Randomized Controlled Trial of Vaginal Cryotherapy for Pelvic Floor Myofascial Pain
Phase: NA
Conditions: Pelvic Floor Myofascial Pain, Pelvic Pain, Myofascial Pain
Sponsor: Washington University School of Medicine

 
 
 
 
 
 
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Randomized controlled trial of vaginal cryotherapy for pelvic floor 
myofascial pain 
 
 
Principal Investigator:   
Melanie Meister, MD, MSCI 
 
 
 
 
 
 
 
Version Date/Number:  
Version 1, 3/15/19 

 
 
 
 
 
 
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TABLE OF CONTENTS 
 
A 
INTRODUCTION ............................................................................................................................... 4 
A1 
STUDY ABSTRACT ......................................................................................................................... 4 
A2 
PRIMARY HYPOTHESIS ................................................................................................................... 5 
A3 
PURPOSE OF THE STUDY PROTOCOL .............................................................................................. 5 
B 
BACKGROUND .................................................................................................................................. 5 
B1 
PRIOR LITERATURE AND STUDIES .................................................................................................. 5 
B2 
RATIONALE FOR THIS STUDY ..................................................ERROR! BOOKMARK NOT DEFINED. 
C 
STUDY OBJECTIVES........................................................................................................................ 8 
C1 
PRIMARY AIM ................................................................................................................................ 8 
C2 
SECONDARY AIM ....................................................................ERROR! BOOKMARK NOT DEFINED. 
C3 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES ....ERROR! BOOKMARK NOT DEFINED. 
D 
INVESTIGATIONAL AGENT .......................................................................................................... 8 
D1 
PRECLINICAL DATA ................................................................ERROR! BOOKMARK NOT DEFINED. 
D2 
CLINICAL DATA TO DATE .............................................................................................................. 8 
D3 
DOSE RATIONALE AND RISK/BENEFITS ......................................................................................... 8 
E 
STUDY DESIGN ................................................................................................................................. 9 
E1 
OVERVIEW OR DESIGN SUMMARY ................................................................................................. 9 
E2 
SUBJECT SELECTION AND WITHDRAWAL....................................................................................... 9 
2.a 
Inclusion Criteria ..................................................................................................................... 9 
2.a 
Exclusion Criteria ..................................................................................................................... 9 
2.b 
Ethical Considerations ............................................................................................................10 
2.c 
Subject Recruitment Plans and Consent Process ....................................................................10 
2.d 
Randomization Method and Blinding ......................................................................................10 
2.e 
Risks and Benefits ....................................................................................................................10 
2.f 
Early Withdrawal of Subjects ..................................................................................................10 
2.g 
When and How to Withdraw Subjects ......................................................................................10 
2.h 
Data Collection and Follow-up for Withdrawn Subjects .........................................................11 
E3 
STUDY DRUG ................................................................................................................................11 
3.a 
Description ..............................................................................................................................11 
3.b 
Treatment Regimen ..................................................................................................................11 
3.c 
Method for Assigning Subjects to Treatment Groups ..............................................................11 
3.d 
Preparation and Administration of Study Drug .......................................................................12 
3.e 
Subject Compliance Monitoring ..............................................................................................12 
3.f 
Prior and Concomitant Therapy ..............................................................................................12 
3.g 
Packaging .................................................................................. Error! Bookmark not defined. 
3.h 
Blinding of Study Drug ............................................................................................................12 
3.i 
Receiving, Storage, Dispensing and Return .............................. Error! Bookmark not defined. 

 
 
 
 
 
 
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F 
STUDY PROCEDURES ....................................................................................................................12 
F1 
SCREENING FOR ELIGIBILITY ........................................................................................................13 
F2 
SCHEDULE OF MEASUREMENTS ....................................................................................................13 
F3 
VISIT 1 ....................................................................................ERROR! BOOKMARK NOT DEFINED. 
F4 
VISIT 2 ETC. ............................................................................ERROR! BOOKMARK NOT DEFINED. 
F5 
SAFETY AND ADVERSE EVENTS ....................................................................................................13 
5.a 
Safety and Compliance Monitoring .........................................................................................13 
5.b 
Medical Monitoring ................................................................... Error! Bookmark not defined. 
i 
Investigator only ...................................................................................... Error! Bookmark not defined. 
ii 
Independent expert to monitor ................................................................. Error! Bookmark not defined. 
iii 
Institutional Data and Safety Monitoring Board ...................................... Error! Bookmark not defined. 
iv 
Independent Data and Safety Monitoring Board ...................................... Error! Bookmark not defined. 
5.c 
Definitions of Adverse Events .................................................... Error! Bookmark not defined. 
5.d 
Classification of Events ............................................................. Error! Bookmark not defined. 
i 
Relationship ............................................................................................. Error! Bookmark not defined. 
ii 
Severity .................................................................................................... Error! Bookmark not defined. 
iii 
Expectedness ........................................................................................... Error! Bookmark not defined. 
5.e 
Data Collection Procedures for Adverse Events ....................... Error! Bookmark not defined. 
5.f 
Reporting Procedures ................................................................ Error! Bookmark not defined. 
5.g 
Adverse Event Reporting Period ................................................ Error! Bookmark not defined. 
5.h 
Post-study Adverse Event .......................................................... Error! Bookmark not defined. 
F6 
STUDY OUTCOME MEASUREMENTS AND ASCERTAINMENT ..........................................................14 
G 
STATISTICAL PLAN ........................................................................................................................14 
G1 
SAMPLE SIZE DETERMINATION AND POWER .................................................................................14 
G2 
INTERIM MONITORING AND EARLY STOPPING ..............................................................................15 
G3 
ANALYSIS PLAN............................................................................................................................15 
G4 
STATISTICAL METHODS ..........................................................ERROR! BOOKMARK NOT DEFINED. 
G5 
MISSING OUTCOME DATA ............................................................................................................15 
G6 
UNBLINDING PROCEDURES .....................................................ERROR! BOOKMARK NOT DEFINED. 
H 
DATA HANDLING AND RECORD KEEPING .............................................................................15 
H1 
CONFIDENTIALITY AND SECURITY ................................................................................................15 
H2 
TRAINING................................................................................ERROR! BOOKMARK NOT DEFINED. 
H3 
CASE REPORT FORMS AND SOURCE DOCUMENTS .........................................................................15 
H4 
RECORDS RETENTION ...................................................................................................................16 
H5 
PERFORMANCE MONITORING .................................................ERROR! BOOKMARK NOT DEFINED. 
I 
STUDY MONITORING, AUDITING, AND INSPECTING .............. ERROR! BOOKMARK NOT 
DEFINED. 
I1 
STUDY MONITORING PLAN .........................................................ERROR! BOOKMARK NOT DEFINED. 
I2 
AUDITING AND INSPECTING ........................................................ERROR! BOOKMARK NOT DEFINED. 
J 
STUDY ADMINISTRATION ...........................................................................................................16 
J1 
ORGANIZATION AND PARTICIPATING CENTERS .................................................................................16 
J2 
FUNDING SOURCE AND CONFLICTS OF INTEREST ..............................................................................16 
J3 
COMMITTEES ...............................................................................ERROR! BOOKMARK NOT DEFINED. 
J4 
SUBJECT STIPENDS OR PAYMENTS ....................................................................................................16 
J5 
STUDY TIMETABLE ...........................................................................................................................16 
K 
PUBLICATION PLAN ......................................................................................................................16 
L 
ATTACHMENTS ...............................................................................................................................16 
L1 
TABLES .........................................................................................................................................16 
L2 
INFORMED CONSENT DOCUMENTS.................................................................................................17 
L3 
PATIENT EDUCATION BROCHURES.................................................................................................17 

 
 
 
 
 
 
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L4 
SPECIAL PROCEDURES PROTOCOLS .........................................ERROR! BOOKMARK NOT DEFINED. 
L5 
QUESTIONNAIRES OR SURVEYS .....................................................................................................17 
M 
REFERENCES ...................................................................................................................................17 
 
A Introduction 
 
A1 Study Abstract 
Pelvic floor myofascial pain, that is, pain in the internal hip (obturator internus, OI) and 
pelvic floor (levator ani, LA) muscles, is common in women with chronic pelvic pain. In 
particular, patients presenting to urogynecologic subspecialists for evaluation of pelvic 
floor disorder symptoms, are frequently found to have concomitant pelvic floor 
myofascial pain. (2). Pelvic floor disorder symptoms include bothersome lower urinary 
tract symptoms (LUTS; urinary urgency, frequency, hesitancy, dysuria, and sensation of 
incomplete bladder emptying), pelvic organ prolapse, defecatory dysfunction, and pelvic 
pain.  
Treatment options for pelvic floor disorders include medications (typically 
anticholinergics for overactive bladder symptoms), pessaries (for vaginal prolapse) or 
surgery (anti-incontinence procedures, vaginal support procedures, etc), but the 
medications are not fully effective and cause bothersome side effects, and surgery is 
invasive. Additionally, some patients presenting with pelvic pressure and heaviness, 
presumed to be vaginal prolapse, are found to have overall good vaginal support on 
examination. These women are not candidates for pessaries or surgeries as they do not 
have a defect in vaginal support.  Thus, a new approach to treating pelvic floor disorder 
symptoms is needed.  
Nearly 25% of women with LUTS are found to have underlying pelvic floor myofascial 
pain2, which refers to pain arising in the skeletal muscle and connective tissue of the 
pelvic floor (levator ani, LA) and internal hip (obturator internus, OI). This number is likely 
an underestimate because, until recently, no standardized and reproducible pelvic floor 
myofascial examination protocol existed. In a recent retrospective analysis from our own 
institution, pelvic floor myofascial pain was significantly correlated with several prolapse 
symptoms as measured on one validated questionnaire, but not with objective prolapse 
severity based on the leading edge [unpublished data] further supporting the role of 
pelvic floor myofascial pain in pelvic floor disorder symptoms.  
Few providers evaluate for pelvic floor myofascial pain, even in patients presenting with 
pelvic pain3. When pelvic floor myofascial pain is identified, women are typically referred 
for pelvic floor physical therapy (PT)4-6. However, pelvic floor PT is performed by PT 
specialists with advanced training in women’s health. Depending on the availability of 
such specialists (who are generally concentrated in large cities or affiliated with 
academic medical centers), women could experience a delay in receiving treatment. 
Additionally, insurance often does not cover PT or only covers it partially. Thus, we must 
identify effective options to treat women with pelvic floor myofascial pain and 
concomitant pelvic floor disorder symptoms aside from PT. 
One treatment that shows promise as an effective means of treating pelvic floor 
myofascial pain is vaginal cryotherapy. This idea is founded on the following. First, 

 
 
 
 
 
 
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physicians and women’s health PT specialists at our institution routinely prescribe 
vaginal cryotherapy in addition to pelvic floor PT for treatment of pelvic floor myofascial 
pain and find, anecdotally, that patients often report improvement in their pelvic floor 
myofascial pain, even before initiating pelvic floor PT. Second cryotherapy has been 
used routinely for treatment of musculoskeletal injuries elsewhere in the body, where it 
functions by decreasing tissue metabolism, blood flow, inflammation, and edema, 
thereby reducing muscle spasm and pain7. Finally, vaginal cryotherapy, referred to as 
‘condom pops’, was reported by focus group participants as an effective treatment option 
for urologic chronic pelvic pain in a recent MAPP Network trial. [Sutcliffe et al] However, 
no studies have rigorously tested whether or not vaginal cryotherapy is an effective 
treatment for pelvic floor myofascial pain. 
Our objective is to conduct a randomized controlled trial to determine the therapeutic 
effect of vaginal cryotherapy on pain severity and LUTS bother in women with moderate-
to-severe pelvic floor myofascial pain. We hypothesize that, compared to control 
(similar device but empty), vaginal cryotherapy will significantly reduce myofascial pain 
score when used independent of and in conjunction with pelvic floor PT.  
A2 Primary Hypothesis 
Here we propose a randomized controlled trial to test the overall hypothesis that, 
compared to control, vaginal cryotherapy will significantly reduce pelvic floor myofascial 
pain scores when used independent of and in conjunction with pelvic floor PT. 
 
A3 Purpose of the Study Protocol 
The purpose of this study protocol is to provide a detailed summary of the study design 
and methods for study personnel to refer to throughout the course of the study.  
B Background 
 
B1 Prior Literature and Studies 
 
The burden of pelvic floor disorder symptoms and inadequacy of treatment 
approaches: Up to 75% of women experience pelvic floor disorder symptoms like lower 
urinary tract symptoms (LUTS), which are classified by the International continence 
Society into storage, voiding, and post-micturition symptoms (1,8). Given that the 
prevalence of LUTS increases with advancing age (1,9) 18.4% more women are 
projected to be affected by at least one LUTS in 2018 than 2008 (10). Depending on the 
presenting symptom, the mainstay of treatment typically involves either medication or 
surgery. Medications to address overactive bladder symptoms (urinary urgency with or 
without incontinence, frequency, and nocturia), typically anticholinergics, are associated 
with a high rate of discontinuation due to bothersome side effects and lack of efficacy 
(11). Surgical procedures for refractory overactive bladder, including botulinum toxin 
injections or sacral neuromodulation, are invasive and may not completely address the 
patient's symptoms. Thus, an effective non-pharmacologic, non-surgical treatment for 
pelvic floor disorder symptoms like LUTS would likely help thousands of women.  
 
Pelvic floor myofascial pain is common and may underlie pelvic floor disorder 

 
 
 
 
 
 
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symptoms: Pelvic floor myofascial pain refers to tenderness and trigger points identified 
within the muscles of the pelvic floor (levator ani, LA) and internal hip (obturator internus, 
OI) (4). Pelvic floor myofascial pain contributes to 60-85% of chronic pelvic pain and 
likely underlies a significant proportion of pelvic floor disorder symptoms, including LUTS 
(2,3,11-14).  
 
Other pelvic floor disorder symptoms, in particular pelvic pressure/heaviness, may 
indicate underlying pelvic organ prolapse, however, not uncommonly, patients 
presenting with pelvic pressure/heaviness are found to have normal vaginal support. 
This suggests that another process may underlie these symptoms other than objective 
pelvic organ prolapse. Findings from a cross-sectional analysis of new patients 
evaluated at our tertiary care institution suggest that moderate-to-severe pelvic floor 
myofascial pain is especially prominent in these patients (14). While pessaries or 
surgery are the mainstay of therapy for pelvic organ prolapse, patients with symptoms of 
pelvic pressure/heaviness but normal vaginal support would not be candidates for this 
treatment. In another regional study, 16% of patients presenting with pelvic floor disorder 
symptoms, without symptoms of chronic pelvic pain, were found to have myofascial pain 
in the LA on examination (2). Unfortunately, pelvic floor myofascial pain has received 
limited attention in the literature and, until recently, a standardized physical examination 
did not exist (3,29). As a result, few providers routinely evaluate the muscles of the 
internal hip (OI) and pelvic floor (LA) in the differential diagnosis for patients presenting 
with chronic pelvic pain or pelvic floor disorder symptoms.  
 
Pelvic floor myofascial pain is treated conservatively: Treatment of pelvic floor 
myofascial pain typically involves pelvic floor physical therapy (PT), often with treatment 
of movement impairment disorders and/or myofascial release (4,20). Due to the 
subspecialty nature of pelvic floor PT, availability is often limited by the number of 
formally trained providers in a geographic area. As a result, patients may experience a 
delay between the diagnosis of pelvic floor myofascial pain and the start of pelvic floor 
PT or not have access to a physical therapist at all. For example, at our institution, 
patients may experience a delay of up to 4 weeks from diagnosis of pelvic floor 
myofascial pain to their first pelvic floor PT visit. Furthermore, insurance carriers often 
impose strict regulation on PT coverage including restricting frequency and number of 
covered PT visits in a calendar year. Pelvic floor PT is not covered by Medicaid. Thus, 
even patients with geographic access to pelvic floor PT may be restricted in their ability 
to use these resources based on their insurance providers.  
 
Evidence for cryotherapy: Cryotherapy, defined as the therapeutic application of a 
device or substance to the body to reduce temperature (7), has long been used as an 
adjunct treatment modality for acute and chronic musculoskeletal injuries. Through 
tissue cooling, cryotherapy decreases tissue metabolism and reduces blood flow to 
injured tissue, which results in diminished inflammation and edema, ultimately leading to 
reduced muscle spasm and pain (7). Additionally, neural conductance velocity is slowed, 
which further contributes to reduction in pain (21). Evidence suggests a beneficial role 
for cryotherapy in addition to physical therapy in musculoskeletal injuries and myofascial 
pain elsewhere in the body (22-24), but cryotherapy has not yet been investigated in 
treatment of pelvic floor myofascial pain. Women’s Health Physical Therapists and 
physicians at our institution routinely recommend vaginal cryotherapy to patients 
presenting with pelvic floor myofascial pain in addition to pelvic floor PT. Anecdotally, we 
have seen a significant improvement, and in some cases resolution of, pelvic floor 
symptoms and myofascial pain when vaginal cryotherapy is used alone or in conjunction 

 
 
 
 
 
 
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with pelvic floor PT. The pelvic floor muscles are easily accessible through the 
transvaginal route. Vaginal cryotherapy is an inexpensive, simple therapeutic option that 
may lead to symptomatic improvement for patients on its own or in conjunction with 
pelvic floor PT. Given rising healthcare costs and increasing restriction on resources like 
PT, this represents a treatment option that is more accessible for many women than 
multiple visits to a specially-trained physical therapist. For women who do have access 
to pelvic floor PT, incorporating vaginal cryotherapy may enable them to decrease the 
number of PT visits or provide additional improvement over pelvic floor PT alone.  
 
Preliminary evidence supporting a correlation between pelvic floor myofascial 
pain and pelvic floor disorder symptoms: To investigate the prevalence of pelvic floor 
myofascial pain in our population of referral patients and investigate a correlation 
between pelvic floor myofascial pain and pelvic floor disorder symptoms, we performed a 
retrospectively-assembled cross-sectional study of all new patients presenting to the 
FPMRS clinic at Washington University in St. Louis from 1/2014 to 4/2016. All new 
patients had a pelvic floor myofascial examination performed regardless of their 
presenting complaint, and pain was recorded on an 11-point verbal pain rating scale (0-
10). Of the 833 new patients evaluated during the study period, most (92%) reported 
bothersome pelvic floor disorder symptoms (13). We found a significant correlation 
between the presence of pelvic floor myofascial pain on examination and degree of 
LUTS bother as captured on the UDI-6 and pelvic pressure/heaviness symptoms (15). 
Most surprisingly, there was no correlation between symptoms of pelvic 
pressure/heaviness and objective pelvic organ prolapse while there was a significant 
correlation between pelvic floor myofascial pain and pelvic pressure/heaviness. These 
results suggest that pelvic floor myofascial pain may be a driver of pelvic floor disorder 
symptoms in a subset of patients.  
 
Anecdotally, we have seen these patients demonstrate improvement in both their pelvic 
floor myofascial pain scores as well as pelvic floor disorder symptoms after treatment of 
their underlying pelvic floor myofascial pain through pelvic floor PT without medications 
or procedures. We are actively investigating this relationship. We aim to demonstrate 
that treatment of underlying pelvic floor myofascial pain through focused pelvic floor PT 
leads to an improvement, not only in pain scores on examination, but also pelvic floor 
disorder symptom bother. Similarly, by targeting and improving pelvic floor myofascial 
pain, vaginal cryotherapy could presumably also lead to an improvement in pelvic floor 
disorder symptom bother.  
 
Development of a standardized myofascial examination protocol. Pelvic floor 
myofascial pain can be a challenging condition to treat, but more importantly, it is often 
not diagnosed. Unfortunately, until recently, a consistent and validated examination 
technique that reliably identifies pelvic floor myofascial pain has not yet been published 
(29). We recently completed a systematic review that found limited consensus on 
methods to assess pelvic floor myofascial pain (30). To address this lack of 
standardization, our team developed a standardized pelvic floor myofascial examination 
protocol in collaboration with Washington University Women’s Health PT faculty. An 
iterative process was used to standardize the examination. Four physicians performed 
an initial examination on a simulated patient from the Washington University 
Standardized Patient Program who provided specific, real-time feedback on location, 
pressure, and technique of palpation among the examiners. The physicians repeated the 
examination until consensus was achieved. A force sensor was then used to formally 
standardize pressure between examiners. This examination protocol has been 

 
 
 
 
 
 
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implemented in our clinics by all providers, and has been shown to have high correlation 
between examiners (29).  
 
C Study Objectives 
 
C1 Specific Aims 
 
Specific Aim 1: To determine the effect of vaginal cryotherapy as an immediate 
treatment modality for patients with pelvic floor myofascial pain.  
Hypothesis 1: Vaginal cryotherapy will result in a significant immediate improvement in 
pelvic floor myofascial pain compared to placebo.  
 
Specific Aim 2: To determine the effect of vaginal cryotherapy as a neoadjuvant 
treatment modality for patients with pelvic floor myofascial pain awaiting pelvic floor PT.  
Hypothesis 2A: Vaginal cryotherapy will result in a significant improvement in pelvic floor 
myofascial pain compared to placebo.  
 
D Investigational Agent  
 
D1 Clinical Data to Date  
Cryotherapy is a well-known and effective adjunct treatment modality for acute and 
chronic musculoskeletal injuries. Through tissue cooling, cryotherapy decreases tissue 
metabolism and reduces blood flow to injured tissue, which results in diminished 
inflammation and edema, ultimately leading to reduced muscle spasm and pain (7). 
Neural conductance velocity is also slowed, which further contributes to pain reduction 
(21).  
 
Women's Health Physical therapists and physicians at our institution routinely 
recommend vaginal cryotherapy to patients presenting with pelvic floor myofascial pain 
in addition to pelvic floor PT. Anecdotally, we have seen a significant improvement, and 
in some cases, resolution of pelvic floor symptoms and myofascial pain is used alone or 
in conjunction with pelvic floor PT. Additionally, patients have self-identified this 
treatment modality as an effective one for urologic chronic pelvic pain (31). Although this 
method is commonly employed by physical therapists and patients, there have been no 
studies on outcomes associated with the use of transvaginal cryotherapy.  
D2 Dose Rationale and Risk/Benefits  
Due to the lack of prior studies on this therapy, there is little evidence aside from 
common clinical practice and anecdote to guide our rationale for application frequency. 
Patients prescribed vaginal cryotherapy by the physicians and physical therapists at our 
institution are told to keep the cryotherapy tube in the vagina for 10 minutes. Patients are 
instructed to perform vaginal cryotherapy at least once per day, or more often on an as-
needed basis, to achieve pain relief. 

 
 
 
 
 
 
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It is also possible that some of the anecdotal benefit we have observed is due to 
myofascial release resulting from massage of the pelvic floor muscles by the tube itself, 
regardless of the temperature. This study will help elucidate the role of the cryotherapy 
in treatment of pelvic floor myofascial pain. Potential benefits to participants include 
improvement or resolution of their pelvic floor pain and pelvic floor disorder symptoms. If 
found to improve symptoms, cryotherapy can be easily incorporated into the treatment 
algorithm and started while patients are waiting to begin pelvic floor PT or added to an 
existing pelvic floor PT regimen. This inexpensive intervention may be especially 
valuable for patients in resource-poor settings without access to a pelvic floor PT 
provider. Given rising healthcare costs and limited access to resources like pelvic floor 
PT for many patients, the addition of vaginal cryotherapy – a simple and inexpensive 
intervention – holds the promise to transform the treatment algorithm for this common 
condition and help relieve symptoms for thousands of women. 
E Study Design  
 
E1 Overview or Design Summary 
This is a placebo-controlled, randomized controlled trial to investigate the role of vaginal 
cryotherapy on pelvic floor myofascial pain in women. This study involves randomizing 
patients who are found to have pelvic floor myofascial pain on examination into one of 
two treatment groups: transvaginal cryotherapy or transvaginal application of a room-
temperature tube. Patients will be followed up at two different time points in order to 
assess response to treatment. Follow-up times include immediately after application 
(Specific Aim #1) and two weeks following use of the intervention alone (Specific Aim 
#2). Patients will be referred to pelvic floor PT, which is considered the standard of care 
for treatment of pelvic floor myofascial pain at this time. As it typically takes 2-3 weeks to 
get in to see one of the pelvic floor PT providers at Wash U, follow up for this study will 
be completed prior to their attendance at pelvic floor PT.  
E2 Subject Selection and Withdrawal  
2.a 
Inclusion Criteria  
Study population and eligibility: All new patients presenting to our facility undergo our 
standardized pelvic floor myofascial examination and are asked to rate their pain on 
palpation of the bilateral OI and LA muscles on a 0-10 verbal pain rating scale (0=none 
1-3=mild, 4-6=moderate, and 7-10=severe). Patients found to have pelvic floor 
myofascial pain of at least 4/10 in severity at any of the four sites will be eligible for 
inclusion. Eligible patients may participate in Specific Aim 1 only or in both Specific Aims 
1 and 2. 
2.a 
Exclusion Criteria  
Exclusion criteria include age <18, non-English speaking, current diagnosis of dementia, 
and limited physical mobility that would prevent full participation in pelvic floor 
PT. Patients will also be excluded if they have performed vaginal cryotherapy in the past 
or present with a complaint or known history of chronic pelvic pain.  

 
 
 
 
 
 
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2.b 
Ethical Considerations  
Human Subjects Involvement and Characteristics  
We will approach adult women presenting to the FPMRS Clinic at Washington University 
in St. Louis for inclusion. Eligible women will be ≥18 years old, English speaking, found 
to have pelvic floor myofascial pain on examination, and willing to participate.  
Inclusion of Women, Minorities, and Children 
Our patient sample is limited to women. St. Louis City is approximately 50% Black or 
African American, but our surrounding suburbs and rural areas have a much lower 
proportion of residents who are African American. We will strive for at least 25% 
racial/ethnic minority representation in our study (25% African Americans, 1% Asian 
American, 1% American Indian/Alaska Native). There are no exclusion criteria in this 
application related to race/ethnicity, however, we will exclude non-English speaking 
individuals. We do not anticipate this negatively affecting the racial/ethnic minority 
representation in our study as the proportion of individuals who do not speak English in 
the St. Louis region is low. We will not include children <18 in our study.  
2.c 
Subject Recruitment Plans and Consent Process 
A member of the research team will approach eligible patients and further describe the 
study. Confidential and informed consent will occur in a private room. Patients will 
receive verbal and written instructions on using the intravaginal tubes by the research 
assistant who will not be blinded to treatment allocation. Providers performing the 
baseline and follow-up pelvic floor myofascial examination and interpreting the data will 
be blinded to treatment allocation. 
2.d 
Randomization Method and Blinding 
Randomization will be in 1:1 allocation to either vaginal cryotherapy or control. The 
examining physician and study PI will be blinded to treatment allocation. The research 
assistant will be aware of study allocation in order to provide instruction and answer 
questions but will not be involved in data collection or analysis. 
2.e 
Risks and Benefits 
The risks of the proposed study primarily include discomfort and embarrassment with the 
pelvic examination. This risk is not unique to study participants as all new patients 
undergo a comprehensive pelvic floor myofascial examination. Participants may also 
experience discomfort or embarrassment with intravaginal tube placement. Finally, 
breach of confidentiality is another risk. Every precaution will be taken to ensure data are 
kept strictly confidential. Only the research team will have access to paper data, which 
will be stored in a locked cabinet in the FPMRS offices. Enrolled patients will be 
assigned unique study identification numbers. A password-protected electronic database 
will be established using REDCap, and only the research team will have access. No 
results will be presented in a personally identifiable manner. 
2.f 
Early Withdrawal of Subjects  
i 
When and How to Withdraw Subjects  
Patients may request withdrawal from the study at any point. Patients who desire to 
withdraw from the study will need to inform the research assistant or PI via telephone or 

 
 
 
 
 
 
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in writing using the contact information in the consent document. Patients who elect to 
withdraw from the study will not be contacted about future study-related tasks. 
ii 
Data Collection and Follow-up for Withdrawn Subjects  
Data collection will stop when the patient requests withdrawal from the study. It is 
possible, depending on the timing of study withdrawal, that some data collection will 
have already occurred. This data will be used according to the protocol for data use in 
the study, however, no further data collection will occur. In the event that a patient 
withdraws and requests that her previously-collected data be destroyed and not included 
in the study outcomes, that will be done according to her wish.  
E3 Study Intervention  
3.a 
Description  
The intervention group will be provided with one vaginal cryotherapy tube, filled with a 
mixture of isopropyl alcohol (2ml) and water (8ml) that has been kept in the freezer. This 
mixture results in a “slushy” consistency and prevents the solution from freezing solid 
thus decreases the risk of discomfort or injury due to the temperature of the tube. They 
will be instructed to store these tubes in their home freezer. 
 
The control group will be provided with an identical tube that is empty. An empty tube 
was chosen as the control because a tube with room-temperature liquid may still be 
perceived as cold.   
 
Patients participating in Specific Aim #1 will insert this tube into the vagina to a 
comfortable depth. A lubricant will be provided for comfort with tube insertion, if 
necessary. At the conclusion of the treatment, this tube will be washed thoroughly and 
given to the patient in a clean plastic baggie for use at home.  
 
Patients in Specific Aim #2 will also be given two tubes according to the group to which 
they were randomized for use at home. 
3.b 
Treatment Regimen  
Both groups will be given the same instructions for use, which will include intravaginal 
placement of one tube for 10 minutes while resting in a supine position. A lubricant may 
be used for comfort with insertion.  
 
Patients participating in Specific Aim #1 will perform their first intervention in the office 
with a repeat examination within 10 minutes of completing therapy. Patients participating 
in Specific Aims #2 will perform the intervention once daily at home. Patients will be 
asked to complete a short diary for each session, which will include the time of day, 
duration of application, pain score prior to and after application, and presence of any 
pelvic floor disorder symptoms prior to and after application.  
3.c 
Method for Assigning Subjects to Treatment Groups  
Randomization will be in 1:1 allocation to either vaginal cryotherapy or control. The 
examining physician and study PI will be blinded to treatment allocation. The research 
assistant will be aware of study allocation in order to provide instruction and answer 
questions but will not be involved in data collection or analysis. 

 
 
 
 
 
 
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3.d 
Preparation and Administration of Study Intervention  
Cryotherapy and control tubes will be prepared by the investigators and stored on-site 
until randomization and treatment allocation. The tubes used for the cryotherapy and 
control interventions are identical, 10 ml conical tubes. Cryotherapy tubes (intervention 
arm) will be prepared using a mixture of isopropyl alcohol (2ml) and water (8ml) and 
stored in the freezer. Using this mixture results in a “slushy” consistency and prevents 
the contents of the tube from freezing solid, thus decreasing the risk of tissue injury. 
Control tubes will be empty and stored at room temperature.  
 
The appropriate tubes will be distributed by the research assistant with instructions 
provided for their appropriate use. Patients participating in Specific Aim #2 will be given 
tubes to take home with instructions to keep the tubes in the freezer or at room 
temperature according to their treatment assignment. The research assistant will not be 
blinded to the treatment allocation in order that she may answer any questions related to 
the intervention.  
 
Patients will self-administer the intervention in the office (Specific Aim #1) or at home 
(Specific Aim #2) while resting in a supine position for 10 minutes. A lubricant may be 
used for comfort with tube insertion.  
3.e 
Subject Compliance Monitoring  
Patients will be asked to complete a short diary for each session, which will include the 
time of day, duration of application, pain score prior to and after application, and 
presence of any pelvic floor symptoms prior to and after application. This survey will be 
completed electronically via REDCap. The link will be sent via a secure email to the 
patient at the email addressed provided at the time of enrollment.  
3.f 
Prior and Concomitant Therapy  
There will be no requirement for prior therapy in order to participate in the study. Patients 
will be excluded from participation if they have previously used vaginal cryotherapy.  All 
participating patients will be referred to pelvic floor physical therapy. There is frequently 
a delay in scheduling pelvic floor physical therapy of up to 2-3 weeks after initial referral 
thus this time was built into the study procedures in order to assess for the effect of 
cryotherapy independent of physical therapy. The 2 week follow up visit will occur 
concurrently or just prior to their first pelvic floor physical therapy visit.  
3.g 
Blinding of Study Drug  
The tubes are identical in appearance with the exception of the temperature to touch and 
contents. The tubes will be distributed to the patients by the research assistant, who is 
not blinded to treatment allocation. The patients will not be blinded to treatment 
allocation. The providers, who are blinded to treatment allocation, will not have contact 
with the tubes once distributed to the patient. 
 
F Study Procedures  
 

 
 
 
 
 
 
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13
F1 Screening for Eligibility 
All new patients presenting to our facility undergo our standardized pelvic floor 
myofascial examination and are asked to rate their pain on palpation of the bilateral OI 
and LA muscles on a 0-10 verbal pain rating scale (0=none 1-3=mild, 4-6=moderate, 
and 7-10=severe). Patients found to have pelvic floor myofascial pain of at least 4/10 in 
severity at any of the four sites will be considered eligible and approached for study 
inclusion. Exclusion criteria include age <18, non-English speaking, current diagnosis of 
dementia, limited physical mobility that would prevent full participation in pelvic floor PT, 
complaint or known diagnosis of chronic pelvic pain or prior use of vaginal cryotherapy. 
We will enroll a total of 66 patients for the trial. 
F2 Schedule of Measurements 
Data collection will occur at baseline and 2 weeks (Figure 2). Patients will complete 
validated questionnaires including the short forms of the Pelvic Floor Distress Inventory 
(PFDI-20), Pelvic Floor Impact Questionnaire (PFIQ-7), and Pelvic Organ 
Prolapse/Urinary Incontinence Sexual Questionnaire IUGA-Revised (PISQ-IR, 24, 25). 
Questionnaires will be scored according to published protocols (26, 27). 
(see attached) 
F3 Safety and Adverse Events  
The risks of the proposed study primarily include discomfort and embarrassment with the 
pelvic examination. This risk is not unique to study participants as all new patients 
undergo a comprehensive pelvic floor myofascial examination. Participants may also 
experience discomfort or embarrassment with intravaginal tube placement. Finally, 
breach of confidentiality is another risk. Every precaution will be taken to ensure data are 
kept strictly confidential. Only the research team will have access to paper data, which 
will be stored in a locked cabinet in the FPMRS offices. Enrolled patients will be 
assigned unique study identification numbers. A password-protected electronic database 
will be established using REDCap, and only the research team will have access. No 
results will be presented in a personally identifiable manner. 
3.a 
Safety and Compliance Monitoring 
Vaginal cryotherapy is recommended routinely by the physicians and physical therapists 
in our Division and, to date, no adverse events related to the cryotherapy have been 
reported. Theoretical adverse events that could be related to use of cryotherapy in the 
vagina include skin irritation or injury from the temperature of the tube or trauma to the 
vagina related to placement of the tube.  
 
Patients will be provided with contact information for study personnel who can be 
reached 24/7 to report an adverse event. At the follow up visit at 2 weeks, patients will 
be asked whether they experienced any adverse events. Follow up questions will be 
asked, as appropriate, for patients reporting adverse events during the study period. 
Adverse events will be monitored and recorded in the REDCap database. Adverse event 
reporting will occur throughout the duration of the study procedure. 
 
Each reported adverse event will be reviewed by the members of the study team and 
graded according to the Dindo-Clavien classification for adverse events (see table). (32). 
Although this classification system is designed for surgical interventions, it is the most 
applicable classification system currently available for the intervention proposed in this 

 
 
 
 
 
 
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14
study. Any Class II or higher complications that are related or possibly related to the 
study intervention will result in a temporary cessation of enrollment and an investigation 
by the study team. A determination as to whether the study may resume will be made by 
the consensus of the study team. If more than 10% of enrolled patients report Class I 
complications that are related or possibly related to the study intervention, a similar 
process will occur.  
 
 
F4 Study Outcome Measurements and Ascertainment 
The data collected will include demographic characteristics; basic medical and 
reproductive health histories; pre- and post-treatment myofascial examination scores; 
PFDI-20, PFIQ-7, and PISQ-IR results at baseline and follow up visits; PGI-I and SAPS 
scores at study conclusion; PFPT assessments. Demographic data, medical and 
reproductive health histories, and pre- and post-treamtnet myofascial examination 
scores will be obtained from the medical record. Baseline questionnaires will be 
completed by the patient electronically directly in REDCap using a secure, password-
protected tablet owned and operated by the research team. Follow up surveys and 
questionnaires will be administered electronically as secure surveys built in REDCap.  
G Statistical Plan  
 
G1  Sample Size Determination and Power 
We expect vaginal cryotherapy to result in at least 3-point improvement in myofascial 
pain scores as reported on a 0-10 verbal pain rating scale. Prior studies investigating 
clinically significant reductions in pain scores report greater than 2 points on a 0-10 scale 
or 30% reduction in pain as clinically significant28. In order to detect a 3-point difference 
with 80% power and alpha 0.05, we would need to enroll 30 patients per group. 
Accounting for a 20% loss-to-follow up rate, we plan to enroll 33 patients per group for a 
total of 66 patients. Patients may participate in Specific Aim #1 only, in Specific Aim #2 
only, or both Specific Aims. If no patients participate in both Specific Aim #1 and Specific 
Aim #2, then 132 patients will be required overall.  

 
 
 
 
 
 
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15
G2  Interim Monitoring and Early Stopping 
This study is designed as a pilot study to test the efficacy and feasibility of vaginal 
cryotherapy for treatment of pelvic floor myofascial pain. As such, we do not have futility 
criteria for early stopping. We will monitor for adverse events and pause/stop enrollment 
for this as indicated above.  
G3  Analysis Plan 
Specific Aim #1: To determine the effect of vaginal cryotherapy as an immediate 
treatment modality for patients with pelvic floor myofascial pain. Primary outcome is 
change in pelvic floor myofascial pain scores at each site (bilateral OI and LA). The 
statistical significance of this change between arms will be evaluated by a Students t-test 
or Wilcoxon rank sum test as appropriate. Secondary outcomes include change in PFDI-
20, PFIQ-7, and PISQ-IR scores. 
Specific Aim #2: To determine the effect of vaginal cryotherapy as a neoadjuvant 
treatment modality for patients with pelvic floor myofascial pain awaiting pelvic floor PT.  
Primary outcome includes change in pelvic floor myofascial pain scores at each site 
(bilateral OI and LA) from baseline to follow-up (2 weeks). The statistical significance of 
this change between arms will be evaluated by a Students t-test or Wilcoxon rank sum 
test as appropriate. Secondary outcomes include change in PFDI-20, PFIQ-7, and 
PISQ-IR scores, and patient satisfaction (PGI-I, SAPS). 
G4  Missing Outcome Data 
Patients with missing outcome data for the primary outcome will be excluded from 
analysis. The primary analysis will be by intention-to-treat with a planned secondary 
analysis per-protocol. Missing outcome data for secondary outcomes of PFDI-20, PFIQ-
7, and PISQ-IR scores will be imputed according to published protcols for imputation of 
missing data within these questionnaires (26, 27). 
H Data Handling and Record Keeping  
 
H1 Confidentiality and Security 
In order to ensure the confidentiality of study participants, recruitment and consent will 
occur in a private examination or consult room. Patients will have ample time to ask 
questions of the study personnel. Patients will be determined to be eligible based on 
examination findings at the time of their initial evaluation. Medical record review will 
occur to confirm eligibility. Study-related activities will occur in a private examination 
room. Only the research team will have access to paper data, which will be stored in a 
locked cabinet in the FPMRS offices. Enrolled patients will be assigned unique study 
identification numbers. A password-protected electronic database will be established 
using REDCap, and only the research team will have access. No results will be 
presented in a personally identifiable manner 
H2 Case Report Forms and Source Documents 
All data will be securely stored in REDCap. Consent documents and hard copy 
documents will be securely stored in a locked cabinet in the FPMRS offices.  

 
 
 
 
 
 
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16
H3 Records Retention 
Records of participating patients will be maintained throughout the study and data 
analysis. Records will be securely destroyed at the earliest possible time after 
completion of the study. Patients requesting withdrawl from the study and requesting any 
previously-captured results/data also be destroyed will have this information securely 
destroyed at the time of receipt of the request.  
 
I Study Administration 
 
I1 
Organization and Participating Centers 
The Female Pelvic Medicine & Reconstructive Surgery Division at Washington 
University in St. Louis is organizing and conducting this study. There are no other 
participating centers.  
I2 
Funding Source and Conflicts of Interest 
This study is being funded by the Female Pelvic Medicine & Reconstructive Surgery 
Division at Washington University in St. Louis. All study personnel are without conflicts of 
interest.  
I3 
Subject Stipends or Payments  
Study subjects will not be paid for their participation in this study. 
I4 
 Study Timetable 
Participation in this still will occur over 2 weeks. On average, we see about 30 new 
patients per month. Analysis from our cross-sectional data suggests that pelvic floor 
myofascial pain of at least 4/10 in severity is present in about 57% of new patients, thus 
we anticipate enrollment to take approximately 4-8 months, depending on the number of 
patients who choose to participate in both Specific Aims.  
 
J Publication Plan  
 
We plan to submit the findings from this study for publication in a high-impact Ob/Gyn 
journal.  
 
 
K  Attachments  
 
K1  Tables  
Figure 1: Study flow 

 
 
 
 
 
 
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17
K2  Informed consent documents 
Informed consent.docx 
K3  Patient education brochures 
Intervention instructions.docx 
K4  Questionnaires or surveys 
REDCap daily postPT.docx 
REDCap daily prePT.docx 
In office pre post.docx 
PFDI.pdf 
PFIQ.pdf 
PGI I.docx 
PISQ.pdf 
SAPS.docx 
 
L References 
 
 
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