Prospective Randomized Trial of Tranexamic Acid Versus Levonorgestrel Intrauterine System for the Treatment of Heavy Menstrual Bleeding in Women With Uterine Fibroids
Phase: PHASE4
Conditions: Heavy Menstrual Bleeding, Menorrhagia, Uterine Fibroids
Sponsor: Shannon K. Laughlin-Tommaso

 
 
Prospective Randomized Trial of Tranexamic Acid versus 
Levonorgestrel Intrauterine System for the Treatment of Heavy 
Menstrual Bleeding in Women with Uterine Fibroids 
 
NCT03317795 
 
July 26, 2019 

LNG-IUS vs. Tranexamic Acid in women with uterine fibroids 
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PROSPECTIVE RANDOMIZED TRIAL OF TRANEXAMIC ACID 
VERSUS LEVONORGESTREL INTRAUTERINE SYSTEM FOR THE 
TREATMENT OF HEAVY MENSTRUAL BLEEDING IN WOMEN WITH 
UTERINE FIBROIDS   
 
 
 
Sponsor-Investigator: 
Shannon K. Laughlin-Tommaso, MD 
Department of OB-GYN 
200 1st Street SW, Rochester MN 55905 
 
 
 
Study Product: 
Tranexamic acid (Lysteda) 
Levonorgestrel Intrauterine system (Mirena)  
Protocol Number: (IRBe) 
16-008671 
 
 
 
 
 
 
 
Initial version: [11.15.2016] Version 1.0 
Revised: 
[07.25.2017] Version 2.0 
Revised: 
[04.12.2018] Version 2.1 
Revised:  
[01.14.2019] Version 2.2 
Revised: 
[07.26.2019] Version 2.3 
 
 
 

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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 5 
1 
INTRODUCTION ................................................................................................................................. 7 
1.1 
BACKGROUND .................................................................................................................................... 7 
1.2 
INVESTIGATIONAL AGENT .................................................................................................................... 8 
1.3 
CLINICAL DATA TO DATE..................................................................................................................... 8 
1.4 
DOSE RATIONALE AND RISK/BENEFITS .................................................................................................. 8 
2 
STUDY OBJECTIVES .......................................................................................................................... 8 
3 
STUDY DESIGN ................................................................................................................................... 9 
3.1 
GENERAL DESIGN ............................................................................................................................... 9 
3.2 
PRIMARY STUDY ENDPOINTS .............................................................................................................. 11 
3.3 
SECONDARY STUDY ENDPOINTS ......................................................................................................... 11 
3.4 
PRIMARY SAFETY ENDPOINTS ............................................................................................................ 11 
4 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL ...................................................... 11 
4.1 
INCLUSION CRITERIA ......................................................................................................................... 11 
4.2 
EXCLUSION CRITERIA ........................................................................................................................ 11 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING ....................................................................... 12 
4.4 
EARLY WITHDRAWAL OF SUBJECTS .................................................................................................... 12 
4.4.1 
When and How to Withdraw Subjects ........................................................................................ 12 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .............................................................. 13 
5 
STUDY DRUG .................................................................................................................................... 13 
5.1 
DESCRIPTION .................................................................................................................................... 13 
5.2 
TREATMENT REGIMEN ....................................................................................................................... 14 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ................................................................ 14 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ......................................................................... 14 
5.5 
SUBJECT COMPLIANCE MONITORING ................................................................................................... 14 
5.6 
PACKAGING ...................................................................................................................................... 15 
5.7 
MASKING/BLINDING OF STUDY........................................................................................................... 16 
5.8 
RECEIVING, STORAGE, DISPENSING AND RETURN ................................................................................. 16 
5.8.1 
Receipt of Drug Supplies .......................................................................................................... 16 
5.8.2 
Storage ................................................................................................................................... 16 
5.8.3 
Dispensing of Study Drug ......................................................................................................... 16 
5.8.4 
Return or Destruction of Study Drug ......................................................................................... 16 
6 
STUDY PROCEDURES ...................................................................................................................... 17 
6.1 
VISIT 1/ ENROLLMENT ....................................................................................................................... 17 
6.2 
VISIT 2 / MONTH 3 ............................................................................................................................. 18 
6.3 
VISIT 3 / MONTH 6 ............................................................................................................................. 18 
6.4 
VISIT 4 / MONTH 9 ............................................................................................................................. 18 
7 
STATISTICAL PLAN ......................................................................................................................... 18 
7.1 
SAMPLE SIZE DETERMINATION ........................................................................................................... 18 
7.2 
STATISTICAL METHODS ..................................................................................................................... 19 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ............................................................................................. 20 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 20 
8.1 
DEFINITIONS ..................................................................................................................................... 21 
8.2 
RECORDING OF ADVERSE EVENTS ....................................................................................................... 22 

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8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS .......................................... 23 
8.3.1 
Sponsor-Investigator reporting: notifying the Mayo IRB ............................................................. 23 
8.3.2 
Sponsor-Investigator reporting: Notifying the FDA ..................................................................... 23 
8.4 
STOPPING RULES ............................................................................................................................... 23 
8.5 
MEDICAL MONITORING ..................................................................................................................... 24 
8.5.1 
Internal Data and Safety Monitoring Plan .................................................................................. 24 
9 
DATA HANDLING AND RECORD KEEPING .................................................................................. 24 
9.1 
CONFIDENTIALITY ............................................................................................................................. 24 
9.2 
SOURCE DOCUMENTS ........................................................................................................................ 24 
9.3 
CASE REPORT FORMS ........................................................................................................................ 25 
9.4 
RECORDS RETENTION ........................................................................................................................ 25 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................ 26 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 26 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 26 
11 
ETHICAL CONSIDERATIONS ......................................................................................................... 26 
12 
STUDY FINANCES ............................................................................................................................ 27 
12.1 
FUNDING SOURCE ......................................................................................................................... 27 
12.2 
SUBJECT STIPENDS OR PAYMENTS .................................................................................................. 27 
13 
PUBLICATION PLAN ....................................................................................................................... 27 
14 
REFERENCES ................................................................................................................................... 27 
 
 
 
 
 
 
 
 

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List of Abbreviations 
 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
                            
IB 
Investigator’s Brochure 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
LNG-IUS 
Levonorgestrel-releasing intrauterine system 
TXA 
Tranexamic Acid 
RCT 
Randomized Controlled Trial 
HMB 
Heavy Menstrual Bleeding 
UFS-QOL 
Uterine Fibroid Symptom – Quality of Life 
MMAS 
Menorrhagia Multi-Attribute Scale 
PBLAC 
Pictorial Blood Loss Assessment Chart 
VAS 
Visual Analog Scale (for pain) 
CI 
Confidence Interval 
LVCF 
Last Value Carry Forward 
 
 
 
 
 
 
 
 
 

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Study Summary 
Title 
 
Prospective Randomized Trial of Tranexamic Acid versus Levonorgestrel 
Intrauterine System for the Treatment of Heavy Menstrual Bleeding in 
women with Uterine Fibroids  
 
Running Title 
LNG-IUS vs. Tranexamic Acid in women with uterine fibroids 
Protocol Number 
16-008671 
Phase 
IV 
Methodology 
Randomized controlled trial, open label  
Overall Study 
Duration 
2 years 
Subject Participation 
Duration 
9 months 
Single or Multi-Site  
Single-site 
Objectives 
Specific Aim #1: To determine the comparative effectiveness [as 
measured by the Menorrhagia Multi-Attribute Scale (MMAS)] and 
duration of use of TXA versus LNG-IUS for the treatment of HMB in 
women with uterine fibroids. 
Specific Aim #2: To determine the clinical and fibroid-related 
predictors of successful medical therapy of HMB in women with 
uterine fibroids. 
 
Number of Subjects 
160 
Diagnosis and Main 
Inclusion Criteria 
Heavy menstrual bleeding in women with uterine fibroids.  
Study Product, Dose, 
Route, Regimen 
Levonorgestrel intrauterine system (20 microgram/24 hour 
levonorgestrel) 
Tranexamic acid 1.3 grams three times per day during first 5 days of 
menses 
Duration of 
Administration 
Up to 5 years for the LNG-IUS and up to 1 year for tranexamic acid 
Reference therapy 
Compared to each other, no placebo arm 

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Statistical 
Methodology 
At 3, 6, and 9 months separately, each of the continuously scaled 
outcomes will be compared between treatment arms based on fitting 
separate linear regression models and analysis of covariance 
(ANOCOVA) models will be fit to compare the measures between the 
two treatment arms after adjusting for baseline levels. Last value carry 
forward (LVCF) methods will be investigated to accommodate drop-
outs. All analyses will be performed based on the intention to treat 
principle. The cumulative incidence (CI) function will be used to 
estimate the cumulative proportion of patients by time t who have 
intentionally discontinued treatment due to the desire or need to stop or 
switch treatment, after accounting for the competing risk of LNG-IUS 
expulsion and censoring all other participants at their date of last 
follow-up or end of study. 
 
 

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1 Introduction 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic research 
policies and procedures.  
1.1 
Background 
 
Background  
Uterine fibroids and especially the heavy menstrual bleeding (HMB) they produce are a common 
and debilitating problem for women. Our work demonstrates 60% of women with fibroids report 
that symptoms affect their quality of life and impede physical activity, and 24% report that 
fibroid symptoms prevent them from reaching their true potential at work (1, 2). HMB, the most 
common symptom of uterine fibroids, affects approximately 1.4 million women per year and 
costs an excess $2,291 per woman annually in lost work and home management activities (3, 4).  
Medical therapy is the first line treatment for HMB, yet, the lack of evidence of medical efficacy 
in women with fibroid-related HMB leads to a high rate of surgical management and especially 
hysterectomy. Fibroids account for more than 40% of hysterectomies in the U.S. which have a 
10-12% complication rate and may lead to the detrimental effects of early menopause, even with 
conservation of the ovaries (5, 6). Randomized studies of the efficacy of medical therapies for 
HMB typically include only women with few or small fibroids (7, 8). The goal of this study is 
to determine the effectiveness of non-estrogenic medical therapy in women with a range of 
fibroid sizes, locations, and number.  
Two effective medical treatments for HMB have limited data in women with fibroids. The 
levonorgestrel intrauterine system (LNG-IUS) was FDA approved for the treatment of HMB in 
2009 and is highly effective for decreasing menstrual bleeding, treating anemia and improving 
quality of life (8-10). Moreover, it can be used continuously for 5 years. Expulsion rate in 
women with fibroids may be as high as 12% and discontinuation rate up to 28% at 2 years based 
on a small sample size and no information is available about predictors of these events (8). 
Tranexamic acid (TXA) is widely used outside the U.S. and was also FDA approved for HMB in 
2009; TXA reduces menstrual blood loss in 40% of women and improves quality of life (11-14). 
In women with fibroids, TXA has been shown to decrease HMB and cause necrosis of the 
fibroids, especially larger fibroids, which should augment its efficacy for women with fibroids 
(15).  
Our preliminary data from a large insurance-claims database show that women with fibroids 
were more likely to continue use of LNG-IUS (62% at 6 months) than TXA (22% at 6 months) 
for the treatment of HMB; however, we were unable to ascertain reasons for discontinuation in 
either group (16). Accurately predicting which women with fibroids are optimal candidates for 
medical therapy is a key unanswered question of the Agency for Healthcare Research and 
Quality (AHRQ) evidence-based review and would have substantial impact on the clinical care 
for women with fibroids (17).  
Thus, we propose a randomized controlled trial (RCT) to assess the comparative 
effectiveness of LNG-IUS to TXA for the treatment of HMB in women with clinically-
significant fibroids. We will measure patient-reported outcomes recognized to be important to 
women with HMB and study the clinical factors (e.g. body mass index, age) and fibroid factors 
(e.g. size, location) that predict successful medical therapy.    
 

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After greater than 1 year of enrollment and randomization, we have found that we have a higher 
rate of drop outs in the TXA arm than expected. Nearly all participants in the TXA arm have 
dropped out (n=4) before 6 months participation due to various side effects. Clinically, we use 
this medication and do not receive the same reported side effects. Thus, we would like to 
evaluate the use of TXA in a population that has self-selected the use of the medication. We will 
add an observational arm to the study for women who otherwise meet study criteria and 
select either TXA or LNG-IUS, but decline randomization.  
1.2 
Investigational Agent 
LNG-IUS was FDA approved for the treatment of HMB in 2009 and previously for 
contraception in 2000. The LNG-IUS is a T-shaped device with a polyethylene body containing 
a hormone reservoir, holding a total of 52 mg of levonorgestrel. LNG-IUS initially releases 20 
micrograms of the progestin per day, which decreases to less than half that amount after 5 years 
of use. The levonorgestrel causes stromal pseudodecidualization, decreases endometrial 
thickness, and lowers uterine vascular density.  
TXA was FDA approved for the treatment of HMB in 2009. TXA is a plasminogen-activator 
inhibitor that blocks fibrinolysis and reduces plasmin activity. A special formulation was 
designed for the treatment of HMB that reduces gastrointestinal side effects (Brand name 
Lysteda): 1300 mg taken three times per day for up to 5 days of the menstrual cycle (Lukes).  
1.3 
Clinical Data to Date 
Several studies have shown good efficacy of both the LNG-IUS and TXA in the treatment of 
HMB in the presence of small uterine fibroids {Grigorieva, 2003 #1010}{Gupta, 2015 
#992}{Lukes, 2010 #986}. We demonstrated in our large insurance-claims database that women 
with clinically significant fibroids were more likely to continue use of LNG-IUS (62% at 6 
months) than TXA (22% at 6 months) for the treatment of HMB. No studies have demonstrated 
the reasons for discontinuation of treatment. A case report published after the start of this study 
shows intratumoral atherosis-like vasculopathy in a fibroid treated with tranexamic acid; no side 
effects were noted in this case but surgery was done due to lack of response to TXA. The side 
effects and reasons for discontinuation noted thus far in our study include diarrhea, abdominal 
cramping, lack of effect, pelvic pain and dysmenorrhea.   
 
1.4 
Dose Rationale and Risk/Benefits 
Both medications are being used at the clinically acceptable dosages as indicated for the 
treatment of HMB. Risks of LNG-IUS related to fibroids include expulsion, perforation, or 
embedment of device. The risk of TXA related to fibroids is necrosis of the fibroids leading to 
pain.  
2 
Study Objectives 
Primary Objective 
To determine the comparative effectiveness [as measured by the Menorrhagia Multi-Attribute 
Scale (MMAS)] and duration of use of TXA versus LNG-IUS for the treatment of HMB in 
women with uterine fibroids. 

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Hypothesis: A user-independent medical therapy (LNG-IUS) will result in better patient reported 
outcomes and longer use compared to self-administered medication (TXA) 
 
Secondary Objective 
To determine the clinical and fibroid-related predictors of successful medical therapy of HMB in 
women with uterine fibroids. 
Hypotheses: Large fibroid size will limit the effectiveness of LNG-IUS compared with TXA; 
elevated BMI predicts higher success with LNG-IUS over TXA.   
 
 
3 Study Design 
3.1 
General Design 
This is a randomized controlled trial of LNG-IUS compared with TXA for the treatment of 
HMB in160 women with uterine fibroids. Subjects with self-reported HMB for 3 months or 
more that have at least one uterine fibroid >1cm in size that is either intramural or 
submucosal on ultrasound will be eligible for the study. Clinical evaluation for HMB needs 
to be completed before enrollment and participants must be eligible for either LNG-IUS or 
TXA. 
Screening for the study will be based on baseline MMAS score with at least one domain 
scoring >2. Additionally, if not already performed for HMB evaluation, screening will 
include uterine sounding length, ultrasound documentation of number and size of fibroids, 
and evaluation of the uterine cavity if indicated. Once consent has been obtained, baseline 
laboratory studies will be completed and participants randomized to one of two arms. 
Placement of the LNG-IUS will be performed by study physicians in the clinic setting. 
Follow-up of treatment effect will continue for 9 months with monthly Pictorial Blood Loss 
Assessment Card (PBLAC) scores and phone calls at 3 and 6 months. A final visit for 
evaluation, collection of lab samples, and ultrasound examination will be conducted at 9 
months.  
For patients that would qualify for the study but choose not to be randomized, we will enroll 
them into an observation arm. We will have them complete the same questionnaires and 
report adverse events/side effects at baseline, 3 months, 6 months and 9 months. We will also 
have them obtain CBC, ferritin, and ultrasound at the end of study. Medications will be 
provided in the clinical setting and not provided by the study. For patients in the observation 
arm, the baseline serum creatinine and ultrasound will be done if clinically indicated, but are 
not required for enrollment.  
 
 
 

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Screening
Randomization
LNG-IUS arm
Follow-up
TXA arm
Follow-up
Declines 
randomization
Selects LNG-
IUS or TXA
Follow-up

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3.2 
Primary Study Endpoints 
The primary endpoints are the difference in self-reported MMAS scores at 6 months between 
LNG-IUS and TXA treatment and the duration of use of TXA versus LNG-IUS 
3.3 
Secondary Study Endpoints 
The secondary endpoints are:  
• Patient and fibroid characteristics that predict successful outcomes 
• Differences in VAS, PBLAC, UFS-QOL and  Rand SF-36 scores 
3.4 
Primary Safety Endpoints 
Safety endpoints include:  
1. The correct placement of LNG-IUS based on type of fibroids present, verified by 
ultrasound after placement of device.  
2. Record of side effects or adverse events of each medication based on questionnaire, 
phone follow-up and self-report. 
4 Subject Selection Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
• Premenopausal women aged 25-50 
• Seeking treatment for HMB with a completed clinical evaluation 
• Image-confirmed uterine fibroids of at least 1 cm in size and either submucosal or 
intramural  
• Monthly menses 
• Completed evaluation of HMB within one year 
• Able to give consent for inclusion in the study 
• Understands the English language for consent and questionnaires  
• Self-reported HMB 3 months or more 
• Not pregnant or breast-feeding 
4.2 
Exclusion Criteria 
• Class 0 fibroids confirmed by hysteroscopy, saline infused sonogram, or 3D ultrasound 
• Uterine sounding length >14 cm  
• Abnormal biopsy (pre-malignant or malignant) or incomplete clinical testing to rule out 
malignancy 
• Venous thromboembolic history, clotting disorder, strong family history of venous 
thromboembolic events 
• Needs hormonal contraception, including estrogen-containing medications 
• Uterine size >20 weeks gestational size 
• Breast, uterine or cervical malignancy 
• Liver disease or liver tumor 
• Pelvic inflammatory disease or infection with gonorrhea or chlamydia in last 3 months 
• Hemoglobin less than 8mg/dL; for women 8-12 mg/dL recommend iron 
• Serum creatinine ≥ 1.4  

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• Pregnant or breast-feeding  
4.3 
Subject Recruitment, Enrollment and Screening 
For recruitment into the study, we will recruit patients from our Mayo Clinic Gynecology clinics, 
but we will look to our colleagues for referrals for the study. Before the start of the study, a letter 
will be sent to all staff providers in Gynecology (n = 69) and Family Medicine at Mayo Clinic   
(n = 166) and primary care providers at affiliated facilities (n= 81), including the Mayo Clinic 
Health System sites, for referrals to our gynecology clinics for the trial. The trial will be listed 
under our current studies section and at clinicaltrials.gov. The advertising brochure will be 
downloadable as a PDF file and flyers created for display in our medical facilities.  
Self-referrals to our clinic for evaluation of the study will be allowed. We will use our Mayo 
Clinic Fibroids social media network (Facebook and Twitter) developed for our current fibroid 
studies and the assistance of our Mayo Clinic Division of Community Engagement for outreach. 
We have established an email address for fibroid studies that will be listed on brochures and 
flyers. Based on an accrual feasibility study, we project that we can recruit all of our patients 
from Mayo Clinic Rochester alone. We can reach out to 3 of our Mayo Clinic Health System 
hubs for additional referrals and outreach if needed as we are currently doing with other trials.  
In addition, all women seeking treatment for HMB will be advised of the study when making 
their appointment. They will be offered a brochure, and the option to talk with a study 
coordinator during their clinical visit. We estimate that we will enroll a minimum of 3 
participants per week (13 months to reach target enrollment of 160 participants).  
Informed consent for study enrollment will be obtained by a study coordinator in the clinic 
setting. The consent document and study treatments will be reviewed with the patient, and she 
will be allowed sufficient time to ask questions.  
4.4 
Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Participants may be withdrawn from the study at any time prior to completion of the study for 
the following reasons:  
• Safety issues including allergic or adverse reaction to either medication 
• If the participant develops clinically significant anemia from on-going HMB, she will be 
offered different treatment options 
• Displacement of LNG-IUS will require removal and participant may opt to withdraw 
from study or have a new device placed 
• Participant decision to withdraw from study (withdrawal of consent) 
• Unable to comply with the study protocol 
 
There are no adverse effects from stopping either treatment suddenly. We will encourage the 
participant to complete the study end measures (clinical laboratories, ultrasound, exam) to 
provide useful information to provide their primary care or gynecological provider on the 
management of their HMB.  This data will be useful to understand the treatment effect on the 
fibroids, bleeding, and well-being of the participants. If withdrawn from the study and not 
agreeable to the additional measures, we will use only data collected to that point. We will plan 
our recruitment to account for 20% attrition from the study so that individual participants will 
not require replacement.  

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4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
We will use the data obtained up until the person withdraws from the study, but will attempt to 
obtain permission for follow-up at 9 months for the subjects who have withdrawn. This endpoint 
will include whether the participant is still using either of the treatments, has any adverse events 
from treatment, had other procedures for HMB, and if there was expulsion of intrauterine device.  
5 Study Drug  
5.1 
Description 
Neither arm will be blinded due to the nature of the therapy.  
 
Mirena (levonorgestrel-releasing intrauterine system) contains 52 mg of LNG, a progestin, and is 
intended to provide an initial release rate of approximately 20 mcg/day of LNG. 
Levonorgestrel USP, (-)-13-Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one, the 
active ingredient in Mirena, has a molecular weight of 312.4, a molecular formula of C21H28O2, 
and the following structural formula: 
 
 
 
 
LYSTEDA is an antifibrinolytic drug. The chemical name is trans-4-
aminomethylcyclohexanecarboxylic acid. The structural formula is: 
 
 
Tranexamic acid is a white crystalline powder. It is freely soluble in water and in glacial acetic 
acid and is very slightly soluble in ethanol and practically insoluble in ether. The molecular 
formula is C 8H15N02 and the molecular weight is 157.2. 
Tranexamic acid tablets are provided as white oval-shaped tablets and are not scored. Each tablet 
is debossed with the marking “FP650.” The active ingredient in each tablet is 650 mg tranexamic 
acid. The inactive ingredients contained in each tablet are: microcrystalline cellulose, colloidal 

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silicon dioxide, pregelatinized corn starch, povidone, hypromellose, stearic acid, and magnesium 
stearate. 
5.2 
Treatment Regimen 
LNG-IUS is effective on placement and can be used up to 5 years. TXA will be dosed at 1300mg 
(2 tablets of 650mg) three times a day at the start of menses and used during the days that 
bleeding is heaviest (not to exceed 5 days per menstrual cycle).  
 
5.3 
Method for Assigning Subjects to Treatment Groups 
After review of enrollment criteria, eligible participants will be randomly assigned to either 
LNG-IUS or TXA treatment. Using a computer generated random numbers sequence; our 
statistician will prepare the randomization code. Randomization will be stratified by BMI (>=30 
or <30), dysmenorrhea (yes/no) and duration of HMB (<1 or >= 1 year) and will be conducted 
using a dynamic allocation approach based on the Pocock-Simon method.  
 
For patients that decline randomization but meet criteria and are interested in participation, they 
will be followed in the treatment group that they choose (either the LNG-IUS or TXA options). 
5.4 
Preparation and Administration of Study Drug 
Levonorgestrel intrauterine system (20microgram/24 hour levonorgestrel) will be sent from the 
manufacturer (Bayer Pharma AG) in sterile packaging to the clinic for insertion by physician as 
per clinical protocol. After pregnancy has been reliably excluded, the patient is placed in the 
lithotomy position and a bimanual examination is performed to assess uterine size and position. 
A speculum is placed in the vagina and the cervix cleaned with antiseptic solution. The uterus is 
sounded. The package is opened and using an aseptic technique, the sterile inserter is removed 
from the package. The slider is pushed forward as far as possible in the direction of the arrow to 
load the LNG-IUS. The inserter is carefully placed in the cervix and advanced to the uterine 
fundus corresponding to the sounding depth. The LNG-IUS arms are opened by pulling back the 
slider, the LNG-IUS positioned at the fundus, and the inserter removed. Strings should be cut to 
3 cm.  
 
Tranexamic acid will be dispensed by the Mayo Clinic Outpatient Research Pharmacy to the 
participant or mailed directly in 3-month supply increments. Participants will be instructed to 
take TXA at the initiation of each menses and use during the heaviest days of bleeding for up to 
5 days. Dosage is 1.3 grams (2 pills of 650mg each) three times per day for up to 5 days.  
 
5.5 
Subject Compliance Monitoring 
The study team will assess use of the medications at each follow-up phone call and visit. 
Subjects will be encouraged to feel for strings of the LNG-IUS to ensure uterine location. The 
TXA arm will be asked about the number of days they are using per menstrual cycle.  
 
Prior and Concomitant Therapy 
Concomitant therapy with NSAIDs will be allowed in both arms for treatment of dysmenorrhea 
or excessive bleeding. We will record NSAID use during the menstrual cycle. Estrogen-

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containing medications are contradicted with TXA and thus, will not be allowed to be used 
during the study.  
 
5.6 
Packaging 
Mirena (levonorgestrel-releasing intrauterine system), containing a total of 52 mg LNG, is 
available in a carton of one sterile unit NDC# 50419-423-01. 
Mirena is supplied sterile. Mirena is sterilized with ethylene oxide. Do not re-sterilize. For 
single-use only. Do not use if the inner package is damaged or open. Insert before the end of the 
month shown on the label. 
 
LYSTEDA (tranexamic acid) tablets are provided as white oval-shaped tablets. Each tablet is 
debossed with the marking “FP650” and are supplied as: 
 
The TXA will be dispensed by the Research Pharmacy to study participants during their clinic 
visit or by mail.  The investigational product will be labeled with patient specific prescription 
labels and the appropriate labels affixed to the prescription bottles/package as required by state 
and federal regulations.  
 
The package of an investigational new drug intended for human use shall bear a label with the 
statement "Caution: New Drug--Limited by Federal (or United States) law to investigational 
use”.  A sample label is provided in the figure below.  Note that the label is subject to change 
format but the information contained therein will not be changed.   
Sample Label 
 
 
                                                                            
    
 
 IRB# 16-008671         Subject # ____ Subject Name _______________________  
  Study Name _______________________ Kit# _____________ 
  Medication Name/Strength Mirena (levonorgestrel-releasing intrauterine system)_ 
  Directions (NO Abbreviations)___________________________________________ 
 
  Caution-New Drug Limited By Law To Investigational Use        
 
   
Sample Label 
 
 
                                                                            
    
 
 IRB# 16-008671       Subject # ____ Subject Name _______________________ 
  Study Name _______________________ Kit# _____________ 
  Medication Name/Strength _ Tranexamic Acid 650mg________________ 
  Directions (NO Abbreviations)_Two tablets three times per day for up to 5 days 
 during the menses_______________________________________________________ 
 
  Caution-New Drug Limited By Law To Investigational Use 
RESEARCH MEDICATION 
200 1ST Street SW 
Rochester, MN  55905 
(507) 284-2511 
Today’s 
Date: 
_____________________ 
Prescriber Name/Number: 
_____________________ 
RESEARCH MEDICATION 
200 1ST Street SW 
Rochester, MN  55905 
(507) 284-2511 
Today’s 
Date: 
_____________________ 
Prescriber Name/Number: 
_____________________ 

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5.7 
Masking/Blinding of Study  
Neither subjects nor researchers can be blinded to the treatment arm due to the nature of the 
study medications.  
5.8 
Receiving, Storage, Dispensing and Return 
5.8.1 Receipt of Drug Supplies 
Mirena will be shipped by Bayer Pharmaceuticals to the Mayo Clinic Outpatient Research 
Pharmacy and dispensed from there. Tranexamic acid tablets will be supplied by the Mayo 
Clinic Outpatient Research Pharmacy. 
 
Upon receipt of the of the study treatment supplies, an inventory must be performed and a drug 
receipt log filled out by the person accepting the shipment.  It is important that the designated 
study staff counts and verifies that the shipment contains all the items noted in the shipping 
invoice. Any discrepancies, damaged or unusable study drug in a given shipment (active drug or 
comparator) will be documented in the study files. The sponsor-investigator must be notified 
immediately of any discrepancies, damaged or unusable products that are received. 
5.8.2 Storage 
Mirena (levonorgestrel-releasing intrauterine system) 
Store at 25°C (77°F); with excursions permitted between 15–30°C (59–86°F) [see USP 
Controlled Room Temperature]. 
 
Tranexamic acid tablets 
Store at room temperature 25° C (77° F); excursions permitted to 15-30° C (59-86° F). [See USP 
Controlled Room Temperature]. 
 
All study drugs will be dispensed from the Mayo Clinic Outpatient Research Pharmacy.  The 
drugs will be stored in a secure location according to product storage guidelines.  
5.8.3 Dispensing of Study Drug 
 
Investigational product will be dispensed by Mayo Clinic Outpatient Research Pharmacy per 
standard methods. 
 
Regular study drug reconciliation will be performed to document drug assigned, drug dispensed, 
drug returns, and drug remaining.  This reconciliation will be logged on the drug reconciliation 
form, and signed and dated by the study team. 
5.8.4 Return or Destruction of Study Drug 
Tranexamic acid and Mirena (levonorgestrel-releasing intrauterine system) 
 
At the completion of the study, there will be a final reconciliation of drug shipped, drug 
dispensed, drug returns, and drug remaining.  This reconciliation will be logged on the drug 
reconciliation form, signed and dated.  Any discrepancies noted will be documented and 

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investigated, prior to return or destruction of unused study drug.  Drug destroyed on site will be 
documented in the study files. 
 
 
6 Study Procedures 
1Will only be performed if the ultrasound is not done for clinical purposes or no pelvic imaging (Saline 
infused sonogram, ultrasound, MRI) has been performed for more than 1 year before enrollment 
2Will be performed if CBC, ferritin were not done for clinical purposes in the 3 months before enrollment 
3Patients without renal disease can have creatinine pending at the time of enrollment, but will be 
withdrawn if result is >=1.4. Creatinine will not be drawn for the observation cohort unless clinically 
indicated at the time of initiation of treatment. 
4If enrolled in the LNG-IUS arm of the randomized cohort. 
5Will be performed 4-6 weeks after placement of LNG-IUS for confirmation of IUS location 
6Or at withdrawal from or termination of the study 
6.1 
Visit 1/ Enrollment 
The screening examination will include any screening elements not already completed during 
clinical evaluation (uterine sounding length, estimation of uterine size by bimanual examination, 
and review of imaging) or completed more than 6 months prior to enrollment. At this visit, subjects 
Table 1.  
 
Enrollment 
4-6 Week Visit 
(Levornorgestrel 
IUS visit) 
 
3 mo 
 
6 mo 
 
9 
mo6 
Study visit 
X 
 
 
 
X 
Informed Consent 
X 
 
 
 
 
Phone follow-up 
 
 
X 
X 
 
Demographic and medical questionnaire 
X 
 
 
 
 
Rand Short Form-36 
X 
 
X 
X 
X 
UFS-QOL 
X 
 
X 
X 
X 
MMAS 
X 
 
X 
X 
X 
PBLAC (for each menses during the 9 mo.) 
X 
 
X 
X 
X 
Visual analogue scale (VAS) for Pain 
X 
 
X 
X 
X 
Adverse events 
 
 
X 
X 
X 
Request for relevant medical records 
X 
 
 
 
X 
Medical records review 
X 
 
 
 
X 
Ultrasound imaging 
X1 
 
 
 
X 
Screening examination (uterine sounding 
length, estimation of uterine size by 
bimanual examination, and review of 
imaging) 
X 
 
 
 
 
Phlebotomy– CBC2, ferritin2  
X 
 
 
 
X 
Phlebotomy– creatinine3 
X 
 
 
 
 
Study remuneration  
 
 
 
 
X 
Pregnancy test (urine) – if needed 
X 
 
 
 
 
History and Physical 
X 
 
 
 
X 
 Ultrasound to confirm placement of 
levonorgestrel IUS 
X4 
 
 
 
 
Levonorgestrel IUS visit  
 
X5 
 
 
 

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will complete the questionnaires listed in the table and have laboratory testing completed. 
Pregnancy test will be performed for those at risk for pregnancy. If patients are current users of 
hormonal treatments for uterine bleeding and wish to enroll, they can be screened for the study. If 
eligible for the randomized cohort, they will need to complete a 1 month washout period with no 
hormone use and with natural resumption of their menses before they can be randomized to 
treatment. If they are current users of hormonal treatments and are switched to TA or LNG-IUS 
(with discontinuation of other hormonal treatments), they are eligible for the observation arm 
without washout. If enrolled in the LNG-IUS arm, ultrasound will be performed following 
placement to ensure the correct position of the LNG-IUS.  If the LNG-IUS is not in the optimal 
position, it will be removed and a new device inserted immediately.  
 
6.2 
Week 4-6 Visit (For women enrolled in the LNG-IUS arm) 
For women enrolled in the LNG-IUS arm, a visit will be scheduled at 4-6 weeks after placement 
to check for IUS strings visible at the cervix. This will serve as confirmation of position of IUS. If 
strings are not visible, clinical evaluation will be performed including pelvic ultrasound and/or x-
ray to confirm location of IUS or expulsion. 
6.3 
Visit 2 / Month 3 
At month 3, subjects will complete questionnaires listed in the table and receive a phone call to 
screen for adverse events. LNG-IUS that are expelled may be replaced one time if patient desires 
to continue device and the expulsion occurred within the prior 7 days. The expulsion occurred 
within one week and. Patient outcome would be recorded as expulsion.  
 
6.4 
Visit 3 / Month 6 
At month 6, subjects will complete questionnaires listed in the table and receive a phone call to 
screen for adverse events.  
 
6.5 
Visit 4 / Month 9 
At month 9, subjects will return for a study visit and examination. Ultrasound will be performed 
for size of fibroids. Laboratory testing will be completed. Subjects will complete questionnaires 
listed in the table and screen for adverse events and finalize study participation. Participants 
assigned to the LNG-IUS arm will be carefully assessed to determine if there are any 
contraindications to continuing therapy. Those with cavity-distorting fibroids (Type I) will be 
counseled regarding removal of the LNG-IUS. 
 
 
7 Statistical Plan 
7.1 
Sample Size Determination 
Aim 1. The primary outcome variable will be the difference in MMAS score at 6 months 
between the treatment arms. Based on the ECCLIPSE trial, the observed effect size at 6 months 
for the MMAS total score was 0.58 standard deviations (8). In order for the proposed trial to 

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have 90% power to detect such a difference, we would need 64 patients per treatment arm. To 
allow for up to 20% loss to follow-up or incomplete data without the potential to carry-forward 
an MMAS score from an earlier assessment, we will enroll 80 patients per treatment arm.  
From our preliminary study of a large insurance-claims database, we found a 40% difference 
(62% vs. 22%) in continued use of the index medication at 6 months. Based on the sample size 
of 80 women per arm, we will have over 90% power to detect such a difference if it exists in the 
data from the proposed trial. These calculations are based on a two-sample t-test and chi-square 
test, respectively, assuming a type I error of 0.05 and a two-sided alternative hypothesis. 
 
Aim 2. As described in Aim 1, we plan to enroll 80 patients in each treatment arm. Among these 
160 patients, we anticipate that at least 80 patients will have intentionally discontinued treatment 
by the end of the study. Table 3 below summarizes the detectable hazard ratios for different 
factor scenarios with varying prevalence. Assuming that 50% of the study participants will have 
a BMI > 30 kg/m2, this aim will have 80% power to detect an association between obesity and 
intentional discontinuation.  
 
 
Table 2. Detectable hazard ratios with 
80% power based on a two-sided logrank 
test with a type I error of 0.05 
 
 
Prevalence  
of factor 
Among the 160 patients 
in both arms 
(assume 80  
intentionally 
discontinue) 
20% 
2.19 
30% 
1.98 
40% 
1.90 
50% 
1.88 
 
7.2 
Statistical Methods 
 
Descriptive Statistics 
Standard descriptive statistics will be generated for measurements at baseline, 3, 6, and 9 
months, including mean, median, standard deviation (SD), and interquartile range (IQR) for 
continuous variables and counts and percentages for categorical variables.  
 
Handling of Missing Data 
Last value carry forward (LVCF) methods will be investigated to accommodate drop-outs.  
 
Primary Hypothesis: A user-independent medical therapy (LNG-IUS) will result in better 
patient reported outcomes and longer use compared to self-administered medication (TXA) 
 
Statistical analysis: The distribution of each of the continuously scaled outcome measures 
(MMAS total score, PBLAC score, ferritin level, hemoglobin level, UFS-QOL scores, and Rand 

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SF-36 composite scores) will be graphically evaluated and logarithmic transformations will be 
applied if the distributions are skewed in order to obtain more normally distributed distributions. 
At 3, 6, and 9 months separately, each of the continuously scaled outcomes will be compared 
between treatment arms based on fitting separate linear regression models. In addition, separate 
analysis of covariance (ANOCOVA) models will be fit to compare the measures between the 
two treatment arms after adjusting for baseline levels. The cumulative incidence (CI)  function 
will be used to estimate the cumulative proportion of patients by time t who have intentionally 
discontinued treatment due to the desire or need to stop or switch treatment, after accounting for 
the competing risk of LNG-IUS expulsion and censoring all other participants at their date of last 
follow-up or end of study. Likewise we will also estimate the CI of expulsion among the LNG-
IUS treatment arm. The CI estimates for intentional discontinuation over the entire 9 months of 
follow-up will be compared between treatment arms using the methods developed by Gray (34).  
All analyses will be performed based on the intention to treat principle and calculated p-values 
will be based on two-sided hypothesis tests. P-values less than 0.05 will be considered 
statistically significant. Statistical analyses will be performed using the SAS version 9.4 software 
package and packages in R (Version 3.1.1). 
 
Secondary Hypothesis 1: Large fibroid size will limit the effectiveness of LNG-IUS compared 
with TXA; elevated BMI predicts higher success with LNG-IUS over TXA. 
 
Statistical analysis: The primary event of interest is unsuccessful medical therapy, defined as the 
intentional discontinuation of treatment due to the desire or need to stop or switch treatment. 
However, the analysis is complicated by the fact that women in the LNG-IUS have a competing 
cause of failure, namely expulsion. Since the covariates associated with intentional 
discontinuation of treatment may be different from those associated with expulsion it will be 
important to analyze expulsion as a competing risk (35). We will first explore the associations 
between the covariates of interest and the competing risks by fitting separate Fine-Gray models 
for each type of failure using the finegray function in the survival package in R. We will also 
utilize the mstate package in R to further explore these associations. We will also explore 
whether the factors associated with intentional discontinuation differ between the two treatment 
arms. 
7.3 
Subject Population(s) for Analysis 
We will analyze all women randomized into the study, regardless of whether they received the 
study medications as an intention to treat analysis. In addition, we will analyze women who 
received at least one dose of TXA or had insertion of LNG-IUS, even if there was immediate 
expulsion.  
8 Safety and Adverse Events 
Adverse events would include perforation or embedment of the LNG-IUS. Adverse events will 
be recorded during the study by study coordinators or personnel and resolution of the AE 
reported, in particular if that required a second surgical procedure to resolve. Allergic reaction to 
either LNG or TXA will be collected and reported to the IRB per protocol. Worsening anemia or 
need for blood transfusion would be considered a safety endpoint.  

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8.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria:  
• Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: (1) 
death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, or 
prolonged; (4) disability/incapacity - persistent or significant; (5) birth defect/anomaly; (6) 
breach of confidentiality and (7) other problems, events, or new information (i.e. 
publications, DSMB reports, interim findings, product labeling change) that in the opinion 
of the local investigator may adversely affect the rights, safety, or welfare of the subjects 
or others, or substantially compromise the research data, AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
• Related: A problem or event is "related" if it is possibly related to the research procedures. 
 
Adverse Event 
An untoward or undesirable experience associated with the use of a medical product (i.e. drug, 
device, biologic) in a patient or research subject. 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  Serious problems/events can be well 
defined and include; 
• death 
• life threatening adverse experience 
• hospitalization 
• inpatient, new, or prolonged; disability/incapacity 
• surgical intervention for complications 
• ectopic pregnancy 
• Pelvic inflammatory disease 
• Venous thromboembolism 
 
and/or per protocol may be problems/events that in the opinion of the sponsor-investigator 
may have adversely affected the rights, safety, or welfare of the subjects or others, or 
substantially compromised the research data. 
 
All adverse events that do not meet any of the criteria for serious, should be regarded as non-
serious adverse events.  
 
Adverse Event Reporting Period 
 

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For this study, the study treatment follow-up period is defined as 9 months after enrollment. 
Events occurring after this visit will be managed clinically. For women with a contraindication to 
LNG-IUS (e.g. a type I fibroid), we will recommend removal of the LNG-IUS at the 9-month 
visit to reduce risks.   
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the sponsor-investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the sponsor-investigator should instruct each subject to report, to the sponsor-
investigator, any subsequent event(s) that the subject, or the subject’s personal physician, 
believes might reasonably be related to participation in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if hemoglobin were 
to drop below 8.0 g/dL during treatment for HMB.  
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol.  Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for an adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances:  
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition.  Surgery should not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
 
8.2 
Recording of Adverse Events 
At each contact with the subject, the study team must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 

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event section of the case report form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic, laboratory or procedure results should recorded in the source document. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been ultimately 
determined that the study treatment or participation is not the probable cause.  Serious adverse 
events that are still ongoing at the end of the study period must be followed up, to determine the 
final outcome.  Any serious adverse event that occurs after the study period and is considered to 
be at least possibly related to the study treatment or study participation should be recorded and 
reported immediately. 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
When an adverse event has been identified, the study team will take appropriate action necessary 
to protect the study participant and then complete the Study Adverse Event Worksheet and log.  
The sponsor-investigator will evaluate the event and determine the necessary follow-up and 
reporting required. 
 
8.3.1 Sponsor-Investigator reporting: notifying the Mayo IRB 
The sponsor-investigator will report to the Mayo IRB any UPIRTSOs and Non-UPIRTSOs 
according to the Mayo IRB Policy and Procedures. 
 
8.3.2 Sponsor-Investigator reporting: Notifying the FDA 
AEs that meet the criteria of serious, related to study drug, and unexpected as determined by the 
PI, qualify for reporting to the regulatory authorities (FDA). The Principal Investigator will 
assess all SAE’s occurring during the study and evaluate for “unexpectedness” and relationship 
to study drug. The PI should complete and submit a voluntary MedWatch Report for events 
determined to meet the criteria as serious, study drug related and unexpected to: 
https://www.accessdata.fda.gov/scripts/medwatch/. 
8.4 
Stopping Rules  
Adverse events and serious adverse events, as defined in Section 8, will be monitored by the study 
team for patient safety. The study team will review the adverse events and determine if there is 
significant difference of adverse events and SAEs between the 2 arms. Review will occur 
frequently and summary of findings will be documented. If there is a clinically and statistically 
significant difference in adverse event and SAEs, the study team will consider placing the project 
on hold. IRB will be notified through the IRB electronic system if the study is placed on hold. 
The study team will formulate an appropriate plan of action to ensure patient safety. Such a plan 
may include, but is not limited to, protocol modifications, immediate termination of accrual, 
adjustments in management of previously enrolled participants continuing to undergo study 
interventions. 

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8.5 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see section 10  “Study Monitoring, Auditing, and Inspecting”).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
8.5.1 Internal Data and Safety Monitoring Plan 
We will utilize the Mayo Clinic Department of Surgery Data Safety Monitoring Board (DSMB) 
for oversight of the study. Adverse events (AE) will be monitored by the study team, who has 
primary responsibility for attribution of the AE to the study.  Events that prompt the activation of 
the protocol-specific stopping rules will be reviewed by the study team, during which time study 
accrual may be halted. The team will formulate a plan of action to ensure patient safety and 
forward the plan to the DSMB. The DSMB will review the action plan and recommend approval 
or provide recommendations to the IRB. A summary of all AEs will be provided to the DSMB 
for review and on-going study approval.   
9 Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (long term survival status that 
the subject is alive) at the end of their scheduled study period. 
9.2 
Source Documents 
We will keep all of the source data including original records of clinical findings, observations, 
or other activities in the trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 

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9.3 
Case Report Forms 
We will use a study case report form (CRF) as the primary data collection instrument for the 
study.  All data requested on the CRF will be recorded and all missing data explained.  All 
entries will be printed legibly in black ink.  If any entry error has been made, to correct such an 
error, we will draw a single straight line through the incorrect entry and enter the correct data 
above it.  All such changes will be initialed and dated.  We will not erase or use “white-out” for 
errors.  For clarification of illegible or uncertain entries, we will print the clarification above the 
item, then initial and date it.  If the reason for the correction is not clear or needs additional 
explanation, we will include the details to justify the correction. 
 
Data Management 
We will use the electronic database REDCap to collect and store study-related data including 
study case report forms. REDCap is password protected and can be used to export the data to a 
statistical analysis program such as SAS.  
 
Data Processing 
Data will be maintained by the small study staff from the data entry into the REDCap system 
through the analysis in SAS by our statisticians. 
 
Data Security and Confidentiality 
 
All patient information will be de-identified and kept in secure locations where only authorized 
study personnel can have access. All computers are password protected and secured behind 
institution firewall. Case report forms will be maintained, in a secure location within the 
institution campus. 
 
Data Quality Assurance and Clarification Process 
 
Data will be entered by trained personnel with randomly-selected double entry to evaluate data 
for errors. Validated fields of entry will ensure data ranges are appropriate. Any data queries will 
be adjudicated by study personnel after review of the original data form.   
9.4 
Records Retention 
The sponsor-investigator will maintain records and essential documents related to the conduct of 
the study.  These will include subject case histories and regulatory documents. 
 
The sponsor-investigator will retain the specified records and reports for the longer of the 
following: 
1. Up to 2 years after the marketing application is approved for the drug; or, if a marketing 
application is not submitted or approved for the drug, until 2 years after shipment and 
delivery of the drug for investigational use is discontinued and the FDA has been so 
notified. OR 
2. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy” http://mayocontent.mayo.edu/research-policy/MSS_669717   
 

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10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
 
The investigator will allocate adequate time for such monitoring activities.  The Investigator will 
also ensure that the monitor or other compliance or quality assurance reviewer is given access to 
all the study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.), and has adequate space to conduct the monitoring visit. 
 
As a service to the sponsor-investigator, this study may be monitored during the conduct of the 
trial by staff from the Mayo Clinic Office of Research Regulatory Support.  Clinical trial 
monitoring may include review of the study documents and data generated throughout the 
duration of the study to help ensure the validity and integrity of the data along with the 
protection of human research subjects.  This will assist sponsor-investigators in complying with 
Food and Drug Administration regulations. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, and government regulatory agencies, of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.).  The investigator 
will ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
11 Ethical Considerations 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study.  The decision of the IRB concerning the conduct of the study will be made in writing to 
the sponsor-investigator before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the Approved IRB consent form, must be 
obtained before that subject undergoes any study procedure.  The consent form must be signed 
by the subject or the subject’s legally authorized representative, and the individual obtaining the 
informed consent.  

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12 Study Finances 
12.1 Funding Source 
The study will be funded through a grant from the National Institutes of Health.  
12.2 Subject Stipends or Payments 
Participants will be provided with $50 remuneration at the end of the study as well as parking 
passes for study-related visits.  
13 Publication Plan 
We plan on publishing the results of the study in a peer-reviewed journal in OB/GYN specialty. 
We will register our trial with ClinicalTrials.gov prior to recruitment and enrollment of the first 
patient.  
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