5.2 
Analysis plan 
 
We will record all data on an electronic tablet using REDCap electric data capture tools 
hosted at the Stanford Center for Clinical Informatics. 25 IBM SPSS Statistics, version 
25.0 (IBM Corp., Armonk, N.Y., USA) will be used for data analysis. We will assess 
sociodemographic and clinical characteristics using descriptive statistics; if comparisons 
are needed, chi square tests or Mann-Whitney U tests will be used, where appropriate. 
We will assess the percent agreement of the binary outcome of HPV positive or negative 
on the menstrual blood sample analysis compared to the clinician swab and the self-
swabs using Cohen’s kappa.  
 
5.3 
Sample size 
 
We chose a convenience sample of 250 women based on the following: Stanford 
Gynecology clinic has approximately 10,000 unique visits per year. A “worst case” HPV 
prevalence rate of 5% (similar to rural Thailand14), yields approximately 500 positives for 
HR-HPV per year and recruitment experiences from similar studies indicates a 
recruitment rate of 50% of the positives for something like this is feasible. In fact, the 
local HPV prevalence rate in our catchment area is likely much higher than 5%. Also 250 
women would allow for adequate precision of 95% relative to agreement of the menstrual 
specimen with the lab-generated HPV result (alpha =.001, beta=.10)15. 
 
 
6.0  
DATA MANAGEMENT CONSIDERATIONS 
 
6.1 
Data management  
 
REDCap will be used for data collection and measures taken to protect identifying 

 
 
    
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information when exporting data. A unique study ID will be used in all statistical 
analyses to protect confidentiality. All electronic devices used in data collection will be 
both encrypted and password protected through Stanford IRT.  
 
Adverse Events, protocol deviations, aggregate data, and individual data will all be 
reviewed by the research team at monthly intervals or as necessary. The Principal 
Investigator, Dr. Paul Blumenthal, with the help of the Family Planning Division 
Research Team will be responsible for Data and Safety Monitoring. Assessments of data 
and events captured by the monitoring will be performed on a continual bases, 
simultaneously with the reporting data from analysis sources (i.e. physician office visits, 
follow up phone calls). If there is an unanticipated problem (UP; unexpected, related to 
research, AND harmful), it will be promptly reported to the IRB. Dr. Paul Blumenthal, as 
the Data Safety Monitoring person, will disseminate the outcome of all reviews to the 
IRB. 
 
6.3 
Confidentiality  
 
Participants in the study will be seen in private rooms for enrollment. No PHI will be left 
on participant’s voicemail and/or email. Prior to enrollment, participants will receive 
HIPAA training and will work to protect the privacy interests of participants. A PHI 
secure website application will be used for data collection and measures taken to protect 
identifying information when exporting data. A unique study ID will be used in all 
statistical analysis to protect confidentiality. All study personnel with direct access to 
subjects’ medical records will take reasonable precautions within the constraints of 
applicable regulatory requirements to maintain the confidentiality of the subjects’ 
identity. 
 
6.4 
Protocol Review and Amendments 
 
The protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the Stanford IRB and Stanford Cancer Center Scientific Review Committee 
(SRC). Any changes made to the protocol will be submitted as a modification and will be 
approved by the IRB prior to implementation. The Protocol Director will disseminate the 
protocol amendment information to all participating investigators. 
 
 

 
 
    
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REFERENCES 
 
1. Woodman CB, Collins SI, Young LS. The natural history of cervical HPV infection: 
unresolved issues. Nature Reviews Cancer. 2007 Jan;7(1):11. 
2. D. Saslow, 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, CA Cancer J. Clin. 62 (3) 
(2012) 147–172. 
3. World Health Organization. International Agency for Research on Cancer. Accessed on 
April 18, 2018 at http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. 
4. Fan Y, Shen Z. The clinical value of HPV E6/E7 and STAT3 mRNA detection in 
cervical cancer screening. Pathology-Research and Practice. 2018 May 1;214(5):767-75. 
5. Y. Nakayama, et al., Evaluation of the human papillomavirus mRNA test for the 
detection of cervical lesions in Japan, Eur. J. Gynaecol. Oncol. 36 (2) (2015) 192–196.  
6. Reid JL, Wright Jr TC, Stoler MH, Cuzick J, Castle PE, Dockter J, Getman D, Giachetti 
C. Human papillomavirus oncogenic mRNA testing for cervical cancer screening: 
baseline and longitudinal results from the CLEAR study. American journal of clinical 
pathology. 2015 Sep 1;144(3):473-83. 
7. Haedicke J, Iftner T. A review of the clinical performance of the Aptima HPV assay. 
Journal of Clinical Virology. 2016 Mar 1;76:S40-8. 
8. Othman NH, Zaki FHM. Self-Collection Tools for Routine Cervical Cancer Screening: A 
Review. Asian Pac J Cancer Prev. 2014;15(20):8563-8569. 
doi:10.7314/APJCP.2014.15.20.8563. 
9. Fokom-Domgue J, Combescure C, Fokom-Defo V, et al. Performance of alternative 
strategies for primary cervical cancer screening in sub-Saharan Africa: systematic review 
and meta-analysis of diagnostic test accuracy studies. 2015. 
http://www.bmj.com/content/351/bmj.h3084.full. Accessed September 26, 2016 
10. Naseri S, Lerma K, Blumenthal PD. Comparative assessment of serum versus menstrual 
blood for diagnostic purposes. 2017. Manuscript submitted for publication.  
11. Cederholm-Williams SA, Rees MC, Turnbull AC. Examination of certain coagulation 
factors in menstrual fluid from women with normal blood loss. Thrombosis and 
haemostasis. 1984 Dec;52(3):224-5. 
12. Van der Molen RG, Schutten JH, van Cranenbroek B, Ter Meer M, Donckers J, Scholten 
RR, van der Heijden OW, Spaanderman ME, Joosten I. Menstrual blood closely 
resembles the uterine immune micro-environment and is clearly distinct from peripheral 
blood. Human reproduction. 2013 Nov 17;29(2):303-14. 
13. Wong SCC, Au TCC, Chan SCS, et al. Human Papillomavirus DNA Detection in 
Menstrual Blood from Patients with Cervical Intraepithelial Neoplasia and Condyloma 
Acuminatum. J Clin Microbiol. 2010;48(3):709-713. doi:10.1128/JCM.01996-09. 
14. Trope LA, Chumworathayi B, Blumenthal PD. Feasibility of community-based careHPV 
for cervical cancer prevention in rural Thailand. Journal of lower genital tract disease. 
2013 Jul 1;17(3):315-9. 
15. Temel G, Erdogan S. Determining the sample size in agreement studies. Marmara 
Medical Journal. 2017;30:101-12. 
 
 
 

 
 
    
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APPENDIX A: Participant Eligibility Checklist  
 
Protocol Title: 
Screening for Cervical Intraepithelial Neoplasia Using Self-
Collected Menstrual Blood 
 
Protocol Number: 
47250 
Principal Investigator: 
Dr. Paul Blumenthal 
 
II. Subject Information: 
 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III. Study Information: 
 SRC Approved 
 IRB Approved 
 Contract Signed 
IV. Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
Supporting Documentation* 
1. 18 years or older 
 
 
      
2. Menstruate regularly 
 
 
      
3. Comfortable using menstrual pads 
 
 
      
4. Comfortable using vaginal swabs  
 
 
      
5. Comfortable committing to using 
condoms from time of self-collection 
and provider collected sample  
 
 
      
Exclusion Criteria 
(From IRB approved protocol) 
 
1. Women younger than 18 years old 
 
 
      
2. Women who are post-menopausal or 
not menstruating regularly 
 
 
      
*All subject files must include supporting documentation to confirm subject eligibility.  
The method of confirmation can include, but is not limited to, laboratory test results, 
radiology test results, subject self-report, and medical record review.   
IV.  Statement of Eligibility 
By signing this form of this trial, I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study. This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the Stanford IRB, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group.   
 

 
 
    
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Treating Physician Signature: 
Date: 
Printed Name: 
 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
 
Study Coordinator Signature: 
Date: 
Printed Name: 
 
 
 
 

 
 
    
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APPENDIX B: Protocol Summary of Changes 
 
Any administrative changes to the protocol including spelling corrections, minor clarifications, 
renumbering, and reformatting are not summarized in the following table. 
 
Section 
Change to Protocol 
Rationale 
Title Page 
Date and version # changed 
Changed due to this revision 
Specific Study Aims 
Added samples from women 
with no previous history of 
HR-HPV to specific aim #1 
The study team assessed the 
funding timeline and the 
current sample (n=70) and the 
goal of n=250 and identified 
the need to expand the 
inclusion criteria. By 
including those without a 
history of HPV, we are able 
to better assess specificity 
and sensitivity. 
 
One challenge our team has 
faced is that far less women 
menstruate regularly than 
anticipated—this is largely 
due to contraceptive use.  
 
Study Enrollment and 
Participant Eligibility 
Created two groups for study 
enrollment to include women 
with no previous history of 
HR-HPV 
To collect as much 
information as possible given 
funding timeline restraints. 
 
See above. 
Study Enrollment and 
Participant Eligibility 
Changed age restrictions to 
include for women over 45 
years of age. 
To allow for menstruating 
women over the age of 45 to 
participate. Upon review of 
our age eligibility, we saw no 
reason to exclude those over 
45 years of age who 
menstruate. Screening still 
occurs in this population. 
Material and Methods 
Changed methods to include 
approaching women 
presenting to clinic for repeat 
cervical cancer screening 
with or without a history of 
HR-HPV. 
To expand enrollment.  
Statistical Considerations 
These changes will not 
impact the statistical 
methods. 
To accommodate expanded 
enrollment. 

 
 
    
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Data Management 
Considerations 
Added section 6.4 
To provide clarity on 
amendment approval.