A Phase 3, Multicenter, Open-Label Study of a Levonorgestrel 52 mg Intrauterine System for the Treatment of Heavy Menstrual Bleeding
Phase: PHASE3
Conditions: Menorrhagia
Sponsor: Medicines360

 
Version 4.0 
CONFIDENTIAL 
 
TITLE PAGE 
Title: 
A Phase 3, Multicenter, Open-Label Study of a 
Levonorgestrel 52 mg Intrauterine System for the 
Treatment of Heavy Menstrual Bleeding 
Test Product: 
LNG20 IUS (levonorgestrel-releasing intrauterine system)  
IND 
105,836 
Indication 
For the treatment of heavy menstrual bleeding 
Protocol Number: 
M360-L105 
Investigators 
Multicenter 
Development Phase: 
Phase 3 
Study Design: 
Open-Label 
Sponsor: 
Medicines360 
Sponsor’s Medical Officer: 
 
Protocol Date: 
05 February 2020 
Version Number:  
Version 4.0  
Replaces version 3.0 dated 01 November 2018 
CONFIDENTIAL STATEMENT 
This document contains proprietary and confidential information of Medicines360.  Acceptance of this document 
constitutes agreement by the recipient that no previously unpublished information contained herein will be 
published or disclosed without the prior written approval of Medicines360 with the exception that this document 
may be disclosed to study personnel under your supervision who need to know the contents for conducting the 
study and appropriate Institutional Review Boards (IRBs), Research Ethics Boards (REBs), and Ethics 
Committees (ECs) under the condition that the personnel have agreed to keep this information confidential. The 
foregoing shall not apply to disclosure required by governmental regulations or laws; however, Medicines360 
shall be promptly notified of any such disclosure. 
 
 

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PROTOCOL SYNOPSIS 
Study Title 
A Phase 3, Multicenter, Open-Label Study of a Levonorgestrel 52 mg 
Intrauterine System for the Treatment of Heavy Menstrual Bleeding 
Short Title 
LNG20 IUS Phase 3 study for heavy menstrual bleeding 
Study Sponsor 
Medicines360 
Protocol Number 
M360-L105 
Study Phase 
3 
Study Objectives 
Primary objective:  Assess the efficacy of a levonorgestrel 52 mg 
intrauterine system (LNG20 IUS) as a treatment for heavy menstrual 
bleeding. 
Secondary objectives: Assess safety, tolerability, bleeding patterns, and 
continuation rates of LNG20 IUS in women using LNG20 IUS for heavy 
menstrual bleeding. 
Planned Study 
Dates 
Start of study/recruitment:  October 2018 
End of recruitment:  December 2020 
End of study treatment:  July 2021 
End of post-treatment follow-up:  August 2021 
Number of 
Investigative Sites 
Approximately 30 sites in the U.S. 
Number of 
Subjects Planned 
Approximately 100 women between the ages of 18 and 50 years, inclusive, 
who request treatment for heavy menstrual bleeding, provide consent, and 
satisfy entry criteria will be enrolled for treatment.   
Study Design 
The study is a multicenter, open-label, evaluation of the efficacy and safety 
of LNG20 IUS for treatment of heavy menstrual bleeding.   
After consent is obtained, screening procedures will be performed and 
eligible subjects enrolled into the trial.  The Screening Phase will include 
up to four visits (Visits 1 to 4) to evaluate menstrual blood loss (MBL) in 

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up to three cycles to establish a diagnosis of heavy menstrual bleeding 
(MBL≥ 80 mL/cycle for two of three cycles) and confirm eligibility.  
Subjects will receive standardized feminine hygiene products and detailed 
instructions on how to record daily vaginal bleeding in a diary.   
Visit 1 will include consent and initial screening activities. Visits 2, 3 and 
4 (if needed) will occur approximately monthly (ideally within 5 days of 
end of menses) to collect feminine hygiene products. The products will be 
evaluated using the alkaline hematin (AH) method to evaluate MBL. 
Subjects who have qualifying MBL in at least two of three screening 
cycles and who meet all other eligibility requirements may enter the six-
month Treatment Phase (Visits 5 to 8). If the qualifying MBL occurs in 
the first two screening cycles, a third cycle and Visit 4 will not occur. 
The Enrollment Visit (Visit 5) is when IUS placement occurs.  The study 
IUS will be inserted by a study Investigator using a standardized insertion 
procedure.  
Subjects will be evaluated during study treatment use for up to 
approximately 6 months.  Study assessments will be performed at a clinic 
visit at Treatment Phase Month 1 (Visit 6), and at the end of Cycle 3 (Visit 
7) and Cycle 6 (Visit 8/study exit).  The IUS will be removed when 
requested or when clinically indicated; if the IUS is removed before Cycle 6, 
Visit 8/study exit procedures will be completed at the visit for removal. At 
the end of the 6 cycle Treatment Phase, unless medically contraindicated, 
study participants may opt to either keep the IUS or have it removed by a 
study investigator.   
All subjects who have the IUS removed during the study will be contacted 7 
to 10 days after the study exit visit to assess bleeding and cramping after 
removal and any IUS-related or IUS procedure-related adverse events.  After 
completion of the Treatment Phase, all subjects with ongoing IUS-related 
adverse events that are not resolved or stabilized will have monthly contacts 
or visits, as appropriate, until the event is resolved or stabilized.   

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Routine safety monitoring (adverse event assessments and vital signs) will 
be conducted for all subjects at all protocol study visits.   
Investigational 
Drugs: 
A levonorgestrel 52 mg IUS (LNG20 IUS, marketed in the U.S. as Liletta®) 
with an initial levonorgestrel release rate of approximately 20 mcg/day will 
be evaluated.  There will be no comparator. 
Dosing Regimen: 
A study Investigator will insert a LNG20 IUS into the uterus using 
standardized procedures in subjects who qualify after screening and 
desire to enroll. 
The IUS may be removed at any time if requested by the subject or 
judged necessary by the Investigator. 
Subjects who experience IUS expulsion (partial or complete) may have 
another study IUS inserted; only one replacement IUS is allowed per 
subject. Replacement can occur only if all of the following conditions are 
met: 
• Reinsertion occurs no more than 14 days after the expulsion; 
• Reinsertion occurs at least 7 days prior to treatment Cycle 3 or 
Cycle 6; 
• Reinsertion cannot occur during treatment Cycle 3 or Cycle 6; 
• Pregnancy can reasonably be excluded. 
An IUS removed during the study will not be replaced with a new LNG20 
IUS except when the IUS is removed because of incorrect IUS placement 
at the enrollment visit (first attempt only) or within two weeks of an 
expulsion (complete or partial) during the Treatment Phase. 
Primary Outcome 
Measure: 
The proportion of subjects with successful treatment, defined as: 
• End of Treatment MBL < 80 mL, and 
• End of Treatment MBL 50% or less than baseline 
Baseline MBL is the MBL averaged over each of the cycles measured 
during the Screening Phase.  End of Treatment MBL is the MBL during 

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the sixth 28-day cycle after initial LNG20 IUS insertion. This outcome 
will be established in the Modified-Intent-To-Treat (MITT) population.   
Key Secondary 
Outcome 
Measures: 
Key secondary outcome measures will be: 
• Absolute change from baseline MBL to mid-treatment MBL (Cycle 3) 
• Percent change from baseline MBL to mid-treatment MBL (Cycle 3) 
• Absolute change from baseline MBL to end of treatment MBL (Cycle 
6) 
• Percent change from baseline MBL to end of treatment MBL (Cycle 6) 
• Changes from baseline to mid-treatment (Cycle 3), from mid-treatment 
(Cycle 3) to end of treatment (Cycle 6) and from baseline to end of 
treatment (Cycle 6) in the number of days of bleeding, spotting, 
bleeding and spotting, and number of bleeding episodes per cycle 
Other Secondary 
Outcome 
Measures: 
Other secondary outcomes that will be assessed for all subjects will include: 
• Percent change in hemoglobin, hematocrit and serum ferritin from 
baseline to mid-treatment (Visit 7), from baseline to end of treatment 
(Visit 8) and from mid-treatment (Visit 7) to end of treatment (Visit 8)  
• Continuation rate during Treatment Phase 
• Subjective assessment of menstrual bleeding changes 
• Adverse events 
Duration of 
Subject 
Participation: 
Up to approximately 12 months (up to 5 months screening, 6 months 
treatment, 1 month follow-up) 
Duration of Study 
Center 
Participation: 
Approximately 3.5 years (assuming 4 months for study start-up activities, 
an enrollment period of 24 months, up to 12 months subject participation 
followed by 4 months for study site close-out)  

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Eligibility 
Criteria: 
 
Subjects must fulfill all of the following criteria to be eligible for study 
enrollment (Treatment Phase): 
Inclusion Criteria 
1. Signed informed consent 
2. Reports subjectively heavy menses for most menses when not 
using hormonal contraception or a copper IUD 
3. Healthy females 18-50 years old, inclusive, at the time of 
enrollment  
4. Able to read and write, as determined by study personnel 
5. FSH value ≤30 mIU/mL at screening 
6. Typical menstrual cycle length of 21-35 days with variation from 
cycle to cycle of typically 5 days or less 
7. Has menstrual blood loss in 2 of the 3 cycles during the Screening 
Phase with ≥ 80 mL per cycle as measured by the AH method 
8. Uterine sound depth of ≥5.5 cm 
9. Willing to comply with study visit schedule and assessments, 
including sanitary product collection and diary completion 
requirements 
10. Documented (i.e., printed report) Pap testing, regardless of 
subject’s age, and any indicated evaluation/treatment that 
demonstrates no need for further evaluation during the course of 
study participation (i.e., within 10 months after consent)  
11. Planning to reside within a reasonable driving distance of a 
research site (approximately 150 miles) for duration of study 
participation 
12. Willing to use a medication other than a NSAID as first-line 
treatment for any pain condition during the duration of study 
participation 
13. Willing to abstain from heterosexual intercourse or use acceptable 
contraception during the screening phase; acceptable 

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contraception includes male or female permanent contraception, 
withdrawal (if has been using as current method prior to 
screening) or a barrier method 
14. If previously pregnant, at least one subjectively heavy menses 
prior to screening 
Exclusion Criteria 
1. Currently pregnant  
2. Planning to attempt to become pregnant during the screening and 
treatment phases of study participation (i.e., up to approximately 
11 months after consent) 
3. Currently lactating or not having a subjectively heavy menses 
since discontinuation of lactation prior to screening 
4. Clinical diagnosis of perimenopause (in the opinion of the 
investigator) based on one or more of the following: changes in 
menstrual regularity (e.g., shorter, longer, absent, irregular), hot 
flashes, sleeping disorder, or changes in mood (e.g., depression, 
nervous tension, and irritability) within 3 months prior to or 
during the screening period 
5. Screening blood laboratory value outside of the normal range that, 
in the opinion of the investigator, requires treatment or further 
work-up (i.e., are considered clinically significant) 
6. Has poor venous access or significant history of inability to have 
blood samples drawn 
7. Body habitus or history of lower genital tract abnormalities or 
prior surgeries which may prohibit proper visualization of the 
cervix or not allow the uterus to be appropriately instrumented 
8. History of bicornuate uterus or any other abnormality of the uterus 
resulting in distortion of the uterine cavity or cervical canal 
incompatible with insertion 

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9. Prior (documented within 6 months) or baseline study ultrasound 
examination demonstrating: 
a. A congenital or acquired uterine anomaly that distorts the 
uterine cavity or cervical canal incompatible with 
insertion; 
b. Endometrial polyps (unless previously removed),  
c. Fibroids meeting any of the following criteria: 
i. Distort the uterine cavity or cervical canal 
incompatible with insertion; 
ii. Submucosal location; 
iii. Exceeding 2 cm in the greatest dimension for any 
individual fibroid; 
iv. More than three fibroids of at least 1.5 cm in 
greatest diameter 
d. Clear evidence of adenomyosis consisting of any of the 
following: 
i. Subendometrial cysts 
ii. Diffuse adenomyosis based on a heterogeneous 
myometrial echotexture consisting of:  
1. Hyperechoic findings (islands of 
endometrial glands); 
2. Hypoechoic findings (associated muscle 
hypertrophy); 
3. "Venetian blind" appearance due to 
subendometrial echogenic linear striations 
and acoustic shadowing where endometrial 
tissues cause a hyperplastic reaction 
10. Recently diagnosed or clinically evident cervicitis or upper genital 
tract infection at the time of IUS insertion (unless successfully 

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treated and considered clinically cured for at least 7 days prior to 
enrollment)  
11. History of pelvic actinomycosis infection (i.e., received antibiotic 
treatment; criterion does not include solely a history of Pap test 
with actinomyces) 
12. Postpartum or post-abortion endometritis unless symptoms 
resolved at least 4 weeks prior to screening 
13. Chronic endometritis on endometrial biopsy at screening (an 
endometrial biopsy performed within 6 months of Visit 1 could be 
used if a report is available with a tissue diagnosis) 
14. Has any of the following premalignant or malignant diseases: 
a. Malignant melanoma  
b. Acute malignancies affecting blood or leukemias 
c. Gestational trophoblastic disease (unless at least one year 
with undetectable beta-hCG) 
d. Known or suspected cervical, ovarian, vaginal or vulvar 
cancer 
e. Uterine cancer or evidence of uterine malignancy, 
endometrial intraepithelial neoplasia (EIN) or hyperplasia 
on an endometrial biopsy at screening (an endometrial 
biopsy performed within 6 months of Visit 1 could be used 
if a report is available with a tissue diagnosis) 
f. History of breast cancer, or suspicion of breast cancer until 
proven otherwise 
15. Has any of the following medical conditions: 
a. Bleeding diathesis (inherited or acquired)  
b. History of von Willebrand’s disease or other known 
coagulopathy 

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c. Uncontrolled significant hypertension defined as a sitting 
systolic blood pressure ≥ 160 mm Hg or diastolic blood 
pressure ≥ 95 mm Hg at any screening or enrollment visit 
unless treated and controlled within two weeks of 
discovery 
d. Presence or history of venous thromboembolic diseases 
(deep vein thrombosis, pulmonary embolism), presence or 
history of arterial thromboembolic diseases (e.g., 
myocardial infarction, stroke) 
e. Uncontrolled thyroid disorder 
f. Sickle cell anemia 
g. Diabetes mellitus that is poorly controlled or with end-
organ/vascular complications 
h. Hyperprolactinemia at screening 
i. Acute or severe liver disease or liver tumor  
j. Poorly controlled bipolar disorder, schizophrenia, 
psychosis, major depressive disorder or other major 
psychiatric disorder according the criteria of the 
Diagnostic and Statistical Manual of Mental Disorders, 
Fourth Edition (DSM-5) 
k. History of a positive HIV test or having a partner who is 
known to be HIV positive 
l. Current or history of alcohol, illicit drug or prescription 
drug abuse within 12 months prior to screening 
16. Use of antifibrinolytics, platelet aggregation inhibitors, 
anticoagulants or other similar medications that can increase or 
decrease bleeding within 30 days prior to and during the screening 
(EXCEPTION: NSAIDs can be used as second-line treatment for 
pain management) 

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17. Use of intrauterine or implantable contraception, progestin-only 
pills, combined hormonal contraceptives or oral progestin therapy 
within 30 days before screening 
18. Depomedroxyprogesterone acetate (DMPA) injection within the 
past 9 months prior to screening (this exclusionary time period can 
be shortened to 6 months if the subject has also had two 
spontaneous menstrual cycles [requires minimum of 3 heavy 
menses] that meet criteria for normal menstrual cycle pattern) 
19. Use of non-contraceptive estrogen, progesterone, progestin, 
testosterone, androgen or other gonadotropins (e.g. hCG) within 
30 days before screening 
20. Prior total or partial endometrial ablation or resection 
21. History of a uterine aspiration or curettage procedure for any 
indication (other than an office biopsy) within 4 weeks of 
screening 
22. Known or suspected allergy to levonorgestrel or hypersensitivity 
to any component of the product 
23. Use of an experimental medication or receipt of an experimental 
treatment for any condition within 30 days of screening  
24. Study staff or a member of the immediate family of a study staff 
25. Any condition or circumstance that, in the opinion of the 
Investigator, would constitute contraindications to participation in 
the study or would compromise ability to comply with the study 
protocol, such as any concurrent medical condition that is not 
stable and well-controlled, that is likely to worsen, or that may 
require recurrent hospitalizations during study participation  
Statistical 
Methods: 
The following analysis populations will be created: 
• Safety (Safety):  All subjects enrolled who underwent the IUS 
insertion procedure, regardless of outcome. 

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• Modified-Intent-To-Treat (MITT): Those subjects with successful 
IUS placement followed by at least one MBL assessment. 
• Per Protocol (PP):  A subset of the MITT population that excludes 
subjects with major protocol deviations (to be identified prior to 
data lock). 
Each treatment cycle will be considered as a 28-day interval with the day 
of IUS placement as day 1.   
The primary efficacy analysis of successful treatment rate will be 
analyzed with 95% confidence interval for subjects in the MITT 
population. A point estimate of 80% or higher successful treatment rate 
with a lower bound of 70% or higher will establish the efficacy of LNG20 
IUS for the treatment of heavy menstrual bleeding in the study.   
All other secondary endpoint analyses will be descriptive. 
All treatment emergent adverse event data will be presented by MedDRA 
system organ class, preferred term and treatment group.  Quantitative 
safety variables (e.g., vital signs) will be summarized at each visit and by 
changes from baseline.   
Sample Size: 
Approximately 100 women will be enrolled into the study treatment 
phase with the goal that 85 women will complete the study to achieve the 
lower bound 70% or higher of a two-sided 95% confidence interval for an 
anticipated successful treatment rate 80% or higher.     

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TABLE OF CONTENTS  
TITLE PAGE 1 
SIGNATURE PAGE ...........................................................................................................2 
PROTOCOL SYNOPSIS ....................................................................................................3 
TABLE OF CONTENTS ...................................................................................................14 
ABBREVIATIONS AND DEFINITIONS ........................................................................20 
1. 
INTRODUCTION .................................................................................................22 
 
STUDY OBJECTIVES ..........................................................................................24 
2.1 
Primary Objective ......................................................................................24 
2.2 
Secondary Objectives.................................................................................25 
 
INVESTIGATIONAL PLAN ................................................................................25 
3.1 
Outcome Measures.....................................................................................28 
3.1.1 
Primary Outcome Measure ......................................................28 
3.1.2 
Key Secondary Outcome Measures .........................................28 
3.1.3 
Other Secondary Outcome Measures.......................................29 
 
STUDY POPULATION SELECTION .................................................................29 
4.1 
Subject Selection ........................................................................................29 
4.2 
Inclusion Criteria .......................................................................................29 
4.3 
Exclusion Criteria ......................................................................................30 
 
STUDY TREATMENT .........................................................................................34 
5.1 
LNG20 IUS (Dosage and Formulation) .....................................................34 
5.2 
IUS Supply and Administration .................................................................34 
5.3 
IUS Storage and Accountability ................................................................34 
5.4 
IUS Replacement .......................................................................................35 
5.5 
Concomitant and Excluded Therapy ..........................................................35 
5.6 
Blinding......................................................................................................36 
 
STUDY PROCEDURES .......................................................................................36 
6.1 
Alkaline Hematin Menstrual Blood Loss Assessment...............................37 

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6.2 
Feminine Hygiene Products .......................................................................37 
6.3 
Clinical Laboratory Tests ...........................................................................37 
6.4 
Screening Transvaginal Ultrasonography ..................................................38 
6.5 
Subjective Assessment of Menstrual Bleeding ..........................................38 
6.6 
IUS Insertion Definitions ...........................................................................38 
6.7 
Screening....................................................................................................39 
6.7.1 
Screening Phase Procedures ....................................................39 
6.7.2 
Screening Visit 1 ......................................................................39 
6.7.2.1 
Part A: Review of medical history ...........................................40 
6.7.2.2 
Part B: Urine pregnancy testing ...............................................40 
6.7.2.3 
Part C: Blood tests ...................................................................40 
6.7.2.4 
Part D: Initial exam ..................................................................41 
6.7.2.5 
Part E: Pelvic assessments .......................................................41 
6.7.2.6 
Part F: Screening Visit 1 completion .......................................42 
6.7.3 
Screening Phase Cycle Assessment Visits:..............................42 
6.7.3.1 
Overview ..................................................................................42 
6.7.3.2 
Between Screening Visits 1 and 2 (Review of any pending test 
results): .....................................................................................43 
6.7.3.3 
Screening Visit 2 (Screening Cycle 1 MBL Collection) .........43 
6.7.3.4 
Between Screening Visits 2 and 3 (Review of Cycle 1 AH results)
..................................................................................................45 
6.7.3.5 
Visit 3 (Screening Cycle 2 MBL Collection) ..........................45 
6.7.3.6 
Between Screening Visits 3 and 4 (Review of Cycle 2 AH results)
..................................................................................................46 
6.7.3.7 
Visit 4 (Screening Cycle 3 MBL Collection) – if necessary ...47 
6.7.3.8 
Between Screening Visit 4 and Enrollment Visit 5 (Review of 
Cycle 3 AH results) ..................................................................48 
6.8 
Treatment Phase Enrollment Visit (Visit 5)...............................................49 
6.8.1 
Enrollment visit (insertion) scheduling ....................................49 

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6.8.2 
Enrollment Procedures .............................................................49 
6.9 
Treatment Phase Visits and Contacts .........................................................51 
6.9.1 
Visit 6 .......................................................................................51 
6.9.2 
Contact Day 50 to Day 56 ........................................................52 
6.9.3 
Visit 7 (Cycle 3) .......................................................................53 
6.9.4 
Contact Day 133 to Day 140 ....................................................54 
6.10 
Study Treatment Phase Completion/Early Discontinuation (Visit 8) ........54 
6.11 
Safety Follow-Up .......................................................................................56 
6.12 
Unscheduled Visits ....................................................................................56 
6.13 
Diagnostic Ultrasound Examinations ........................................................56 
6.14 
Pap Testing.................................................................................................57 
6.15 
Management of Abnormal Testing During the Study................................57 
6.16 
Management of Unevaluable Testing During the Study ............................57 
 
RISK-BENEFIT AND SAFETY ASSESSMENTS ..............................................57 
7.1 
Risk-Benefit ...............................................................................................57 
7.1.1 
Menstrual Changes...................................................................57 
7.1.2 
Contraception ...........................................................................59 
7.1.3 
Pregnancy .................................................................................60 
7.1.3.1 
Miscarriage ..............................................................................60 
7.1.3.2 
Ectopic Pregnancy ...................................................................61 
7.1.3.3 
Effects on gestation and offspring ...........................................61 
7.1.4 
Difficult Insertion/Removal .....................................................61 
7.1.5 
Expulsion .................................................................................62 
7.1.6 
Pelvic Infection ........................................................................62 
7.1.7 
Perforation................................................................................62 
7.1.8 
Pelvic/Abdominal Pain ............................................................62 
7.1.9 
Systemic Side Effects ..............................................................63 
7.1.10 
Mortality ..................................................................................63 

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7.1.11 
Missing Strings ........................................................................63 
7.1.12 
Phlebotomy ..............................................................................63 
7.1.13 
Pelvic Examination ..................................................................63 
7.1.14 
Endometrial Biopsy .................................................................64 
7.1.15 
Vaginal Ultrasound ..................................................................64 
7.1.16 
Local Anesthesia ......................................................................64 
7.1.17 
Emotional Discomfort ..............................................................64 
7.2 
Overall Assessment of Benefits and Risks ................................................64 
7.3 
General Plan to Manage Safety ..................................................................64 
7.4 
Pregnancy Assessment and Reporting .......................................................65 
7.5 
Adverse Events Assessments .....................................................................65 
7.6 
Definition of an Adverse Event .................................................................66 
7.7 
Definition of a Serious Adverse Event ......................................................67 
7.8 
Prompt Reporting of SAEs to Sponsor ......................................................68 
7.9 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events and Serious Adverse Events ............................................68 
7.10 
Reporting of Adverse Events .....................................................................69 
7.10.1 
Adverse Event CRFs ................................................................69 
7.10.2 
Causality Assessment: Adverse Event Relationship................70 
7.10.3 
Adverse Event Severity............................................................71 
7.10.4 
Adverse Event Outcome ..........................................................72 
7.11 
Clarification of Action Taken with IUS.....................................................72 
7.12 
Clarification of “Other Action Taken” ......................................................73 
7.13 
Clarification of Adverse Events Related to Study Procedures ..................73 
7.14 
Follow-up of Adverse Events and Serious Adverse Events ......................74 
7.15 
Clarification in Reporting of Deaths ..........................................................74 
7.16 
Post-Study Treatment Reporting Requirements ........................................74 
7.17 
Subject Withdrawal ....................................................................................75 
7.17.1 
Criteria for Withdrawal of Subject from Treatment ................75 

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7.17.2 
Withdrawal from the Study ......................................................75 
7.17.3 
Screen Failures .........................................................................76 
7.17.4 
Missed Visits/Contacts and Lost to Follow Up .......................76 
7.17.4.1 
During Screening .....................................................................76 
7.17.4.2 
After Enrollment ......................................................................77 
7.17.5 
Withdrawal of Consent ............................................................78 
 
DATA QUALITY CONTROL AND ASSURANCE ...........................................78 
 
PLANNED STATISTICAL METHODS ..............................................................78 
9.1 
Sample Size ................................................................................................79 
9.2 
Analysis Populations ..................................................................................79 
9.3 
Disposition of Subjects ..............................................................................80 
9.4 
Demographic and Other Subject Characteristics .......................................80 
9.5 
Extent of Exposure .....................................................................................80 
9.6 
Pre-trial and Concomitant Medications .....................................................80 
9.7 
Primary Outcome .......................................................................................80 
9.8 
Key Secondary Outcomes ..........................................................................81 
9.9 
Other Secondary Outcomes .......................................................................81 
9.10 
Study Stopping Rules Based on Safety ......................................................83 
 
ADMINISTRATIVE CONSIDERATIONS ..........................................................83 
10.1 
Ethical Considerations ...............................................................................83 
10.2 
Administrative Structure ............................................................................84 
10.3 
Responsibilities ..........................................................................................84 
10.3.1 
Good Clinical Practice .............................................................84 
10.3.2 
Institutional Review Board (IRB) Approval ............................84 
10.3.3 
Informed Consent.....................................................................85 
10.3.4 
Confidentiality .........................................................................85 
10.3.5 
Study Files and Retention of Records ......................................86 
10.3.6 
Case Report Forms and Record Maintenance ..........................87 

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10.3.7 
Drug Accountability.................................................................87 
10.3.8 
Inspections ...............................................................................88 
10.3.9 
Protocol Compliance ................................................................88 
10.3.10 
Study Report and Publications .................................................88 
10.3.11 
Investigator Responsibilities ....................................................89 
10.3.12 
Sponsor Responsibilities ..........................................................89 
10.3.13 
Protocol Modifications.............................................................89 
10.3.14 
Access to Information for Monitoring .....................................90 
10.3.15 
Financial Disclosure.................................................................90 
10.3.16 
Study Discontinuation ..............................................................90 
 
REFERENCES ......................................................................................................91 
 
APPENDIX A: SCHEDULE OF EVENTS SCREENING ...................................93 
 
APPENDIX B: SCHEDULE OF EVENTS ENROLLMENT AND FOLLOW-UP .
 ..................................................................................................................94 
 
APPENDIX C: PRE-SCREEN QUESTIONNAIRE .............................................95 
 
APPENDIX D: BASELINE VISUAL ANALOG SCALE QUESTIONS ............96 
 
APPENDIX E: 3-MONTH AND 6-MONTH VISUAL ANALOG SCALE 
QUESTIONS ............................................................................................98 
 
APPENDIX F: MANAGEMENT OF PREGNANCY ........................................100 
 
APPENDIX G: MANAGEMENT OF IUS ISSUES ...........................................103 
 
APPENDIX H: PROTOCOL SUMMARY OF CHANGES ...............................106 
 
 
 

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ABBREVIATIONS AND DEFINITIONS 
AE 
Adverse event 
AH 
Alkaline hematin 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
C 
Celsius 
CDC 
Centers for Disease Control 
CFR 
Code of Federal Regulations 
CHC 
Combined hormonal contraceptives 
CI 
Confidence interval 
cm 
Centimeter 
COC 
Combined oral contraceptive 
CRF 
Case Report Form 
dL 
Deciliter 
DMPA 
Depomedroxyprogesterone Acetate 
EDC 
Electronic data capture 
eCRF 
Electronic Case Report Form 
EIN 
Endometrial intraepithelial neoplasia 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
g 
Gram 
GCP 
Good Clinical Practice 
hCG 
Human chorionic gonadotropin 
Hg 
Mercury 
HIV 
Human immunodeficiency virus 
HMB 
Heavy menstrual bleeding 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 

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IND 
Investigational new drug 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
LNG 
Levonorgestrel 
LTFU 
Lost to Follow-Up 
MBL 
Menstrual blood loss 
mcg 
Microgram 
mg 
Milligram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mIU 
Milli-international Units 
MITT 
Modified-intent-to-treat 
mL 
Milliliter 
mm 
Millimeter 
MMAS 
Menorrhagia Multi-Attribute Scale 
NDA 
New drug application 
NSAID 
Nonsteroidal anti-inflammatory drug 
PID 
Pelvic inflammatory disease  
PP 
Per protocol 
PRL 
Prolactin 
SAE 
Serious adverse event 
STI 
Sexually transmitted infection 
TSH 
Thyroid stimulating hormone 
US 
United States 
VAS 
Visual Analog Scale 
vWF 
von Willebrand Factor 
WHO 
World Health Organization 

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1. 
INTRODUCTION 
Normal menstrual blood loss (MBL) ranges between 20 and 60 mL/cycle.  Heavy menstrual 
bleeding (HMB), formerly referred to as menorrhagia, is defined as excessive blood loss that 
occurs alone or in combination with other symptoms and has a negative impact on a 
woman’s physical, social, emotional, and material quality of life (Qiu et al., 2014). 
Approximately 30% of women are affected by HMB during their reproductive years, 
resulting in increased health costs (OHTAC, 2016). A variety of functional, structural, and 
non-structural conditions can cause HMB, including adenomyosis, leiomyomas, and 
coagulopathies as well as iatrogenic causes. In many women, the underlying cause of HMB 
is unknown and is referred to as functional HMB (Mawet et al., 2014). Heavy menstrual 
bleeding is commonly defined as MBL exceeding 80 mL of blood loss per cycle, although 
only about half of women who complain of HMB actually meet these criteria (Qiu et al., 
2014; Bahamondes et al., 2015). Clinical guidelines recognize that because HMB has a major 
impact on a woman’s quality of life, the diagnosis should be based on subjective measures 
rather than the objective measure of MBL (NCCWCH, 2007). However, the quantity of MBL 
is still important for predicting outcomes as iron depletion and anemia can occur when 
menstrual flow exceeds 60 and 120 mL, respectively (NCCWCH, 2007).  
Although hysterectomy is the preferred option for definitive treatment for women with HMB, 
medical management is always indicated first; hysterectomy, like any major surgical 
procedure, has potential significant complications and incurs social and economic costs, 
including incompatibility with a woman’s wish to remain fertile (Maybin and Critchley, 
2015, 2016; OHTAC, 2016). Endometrial ablation emerged as a more conservative surgical 
treatment for HMB in the 1990’s but still results in impaired fertility. Currently, reversible 
non-hormonal and hormonal medical treatments are available as first-line therapy for most 
women with HMB regardless of their desire for future fertility.   
Non-hormonal treatments for HMB include antifibrinolytics and non-steroidal anti-
inflammatory drugs (NSAIDs), which are off-label uses of these products in the U.S. Both 
antifibrinolytics and NSAIDs produce gastrointestinal side effects but only require dosing 
during periods of heavy menstrual flow. Tranexamic acid is an antifibrinolytic medication 

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that counteracts the degradation of fibrin clots that form to induce hemostasis during the 
menstrual phase. Nonsteroidal anti-inflammatory drugs inhibit cyclooxygenase and limit the 
production of inflammatory mediators that can lead to increased and prolonged tissue 
damage during menstruation (Maybin and Critchley, 2016).  
Hormonal treatments for HMB include oral or injectable progestins, combined hormonal 
contraceptives (CHCs) and intrauterine systems (IUSs).  CHCs decrease menstrual flow and 
reduced symptoms for women with HMB (Bahamondes et al., 2015). During the menstrual 
cycle, progesterone levels sharply decline in the absence of pregnancy and trigger an influx 
of inflammatory mediators into the endometrial environment, leading to shedding and 
menstruation. However, maintenance of progesterone levels, as with progestin-only therapies 
or contraceptives containing estrogen and progestin, limits endometrial inflammation and 
prevents menstruation, resulting in an effective HMB treatment (Maybin and Critchley, 
2016). CHCs are available as oral pills taken daily, vaginal rings used monthly, or patches 
changed weekly.  
In the early 1990s, the progestin-releasing IUS containing levonorgestrel (LNG) 52 mg 
emerged as an option for medical management of HMB. While combined oral 
contraceptives, NSAIDs, and antifibrinolytics can reduce MBL by 50% within a few cycles 
of treatment, a LNG 52 mg IUS can decrease menstrual loss by 71% within 6 months and up 
to 94% after 1 year.  Additionally, the LNG IUS can lead to greater improvement in women’s 
assessment of the effect of HMB on their daily routine and psychological and physical well-
being compared to usual medical treatment (Gupta et al., 2013; Qiu et al., 2014; Maybin and 
Critchley, 2016; Kaunitz et al., 2010). An IUS has the additional advantage of a “fit and 
forget” method that increases patient compliance. 
A substantial body of literature has demonstrated the efficacy of the LNG 52 mg IUS in the 
treatment of HMB, including idiopathic HMB, HMB associated with leiomyomas and 
adenomyosis, and abnormal uterine bleeding. In these studies, reductions in MBL, resolution 
of anemia, and improvements in health-related quality of life were noted. The LNG 52 mg 
IUS is considered a first-line treatment for HMB (Espey, 2013). Currently only one LNG 
IUS, Mirena®, is approved in the U.S. for HMB treatment in women who choose to use 
intrauterine contraception as their method of contraception (Mirena Package Insert). The 

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other approved LNG 52 mg IUS, LNG20 IUS (brand name Liletta®), is currently approved 
only for contraception in the U.S. although it is approved for HMB treatment in Europe and 
Africa (under the brand names Levosert®, Avibela®, MireffikTM, BenilexaTM, DonasertTM, 
LevonortisTM, and TresovelleTM). If approved for HMB treatment in the U.S., LNG20 IUS 
would offer prescribers and patients another HMB treatment option. Other currently available 
lower-dose LNG IUS products are not approved for HMB treatment. 
LNG20 IUS has been investigated in a Phase 3, multicenter, single-blind randomized trial in 
Europe to assess the non-inferiority as compared to Mirena in patients with HMB utilizing a 
pictorial blood loss chart to assess MBL.  Enrollment of 280 subjects was completed in 
January 2009 and 50% were randomized to LNG20 IUS.  LNG20 IUS substantially reduced 
MBL in these women and based on this trial was approved in 2012 for the treatment of HMB 
in multiple European countries. A review of all safety data in a post hoc analysis supports 
that LNG20 IUS was generally well tolerated in female subjects with HMB.   
The LNG20 IUS consists of a T-shaped polyethylene frame (T-body) with a steroid reservoir 
around the vertical stem.  The steroid reservoir is covered with a polydimethylsiloxane 
membrane which controls the release rate of levonorgestrel from the reservoir.  The reservoir 
contains levonorgestrel 52 mg, providing an initial release rate of approximately 20 mcg/day 
(Creinin et al., 2016).  A polypropylene monofilament blue thread is attached to the end of 
the vertical stem.  Refer to the Investigator’s Brochure for full details on the components of 
LNG20 IUS. 
 
STUDY OBJECTIVES 
This study is being performed to evaluate the Medicines360 levonorgestrel 52 mg IUS, 
LNG20 IUS.  LNG20 IUS is expected to be an effective treatment of heavy menstrual 
bleeding.  
2.1 
Primary Objective 
The primary objective of this study is to assess the impact of LNG20 IUS on menstrual blood 
loss (MBL) from baseline to 6 months (during the sixth 28-day cycle) after initial LNG20 IUS 
insertion in women with HMB.  The primary outcome measure is the proportion of subjects 

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with successful treatment defined as: 
o end of treatment MBL <80 mL, and 
o end of treatment MBL 50% or less than baseline 
2.2 
Secondary Objectives 
The secondary objectives of this study are to assess: 
• The absolute change from baseline MBL to mid-treatment MBL (Cycle 3) 
• The percent change from baseline MBL to mid-treatment MBL (Cycle 3) 
• The absolute change from baseline MBL to end of treatment MBL (Cycle 6)  
• The percent change from baseline MBL to end of treatment MBL (Cycle 6) 
• Changes from baseline to mid-treatment Cycle 3, from baseline to end of treatment 
Cycle 6, and from mid-treatment Cycle 3 to end of treatment Cycle 6 in the number of 
days of bleeding, spotting, bleeding and spotting and number of bleeding episodes. 
• Percent change in hemoglobin, hematocrit and serum ferritin from baseline to mid-
treatment (Visit 7), from baseline to end of treatment (Visit 8), and from mid-treatment 
(Visit 7) to end of treatment (Visit 8) 
• Continuation rate during Treatment Phase 
• Subjective assessment of menstrual bleeding changes 
• Adverse events 
 
INVESTIGATIONAL PLAN 
This is a Phase 3, open-label, multicenter evaluation of the efficacy of a levonorgestrel 52 mg 
intrauterine system (LNG20 IUS) for the treatment of heavy menstrual bleeding.   
Approximately 100 eligible women, 18-50 years of age, will be enrolled to receive LNG20 IUS.  
This study will not restrict enrollment based on parity, weight or BMI.  Women who do not 
require contraception (e.g., not heterosexually active, using permanent contraception) may be 
included. 
Only women who are willing to forgo contraindicated confounding treatments and systemic 
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Treatment Phase may be enrolled.  Women who are heterosexually active must use appropriate 
contraceptive methods during the screening phase, such as male or female permanent 
sterilization, be willing to use a barrier method, withdrawal (if has been using as current method 
prior to screening) or abstinence.  No other contraceptive is required during the treatment phase, 
although subjects may choose to do so as long as contraindicated products are not used. 
After written consent is obtained, the subject will undergo a Screening Phase to establish 
eligibility and confirm the diagnosis of HMB.  At the initial screening visit (Visit 1), medical 
history and vital signs including height and weight will be obtained and a gynecologic exam, 
uterine ultrasound (unless performed within 6 months), endometrial biopsy (unless 
performed within 6 months), high sensitivity urine pregnancy test, gonorrhea/Chlamydia 
testing and blood tests to evaluate eligibility criteria will be performed.  Women who meet 
entry criteria at Visit 1, exclusive of pending testing results (e.g., blood tests, endometrial 
biopsy, Pap test, etc.) will initiate participation in up to 3 more screening visits (Visit 2, Visit 
3 and Visit 4) over approximately 90 days to establish the diagnosis of HMB based on MBL 
of ≥80 mL/cycle in at least 2 of 3 cycles as assessed by the alkaline hematin (AH) method.   
The subject will be provided specific brands of feminine hygiene products and trained to 
complete a daily bleeding diary.  Any subject for whom a pending test result from Visit 1 is 
reported with an exclusionary result will be discontinued from screening (screen failure). 
The diagnosis of HMB will be established in 2-3 screening phase cycles. 
A Screening Cycle may be repeated under the following conditions: 
• If a subject indicates she was unable to collect all used feminine hygiene products 
during a menses and, in the opinion of the Investigator, the discarded products 
contained a substantial volume of blood, then that cycle collection may be discarded 
and the cycle collection repeated; 
• If a subject indicates she used non-study feminine hygiene products and, in the 
opinion of the Investigator, these products contained a substantial volume of the 
blood to be assayed, then that cycle collection may be discarded and the cycle 
collection repeated.  

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• If subject indicates that the first cycle had significantly less bleeding than her usual 
cycle, then that cycle collection may be discarded and the cycle collection repeated 
(first cycle only). 
Only one screening cycle may be repeated.  Any screening cycle collection that is assayed 
cannot be repeated. 
All screening cycles, including a repeated screening cycle, must be consecutive. 
The Screening Phase MBL is the MBL averaged over all cycles measured during the 
Screening Phase.  Each Screening Phase visit will include a high sensitivity urine pregnancy 
test.   
Enrollment (Visit 5) will occur when the LNG20 IUS is inserted by a study Investigator 
using standardized procedures and must occur within 45 days of the Screening Phase visit 
(i.e., Visit 3 or Visit 4) in which eligibility is established.  Up to two insertion attempts will 
be allowed within 30 days.  Visit 5 will include a high sensitivity urine pregnancy test which 
will be repeated if a second insertion attempt is required on a separate day. Additionally, 
gonorrhea/Chlamydia testing will be repeated for any women with a change in sexual partner 
since last tested, but IUS insertion does not require waiting for the results.  The following 
baseline assessments will occur on the day of the initial insertion attempt and not repeated 
should a second attempt on a different day be needed: hemoglobin, hematocrit and ferritin 
testing, and a subjective assessment of menstrual bleeding using a Visual Analog Scale 
(VAS) questionnaire. 
In the Treatment Phase subjects will continue to use only the study provided feminine hygiene 
products and record their bleeding on a daily diary.  Feminine hygiene product collection will be 
limited to Cycle 3 and Cycle 6 during the Treatment Phase; no repeat collection is permitted.  
Study assessments will be performed at clinic visits at Treatment Phase Month 1 (Visit 6), and 
at the end of Cycle 3 (Visit 7) and Cycle 6 (Visit 8).  Each visit will include a high sensitivity 
urine pregnancy test.  Ferritin/hematology assessments and a subjective bleeding assessment 
using a VAS questionnaire will be performed at Visits 7 and 8.  The IUS can be removed during 
the study when requested by the subject or when clinically indicated.  At the end of 6 28-day 
cycles of use, unless medically contraindicated, study participants may opt to keep the IUS or 
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Participation will end at Visit 8 except for the following circumstances: 
• The IUS was removed at Visit 8: these subjects will be contacted 7 to 10 days after the 
visit to assess bleeding and cramping after removal and any IUS-related or IUS 
procedure-related adverse events.   
• Subjects with ongoing IUS-related adverse events after completion of the Treatment 
Phase that are not resolved or stabilized will have monthly contacts or visits, as 
appropriate, until the event is resolved or stabilized. 
Routine safety monitoring (including clinically indicated physical exams, adverse event 
assessments, and vital signs) will be conducted for all subjects.   
3.1 
Outcome Measures 
3.1.1 Primary Outcome Measure 
The primary outcome measure will be the proportion of subjects with successful treatment of 
heavy menstrual bleeding based on the decrease in MBL from baseline to 6 months (during 
the sixth 28-day cycle) after initial LNG20 IUS insertion.  This outcome will be established 
in the Modified-Intent-To-Treat (MITT) population measuring the change in absolute value 
from baseline MBL to the end of treatment MBL.  Baseline MBL is the MBL averaged over 
all of the cycles measured during the Screening Phase.  A subject with successful treatment 
will be defined as:   
• end of treatment MBL <80 mL, and 
• a decrease to a value of no greater than 50% of the baseline MBL 
3.1.2 Key Secondary Outcome Measures 
Key secondary outcome measures will be: 
• Absolute change from baseline MBL to mid-treatment MBL (Cycle 3) 
• Percent change from baseline MBL to mid-treatment MBL (Cycle 3) 
• Absolute change from baseline MBL to end of treatment MBL (Cycle 6) 
• Percent change from baseline MBL to end of treatment MBL (Cycle 6) 
• Changes from baseline to mid-treatment (Cycle 3), from mid-treatment (Cycle 3) to end 

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of treatment (Cycle 6) and from baseline to end of treatment (Cycle 6) in the number of 
days of bleeding, spotting, bleeding and spotting and number of bleeding episodes 
3.1.3 Other Secondary Outcome Measures 
Other secondary outcomes that will be assessed for all subjects will include: 
• Percent change in hemoglobin, hematocrit and serum ferritin from baseline to mid-
treatment (Visit 7), from baseline to end of treatment (Visit 8) and from mid-treatment 
(Visit 7) to end of treatment (Visit 8)  
• Continuation rate during Treatment Phase 
• Subjective assessment of menstrual bleeding changes 
• Adverse events 
 
STUDY POPULATION SELECTION 
4.1 Subject Selection 
Approximately 100 subjects who qualify after screening will be enrolled in this study. Study 
entry (enrollment) is defined as the initiation of a study IUS insertion procedure.  Subjects must 
fulfill all of the inclusion criteria and not meet any of the exclusion criteria to be eligible for 
enrollment. 
4.2 Inclusion Criteria 
1. Signed informed consent 
2. Reports subjectively heavy menses for most menses when not using hormonal 
contraception or a copper IUD 
3. Healthy females 18-50 years old, inclusive, at the time of enrollment  
4. Able to read and write, as determined by study personnel 
5. FSH value ≤30 mIU/mL at screening 
6. Typical menstrual cycle length of 21-35 days with variation from cycle to cycle of 
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7. Has withdrawal bleeding in 2 of the 3 cycles during the Screening Phase with ≥ 80 
mL per cycle as measured by the AH method 
8. Uterine sound depth of ≥5.5 cm 
9. Willing to comply with study visit schedule and assessments, including sanitary 
product collection and diary completion requirements 
10. Documented (i.e., printed report) Pap testing, regardless of subject’s age, and any 
indicated evaluation/treatment that demonstrates no need for further evaluation during 
the course of study participation (i.e., within 10 months after consent) 
11. Planning to reside within a reasonable driving distance of a research site 
(approximately 150 miles) for duration of study participation 
12. Willing to use a medication other than a NSAID as first-line treatment for any pain 
condition during the duration of study participation 
13. Willing to abstain from heterosexual intercourse or use acceptable contraception 
during the screening phase; acceptable contraception includes male or female 
permanent contraception, withdrawal (if has been using as current method prior to 
screening) or a barrier method 
14. If previously pregnant, at least one subjectively heavy menses prior to screening 
4.3 Exclusion Criteria 
1. Currently pregnant  
2. Planning to attempt to become pregnant during the screening and treatment phases 
(i.e., up to approximately 11 months after consent) 
3. Currently lactating or not having a subjectively heavy menses since discontinuation 
of lactation prior to screening 
4. Clinical diagnosis of perimenopause (in the opinion of the investigator) based on one 
or more of the following: changes in menstrual regularity (e.g., shorter, longer, 
absent, irregular), hot flashes, sleeping disorder, or changes in mood (e.g., depression, 
nervous tension, and irritability) within 3 months prior to or during the screening 
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5. Screening blood laboratory value outside of the normal range that, in the opinion of 
the investigator, requires treatment or further work-up (i.e., are considered clinically 
significant) 
6. Has poor venous access or significant history of inability to have blood samples 
drawn 
7. Body habitus or history of lower genital tract abnormalities or prior surgeries which 
may prohibit proper visualization of the cervix or not allow the uterus to be 
appropriately instrumented 
8. History of bicornuate uterus or any other abnormality of the uterus resulting in 
distortion of the uterine cavity or cervical canal incompatible with insertion 
9. Prior (documented within 6 months) or baseline study ultrasound examination 
demonstrating: 
a. A congenital or acquired uterine anomaly that distorts the uterine cavity or 
cervical canal incompatible with insertion; 
b. Endometrial polyps (unless previously removed),  
c. Fibroids meeting any of the following criteria: 
i. Distort the uterine cavity or cervical canal incompatible with insertion; 
ii. Submucosal location; 
iii. Exceeding 2 cm in the greatest dimension for any individual fibroid; 
iv. More than three fibroids of at least 1.5 cm in greatest diameter 
d. Clear evidence of adenomyosis consisting of any of the following: 
i. Subendometrial cysts 
ii. Diffuse adenomyosis based on a heterogeneous myometrial 
echotexture consisting of:  
1. Hyperechoic findings (islands of endometrial glands); 
2. Hypoechoic findings (associated muscle hypertrophy); 
3. "Venetian blind" appearance due to subendometrial echogenic 
linear striations and acoustic shadowing where endometrial 
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10. Recently diagnosed or clinically evident cervicitis or upper genital tract infection at 
the time of IUS insertion (unless successfully treated and considered clinically cured 
for at least 7 days prior to enrollment)  
11. History of pelvic actinomycosis infection (i.e., received antibiotic treatment; criterion 
does not include solely a history of Pap test with actinomyces) 
12. Postpartum or post-abortion endometritis unless symptoms resolved at least 4 weeks 
prior to screening 
13. Chronic endometritis on endometrial biopsy at screening (an endometrial biopsy 
performed within 6 months of Visit 1 could be used if a report is available with a 
tissue diagnosis) 
14. Has any of the following premalignant or malignant diseases: 
a. Malignant melanoma  
b. Acute malignancies affecting blood or leukemias 
c. Gestational trophoblastic disease (unless at least one year with undetectable 
beta-hCG) 
d. Known or suspected cervical, ovarian, vaginal or vulvar cancer 
e. Uterine cancer or evidence of uterine malignancy, endometrial intraepithelial 
neoplasia (EIN) or hyperplasia on an endometrial biopsy at screening (an 
endometrial biopsy performed within 6 months of Visit 1 could be used if a 
report is available with a tissue diagnosis) 
f. History of breast cancer, or suspicion of breast cancer until proven otherwise 
15. Has any of the following medical conditions: 
a. Bleeding diathesis (inherited or acquired)  
b. History of von Willebrand’s disease or other known coagulopathy 
c. Uncontrolled significant hypertension defined as a sitting systolic blood 
pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 95 mm Hg at any 
screening or enrollment visit unless treated and controlled within two weeks 
of discovery 

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d. Presence or history of venous thromboembolic diseases (deep vein 
thrombosis, pulmonary embolism), presence or history of arterial 
thromboembolic diseases (e.g., myocardial infarction, stroke) 
e. Uncontrolled thyroid disorder 
f. Sickle cell anemia 
g. Diabetes mellitus that is poorly controlled or with end-organ/vascular 
complications 
h. Hyperprolactinemia at screening 
i. Acute or severe liver disease or liver tumor  
j. Poorly controlled bipolar disorder, schizophrenia, psychosis, major depressive 
disorder or other major psychiatric disorder according the criteria of the 
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-
5) 
k. History of a positive HIV test or having a partner who is known to be HIV 
positive 
l. Current or history of alcohol, illicit drug or prescription drug abuse within 12 
months prior to screening 
16. Use of antifibrinolytics, platelet aggregation inhibitors, anticoagulants or other similar 
medications that can increase or decrease bleeding within 30 days prior to or during 
screening (EXCEPTION: NSAIDs can be used as second-line treatment for pain 
management) 
17. Use of intrauterine or implantable contraception, progestin-only pills, combined 
hormonal contraceptives or oral progestin therapy within 30 days before screening 
18. Depomedroxyprogesterone acetate (DMPA) injection within the past 9 months prior 
to screening (this exclusionary time period can be shortened to 6 months if the subject 
has also had two spontaneous menstrual cycles [requires minimum of 3 heavy 
menses] that meet criteria for normal menstrual cycle pattern) 
19. Use of non-contraceptive estrogen, progesterone, progestin, testosterone, androgen or 
other gonadotropins (e.g. hCG) within 30 days before screening 
20. Prior total or partial endometrial ablation or resection 

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21. History of a uterine aspiration or curettage procedure for any indication (other than an 
office biopsy) within 4 weeks of screening 
22. Known or suspected allergy to levonorgestrel or hypersensitivity to any component of 
the product 
23. Use of an experimental medication or receipt of an experimental treatment for any 
condition within 30 days of screening  
24. Study staff or a member of the immediate family of a study staff 
25. Any condition or circumstance that, in the opinion of the Investigator, would 
constitute contraindications to participation in the study or would compromise ability 
to comply with the study protocol, such as any concurrent medical condition that is 
not stable and well-controlled, that is likely to worsen, or that may require recurrent 
hospitalizations during study participation 
 
STUDY TREATMENT 
5.1 LNG20 IUS (Dosage and Formulation) 
This T-shaped polyethylene device contains levonorgestrel 52 mg.  For further details, see the 
LNG20 IUS Investigator’s Brochure. 
5.2 IUS Supply and Administration  
Each IUS is packaged as a single use sterile system.  An inserter for placement of the IUS 
into the uterine cavity which does not remain in permanent contact with the subject is 
included in the sterile package with the IUS.  The IUS with the inserter should be stored in its 
sterile sealed package until insertion. 
See the Investigator’s Brochure for LNG20 IUS product description, and insertion and 
removal instructions. 
5.3 IUS Storage and Accountability 
LNG20 IUS should be stored at 25°C (77°F); with excursions permitted between 15-30°C (59-
86°F) [See USP Controlled Room Temperature] prior to use.  Temperature excursions outside 

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of the permitted range must be reported to the Sponsor or designee.  Study drug accountability, 
reconciliation and record maintenance are responsibilities that must be performed in 
accordance with all applicable regulatory requirements.  All unused IUSs will be stored for 
inventory and collection.  Storage and shipping procedures to return unused IUSs are detailed 
in the Study Reference Manual. 
All expelled (when available) and removed IUSs will be stored.  All retained used IUSs will be 
appropriately disposed of only after accountability verification by a study monitor. 
5.4 IUS Replacement 
Subjects experiencing an expulsion (complete or partial) may have another study IUS inserted; 
only one replacement IUS is allowed per subject. Two insertion attempts are allowed as long as 
replacement criteria are met for both attempts.  Replacement can occur only if all of the 
following conditions are met: 
• Reinsertion occurs no more than 14 days after the expulsion; 
• Reinsertion occurs at least 7 days prior to treatment Cycle 3 or Cycle 6; 
• Reinsertion cannot occur during treatment Cycle 3 or Cycle 6.  
• Pregnancy can reasonably be excluded 
5.5 Concomitant and Excluded Therapy 
Concomitant medications are any prescription medications or over-the-counter preparations 
used by the subject beginning 30 days prior to screening through IUS discontinuation (Visit 
8/Early Discontinuation) and for those subjects with continuing evaluation of an ongoing IUS-
related or IUS procedure-related adverse event through resolution or stabilization.  All 
concomitant medications, including excluded therapies, must be documented in the 
Concomitant Medication CRF.  Subjects who use excluded therapies may require 
discontinuation from the study.  The Medical Monitor should be contacted to discuss possible 
discontinuation of these subjects. 
The following concomitant therapies are excluded while on study treatment: 

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• Hormonal contraceptives  
o EXCEPTION: emergency contraception in any situation when the subject feels the 
IUS expelled, she subsequently had intercourse and was not using any other 
permitted method of contraception (e.g., barrier or sterilization) 
 
o Subjects will not be discontinued from the study because of emergency 
contraceptive use if the IUS is eventually identified to be in the correct location in 
the uterine cavity 
• Use of antifibrinolytics, platelet aggregation inhibitors, anticoagulants or other similar 
medications that can increase or decrease bleeding 
o EXCEPTION: NSAIDs can be used as second-line treatment for pain 
management. Acetaminophen should be the first line treatment for pain 
management but if not effective then NSAID use is allowed   
• Iron or folate supplement use are allowed if currently in use at screening entry but initiation 
of any new iron or folate supplementation during study participation is allowed only for the 
treatment of clinically significant iron-deficiency anemia 
• Any non-contraceptive estrogen, progesterone, testosterone, or gonadotropin (e.g. hCG) 
• Misoprostol on the day before or day of IUS insertion or removal 
• Any investigational treatment or medication other than the LNG20 IUS (experimental 
diagnostic testing is allowed but may not substitute for any study required evaluations) 
5.6 Blinding 
This is an unblinded, open-label study. 
 
STUDY PROCEDURES 
A flowchart of study screening assessments is in Appendix A and of enrollment and follow-
up assessments in Appendix B. 

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6.1 Alkaline Hematin Menstrual Blood Loss Assessment 
This study will utilize the AH method to assess MBL. Participants will be provided with 
branded study-specific feminine hygiene products to be used exclusively during study 
participation.  During the Screening Phase all feminine hygiene products used during a 
menses with any evident bleeding will be collected for analysis, stored at room temperature 
and provided to the site.  During the Treatment Phase, all feminine hygiene products used 
during only Cycles 3 and 6 will be collected for analysis.  A daily bleeding diary will be 
completed indicating the highest level of bleeding experienced for each day.  A venous blood 
sample will be obtained after each menses or cycle evaluated.  The collected venous blood 
samples and feminine hygiene products will be shipped to KCAS, LCC laboratory for AH 
analysis after each Screening Phase Visits 2-4, as applicable, and Treatment Phase Visits 7 
and 8.  Used feminine hygiene products that are brought by the subject to the site that do not 
require analysis will be appropriately disposed of. 
6.2 Feminine Hygiene Products 
Each participant will be provided a sufficient supply of study-specific feminine hygiene 
products:  
• Tampax Regular Tampons with flushable applicator; 
• Tampax Super or Super Plus tampons with flushable applicator 
• Kotex Regular Maxi Pads; 
• Kotex Super Long Maxi Pads; 
• Kotex Overnight Maxi Pads with Wings. 
• Carefree Body Shape Pantiliners with Actifresh, Extra Long 
No other feminine hygiene products or brands can be used during the study.   
6.3 Clinical Laboratory Tests 
The site’s local laboratory will be used for hematology, ferritin, vWF, TSH, FSH, prolactin, 
chemistry (basic metabolic panel), AST, ALT, Chlamydia, and gonorrhea testing 
(documented test results obtained within 30 days prior to Visit 1 are acceptable if applicable 

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laboratory normal ranges are available). Blood testing does not require fasting. Documented 
Pap test results indicating that no further testing or follow-up during the duration of study 
participation is indicated may be used for screening.  Additionally, endometrial biopsies will 
be performed by the site (unless a documented biopsy result obtained within 6 months prior 
to screening is available).  High sensitivity urine pregnancy testing may be performed in the 
clinic.   
6.4 Screening Transvaginal Ultrasonography 
A transvaginal ultrasound during initial screening (unless documented by a formal report 
within 6 months prior to screening) should document any uterine fibroid size and location 
and determine the presence of any uterine abnormality that may be exclusionary to eligibility. 
6.5 Subjective Assessment of Menstrual Bleeding 
The subject will complete subjective assessment of menstrual bleeding, pain and the impact of 
bleeding and pain on daily activities using VAS questionnaires at baseline (Visit 5), and after 
3 cycles (Visit 7) and 6 cycles (Visit 8) of treatment. 
6.6 IUS Insertion Definitions 
Up to two insertion attempts are permitted.   
• An insertion attempt starts with placement of the IUS inserter through the external 
cervical os.  IUS insertion ends with completion of cutting the IUS threads following 
successful intrauterine IUS placement or IUS insertion failure. 
▪ IUS insertion failure is considered to occur when after the IUS inserter passes 
through the external os of the cervix and completion of IUS insertion is not 
achieved.   
▪ Successful IUS insertion is considered as retention of the IUS in the uterus 
through cutting of the strings, unless removed for incorrect placement as 
determined by ultrasound or other means within the duration of the same clinic 
visit; the day of successful IUS insertion is considered Study Day 1. 

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• Note that IUS insertion is the general process that starts with opening of the LNG20 
IUS kit with the intent to perform an insertion. The insertion process may stop before 
IUS insertion is attempted (see definition above); in such circumstances, an IUS 
insertion attempt has not occurred.  Examples of procedure discontinuation prior to an 
insertion attempt include: 
▪ notable defect upon inspection of the product 
▪ loss of product sterility 
▪ inability to sound the uterus 
▪ subject intolerance of the procedure prior to LNG20 IUS contact with the 
external cervical os 
6.7 Screening 
Screening is considered to start with the signing of the Informed Consent Form by the 
participant.   
6.7.1 Screening Phase Procedures 
All screening procedures must be performed before the Treatment Phase Enrollment (Visit 5) 
procedures.  Screening will consist of up to 4 visits approximately 30 days apart; actual 
Screening visit timing is based on the occurrence of the individual subject’s menses.  Initial 
screening procedures must start within 30 days of obtaining written informed consent or the 
subject must be re-consented.  Subject interview for past medical history, medications, 
demographics and venous access history, should be conducted prior to performing study 
required laboratory tests or ultrasonography so that those women not eligible based on non-
invasive entry criteria are excluded without unnecessary invasive evaluations.  If a subject is 
determined to be a screen failure any collected un-assayed used feminine hygiene products 
should be disposed. All screening cycles, including a repeated screening cycle, must be 
consecutive. 
6.7.2 Screening Visit 1 
Written informed consent will be obtained prior to conducting any study specific procedures. 

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The screening procedures should be completed in order (Parts A through E) and may occur on 
separate days.  All activities for Visit 1 should be completed within the following time frames: 
• 30 days of signing of consent for women not requiring cessation of exclusionary 
medications (see Section 4.3 Exclusionary Criteria #16, #17 & #19) 
• 60 days of signing consent for women requiring cessation of exclusionary 
medications (see Section 4.3 Exclusionary Criteria #16, #17 & #19) and Parts C 
through F (Sections 6.7.2.3 through 6.7.2.6) should be delayed until at least 30 days 
after the medication is stopped. 
6.7.2.1 Part A: Review of medical history 
• Pre-screening questionnaire (Appendix C) 
• Demographics 
• Gynecologic history 
• Menstrual history 
• Medical history review including psychiatric history 
• Concomitant medication review 
• Verify if significant history of poor venous access 
If the subject meets any exclusion criterion then the subject is a screen failure; do not proceed 
further.  
6.7.2.2 Part B: Urine pregnancy testing 
• High sensitivity urine pregnancy test (if test is positive then subject is a screen 
failure; do not proceed further) 
6.7.2.3 Part C: Blood tests 
• Collect blood sample for FSH, TSH, PRL, vWF, hematology panel, ferritin, ALT, 
AST, chemistry panel (if not performed and documented within 30 days prior to 
screening) 
o Blood testing does not require fasting 
o If unable to draw blood then the subject is a screen failure; do not proceed 
further 

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6.7.2.4 Part D: Initial exam 
• Obtain blood pressure, pulse, height, weight 
• Breast exam- suspicion of cancer would make subject a screen failure (may be 
rescreened if breast cancer is ruled out) 
• Pelvic exam- assess if anatomy compatible with IUS insertion (except uterine 
sounding) and for any acute cervical infection 
If the subject meets any exclusion criterion then the subject is a screen failure; do not proceed 
further.  Discard blood test samples if fails Part C on the same day. 
6.7.2.5 Part E: Pelvic assessments 
• Pap test (if required) 
• Chlamydia and gonorrhea testing for all subjects (should be vaginal swab ideally but 
urine test acceptable) if not performed and documented within 30 days prior to 
screening 
• Transvaginal ultrasound (if not documented within 6 months)   
o If immediate interpretation is available review for any exclusion criteria (e.g., 
endometrial polyp, subendometrial cysts, adenomyosis, fibroids that distort the 
uterine cavity or cervical canal; submucosal location; exceeding 2 cm in the 
greatest dimension for any individual fibroid; more than three fibroids of at least 
1.5 cm in greatest diameter, etc.)  
• Perform endometrial biopsy (if not documented within 6 months) 
o Perform high sensitivity urine pregnancy test before biopsy if the biopsy is 
occurring at a visit at which a test has not already been performed; if test is 
positive, do not perform biopsy and subject is a screen failure 
o If unable to obtain biopsy then the subject is a screen failure 
If the subject meets any exclusion criterion then the subject is a screen failure; do not proceed 
further. Discard blood, Pap or Chlamydia/gonorrhea test samples if subject fails Part D on the 
same day of the specimen collection. 
 
 

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6.7.2.6 Part F: Screening Visit 1 completion 
The screening phase can proceed once all testing is obtained even if laboratory or testing results 
are not yet available. Review eligibility criteria and continue screening of women who meet 
eligibility criteria (except for pending test results). 
• Dispense diary for daily bleeding and instruct subject on completion  
• Dispense patient instructions, feminine hygiene products and feminine hygiene 
product collection kit  
• Instruct subject on collection of all feminine hygiene products (pads, tampons and 
liners) used from onset to end of menses (excluding those products with no evident 
blood collection)  
• Schedule Visit 2 based on anticipated end of next menses 
▪ Instruct subject to contact site with onset of next menses to confirm dates 
and reschedule Visit 2 if needed 
• If the subject is having her menses during the initial screening Visit 1, the collection 
of feminine hygiene products should begin with the onset of her next menses 
6.7.3 Screening Phase Cycle Assessment Visits: 
6.7.3.1 Overview 
• The diagnosis of HMB will be established in the 2-3 cycles of the screening 
phase. If she meets the diagnosis of HMB in the first two cycles, she will be 
enrolled into the Treatment Phase and the third cycle will not be performed (i.e., 
no Visit 4). 
• Screening Visit 2, Visit 3 and Visit 4 are ideally expected to occur within 5 days 
after the end of menses for the site to collect the used feminine hygiene products 
and to obtain venous blood sampling for AH determination, but may occur up to 
21 days after the end of her menses; otherwise she is a screen failure 
• A Screening Cycle may be repeated. Only one screening cycle may be repeated.  
Any screening cycle collection that is assayed cannot be repeated. A screening 
cycle can be repeated under the following conditions: 

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o If subject indicates she was unable to collect all used feminine hygiene 
products during a menses, and, in the opinion of the Investigator, the 
discarded products contained a substantial volume of blood, then that 
cycle collection may be discarded and the cycle collection repeated 
o If subject indicates the use of non-study feminine hygiene products during 
a menses, and in the opinion of the Investigator these products contained a 
substantial volume of blood, then that cycle collection may be discarded 
and the cycle collection repeated 
o If subject indicates that the first cycle had significantly less bleeding than 
her usual cycle, then that cycle collection may be discarded and the cycle 
collection repeated (first cycle only) 
• Subjects determined to be screen failures between study clinic visits should be 
contacted to inform them that their study participation is over 
6.7.3.2 Between Screening Visits 1 and 2 (Review of any pending test results): 
• Check daily for report of pending test results and review within 3 business days of 
receipt 
• If any exclusion criterion is met: 
o Subject is to be discontinued as a screen failure: do not proceed further 
o Subject to be contacted to inform her that she is discontinued from the 
study (she does not need to return the dispensed feminine hygiene 
products) 
• If a lab or test result is reported as unevaluable (e.g., insufficient quantity, lab 
error, etc.) subject should be asked to return as soon as possible for repeat testing 
(unscheduled visit).  Alternatively, although less preferred, repeat testing may be 
performed at Visit 2. 
6.7.3.3 Screening Visit 2 (Screening Cycle 1 MBL Collection) 
• Review screening lab and test results if available and any repeat testing if required 
o If any results meet any exclusion criterion then the subject is a screen failure 
• Blood pressure and pulse  

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• Interview for change in medical history status (e.g., new medical conditions) 
• Obtain urine for high sensitivity pregnancy test (if test is positive then subject is a 
screen failure: do not proceed further) 
• Chlamydia and gonorrhea testing for any subject following a change in sexual 
partner since the last study visit. 
• Collect venous blood sample for AH (ideally within 5 days of end of menses) 
o If the blood draw for AH cannot be made within 21 days of the end of 
menses, the subject is a screen failure and any collected feminine hygiene 
products for Screening Cycle 1 should be disposed of 
• Collect and review daily diary for completeness and verify menstrual flow severity 
o If needed, have subject correct any unclear or incomplete entries 
o The Investigator and study staff should discuss with the subject, while reviewing 
the diary, if this cycle represents a typical heavy cycle, if she used only study 
specific products, and if she collected all used products 
o The Investigator and staff should use this information to decide if the subject 
meets the criteria to submit the collection, repeat a cycle or be discontinued 
▪ If the Investigator determines the cycle should be repeated, no other 
cycle collections can be repeated 
▪ If the Investigator determines the specimen collection is likely less than 
60 mL and chooses not to submit (e.g., the subject states this collection 
represents a typical very heavy cycle and she only returns 4 lightly 
stained pads), the subject should be discontinued 
• Collect all used feminine hygiene products for shipping to KCAS lab 
o Interview subject for feminine hygiene collection compliance 
o Dispense feminine hygiene product collection kit 
o Ship collected feminine hygiene products and venous blood sample to 
KCAS Lab  
• Dispense any needed additional feminine hygiene products and instruct subject on 
collection of all feminine hygiene products (pads, tampons and liners) used from 
onset to end of next menses (excluding those products with no blood collection) 
• Scheduling of Visit 3: 

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o Schedule Visit 3 to occur ideally ≤5 days after the expected end of menses  
based on her menstrual history 
o Instruct subject to contact site with onset of next menses to confirm dates 
and reschedule Visit 3 if needed  
6.7.3.4 Between Screening Visits 2 and 3 (Review of Cycle 1 AH results) 
• Check pending MBL reports daily starting at 7 business days after shipment and 
review within 3 business days of receipt 
o If MBL for Cycle 1 is ≥80 mL, Cycle 1 is a qualifying cycle and the subject 
may continue to Visit 3 
o If MBL for Cycle 1 is <80 mL but ≥60 mL, Cycle 1 is not a qualifying cycle 
but she may continue to Visit 3 
o If MBL for Cycle 1 is <60 mL, the subject is to be discontinued (screen 
failure) and contacted to inform her that she is discontinued from the study 
o If MBL results for Cycle 1 has not been reported before the scheduled visit 
the subject may continue to Visit 3 
6.7.3.5 Visit 3 (Screening Cycle 2 MBL Collection) 
• Blood pressure and pulse  
• Interview for change in medical history status (e.g., new medical conditions) 
• Obtain urine for high sensitivity pregnancy test (if test is positive then subject is a 
screen failure) 
• Chlamydia and gonorrhea testing for any subject following a change in sexual 
partner since the last study visit. 
• Collect venous blood sample for AH (ideally within 5 days of end of menses).   
o If the blood draw for AH cannot be made within 21 days of the end of 
menses, the subject is a screen failure and any collected feminine hygiene 
products for Screening Cycle 2 should be disposed of. 
• Collect and review daily diary for completeness and verify menstrual flow severity 
o If needed, have subject correct any unclear or incomplete entries 

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o The Investigator and study staff should discuss with the subject, while reviewing 
the diary, if this cycle represents a typical heavy cycle, if she used only study 
specific products, and if she collected all used products 
o The Investigator and staff should use this information to decide if the subject 
meets the criteria to submit the collection, repeat a cycle (if a cycle not 
previously repeated) or be discontinued 
▪ If the Investigator determines the cycle should be repeated, no other 
collections can be repeated 
▪ If the first cycle was repeated or between 60 to 79 mL, and the 
Investigator determines this specimen is likely less than 80 mL and 
chooses not to submit (e.g., the subject states this collection represents a 
typical very heavy cycle and she only returns 4 lightly stained pads), the 
subject should be discontinued 
• Collect all used feminine hygiene products for shipping to KCAS lab 
o Interview subject for feminine hygiene collection compliance 
o Dispense feminine hygiene product collection kit 
o Ship collected feminine hygiene products and venous blood sample to 
KCAS Lab  
• Dispense any needed additional feminine hygiene products and instruct subject on 
collection of all feminine hygiene products (pads, tampons and liners) used from 
onset to end of next menses (excluding those products with no blood collection) 
• Scheduling of Visit 4: 
o Schedule Visit 4 to occur ideally ≤5 days after end expected end of menses 
based on her menstrual history 
o Instruct subject to contact site with onset of next menses to confirm dates 
and reschedule Visit 4 if needed  
6.7.3.6 Between Screening Visits 3 and 4 (Review of Cycle 2 AH results) 
• Check pending MBL reports daily starting at 7 business days after shipment and 
review within 3 business days of receipt 
o If MBL for Cycle 2 is ≥80 mL, determine next visit based on Cycle 1 MBL: 

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▪ MBL for Cycle 1 was <80 mL, the subject may continue to Visit 4 
▪ MBL for Cycle 1 was ≥80 mL, the subject meets MBL eligibility and 
Visit 4 is not to be performed 
• Contact subject to inform her the next visit will be for study 
IUS insertion and that she does not have to collect feminine 
hygiene products this cycle/discard any used feminine 
hygiene products from this cycle 
• Schedule for IUS insertion as per Visit 5 instructions (see 
Section 6.8.1) 
o If MBL for Cycle 2 is <80 mL, determine next visit based on Cycle 1 MBL: 
▪ MBL for Cycle 1 was ≥80 mL, the subject may continue to Visit 4 
▪ MBL Cycle 1 was <80 mL the subject is to be discontinued (screen 
failure) and contacted to inform her that she is discontinued from the 
study 
o If MBL for Cycle 2 has not been reported before the scheduled visit the 
subject may continue to Visit 4 
6.7.3.7 Visit 4 (Screening Cycle 3 MBL Collection) – if necessary 
• Blood pressure and pulse  
• Interview for change in medical history status (e.g., new medical conditions) 
• Obtain urine for high sensitivity pregnancy test (if test is positive then subject is a 
screen failure) 
• Chlamydia and gonorrhea testing for any subject following a change in sexual 
partner since the last study visit 
• Collect venous blood sample for AH (ideally within 5 days of end of menses)  
o If the blood draw for AH cannot be made within 21 days of the end of 
menses, the subject is a screen failure and any collected feminine hygiene 
products for Screening Cycle 3 should be disposed 
• Collect and review daily diary for completeness and verify menstrual flow severity 
o If needed, have subject correct any unclear or incomplete entries 

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o The Investigator and study staff should discuss with the subject, while reviewing 
the diary, if this cycle represents a typical heavy cycle, if she used only study 
specific products, and if she collected all used products 
o The Investigator and staff should use this information to decide if the subject 
meets the criteria to submit the collection, repeat a cycle (if a cycle not 
previously repeated) or be discontinued 
▪ If the Investigator determines the cycle should be repeated, no other 
collections can be repeated 
▪ If the Investigator determines this specimen is likely less than 80 mL and 
chooses not to submit (e.g., the subject states this collection represents a 
typical very heavy cycle and she only returns 4 lightly stained pads), the 
subject should be discontinued 
• Collect all used hygiene products for shipping to KCAS lab 
o Interview subject for feminine hygiene collection compliance  
o Dispense additional hygiene products as needed  
• Scheduling of Visit 5: 
o Schedule for IUS insertion at a time after expect to receive AH results and as 
per Visit 5 instructions (see Section 6.8.1) 
o Instruct subject to contact site with onset of next menses if occurs before 
next scheduled appointment 
o If the subject is unable to comply with the scheduling requirements then she 
is a screen failure; do not proceed further 
6.7.3.8 Between Screening Visit 4 and Enrollment Visit 5 (Review of Cycle 3 AH results) 
• Check pending test results for return daily starting at 7 business days after shipment 
and review within 3 business days of receipt 
o If MBL is ≥80 mL, the subject the subject meets MBL eligibility and 
continues to Visit 5 as scheduled 
o If MBL is <80 mL the subject is to be discontinued (screen failure) and 
contacted to inform her that she is discontinued from the study 

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6.8 
Treatment Phase Enrollment Visit (Visit 5) 
The Treatment Phase Visit 5 should occur within 45 days of the screening visit (i.e., Visit 3 or 
Visit 4) that determined eligibility.  An IUS insertion attempt enrolls the subject into the 
Treatment Phase.  Second insertion attempts are allowed and can occur on the same day or 
different day, but a second attempt must be within 30 days of the first attempt.  The day of 
successful IUS insertion is considered Study Day 1.   
6.8.1 Enrollment visit (insertion) scheduling 
• The LNG20 IUS can be inserted at any time the provider is reasonable certain the 
woman is not pregnant.  Consider the possibility of ovulation and conception 
prior to initiation of the product 
• If the LNG20 IUS is inserted after the first 7 days of the menstrual cycle and the 
subject is not using permanent contraception, she should use a barrier 
contraceptive method or abstain from heterosexual vaginal intercourse for 7 days 
after insertion to prevent pregnancy 
6.8.2 Enrollment Procedures 
• Prior to IUS insertion attempt: 
o Review medical history changes since the prior visit 
o Review medication history changes since the prior visit 
o Obtain blood pressure, pulse and weight 
o Obtain high sensitivity urine pregnancy test (if test is positive then subject is 
a screen failure) 
o Confirm eligibility criteria 
o Subject completion of Baseline VAS questionnaire (Appendix D) 
o Collect venous blood sample for hemoglobin, hematocrit, ferritin 
o Perform pelvic exam (repeat exam if second insertion attempt on separate 
day) 
▪ Perform Chlamydia and gonorrhea testing if the subject has a new 
sexual partner since the Screening Phase Visit 1  

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• IUS insertion can occur without test results 
• Women with positive tests should be contacted and receive 
treatment as soon as possible without waiting for the next 
study clinic visit 
▪ If a pelvic exam demonstrates signs of acute cervical or uterine 
infection, provide appropriate antibiotic treatment and postpone the 
insertion attempt until subject is considered clinically cured for at 
least 7 days 
▪ Vaginal infections (e.g., trichomaniasis, symptomatic bacterial 
vaginosis or symptomatic vaginal candidiasis) can be treated at the 
time of IUS insertion 
• Insert the study IUS using the techniques described in the Investigator’s Brochure 
o Up to two attempts for insertion can be made (on the same day or 30 days of 
each other) 
▪ If a second attempt is performed on a different day, repeat all steps 
listed under “Prior to IUS insertion attempt” except blood testing and 
VAS questionnaire 
▪ Each attempt should use a new IUS 
o If the IUS is unable to be inserted after two attempts or the uterus sounds to 
<5.5 cm: 
▪ If there are no AEs related to the insertion attempt (s), the subject 
will be discontinued from the study and is not required to have any 
subsequent study-related follow-up 
▪ If there are AEs related to the insertion attempt (s) the subject should 
be followed at appropriate intervals by clinic visit or telephone 
contact until the adverse event resolves or has stabilized, after which 
the subject can be discontinued from the study 
• Evaluate for adverse events related to IUS placement procedure 
• Distribute study-specific feminine hygiene products and diaries as needed 
• Instruct subjects on the following 

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o How to correctly check for the IUS string in the vagina (subjects will not be 
required to routinely check for IUS placement but if a subject believes the 
IUS is expelled or no longer in the correct place, she can check for the IUS 
string if she desires) 
o Do not use a Diva Cup to collect bleeding because it could cause IUS 
expulsion; only use the provided feminine hygiene products 
o Call for an urgent study visit if she: 
▪ Suspects she is pregnant 
▪ Has expelled the IUS (if subject has the expelled IUS, she should 
bring it to the study site at the next visit) 
▪ Has symptoms of a pelvic infection 
▪ Attempts to feel the strings and cannot feel them 
▪ Believes she feels the IUS in her cervix or vagina 
o If an urgent study visit is required, she should refrain from having sex or use 
appropriate non-hormonal contraception until a study evaluation is 
completed 
• Counsel regarding STI precautions 
• Schedule Visit 6 for 4 to 6 weeks after successful study IUS insertion (Day 28 to 
Day 42) 
• Register subject in the Enrollment eCRF 
6.9 Treatment Phase Visits and Contacts 
All follow-up will be based on 28-day Cycles.  Post-insertion study evaluations will occur at 
Treatment Phase Visit 6 (Day 28 to Day 42) and Visit 7 (Day 85 to Day 105).   
6.9.1 Visit 6 
• Timing:  Day 28 to 42 
• Procedures: 
o Review of adverse events or changes in medical history since the prior visit 
o Review of concomitant medications 
o Inquire about change in sexual partner 

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o Collect and review daily diary for completeness 
o Dispense additional diaries and feminine hygiene products as needed 
o Physical examination and testing 
▪ High sensitivity urine pregnancy test (if positive, see Section 7.4) 
▪ Blood pressure, pulse and weight 
▪ Any clinically indicated physical examination 
▪ Clinically verify presence of IUS by palpation or direct visualization of 
strings (for missing strings management see Section 6.13 and Appendix 
G) 
▪ Chlamydia and gonorrhea testing for any subject following a change in 
sexual partner since the last study visit 
• Women with positive tests should be contacted and receive 
treatment as soon as possible without waiting for the next study 
clinic visit 
o Instruct her to start collecting all used feminine hygiene products with evident 
blood between Day 57 and Day 84  
▪ Day 57 would include any products initiated prior to going to sleep the 
night before but removed on Day 57 
▪ Any products initiated the evening of Day 84 but removed the next 
morning would not be collected 
o Schedule next appointment (Visit 7) ideally for Day 85 to Day 89, but up to Day 
105 is allowed 
6.9.2 Contact Day 50 to Day 56 
• Remind subject to: 
o Start collecting all used feminine hygiene products with evident blood collection 
between Day 57 and Day 84 
▪ Day 57 would include any products initiated prior to going to sleep the 
night before but removed on Day 57 
▪ Any products initiated the evening of Day 84 but removed the next 
morning would not be collected 

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o Dispose of any used products from prior to Day 57 or after Day 84  
o Confirm date and time for Visit 7 appointment 
6.9.3 Visit 7 (Cycle 3) 
• Timing: 
o Ideal:  Day 85 to 89 (Cycle 3, days 1-5) 
o Allowable:  up to day 105 (Cycle 3, days 1-21) 
• Follow-up Procedures: 
o Review of adverse events or changes in medical history since the prior visit 
o Review of concomitant medications 
o Inquire about change in sexual partner 
o Collect and review daily diary for completeness 
o Subject completion of Treatment VAS questionnaire (Appendix E) 
o Dispense additional diaries and feminine hygiene products as needed 
o Physical examination and testing 
▪ High sensitivity urine pregnancy test (if positive, see Section 7.4) 
▪ Blood pressure, pulse and weight 
▪ Any clinically indicated physical examination 
▪ Clinically verify presence of IUS by palpation or direct visualization of 
strings (for missing strings management see Section 6.13 and Appendix 
G) 
▪ Chlamydia and gonorrhea testing for any subject following a change in 
sexual partner since the last study visit.  
• Women with positive tests should be contacted and receive 
treatment as soon as possible without waiting for the next study 
clinic visit 
o Collect all feminine hygiene products collected between Day 57 and Day 84 
o Interview subject for feminine hygiene collection compliance  
o Collect venous blood for: 
▪ Hemoglobin/hematocrit and ferritin 
▪ AH assay sample 

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o Instruct her to start collecting all used feminine hygiene products with evident 
blood between Day 141 and Day 168  
▪ Day 141 would include any products initiated prior to going to sleep the 
night before but removed on Day 141 
▪ Any products initiated the evening of Day 168 but removed the next 
morning would not be collected 
o Schedule next appointment (Visit 8) ideally for Day 169 to Day 174, but up to 
Day 189 is allowed 
6.9.4 Contact Day 133 to Day 140 
• Remind subject to: 
o Start collecting all used feminine hygiene products with evident blood collection 
between Day 141 and Day 168  
▪ Day 141 would include any products initiated prior to going to sleep the 
night before but removed on Day 141 
▪ Any products initiated the evening of Day 168 but removed the next 
morning would not be collected 
o Dispose of any used products from prior to Day 141 or after Day 168  
o Confirm date and time for Visit 8 appointment 
6.10 
Study Treatment Phase Completion/Early Discontinuation (Visit 8) 
• Timing:  
o Completion of 6 cycles of LNG20 IUS use 
▪ Ideal:  Day 169 to Day 174 (within 5 days of completing 6 cycles) 
▪ Allowable:  up to Day 189 allowed (up to 21 days after completing 6 
cycles) 
o Early discontinuation 
• Procedures: 
o Review of adverse events or changes in medical history since the prior visit 
o Review of concomitant medications 
o Inquire about change in sexual partner 
o Collect and review daily diary for completeness 

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o Subject completion of Treatment VAS questionnaire 
o High sensitivity urine pregnancy test (if positive, see Section 7.4) 
o Weight, pulse and blood pressure  
o Any clinically indicated physical examination 
o Clinically verify presence of IUS by palpation or direct visualization of strings 
(for missing strings management see Section 6.13 and Appendix G) 
o Chlamydia and gonorrhea testing for any subject following a change in sexual 
partner since the last study visit. 
▪ Women with positive tests should be contacted and receive treatment as 
soon as possible  
o Breast and pelvic exam (if not performed within the last 3 months) 
o IUS removal 
▪ If participant has contraindication to continuing IUS use or desires 
removal then perform IUS removal procedure 
▪ If no indication for removal, discuss option of continuing IUS or 
removal; remove IUS for all women that desire to discontinue IUS 
o Retain all removed or expelled IUSs as described in the Study Reference Manual 
o Collection of feminine hygiene products: 
▪ If completed full protocol: collect all products collected between Day 
141 and Day 168  
▪ If early discontinuation coinciding with Visit 7 (Cycle 3): collect all 
products collected between Day 57 and Day 84 
▪ If early discontinuation not coinciding with a complete Visit 7 or Visit 8 
collection window: no product collection 
o If collected feminine hygiene products: 
▪ Interview subject for feminine hygiene collection compliance  
▪ Collect venous blood for: 
• hemoglobin/hematocrit and ferritin (if not obtained within the 
prior 6 weeks) 
• AH assay sample  

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6.11 
Safety Follow-Up 
All subjects for whom the IUS was removed will be contacted 7 to 10 days after the study exit visit 
to assess for any post-IUS removal bleeding and cramping (if applicable), and any IUS-related or 
IUS procedure-related adverse events.  After completion of the Treatment Phase, all subjects with 
ongoing IUS-related adverse events that are not resolved or stabilized will have monthly contacts or 
visits, as appropriate, until the event is resolved or stabilized.   
 
6.12 
Unscheduled Visits 
Subjects may require an evaluation at times other than the scheduled visits.  An unscheduled visit 
should only be conducted when the subject reports problems that are related to the IUS, study 
safety issues or if repeat laboratory testing is required.  In such circumstances, the unscheduled 
visit should be performed by a study clinician to review any change in medical history and 
perform any examination and testing as clinically indicated. 
6.13 
Diagnostic Ultrasound Examinations 
Diagnostic ultrasound examinations may be required during the study for pregnancy (see 
Appendix F), missing IUS strings (see Appendix G), confirmation of IUS location or possible 
IUS related adverse events.  Any time an ultrasound examination is performed for diagnostic 
purposes, the image must be documented in a photo or digital image to be included in the source 
documentation.  If the exam is not documented in a formal report, a high resolution copy of the 
image documentation should be forwarded within 5 business days for a verifying review by the 
Sponsor as described in the Study Reference Manual.  All ultrasound findings should be 
documented as follows: 
• Printed image(s) with the subject’s study number on the image 
• Indication, impression and plan related to the images written in the source documentation 
All ultrasound examination documentation should be maintained with the subject’s study source 
documentation.   
For details regarding the sponsor review of study-related ultrasound exams see the Study 
Reference Manual. 

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6.14 
Pap Testing  
Screening Pap testing must demonstrate that no further evaluation or treatment is required during 
the course of study participation (i.e., within approximately 10 months after screening).  A prior 
printed cytology report may be used in place of performing Pap testing at the Screening Visit 1. 
6.15 
Management of Abnormal Testing During the Study 
Clinically significant study-related results should be managed as follows: 
• Gonorrhea or Chlamydia:  treatment in accordance with current Centers for Disease Control 
and Prevention (CDC) guidelines.  The IUS should not be removed because of a positive 
test or a diagnosis of cervicitis  
• Hemoglobin/hematocrit and ferritin:  a value consistent with clinically significant anemia 
should be evaluated and treated within the local standard of care 
6.16 
Management of Unevaluable Testing During the Study 
An unevaluable test is any test for which the sample or specimen could not produce a result. 
• Screening Phase Tests: 
o Visit 2 allows for repeat of unevaluable tests 
o If the samples or specimens from Visit 2 are also unevaluable then repeat at Visit 3 –
the results must be available and reviewed for eligibility prior to enrollment 
• Treatment Phase Tests (including Treatment Phase Discontinuation/Early Discontinuation) 
o Unevaluable hemoglobin/hematocrit or ferritin should be repeated as soon as 
possible at an Unscheduled Visit 
 
RISK-BENEFIT AND SAFETY ASSESSMENTS 
7.1 
Risk-Benefit 
7.1.1 Menstrual Changes 
Women with heavy menstrual bleeding who use a LNG 52 mg IUS generally experience a 
change in bleeding patterns with a trend toward reduction of MBL (Lethaby et al., 2009).  The 
reduction in MBL with LNG 52 mg IUS is greater than that achieved with combined oral 

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contraceptives (COC), tranexamic acid, or long-course (≥3weeks/cycle) oral progestins (Bitzer et 
al., 2015).   
In a randomized study comparing LNG 52 mg IUS to MPA over 6 months, approximately 85% 
of the LNG IUS users had successful treatment compared to 22% of MPA users.  Treatment 
success was defined as achieving MBL of <80 mL and at least a 50% reduction from baseline.  
Additionally, bleeding was rated as significantly improved according to investigator assessment 
(93.6% LNG IUS vs. 61.0% MPA) and self-assessment (93.6% LNG IUS vs. 67.1% MPA) 
(Kaunitz et al., 2010).  In a randomized study in Europe comparing LNG20 IUS to Mirena, both 
products produced similar reductions in MBL after the 6 months of study treatment (79.0% vs. 
79.2%, respectively) (Mawet et al., 2014). 
A study comparing the LNG 52 mg IUS to a usual-treatment group (tranexamic acid, mefenamic 
acid, COC or oral progesterone) demonstrated that improvements as measured by the patient-
reported Menorrhagia Multi-Attribute Scale (MMAS) were significantly higher at the end of 6 
months of treatment with the LNG IUS group compared to the usual treatment group (32.7 points 
and 21.4 points, respectively).  Additionally, improvements in all MMAS domains (practical 
difficulties, social life, family life, work and daily routine, psychological well-being, and 
physical health) were significantly better for the LNG IUS group.  At the end of two-years 64% 
of the LNG IUS group continued to use the product compared to 38% of the usual-treatment 
group (Gupta et al., 2013).   
Hemoglobin and ferritin values increase with LNG 52 mg IUS use in women with HMB.  In a 
randomized study assessing the efficacy of a LNG IUS and oral MPA (10 mg/day for 10 days) in 
women with confirmed HMB, hemoglobin and serum ferritin levels were assessed at baseline, 
and at Cycles 3 and 6 of treatment.  Baseline median hemoglobin and ferritin levels were 12.4 
g/dL and 19.0 mcg/L with the LNG IUS and 12.2 g/dL and 19.0 mcg/L with oral MPA, 
respectively. At Cycle 6, the corresponding medians were 13.4 g/dL and 34.0 mcg/L with the 
LNG IUS and 12.6 g/dL and 21.0 mcg/L with oral MPA (Kaunitz et al., 2010). The increases 
from baseline to Cycle 6 were greater in the LNG IUS group than in the oral MPA group for 
hemoglobin levels (7.5% vs. 1.9%; p<.001) and median serum ferritin levels (68.8% vs. 14.3%; 
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Of note, amenorrhea rates in women who use the LNG 52 mg IUS for HMB are lower than the 
rates reported in women who use the LNG 52 mg IUS primarily for contraception. In 
contracepting women, approximately 20% of women are amenorrheic for a period of 90 days or 
more by the end of the first year of use (Andersson et al., 1994, Schreiber et al., 2018); this 
amenorrhea rate is reached within about 9 months of use (Schreiber et al., 2018).  Pooled data 
from four randomized trials comparing the levonorgestrel 52 mg IUS to medroxyprogesterone 
acetate orally, tranexamic acid orally, mefenamic acid orally and endometrial resection in 163 
women with HMB demonstrates the change in bleeding seen in this specific population (Jensen 
et al., 2013).  Amenorrhea rates in this population were 2% at 6 months and 9% at one year.  By 
one year, an additional 24% were reporting infrequent bleeding/spotting.  Only 6% of women 
using the LNG 52 mg IUS for HMB in these trials discontinued for bleeding complaints. 
Overall, participants are expected to primarily experience a reduction in flow with study product 
use. 
7.1.2 Contraception 
Subjects at risk for pregnancy should be using a contraceptive method during screening phase. 
However, during the Treatment Phase, subjects are not required to use a contraceptive other than 
the LNG20 IUS. Any method of contraception may not prevent pregnancy.  LNG20 IUS is 
currently FDA-approved for contraception for up to 6 years of use.  
 
 
 
 
 
 
 
 
 

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expulsion.  
 
 
7.1.3.2 Ectopic Pregnancy 
Women who become pregnant while using an LNG IUS can experience an ectopic (extrauterine) 
pregnancy.  Overall, the risk of a woman having an ectopic pregnancy is lower than the general 
population because the risk of pregnancy is significantly decreased.  
 
 
 
 
 
7.1.3.3 Effects on gestation and offspring 
When pregnancy continues with the LNG20 IUS in place, the risks of long-term effects on the 
offspring are unknown.  Based on data from copper IUDs, pregnancies that continue are at an 
increased risk of pre-term (<37 weeks) delivery as compared to women who conceive without an 
IUD in place (Ganer et al., 2009).  The risk is highest if the IUD is not removed (18%) as 
compared to if the IUD is removed (14%); the risk in the general population is around 7%.  
Additionally, pregnancies that continue are also at a higher risk of being complicated by 
chorioamnionitis; 7% if the IUD remains, 4% if the IUD is removed, and slightly less than 1% in 
the general population (Ganer et al., 2009).  It is unknown whether these risks are similar for 
women who conceive while using a LNG IUS. 
7.1.4 Difficult Insertion/Removal 
 
  
 
 
 
 
 

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Management of difficult insertion and removal are outlined in Appendix G. 
7.1.5 Expulsion 
  
The expulsion rate in the first year in women using a LNG 52 mg IUS for HMB is approximately 
the same (3.9%) (Mawet et al., 2014).  Expulsion management is outlined in Appendix G. 
7.1.6 Pelvic Infection 
 
 
  Pelvic infection management is outlined in 
Appendix G. 
7.1.7 Perforation 
The incidence of uterine perforation during a LNG20 IUS placement attempt in the M360-L102 
study is 0.1% (Eisenberg et al., 2015).  Perforation management is outlined in Appendix G. 
7.1.8 Pelvic/Abdominal Pain 
Some women experience pelvic pain or cramping with insertion and a small percentage notice 
continued or intermittent pain with continued use of LNG20 IUS.  Pain may be due to uterine 
cramping (perhaps related to placement or the presence of the IUS) or functional ovarian cysts.  
However, there is no clear data on whether the incidence of functional ovarian cysts is increased 
in LNG20 IUS users as compared to the general population.  In the M360-L102, ovarian cysts 
over multiple years of use are reported in 4.5% of women and discontinuation for ovarian 
functional cysts occurred in only 0.3% (Teal et al., 2019). 
 

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7.1.9 Systemic Side Effects 
Although systemic levonorgestrel levels are very low, women using LNG20 IUS do report 
progestin-related side effects, albeit at low rates.  Use of a LNG IUS may affect glucose 
tolerance; subjects with diabetes should continue routine monitoring of blood glucose 
concentration with their diabetes care provider. 
7.1.10 Mortality  
The risk of death with IUD use ranges from 1 to 6 per million users per year.  This rate is lower 
than all other female methods of contraception and lower than use of no contraception when 
considering the risk of pregnancy (Harlap et al., 1991). 
7.1.11 Missing Strings 
Rarely, the IUS strings may not be visible during a speculum examination.  The IUS is most 
typically in the uterus when strings are missing.  However, the strings could be missing because 
of a perforation or expulsion.  Missing string management, including appropriate imaging to 
determine the location of the IUS, is outlined in Appendix G. 
7.1.12 Phlebotomy 
There is an infrequent chance of pain, bruising, or bleeding at the site of the needle puncture, and 
a rare chance of fainting, inflammation of the vein, or infection.   
7.1.13 Pelvic Examination 
The subject may infrequently experience some discomfort during the pelvic exams, Pap test, and 
Chlamydia and gonorrhea testing.  Any reaction would most likely include redness, itching, 
irritation, or vulvovaginal discomfort.  Infrequently the subject may have a small amount of 
vaginal bleeding after a Pap test, Chlamydia or gonorrhea testing. 
 
 
 

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7.1.14 Endometrial Biopsy 
An endometrial biopsy commonly causes light bleeding the day of the procedure and 
uterine/pelvic cramping for a few minutes, primarily during the procedure.  Rarely, a biopsy can 
result in infection or uterine perforation.  
7.1.15 Vaginal Ultrasound 
A formal vaginal ultrasound examination will be performed for women at screening (if not 
performed within the last 6 months), if a subject has missing IUS strings, if a subject becomes 
pregnant, and for other indications that would clinically require such an examination.  Typically, 
the subject may feel mild discomfort similar to a pelvic examination.  
7.1.16 Local Anesthesia  
If the clinician uses cervical anesthesia during insertion or removal, there is an infrequent risk of 
the subject experiencing an unusual taste in her mouth, ringing in her ears, nausea or light-
headedness.  Rarely, a seizure or death can occur. 
7.1.17 Emotional Discomfort 
Some of the questions asked in this study may make the subject feel uncomfortable or 
embarrassed.  A subject can refuse to answer any question that causes emotional discomfort, 
from any person, at any time. 
7.2 
Overall Assessment of Benefits and Risks 
All available information supports a favorable risk-benefit ratio. 
7.3 
General Plan to Manage Safety 
The safety profile of currently available IUSs, as reported during clinical trials and since 
marketing approval, has been well-characterized.  Adverse events that have been reported in 
relation to IUS use, such as expulsion, vaginal bleeding, uterus perforation, and infection will be 
specifically monitored.  Serious Adverse Events will be reported as per FDA guidance. 

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7.4 
Pregnancy Assessment and Reporting 
High sensitivity urine pregnancy tests are performed at each study visit.  For any positive 
pregnancy test on IUS treatment through Visit 8/Early Discontinuation: 
• Immediately obtain a serum quantitative hCG 
• Within 3 calendar days conduct a transvaginal ultrasound for pregnancy confirmation, 
pregnancy location and date of conception 
o If the pregnancy is too early for ultrasound verification have the subject return in 
approximately 1-2 weeks for an unscheduled visit and repeat ultrasound 
examination 
• Complete a Pregnancy Narrative (See Study Reference Manual) 
If the subject reports a positive pregnancy test on her own (performed at home) she should be 
seen as soon as possible for a high-sensitivity urine pregnancy test to be performed at the clinic 
and if the test is positive perform the required procedures above.  
For pregnancies occurring before IUS discontinuation, ultrasonography will also be used to 
verify presence of the IUS in the uterus.   
All confirmed pregnancies occurring during study treatment will be followed to completion.  
Pregnancy outcomes, including normal births, septic abortions, ectopic pregnancies, birth defects, 
and premature deliveries, whenever this information is available, will be obtained. Pregnancy 
reporting should include a Pregnancy Report Form Case Report Form (CRF) and Pregnancy 
Outcome CRF.  
Pregnancy management is outlined in Appendix F. 
7.5 
Adverse Events Assessments 
During the study, the Investigator or study site personnel will be responsible for querying and 
recording adverse events (AEs) and serious adverse events (SAEs), as detailed below.  For the 
Sponsor to fulfill safety assessment obligations the Investigator should report all SAEs resulting 
from study participation (e.g., complications resulting from a study-required procedure, such as 
the taking of a blood sample).   

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7.6 
Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (that could include a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.  The Investigator should attempt to establish a diagnosis of the 
event based on signs, symptoms, and/or other clinical information.  In such cases, the diagnosis 
should be documented as the AE/SAE and not the individual signs/symptoms. 
• Any medical condition or clinically significant laboratory abnormality with an onset 
before the study IUS insertion is considered to be pre-existing and should not be 
documented in the CRF as an AE, but should be recorded as medical history.   
• Any AE (i.e., a new event or an exacerbation of a pre-existing condition) with an onset 
from the beginning of study IUS insertion through Visit 8/Early Discontinuation and the 
post-Treatment Phase safety contact (if applicable) should be recorded.   
• All AEs must be recorded regardless of the severity or relationship to study medication.   
• All AEs that result in permanent discontinuation of the investigational product must be 
reported, whether serious or non-serious. 
• An AE does include: 
o exacerbation of a pre-existing illness 
o increase in frequency or intensity of a pre-existing episodic event or condition 
o condition occurring after study IUS insertion  
o continuous persistent disease or symptoms present at baseline that worsen 
following the start of the study 
• An AE does not include: 
o medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion); the condition that leads to the procedure may be an adverse event if 
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o pre-existing diseases or conditions present or detected prior to start of study drug 
administration that do not worsen 
o situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery, social and/or convenience admissions) 
o disease or disorder being studied or sign or symptom associated with that disease 
o overdose of concomitant medication without any signs or symptoms 
7.7 
Definition of a Serious Adverse Event 
A serious adverse event (SAE) is any adverse event occurring within the timelines specified in 
the protocol that results in any of the following outcomes:  
• Death 
• Life-threatening situation  
o The subject was at immediate risk of death from the event as it occurred 
o Does not include an event that might have led to death, if it had occurred with 
greater severity 
• Inpatient hospitalization or prolongation of existing hospitalization  
o Does not require inclusion of elective surgery; however, any adverse event 
occurring during that hospitalization that prolongs the hospital stay would be an 
SAE 
o Does not have a requirement to be greater than a twenty-four hour stay; if the 
subject was admitted to the hospital for less than a day for treatment or 
observation, the definition of “Inpatient hospitalization” is met 
o Treatment in an outpatient clinic or Emergency department does not constitute 
“inpatient hospitalization” 
o Complications that occur during hospitalizations are AEs; if a complication 
prolongs hospitalization, it is an SAE 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect in the offspring of a subject who received study drug 
• Important medical events that may not result in death, be immediately life-threatening, or 
require hospitalization, may be considered an SAE when, based upon appropriate medical 

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judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias, or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
7.8 
Prompt Reporting of SAEs to Sponsor  
The Sponsor has requirements for reporting serious adverse events to regulatory agencies for a 
drug under clinical investigation.  The Sponsor must be notified within 24 hours of discovery 
and the Investigator determines that an adverse event meets the protocol definition of an SAE.  
Any fatal or life-threatening events should be reported immediately by telephone to the Sponsor. 
All SAEs occurring from the beginning of study screening through Visit 8/Early Discontinuation 
and the post-Treatment Phase safety contact (if applicable) require reporting to the Sponsor.  
Investigators should not wait to receive additional information to fully document the event prior 
to notifying the Sponsor but should provide as much relevant information as immediately 
available.  Further details of the event can be provided as they become available.  The procedures 
for reporting SAEs are in the Study Reference Manual. 
• It is very important that the Investigator provides an assessment of the causal relationship 
between the event and the study drug at the time of the initial report (see 7.10.2 for 
Causality definitions) 
• The Investigator, or responsible person according to local requirements, must comply 
with the applicable local regulatory requirements concerning the reporting of SAEs to 
regulatory authorities and the IRB 
7.9 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse 
Events and Serious Adverse Events 
Abnormal laboratory findings (e.g., clinical chemistry, hematology) or other abnormal 
assessments (e.g., X-rays, vital signs) per se are not reported as AEs.  However, abnormal 
findings that are deemed clinically significant (i.e., associated with signs and/or symptoms or 
requiring therapeutic intervention) must be recorded as AEs if they meet the definition of an 

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adverse event (and recorded as an SAE if they meet the criteria of being serious) as described 
previously.  Clinically significant abnormal laboratory or other abnormal findings that are 
detected after IUS insertion or that are present at baseline and worsen following study IUS 
insertion are included as AEs (and SAEs if serious).   
The Investigator should exercise his or her medical judgment in deciding whether an abnormal 
laboratory finding or other abnormal assessment is clinically significant.  A clinically significant 
laboratory abnormality in the absence of clinical symptoms may also jeopardize the subject and 
may require intervention to prevent immediate consequences (e.g., a markedly high serum 
potassium concentration may not be accompanied by arrhythmia, yet be of a magnitude to 
require potassium-binding resin administration to prevent such sequelae).  Subjects should 
undergo repeat testing of clinically significant abnormal laboratory findings as soon as they are 
recognized. 
7.10 Reporting of Adverse Events 
Any AE with an onset after study IUS insertion or until the final safety contact after study 
discontinuation must be documented in the subject’s study records and appropriate CRF.  
7.10.1 Adverse Event CRFs 
Specific Adverse Events are recorded on different CRFs. 
AEs related to bleeding or cramping/pain 
• With insertion - report on the IUS Insertion Questionnaire CRF 
• With removal - report on the IUS Removal Questionnaire CRF   
• During IUS use 
o The subject’s diary acts as the menstrual bleeding or cramping/pain AE CRF   
▪ Menstrual bleeding or cramping/pain should also be reported on the general 
AE CRF only if:  
• Bleeding or cramping/pain are not related to the IUS or a 
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• Bleeding or cramping/pain meet serious criteria; an SAE report 
would also have to be submitted (this exception is due to data 
system requirements)  
• Bleeding or cramping/pain result in the IUS being removed (this 
exception is due to data system requirements)  
o Bleeding and cramping event terminology-consistent use of adverse event 
terminology is essential for characterization of the product: 
▪ Heavy menstrual bleeding (increase in flow worse than baseline) 
▪ Irregular bleeding (variation in bleeding pattern) 
▪ Infrequent bleeding (bleeding episodes that are too rare) 
▪ Amenorrhea (no bleeding or spotting) 
▪ Frequent bleeding (too many bleeding/spotting episodes) 
▪ Prolonged bleeding (persistent bleeding/spotting) 
7.10.2 Causality Assessment: Adverse Event Relationship 
The Investigator’s causality assessment should consider the potential etiologies for the observed 
adverse event.  An adverse event may be related to the study drug, other concomitant 
medications, the underlying disease pathology, intercurrent illness, a procedure performed in the 
course of the study, or another reason.  Among the potential etiologies, the Investigator should 
make a determination based on the most likely causal relationship.  When a causality assessment 
is provided for a serious adverse event, it is important to include a rationale for the assessment so 
that a better understanding of the reported event can be compiled.  The rationale should be 
accompanied by all available supporting evidence, including relevant laboratory tests, 
histopathology evaluations and the results of other diagnostic procedures.  The Investigator’s 
rationale with supporting evidence is valuable when the Sponsor performs a cumulative analysis 
of similar events. 
The Investigator will assess the relationship of the AE to the study IUS or the IUS insertion or 
removal procedures by using the following general guidelines: 

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• Not Related: A causal relationship between the study IUS/procedures and the AE can be 
ruled out (e.g., based on the temporal sequence, absence of a reasonable 
pathophysiological mechanism, or direct evidence of actual cause).  
• Unlikely related: A clinical event, including a laboratory test abnormality, with a 
temporal relationship to IUS insertion or the onset of an IUS insertion or removal 
procedure which makes a causal relationship improbable, and in which other drugs, 
chemicals or underlying disease provide plausible explanations.  
• Probably Related: A clinical event, including a laboratory test abnormality, with a 
reasonable time sequence to IUS insertion or the onset of an IUS insertion or removal 
procedure, unlikely to be explained by concurrent disease or other drugs or chemicals.  
Information on drug withdrawal may be lacking or unclear.  
• Related: A clinical event, including a laboratory test abnormality, with a reasonable time 
sequence to IUS insertion or the onset of an IUS insertion or removal procedure, cannot 
be attributed to concurrent disease or other drugs or chemicals, and which follows a 
clinically reasonable response on withdrawal. 
7.10.3 Adverse Event Severity 
The Investigator will assess the severity of the AE using the following general guidelines:  
• Mild:  An AE that is usually transient, requiring no special treatment, and does not 
interfere with the subject’s daily activities 
• Moderate:  An AE that introduces a low level of inconvenience or concern to the subject 
and may interfere with daily activities, but is usually ameliorated by simple therapeutic 
measures 
• Severe:  An AE that interrupts a subject’s usually daily activity and typically requires 
systemic drug therapy or other treatment (a severe AE may not necessarily qualify as a 
SAE) 
• Life-threatening:  An AE that put the subject at immediate risk of death from the event 
as it occurred.  This does not include an event that might have led to death if it had 
occurred with greater severity. 
 

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7.10.4 Adverse Event Outcome 
The Investigator will categorize the outcome of each Adverse Event according to the definitions 
below: 
• Resolved: The subject recovered from the AE  
• Resolved with sequelae / Stable: A condition whereby the consequences of a disease or 
injury include lingering effects that are not worsening 
• Ongoing: At the time of the last assessment, the event is ongoing, with an undetermined 
outcome.  Note: Ongoing AEs are not considered resolved as a result of death and no AE 
stop date should be recorded for an AE that is ongoing at the time of death. 
• Fatal: Adverse Event directly caused death.  The Sponsor may request that the Investigator 
perform or arrange for the conduct of supplemental measurements and/or evaluations.  If a 
subject dies during participation in the study or during a recognized follow-up period, the 
Sponsor should be provided with a copy of any post-mortem findings, including 
histopathology. 
• Unknown: The outcome is not known and cannot otherwise be categorized (e.g., subject 
became lost to follow-up (LTFU) or withdrew consent) 
The Investigator should attempt to establish a diagnosis of the event based on the signs, 
symptoms and/or other clinical information.  In such cases, the diagnosis should be documented 
as the AE (and SAE if serious) and not the individual signs/symptoms. 
In the case of abnormal labs or diagnostic tests judged to be clinically significant by the 
Investigator a diagnosis, if known, or clinical signs or symptoms if the diagnosis is unknown, 
rather than the clinically significant laboratory finding or abnormal assessment, should be used to 
complete the AE/SAE page.  If no diagnosis is known and clinical signs or symptoms are not 
present, then the abnormal finding should be recorded on the AE/SAE page.  If an SAE report is 
completed, pertinent laboratory data should be recorded on the SAE form, preferably with 
baseline values and copies of laboratory reports. 
7.11 Clarification of Action Taken with IUS 
The Investigator will categorize the Action Taken with IUS according to the definitions below: 
• None:  The IUS was not removed as result of the Adverse Event  

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o IUS was left in place  
o IUS was removed at the time of the AE but due to: 
▪ A different AE 
▪ A different reason 
▪ The subject wanting the IUS removed because of the AE despite the 
investigator stating the AE was not a reason to have the IUS removed 
o IUS was already removed prior to the AE start date 
o AE was a full expulsion 
o subject was LTFU or withdrew consent prior to IUS removal 
• IUS Removed for Non-Safety Reasons: The IUS was removed for an Adverse Event 
even though the IUS could have remained in place without placing the subject at 
immediate risk for a serious complication related to the IUS 
• IUS Removed for Safety Reasons: The IUS was removed for an Adverse Event because 
the subject was at immediate risk for a serious complication as a direct result of the AE if 
the IUS had not been removed 
• Unknown:  The IUS was removed by another provider 
7.12 Clarification of “Other Action Taken” 
The investigator will indicate the specific treatment provided as a result of the Adverse Event (this 
does not include diagnostic tests or referrals). 
7.13 Clarification of Adverse Events Related to Study Procedures 
Any untoward event that occurs from the beginning of the IUS insertion procedure until 
completion of insertion, or from the beginning of the removal procedure until the completion of 
removal, will be reported as an AE.  Bleeding and cramping/pain occurring during IUS insertion 
or removal will be recorded on the IUS Insertion and Removal CRFs, as appropriate.  Any other 
insertion or removal AEs should be recorded on the AE CRF with a causality assessment of 
“related to IUS procedure.”  If any AE meets the definition of a Serious Adverse Event, even if it 
is recorded on the diary or Insertion or Removal CRF, it should also be reported on the AE and 
SAE CRFs and submitted to Sponsor.   

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7.14 Follow-up of Adverse Events and Serious Adverse Events 
All AEs and SAEs must be followed through the Safety Follow-up, and any IUS or IUS 
procedure related AEs or SAEs followed until resolution, or until the condition stabilizes, or until 
all queries are resolved, or until the subject dies or is lost to follow-up (including withdrawal of 
consent).  The Investigator is responsible to ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate as completely as practical the nature and/or 
causality of the AE/SAE.  This may include additional laboratory tests or investigations, 
histopathologic examinations, or consultation with other health care professionals.  Follow-up 
information should be submitted to the Sponsor in a timely many as the information is obtained. 
7.15 Clarification in Reporting of Deaths 
All subject deaths (regardless of relationship to study drug) should be reported that occur from 
the signing informed consent through declaring the subject as a screen failure or Visit 8/Early 
Discontinuation and the post-Treatment Phase safety contact (if applicable).  The information 
should be recorded on the Subject Death form and the SAE form.   
Death is an outcome of an adverse event and not an adverse event itself.  All reports of subject 
death should include an adverse event term (other than “death”) for the cause of the death.  Since 
reporting of an SAE is required within 24 hours of discovery, death can be reported as an initial 
event term and updated to the final diagnosis in a follow-up report.  If an adverse event term is 
not provided, the Investigator will be queried to obtain the cause of death.  Only in the rare 
occurrence that no verbatim description of an adverse event can be obtained from the 
investigative site will “Death – Unknown Cause” be used as the event term. 
7.16 Post-Study Treatment Reporting Requirements 
For all enrolled subjects, all AEs and SAEs, regardless of cause or relationship that occur from 
IUS discontinuation through the Safety Follow-up require reporting to the Sponsor.  In addition, 
if the Investigator learns of any SAE at any time after a subject has discontinued study drug, and 
such event seems reasonably related to study drug, the Investigator should promptly notify the 
Sponsor. 

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7.17 Subject Withdrawal 
7.17.1 Criteria for Withdrawal of Subject from Treatment 
The following criteria will be used to determine when a subject should be withdrawn from 
treatment (removal of study IUS): 
• Subjects may choose to discontinue IUS use at any time during the study  
• Subjects who become pregnant during study participation will have the IUS removed   
o Subjects who become pregnant during study treatment will continue to be followed 
until pregnancy completion or termination to determine health-related outcomes of 
the pregnancy 
o The Investigator will provide pregnancy outcome information as a follow up to the 
initial pregnancy reporting form 
• When IUS perforation occurs during insertion or while on treatment, the IUS will be 
removed and the subject will be discontinued 
• Subjects who experience an IUS expulsion (partial or complete) unless a second study IUS 
can be inserted within 2 weeks (one-time only) and reinsertion occurs at least 7 days prior to 
and not during either treatment Cycle 3 or Cycle 6 
• The Investigator or Sponsor may discontinue a subject from treatment for other reasons.  
These may include, but are not limited to, the following:   
o Noncompliance with return visit schedule, diary completion, or use of an excluded 
therapy 
o A clinically significant IUS-related adverse event or the development of a new 
significant medical condition that compromises the subject’s ability to participate in 
the study 
o Determination that it is not in the subject’s best interest to continue treatment 
7.17.2 Withdrawal from the Study 
The following criteria will be used to determine when a subject should be withdrawn from the 
study:   
• A subject may withdraw consent for further participation in the study at any time without 
giving a reason   

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• A subject may choose to stop participation in the study for any reason.  If the subject has 
not withdrawn consent and has an IUS in place they should be brought in for IUS 
removal and have appropriate safety follow-up procedures.  
• A subject may also be discontinued from the study at the request of the Investigator or the 
Sponsor.  If the subject has an IUS in place they should be brought in for removal and 
have appropriate safety follow-up procedures.   
• Sponsor decision to terminate the study or discontinue the investigative site’s 
participation 
Reasons for subject withdrawal from the study should be documented in the subject's file and 
entered into the CRF. 
Subjects that are designated as withdrawn from the study, lost to follow-up or who withdraw 
consent may not re-enter the study and no further data collection will occur. 
7.17.3 Screen Failures 
A Screen Failure is defined as any subject that has given consent to participate in the study (i.e. 
signed an Informed Consent Form) and subsequently was not enrolled for IUS insertion. 
7.17.4 Missed Visits/Contacts and Lost to Follow Up  
All reasonable efforts should be made to ensure that subjects in screening and enrolled subjects 
return to the investigational site for all study visits. Once a subject is designated as lost to follow-
up, no additional information is to be obtained on any outcomes and no further study-related 
activities are to be conducted, even if the subject later resumes contact. 
7.17.4.1 During Screening 
Any subject who misses a scheduled visit should have further contact attempts by the study staff 
as follows: 
• At least three documented attempts to contact the subject by phone, e-mail or similar 
mode of communication 

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• If the subject cannot be contacted, or is contacted and still fails to come in for a scheduled 
visit, a certified letter must be sent to the subject indicating that she will be considered a 
screen failure (lost to follow-up) and cannot continue in the study 
7.17.4.2 After Enrollment 
Any subject who misses a scheduled visit should have further contact attempts by the study staff 
as follows: 
• At least three documented attempts to contact the subject by phone, e-mail or similar 
mode of communication 
• If the subject cannot be contacted, or is contacted and still fails to come in for a scheduled 
visit, a certified letter must be sent to the subject indicating the importance of follow-up 
and instructed to contact the site immediately 
• If subject contact for either a missed Visit 6 or Visit 7 is unsuccessful then future 
attempts should be made at the time of the next expected study visit  
o At least three documented attempts to contact the subject by phone, e-mail or 
similar mode of communication should be completed 
o If the subject cannot be contacted or is successfully contacted but still fails to be 
seen for a scheduled study visit, a certified letter must be sent to the subject 
indicating the importance of follow-up and should be instructed to contact the site 
immediately. The letter should indicate that failure to reply within 30 days of the 
letter date will result in study discontinuation and no future study-related 
activities will be provided.  Certified letters do not need to be sent for subsequent 
missed study visits if a previous delivery attempt was unsuccessful (letter returned 
or accepted with no subsequent response). 
A subject should be considered lost to follow-up when: 
• A subject in the Treatment Phase does not report for V8 
• The safety follow-up contact (if applicable) is missed and three documented contacts and 
a certified letter do not result in subject contact within 14 days of the end of the expected 
contact window 

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7.17.5 Withdrawal of Consent 
Subjects expressing a desire to withdraw consent for participation in this study should have no 
further study-related activities conducted.  It is preferable that a subject documents her 
withdrawal of consent in writing.   
 
DATA QUALITY CONTROL AND ASSURANCE 
Electronic Case Report Forms (eCRFs) for this study will be designed and provided by 
  eCRFs will be completed by authorized study staff at each study location and 
transmitted to 
  Daily diary entries by the subject will be entered into an eCRF by site 
staff.  
 will be responsible for data management of this trial, including quality checking 
of CRFs.  In the event of incomplete or inconsistent data, requests for data correction will be sent 
to the sites for resolution.  A complete audit trail of changes to the data will be maintained and 
available from the clinical trial database.  Laboratory data (e.g., hemoglobin/hematocrit, ferritin, 
chemistry, quantitative hCG, urine pregnancy, Chlamydia, gonorrhea, FSH, TSH, PRL, vWF, 
ALT, AST) will be collected utilizing the site’s local accredited laboratory (unless performing 
CLIA-waived tests).  The site will enter the laboratory values for subjects in the clinical trial 
electronic database.  The Data Management Plan will describe the quality checks that will be 
performed on the CRFs and the electronic data.  CRFs and correction documentation will be 
converted to pdf format and bookmarked for indexing.  Records retention for study data will be 
consistent with 
 standard procedures.  Routine system backup and archiving will also 
be performed based on 
 standard procedures. 
This study will be conducted in accordance with all applicable FDA guidances and regulations. 
 
PLANNED STATISTICAL METHODS 
The following statistical methods will be used to assess the efficacy and safety of LNG20 IUS 
for the treatment of HMB.  Prior to implementing the analysis a detailed statistical analysis plan 
will be written. 

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9.1 
Sample Size 
Eligible subjects 18-50 years of age will include approximately 100 subjects using LNG20 IUS.  
The sample size estimate is based on results from previous studies with similar endpoints as well 
as the goal of a lower 95% confidence around the point estimate of the primary outcome with 
acceptable precision, i.e., being no more than 10% lower than the point estimate. The estimation 
of the required number of subjects needed to evaluate the efficacy of the LNG20 IUS is based on 
the following assumptions:  
• The expected successful treatment rate is estimated to be 80% or higher 
• The lower bound of 95% confidence interval should be within 10% from the point 
estimate, i.e., 70% or higher to establish the efficacy of LNG20 IUS for the treatment of 
HMB 
• Early discontinuations due to dropouts, IUS expulsions, pregnancies and other reasons 
will not exceed 15% 
A sample size of 85 will provide at least 71.5% lower bound of the 95% confidence interval for 
an expected successful treatment rate of 80% or higher based on normal approximation. 
Therefore, 100 subjects using LNG20 IUS will provide sufficient number of subjects, for the 
goal of approximately 85 subjects completing the trial.  
Subjects who discontinue treatment for any reason other than a one-time study IUS replacement 
within two weeks of a complete or partial expulsion will not be replaced. 
9.2 
Analysis Populations 
The following subject populations will be created: 
• Safety (Safety):  All subjects enrolled who underwent the IUS insertion procedure, 
regardless of outcome. 
• Modified-Intent-To-Treat (MITT):  All subjects at study entry for whom the IUS is 
successfully placed in the uterus with valid baseline data and for whom there is at least 
one assessment of MBL during the treatment phase. 
• Per Protocol (PP):  A subset of the MITT population that excludes subjects with major 
protocol deviations (to be identified prior to data lock). 

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9.3 
Disposition of Subjects 
The number of subjects, who are enrolled, receive an IUS, are discontinued due to failed IUS 
insertion, have an IUS removal or expulsion, completed each scheduled study visit and who 
complete the study will be summarized. 
9.4 
Demographic and Other Subject Characteristics 
Subject demographics and pre-treatment characteristics will be summarized.  
9.5 
Extent of Exposure 
Exposure to study IUS will be summarized by treatment duration.  
9.6 
Pre-trial and Concomitant Medications 
Concomitant medications include any medication or health product (any prescription 
medications or over-the-counter preparations) taken during the screening phase through the 
active study treatment phase.  Pre-trial medications include any medications taken within seven 
days (30 days for anticoagulants) of Screening Visit 1.  The number and percentage of subjects 
using medications, as captured on the Concomitant Medication CRF form, will be tabulated 
according to the medication’s World Health Organization Anatomical Therapeutic Drug Class 
and Generic Name by treatment group and overall.  Pre-trial and concomitant medications will 
be presented separately. 
9.7 
Primary Outcome  
The primary outcome measure will be the proportion of subjects with successful treatment of 
heavy menstrual bleeding based on the decrease in MBL from baseline to 6 months (during the 
sixth 28-day cycle) after initial LNG20 IUS insertion. This outcome will be established in the 
Modified-Intent-To-Treat (MITT) population measuring the change in absolute value from 
baseline MBL to the end of treatment MBL. Baseline MBL is the MBL averaged over each of 
the cycles measured during the Screening Phase. A subject with successful treatment will be 
defined as: 
• the end of treatment MBL <80 mL, and 

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• a decrease to a value of no greater than 50% of the baseline MBL 
The primary outcome measure will be analyzed with 95% confidence interval based on normal 
approximation. The efficacy of LNG20 IUS for the treatment of heavy menstrual bleeding will 
be established in this study if the lower bound of the 95% confidence interval equals or exceeds 
70%.  
9.8 
Key Secondary Outcomes 
All key secondary outcomes will be summarized by descriptive statistics using the MITT 
Population except that the bleeding and/or spotting analyses will be summarized using both Safety 
and MITT Populations. 
• Absolute change in baseline MBL to mid-treatment MBL (Cycle 3) 
• Percent change from baseline MBL to mid-treatment MBL (Cycle 3) 
• Absolute change from baseline to end of treatment (Cycle 6) 
• Percent change from baseline MBL to end of treatment MBL (Cycle 6) 
• Changes from baseline to mid-treatment (Cycle 3), from mid-treatment (Cycle 3) to end 
of treatment (Cycle 6) and from baseline to end of treatment (Cycle 6) in the number of 
days of bleeding, spotting, bleeding and spotting and number of bleeding episodes 
9.9 
Other Secondary Outcomes 
All other secondary outcomes will be analyzed using the Safety Population unless noted 
otherwise. 
• Percent change in hemoglobin, hematocrit and serum ferritin from baseline to mid-treatment 
(Visit 7), from baseline to end of treatment (Visit  8) and from mid-treatment (Visit 7) to end 
of treatment (Visit 8) 
• Continuation rate during Treatment Phase 
• Cumulative IUS continuation rates at Treatment Phase Visit 6, Visit 7 and Visit 8 will be 
summarized using Kaplan-Meier methods 
• Adverse events 
The number and percentage of subjects with each adverse event and serious adverse event 
will be presented by MedDRA system organ class, preferred term, and treatment group.  

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Summaries will also be presented by relationship to the type of IUS or IUS insertion or 
removal procedure and the severity of the adverse event.  All adverse events will be 
summarized with special attention to those events that may be related to an IUS, including: 
o Perforation of the uterus; 
o Low abdominal pain (not classified as dysmenorrhea); 
o Uterine infection (including PID); and 
o Other urogenital infections 
• IUS Expulsion Rates 
o Cumulative IUS expulsion rates at Treatment Phase Visit 6, Visit 7 and Visit 8 
will be summarized using Kaplan-Meier methods 
• IUS Safety-Related Removal Rates 
o Cumulative IUS safety-related removal rates at Treatment Phase Visit 6, Visit 7 
and Visit 8 will be summarized using Kaplan-Meier methods 
• Vaginal Bleeding Flow 
o Vaginal bleeding flow (none, spotting, and light, normal, or heavy flow 
[bleeding]) will be summarized by incidence and duration of bleeding.  Vaginal 
bleeding is recorded on the daily diary during the Screening Phase and baseline 
will be considered the worst flow severity during the screening cycles.   
▪ Based on World Health Organization (WHO) terminology, bleeding and 
spotting are defined as:  
- 
Bleeding: any bloody vaginal discharge for which protection, such 
as pads is used 
- 
Spotting: any bloody vaginal discharge for which protection is not 
used (for women who use mini pads for daily protection, extra 
protection is not required); if spotting and bleeding occur on the 
same day, it is recorded as a bleeding day 
o Vaginal Bleeding Episodes 
▪ Based on the individual subject’s daily dairy of bleeding 
- 
A bleeding day is when sanitary protection is used 

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- 
A bleeding episode is defines as light, normal or heavy bleeding 
during a minimum of one day as defined by a subject’s subjective 
assessment 
- 
A bleeding-free day is defined as a day with either no bleeding or 
only spotting (defined as not requiring sanitary protection except 
for panty liners) 
- 
A single bleeding episode will consist of all bleeding days 
separated by no more than one bleeding-free day.  Separate 
bleeding episodes will consist of bleeding days separated by more 
than one bleeding-free day.  An episode will be considered stopped 
with two consecutive bleeding-free cycles. 
• Dysmenorrhea 
Dysmenorrhea (none, mild, moderate, or severe) will be summarized by the number and 
percentage of days with a particular pattern during each 28-Day interval and the last 90-
day interval after enrollment through IUS Discontinuation.  In addition, dysmenorrhea 
changes from baseline (as established by the worst cramping during the screening cycles) 
will be summarized using shift tables.  
• Other Outcomes 
Changes in other outcomes such as physical exam, vital signs and pelvic exam, will be 
summarized using descriptive statistics as appropriate. 
9.10 
Study Stopping Rules Based on Safety 
The study will be stopped if safety issues arise that are inconsistent with the medical and 
scientific understanding of the expected benefits of treatment with a LNG 52 mg IUS in women 
with HMB. 
 
ADMINISTRATIVE CONSIDERATIONS 
10.1 
Ethical Considerations 
All subjects will be counseled that IUS use does not protect against HIV infection or other sexually 
transmitted infections (STIs).  If a subject feels she is at risk of contracting a sexually transmitted 

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infection, she will be advised to use a male condom until the risk abates.  If a subject becomes HIV 
positive or contracts a sexually transmitted infection during the course of the study, the subject will 
be treated or referred for treatment and, as appropriate, referred to counseling services per CDC 
guidelines. 
10.2 
Administrative Structure 
This trial will be sponsored by Medicines360 and managed with 
  Approximately 30 
sites in the U.S. will participate in this study to enroll approximately 100 subjects.   
10.3 
Responsibilities 
10.3.1 Good Clinical Practice 
The Investigator and Sponsor will ensure that this study is conducted in full compliance with 
“Declaration of Helsinki” (as amended in Tokyo, Venice, Hong Kong, South Africa, Edinburgh 
and clarified in Washington and Tokyo), International Conference on Harmonisation (ICH) 
guidelines, and all applicable FDA guidances and regulations. 
10.3.2 Institutional Review Board (IRB) Approval 
The protocol, informed consent form and Investigator’s Brochure must be submitted to the 
appropriate IRB for the investigative site. The investigative site should use the central IRB if that 
site has no local IRB or if the institutional IRB has a reliance agreement with the central IRB. 
The protocol and informed consent form for this study must be approved in writing by the IRB in 
accordance with current FDA and local regulations prior to any subject being consented or 
enrolled in this study at that site.   
The Investigator is responsible for obtaining continued review of the clinical research as 
specified by the responsible IRB.  The Investigator must supply Sponsor or designee with written 
documentation of continued review of the clinical research.  All advertisements must be 
reviewed and approved by the IRB prior to use. 

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The Investigator is responsible for reporting the following to the IRB: 
• Significant findings that become known in the course of the study that might affect the 
willingness of subjects to continue to participate (e.g., revised Investigator’s Brochure, 
safety reports); 
• Protocol and consent amendments prior to implementing the change; 
• Notification of study completion or termination. 
10.3.3 Informed Consent 
Voluntary informed consent will be obtained from all subjects, or the legally authorized 
representative of the subject participating in this study, in accordance with FDA regulations.  The 
subject’s informed consent must be obtained in writing prior to performance of any study-
specific activity.  The informed consent form used to consent the subject must be approved by 
both the reviewing IRB and by the Sponsor.  The original signed consent form shall be 
maintained in the subject’s study file.  
All subjects must be consented utilizing the most current approved version of the informed 
consent form, and re-consented if required by the IRB for any protocol amendments, or in the 
event that significant safety information is released by the Sponsor during the course of the trial.  
A revised consent document must be signed by subjects active in study follow-up only if 
required by the IRB.  Once the IRB approved revised ICF becomes available, the updated 
consent should be signed, generally at the next scheduled study visit, or sooner if required by the 
IRB. 
The principles of informed consent must be followed to be in compliance with health authorities’ 
regulations for the conduct and monitoring of clinical investigations. 
10.3.4 Confidentiality 
The Investigator must ensure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  Only subject initials and an identification 
code (i.e., not names) should be recorded on any form submitted to the Sponsor and IRB.   
The Investigator agrees that all information contained in this protocol and information related to 
the study drug, including but not limited to the Investigator’s Brochure, this protocol, CRFs, the 

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study drug, and any other study information, remain the sole and exclusive property of the 
Sponsor.  This information is not to be disclosed to any third party (except employees or agents 
directly involved in the conduct of the study, regulatory authority or health authority inspectors, 
or as required by law) without prior written authorization from the Sponsor.  The Investigator 
further agrees to take all reasonable precautions to prevent the disclosure by any employee or 
agent of the study site to any third party or otherwise into the public domain. 
10.3.5 Study Files and Retention of Records 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 
be classified into two separate categories: (1) Investigator’s study file, and (2) subject clinical 
source documents. 
The Investigator’s study file will contain the protocol, any amendment or administrative change 
letter, IRB approvals with correspondence, informed consent forms, drug records, clinic records, 
staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence, as per FDA regulations. 
Subject clinical source documents include, but are not limited to, the subject's progress notes, 
laboratory reports, daily diaries and correspondence. 
All clinical study documents must be retained by the Investigator for at least 10 years or at least 
2 years after the last approval of a marketing application and until there are no pending 
marketing applications or if no application is filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and regulatory authorities have 
been notified.  Investigators may be required to retain documents longer if required by applicable 
regulatory requirements or request by the Sponsor.  The Investigator must notify the Sponsor 
prior to destroying any clinical study records. 
Should the Investigator wish to assign the study records to another party or move them to another 
location, the Sponsor must be notified. 
If the Investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the Investigator and the Sponsor to 

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store these outside of the site so that they can be returned to the Investigator in case of a 
regulatory audit.  Where source documents are required for the continued care of the subject, 
appropriate copies should be made for storage outside of the site. 
10.3.6 Case Report Forms and Record Maintenance 
eCRFs will be supplied by the Sponsor or designated representative and should be handled in 
accordance with instructions from the Sponsor.  The CRFs are electronic and data entry 
performed via secure internet access.  All eCRFs should be filled out completely by Investigators 
or their assigned personnel or other trained study staff.  Daily diary entries by the subject will be 
made directly onto paper source documents and regularly faxed at study clinic visits to 
Data Management and converted into eCRFs.  The completed set of eCRFs will 
be reviewed by the Investigator who will then sign and date the Investigator’s Statement of 
Verification CRF.  Each authorized study staff member will receive a unique access account 
which will indicate individual use.  Access accounts will not be shared among study staff. 
The FDA regulations require that the Investigator must retain drug accountability logs, financial 
records, CRFs, subject files, and other source data for at least two years following completion of 
the entire study and FDA marketing approval of the New Drug Application (NDA), or two years 
after the Investigational New Drug Application (IND) is withdrawn by Sponsor.  In either case, 
records should not be destroyed without written approval from Sponsor. 
Should the Investigator wish to assign the study records to another party or move them to another 
location, the Sponsor must be notified. 
10.3.7 Drug Accountability  
Medicines360, or its designee, will provide drug accountability records for this study for use by 
the investigative sites.  The recipient will acknowledge receipt of all study drug shipments, 
indicating content and condition.  Damaged supplies will be replaced.  Accurate records of all 
study drug received, dispensed to subjects, returned to the Sponsor, or designee, or destroyed at 
the study site, should be maintained by the site.  No study IUS is to be destroyed or returned 
without authorization from the Sponsor, or designee. 

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10.3.8 Inspections 
The Investigator must ensure that source documents for this study should be made available to 
appropriately qualified personnel from the Sponsor or designee, or regulatory and health 
authority inspectors. 
10.3.9 Protocol Compliance 
The Investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol, and as agreed per their signature on the 
Protocol Signature Page and Form FDA 1572. 
10.3.10 Study Report and Publications 
The information obtained through this study will be used by Sponsor in connection with the 
development of the investigational drug and, therefore, may be used in submission(s) to 
regulatory authorities.  In addition, the results of this study may be used in publications or 
presented at scientific meetings. 
No individual site Investigator or designee will publish, present, or communicate study results 
without written approval from the Sponsor.  After conclusion of the study, Investigators in this 
study may not communicate orally, present, or publish in scientific journals or other scholarly 
media any results of this study without prior written approval from the Sponsor.  If approval is 
granted by the Sponsor, the Sponsor maintains the right to review proposed presentations and 
publications.  Investigators will submit to the Sponsor any proposed publication or presentation 
along with the respective scientific journal or presentation forum at least 30 days prior to 
submission of the publication or presentation.  The Investigator will comply with any Sponsor or 
supporter request to delete references to its confidential information (other than the study results) 
in any paper or presentation and agrees to withhold publication or presentation for an additional 
60 days in order to obtain patent protection if deemed necessary. 
No such communication, presentation, or publication will include the Sponsor’s confidential 
information (see Section 10.3.4). 
 

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10.3.11 Investigator Responsibilities 
A complete list of Investigator responsibilities are outlined in the clinical study research 
agreement and the Statement of Investigator Food and Drug Administration (FDA) Form 1572, 
both of which are signed by the Investigator before commencement of the study.  In summary, 
the Investigator will conduct the study according to the current protocol; will read and 
understand the Investigator’s Brochure; will obtain IRB approval to conduct the study; will 
obtain informed consent from each study participant; will maintain and supply to the Sponsor or 
designee, auditors and regulatory agencies adequate and accurate records of study activity and 
drug accountability for study-related monitoring, audits, IRB reviews and regulatory inspections; 
will report SAEs to the Sponsor or designee and IRB according to the specifics outlined in this 
protocol; will personally conduct or supervise the study; and will ensure that colleagues 
participating in the study are informed about their obligations in meeting the above 
commitments. 
10.3.12 Sponsor Responsibilities 
A complete list of the Sponsor responsibilities is outlined in the clinical study research 
agreement.  In summary, the Sponsor will select qualified Investigators, provide them with the 
information they need to properly conduct the study, ensure adequate monitoring of the study, 
conduct the study in accordance with the general investigational plan and protocols, and 
promptly inform Investigators, health and regulatory agencies/authorities as appropriate of 
significant new adverse effects or risks with respect to the drug. 
10.3.13 Protocol Modifications 
Changes in any portion of this protocol must be documented in the form of an amendment from 
the Sponsor and, if required, approved by the site’s IRB before the amendment may be 
implemented at that site.  The IRB chairperson may approve minor changes, or may designate 
one or more regulatory members to approve revisions.  Only the most current approved informed 
consent form should be used when obtaining consent from a new subject. 

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10.3.14 Access to Information for Monitoring 
In accordance with FDA and ICH-GCP guidelines, the study monitor must have direct access to 
the Investigator’s source documentation in order to verify the data recorded on the CRFs for 
accuracy. 
The monitor is responsible for routine review of the CRFs at regular intervals throughout the 
study, to verify adherence to the protocol, and the completeness, consistency and accuracy of the 
data being entered on them.  The monitor should have access to any subject records needed to 
verify the entries on the CRFs.  The Investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved. 
10.3.15 Financial Disclosure 
Per Title 21 CFR Part 54, all Investigators will complete a Financial Disclosure Form that 
permits Sponsor to demonstrate that an Investigator has no personal or professional financial 
incentive regarding study outcome or the future approval or disapproval of an investigational 
drug such that the Investigator’s research might be biased by such incentive. 
10.3.16 Study Discontinuation 
The Sponsor reserves the right to terminate the study at any time.  Should this be necessary, both 
the Sponsor and the Investigator will arrange discontinuation procedures.  In terminating the 
study, the Sponsor and the Investigator will assure that adequate consideration is given to the 
protection of the subjects’ interests. 
 

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REFERENCES 
Andersson K, Odlind V, Rybo G.  Levonorgestrel-releasing and copper-releasing (Nova T) IUDs 
during five years of use: A randomized comparative trial. Contraception 1994;49:56-72. 
 
Backman T, Rauramo I, Huhtala S, Koskenvuo M. Pregnancy during the use of levonorgestrel 
intrauterine system.  Am J Obstet Gynecol 2004;190:50-4. 
 
Bahamondes L, Ali M. Recent advances in managing and understanding menstrual disorders. 
F1000Prime Rep 2015;7:33. 
 
Bitzer J, Heikinheimo O, Nelson A, Calaf-Alsina J, Fraser I. Medical management of heavy 
menstrual bleeding: a comprehensive review of the literature. Obstet Gynecol Surv 2015;70:115-
30. 
 
Creinin MD, Jansen R, Starr RM, Gobburu J, Gopalakrishnan M, Olariu A.  Levonorgestrel 
release rates over 5 years with the Liletta® 52-mg intrauterine system. Contraception 
2016;94:353-6. 
 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). 
 
Eisenberg DL, Schreiber CA, Turok DK, Teal SB, Westhoff CL, Creinin MD. Three-year 
efficacy and safety of a new 52-mg levonorgestrel-releasing intrauterine system. Contraception 
2015;92:10–6. 
 
Espey E. Levonorgestrel intrauterine system - first-line therapy for heavy menstrual bleeding. 
New Engl J Med 2013;368:184-5. 
 
Ganer H, Levy A, Ohel I, et al. Pregnancy outcome in women with an intrauterine contraceptive 
device. Am J Obstet Gynecol 2009;201:1.e1-1.e4. 
 
Gupta J, Kai J, Middleton L, Pattison H, Gray R, Daniels J. Levonorgestrel intrauterine system 
versus medical therapy for menorrhagia. N Engl J Med 2013;368,128-37. 
 
Harlap S, Kost K, Forrest JD.  Preventing pregnancy, protecting health:  a new look at birth 
control choices in the U.S.  The Alan Guttmacher Institute, 1991:1-129. 
 
Jensen J, Mansour D, Lukkari-Lax E, Inki P, Burock K, Fraser IS. Bleeding patterns with the 
levonorgestrel-releasing intrauterine system when used for heavy menstrual bleeding in women 
without structural pelvic pathology: a pooled analysis of randomized controlled studies.  
Contraception 2013;87:107-12.  
 
Lethaby A, Hussain M, Rishworth JR, Rees MC. Progesterone or progestogen-releasing 
intrauterine systems for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 
2015, Issue 4. Art. No.: CD002126. DOI: 10.1002/14651858.CD002126.pub3. 
 

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Kaunitz MA, Bissonnette F, Monteiro I, Lukkari-Lax E, Muysers C, Jensen JT, Levonorgestrel-
Releasing Intrauterine System or Medroxyprogesterone for Heavy Menstrual Bleeding. Obstet 
Gynec 2010;116:625-32. 
 
Mawet M, Nollevaux F, Nizet D, Wijzen F, Gordenne V, Tasev N, et al. Impact of a new 
levonorgestrel intrauterine system, Levosert((R)), on heavy menstrual bleeding: results of a one-
year randomised controlled trial. Eur J Contracept. Reprod Health Care 2014;19:169-79. 
 
Maybin JA, Critchley HO. Menstrual physiology: implications for endometrial pathology and 
beyond. Hum Reprod Update 2015;21:748-61. 
 
Maybin JA, Critchley HO. Medical management of heavy menstrual bleeding. Women's Health 
(Lond) 2016;12;27-34. 
 
Mirena Approved Product Labeling (2017). Bayer HealthCare Pharmaceuticals. 
 
NCCWCH (2007). Heavy Menstrual Bleeding (London, UK: RCOG Press). 
 
Health Quality Ontario. Levonorgestrel-Releasing Intrauterine System (52 mg) for Idiopathic 
Heavy Menstrual Bleeding: A Health Technology Assessment. Ont Health Technol Assess Ser 
2016;16):1-119.. 
 
Qiu J, Cheng J, Wang Q, Hua J. Levonorgestrel-releasing intrauterine system versus medical 
therapy for menorrhagia: a systematic review and meta-analysis. Med Sci Monit 2014;20:1700-
13. 
 
Schreiber CA, Teal SB, Blumenthal PD, Keder LM, Olariu AI, Creinin MD. Bleeding patterns 
for the Liletta® levonorgestrel 52 mg intrauterine system, Eur J Contracep Reprod Health Care 
2018;23:116-20. 
 
Teal SB, Turok DK, Chen BA, Kimble T, Olariu AI, Creinin MD.  Five-Year Contraceptive 
Efficacy and Safety of a Levonorgestrel 52-mg Intrauterine System. Obstet Gynecol. 
2019;133:63-70. 
 
Westhoff CL, Keder LM, Gangestad A, Teal SB, Olariu AI, Creinin MD.  Six-Year 
Contraceptive Efficacy and Continued Safety of a Levonorgestrel 52 mg Intrauterine System. 
Contraception (Published online 28 November 2019). 
https://doi.org/10.1016/j.contraception.2019.10.010. 
 

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APPENDIX A: SCHEDULE OF EVENTS SCREENING 
1 If visits for part 1 are not done on the same day, perform 
as needed 
2 If not documented within the last 30 days  
3 Perform urine pregnancy test if this part of Visit 1 is 
performed on a day different than earlier parts 
4 Only performed as part of endometrial biopsy 
5 Test indicated if no Pap report available indicating no clinical need for 
testing or follow-up during planned study participation 
6 If not documented within the last 6 months  
7 Test indicated only if change in sexual partner 
 
 
 
ASSESSMENTS 
VISIT 
1A 
VISIT 
1B 
VISIT 
1C 
VISIT 
1D 
VISIT 
1E 
VISIT 
1F 
VISIT 
2 
VISIT 
3 
VISIT 
4 
 
SCREENING INITIATION 
SCREEN 
CYCLE 1 
SCREEN 
CYCLE 2 
SCREEN 
CYCLE 3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Pre-screen Questionnaire 
X 
 
 
 
 
 
 
 
 
Gynecological and Menstrual History 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
X1 
X1 
X1 
X1 
X1 
X 
X 
X 
Concomitant Medication Review 
X 
X1 
X1 
X1 
X1 
X1 
X 
X 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
Assess history of poor venous access 
X 
 
 
 
 
 
 
 
 
Confirm Eligibility to this point 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test 
 
X 
 
X 
X3 
 
X 
X 
X 
Hemoglobin/Hematocrit, Ferritin 
 
 
X2 
 
 
 
 
 
 
FSH, TSH, PRL, vWF, ALT, AST, 
chemistry (basic metabolic panel) 
 
 
X2 
 
 
 
 
 
 
Blood Pressure/Pulse 
 
 
 
X 
 
 
X 
X 
X 
Weight 
 
 
 
X 
 
 
 
 
 
Height  
 
 
 
X 
 
 
 
 
 
Breast Exam 
 
 
 
X 
 
 
 
 
 
Pelvic Exam 
 
 
 
X 
X4 
 
 
 
 
Pap test 
 
 
 
 
X5 
 
 
 
 
Gonorrhea/Chlamydia 
 
 
 
 
X2 
 
X7 
X7 
X7 
Transvaginal Ultrasound 
 
 
 
 
X6 
 
 
 
 
Endometrial Biopsy 
 
 
 
 
X6 
 
 
 
 
Instruct/Dispense Diaries 
 
 
 
 
 
X 
X 
X 
X 
Instruct/Dispense Sanitary Products 
 
 
 
 
 
X 
X 
X 
X 
Instruct/Dispense Collection Keg 
 
 
 
 
 
X 
X 
X 
X 
Collect Sanitary Products and Collection 
Keg/Assess for Compliance 
 
 
 
 
 
 
X 
X 
X 
Collect Diary/Assess for Compliance 
 
 
 
 
 
 
X 
X 
X 
Venous Blood for AH Analysis 
 
 
 
 
 
 
X 
X 
X 
Schedule Next Visit/Contact 
X1 
X1 
X1 
X1 
X1 
X1 
X 
X 
X 

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APPENDIX B: SCHEDULE OF EVENTS ENROLLMENT AND FOLLOW-UP 
1 Test indicated only if change in sexual partner 
2 Visit to occur ideally within the 5 day window but may be 
up to 21 days (V7 window Days 85-105: V8 window 
Days 169-189) 
3 If not collected within 6 weeks 
4 As applicable; subject may keep IUS if not contraindicated 
5 If has IUS removed 
6 For subjects with IUS removed 
7 For ongoing IUS or IUS removal-related AEs 
 
 
ASSESSMENTS 
ENROLLMENT 
TREATMENT 
7-DAY FU 
CONTACT6 
ADDITIONAL 
FOLLOW-UP7 
 
VISIT 5 
VISIT 
6 
CONTACT 
VISIT 
7 
CONTACT 
VISIT 8 
or ED 
 
 
 
IUS INSERT 
DAY 
28-42 
DAY 
50-56 
DAY 
85-892 
DAY 
133-140 
DAY 
169-1742  
7-10 DAYS 
AFTER IUS 
REMOVAL 
AS 
NEEDED 
Blood Pressure/Pulse 
X 
X 
 
X 
 
X 
 
 
Weight 
X 
X 
 
X 
 
X 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Urine Pregnancy Test 
X 
X 
 
X 
 
X 
 
 
Breast Exam 
 
 
 
 
 
X 
 
 
Pelvic Exam 
X 
 
 
 
 
X 
 
 
Gonorrhea/Chlamydia 
X1 
X1 
 
X1 
 
X1 
 
 
Hemoglobin/Hematocrit, Ferritin 
X 
 
 
X 
 
X3 
 
 
Venous blood for AH Analysis 
 
 
 
X 
 
X 
 
 
Confirm Eligibility 
X 
 
 
 
 
 
 
 
Instruct/Dispense Diaries 
X 
X 
 
X 
 
 
 
 
Instruct/Dispense Sanitary Products 
X 
X 
 
X 
 
 
 
 
Instruct/Dispense Collection Kit 
 
X 
 
X 
 
 
 
 
Collect Sanitary Products/Collection 
Kit/Assess for Compliance 
 
 
 
X 
 
X 
 
 
Collect Diary/Assess for Compliance 
X 
X 
 
X 
 
X 
 
 
VAS Questionnaire 
X 
 
 
X 
 
X 
 
 
Insertion of IUS 
X 
 
 
 
 
 
 
 
Review of Adverse Events 
X 
X 
 
X 
 
X 
X 
X 
Review Concomitant Meds 
X 
X 
 
X 
 
X 
X 
X 
Verify IUS Presence 
 
X 
 
X 
 
X 
 
 
Removal of IUS 
 
 
 
 
 
X4 
 
 
Schedule Next Visit/Contact 
X 
X 
 
X 
 
X5 
 
 
Remind when to collect Products 
 
 
X 
 
X 
 
 
 
Confirm Next Visit 
 
 
X 
 
X 
 
 
 
 

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APPENDIX C: PRE-SCREEN QUESTIONNAIRE 
1. Are you 18 to 50 years old? 
2. Do you have heavy periods (heavy menstrual bleeding)? 
3. Do you have regular (predictable) periods? 
4. Have you ever been told you have large uterine fibroids? 
5. Do you soak through one or more pads or tampons every hour for several hours? 
6. During your typical period do you ever have blood stain your thighs?    
7. Do you sometimes use a pad and tampon at the same time?  
8. Do you sometimes sleep with a towel between your legs to prevent staining?   
9. Do you get up to change your pad/tampon during the night?  
Pre-screening Questionnaire Response Requirements:  
• May continue screening if meets all of these requirements: 
o Yes to #1, #2 and #3; 
o No to #4; 
o Yes to any one or more questions #5 through #9 
 

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APPENDIX D: BASELINE VISUAL ANALOG SCALE QUESTIONS 
For these questions we are going to ask you to make a mark on a line. 
 
For example, let's say you are asked how much you like Oreo cookies: 
How much do you like Oreo cookies?   (make a mark on the line) 
 
        very 
very 
        little 
   much 
 
You answer the question by making a mark on the line according to how much you like or dislike 
Oreo cookies. 
 
 
If you liked Oreo cookies a lot, then you might make a mark on the line like so: 
 
        very 
very 
        little 
   much 
 
 
If you liked Oreo cookies more than life itself(!), then you might make a mark on the line like 
so: 
 
        very 
very 
        little 
   much 
 
 
If you hated Oreo cookies, then you might make a mark like so: 
 
        very 
very 
        little 
   much 
 
 
If you thought Oreo cookies were just "OK," then you might make a mark like so: 
 
        very 
very 
        little 
   much 
 
 
The idea is that if you like Oreo cookies, you make a mark on the line closer to the phrase "very 
much;" the closer you make the mark, the more you are saying you like Oreo cookies.  If you don't 
like Oreo cookies, you make a mark on the line closer to the phrase "very little;" the closer you 
make the mark, the more you are saying you don't like Oreo cookies. 
 
PLEASE TURN TO THE NEXT PAGE AND ANSWER THE QUESTIONS. 

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Make a mark on the line to indicate: 
 
When you think of your typical period, how heavy is your bleeding? 
 
  
no 
heaviest flow I 
  
flow 
ever experienced 
 
 
 
When you think of your typical period, how acceptable is your bleeding? 
 
  
not 
completely 
  acceptable 
acceptable 
 
 
 
When you think of your typical period, how much cramping pain do you have? 
 
  
no 
worst pain I 
  
pain 
ever experienced 
 
 
 
When you think of your typical period, how much does it interfere with your ability to do 
daily activities? 
 
  
no 
I cannot do any 
  
effect 
daily activities 
 
 
 
When you think of your typical period, how much does it affect your ability to sleep? 
 
  
no 
I do not get  
  
effect 
any sleep 
 
 
 
 
 
 
 
 
 
 
Date 
Subject’s signature 
 

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APPENDIX E: 3-MONTH AND 6-MONTH VISUAL ANALOG SCALE 
QUESTIONS 
For these questions we are going to ask you to make a mark on a line. 
 
For example, let's say you are asked how much you like Oreo cookies: 
How much do you like Oreo cookies?   (make a mark on the line) 
 
        very 
very 
        little 
   much 
 
You answer the question by making a mark on the line according to how much you like or 
dislike Oreo cookies. 
 
 
If you liked Oreo cookies a lot, then you might make a mark on the line like so: 
 
        very 
very 
        little 
   much 
 
 
If you liked Oreo cookies more than life itself(!), then you might make a mark on the line 
like so: 
 
        very 
very 
        little 
   much 
 
 
If you hated Oreo cookies, then you might make a mark like so: 
 
        very 
very 
        little 
   much 
 
 
If you thought Oreo cookies were just "OK," then you might make a mark like so: 
 
        very 
very 
        little 
   much 
 
 
The idea is that if you like Oreo cookies, you make a mark on the line closer to the phrase "very 
much;" the closer you make the mark, the more you are saying you like Oreo cookies.  If you 
don't like Oreo cookies, you make a mark on the line closer to the phrase "very little;" the closer 
you make the mark, the more you are saying you don't like Oreo cookies. 
 
PLEASE TURN TO THE NEXT PAGE AND ANSWER THE QUESTIONS. 

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Make a mark on the line to indicate: 
 
When you think of the bleeding you have had over the last 4 weeks, how heavy was your 
bleeding? 
 
  
no 
heaviest flow I 
  
flow 
ever experienced 
 
 
 
When you think of the bleeding you have had over the last 4 weeks, how acceptable was 
your bleeding? 
 
  
not 
completely 
  acceptable 
acceptable 
 
 
 
When you think of the cramping pain you have had over the last 4 weeks, how much 
cramping pain did you have? 
 
  
no 
worst pain I 
  
pain 
ever experienced 
 
 
 
When you think of the bleeding and cramping you have had over the last 4 weeks, how 
much did it interfere with your ability to do daily activities? 
 
  
no 
I cannot do any 
  
effect 
daily activities 
 
 
 
When you think of the bleeding and cramping you have had over the last 4 weeks, how 
much did it affect your ability to sleep? 
 
  
no 
I do not get  
  
effect 
any sleep 
 
 
 
 
 
 
 
Date 
Subject’s signature 
 
 

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APPENDIX F: MANAGEMENT OF PREGNANCY 
Among women who conceive with an IUS in situ, the spontaneous abortion rate is two-fold 
higher than that of the general obstetric population.  A retained IUS also increases the risk of 
several late gestational adverse maternal and neonatal outcomes; this risk is reduced, but not 
eliminated, with early removal of the IUS.   
For any subject who has a positive urine pregnancy test, the pregnancy should be confirmed by 
ultrasonography and serum hCG testing.  The location of the pregnancy must be determined 
(intrauterine or extrauterine) using ultrasonography.  Determine the location of the IUS using 
physical examination, ultrasonography and/or radiography as appropriate. 
 
1. Management of intrauterine pregnancy with IUS in place 
The following steps may be considered in the evaluation and management of intrauterine 
pregnancy in a subject with an IUS in situ: 
• First trimester intrauterine pregnancy: 
o If the IUS strings are visible on speculum examination, remove the IUS to 
decrease the risk of subsequent miscarriage and infection.  Antibiotics are 
unnecessary.  
o If the strings are not visible and the patient wishes to continue the pregnancy, 
remove the IUS under ultrasound guidance using an alligator forceps or an IUS 
hook.  Removal can also be attempted by hysteroscopy.  Data on hysteroscopic 
removal of IUS in early pregnancy are limited; therefore, it is not clear whether 
this technique poses greater or lesser risk of pregnancy loss than instrument 
removal under ultrasound guidance.  Antibiotic prophylaxis is recommended 
when instrument removals are performed during pregnancy, including when IUS 
removal is to be followed by pregnancy termination (see below).  The IUS may be 
left in situ if findings on ultrasound examination suggest removal will be difficult 
or disrupt the pregnancy (e.g., IUS embedded in the placenta or membranes).  
o If the woman desires pregnancy termination, IUS removal can be performed at the 
time of the termination.  Manual or electric vacuum aspiration or an instrument 
such as an IUS hook, alligator forceps, ring forceps, or ovum forceps can be used 
to remove the IUS.  

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o In the setting of spontaneous abortion with IUS in place, it is recommended to 
remove the IUS and prescribe antibiotics (e.g., doxycycline 100 mg twice a day or 
ampicillin 500 mg four times a day for seven days). 
• Second trimester pregnancy —Counsel subject if the IUS remains in situ, that there is an 
increased risk of preterm labor and delivery (fourfold increase), second trimester fetal 
loss, and infection, but no proven increase in risk of birth defects.  Removal of the IUS 
may cause rupture of membranes, bleeding, pregnancy loss, or fetal trauma; however, if 
the IUS is removed or expelled without complications, there is no increased risk of 
miscarriage. 
o Given this information, for pregnancies after 12 weeks, consider removing the 
IUS by pulling on the strings if the strings are visible and removal is unlikely to 
disrupt the placenta or membranes (based upon ultrasound localization of the IUS 
and placenta).  
o If the strings are not visible in the early second trimester, the IUS may be 
removed under ultrasound guidance if removal appears feasible, the IUS is not 
located behind the placenta, and it does not appear to be incorporated into the 
gestational sac.  In particular, ultrasound guided removal is recommended in these 
cases if the IUS is in the lower uterine segment. If the IUS appears embedded in 
the placenta, located behind the placenta, or protrudes into the gestational sac, we 
suggest leaving the IUS in situ. 
o In the later second trimester, if the strings are not visible, the IUS should be left in 
place. The subject should be counseled that her risk of spontaneous abortion and 
premature delivery is increased relative to women whose IUSs may be easily 
removed. 
2. Management of intrauterine pregnancy with extrauterine IUS 
• If the IUS was expelled, the pregnancy should be managed as any other intrauterine 
pregnancy. 
• If the IUS is extrauterine (perforation), the pregnancy should be managed without removal 
of the IUS until after the pregnancy is complete or, if applicable, at the time of cesarean 
delivery. 
 

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3. Management of extrauterine pregnancy 
• Management should be performed within the local standard of care for the extrauterine 
pregnancy. 
• If the IUS is intrauterine, the IUS should be removed and the subject discontinued from the 
study following appropriate safety follow-up. 
 
 

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APPENDIX G: MANAGEMENT OF IUS ISSUES 
1. Difficult Insertion 
If insertion is difficult because the cervix cannot be properly visualized then the subject should 
have been excluded prior to randomization. 
• If insertion is difficult because the uterus cannot be instrumented, the following measures 
are allowed: 
o Use of cervical anesthesia to make sounding and manipulation more tolerable 
o Use of rigid dilators to dilate the cervix if needed to allow passage of the sound.  
If needed, a lacrimal duct probe or os finder may be used to start dilation.   
o Abdominal ultrasound guidance during dilation and/or insertion. 
If the uterus still cannot be appropriately instrumented after the above measures are taken, 
or the uterus sounds to less than 5.5cm, then the subject should be considered an insertion 
failure and discontinued from the study.  No further follow-up or visits are required. 
2. Perforation 
• Perforation may occur during insertion. The risk of perforation is increased in women 
with fixed retroverted uteri, during lactation, and postpartum.  If during or after insertion 
there is clinical concern or exceptional pain or bleeding, appropriate and timely measures 
and assessments, such as ultrasound, should be performed to exclude perforation. 
• Perforation or penetration of the uterine wall or cervix may occur during insertion 
although the perforation may not be detected until sometime later.  The IUS must be 
located and removed; surgery may be required. Delayed detection of perforation may 
result in migration outside the uterine cavity, adhesions, peritonitis, intestinal 
perforations, intestinal obstruction, abscesses and erosion of adjacent viscera.  Ensure a 
radiographic image of the entire abdomen is obtained to ensure the IUS hasn’t migrated.   
• If recognized and the IUS is intra-abdominal, a laparoscopy should be performed by a 
clinician experienced in such procedures to remove the IUS.  Typically, minimal 
adhesions are present with intra-abdominal IUSs.  If necessary, a laparotomy should be 
performed. 
If the IUS is partially into or through the myometrium, it is reasonable to attempt removal 
with transcervical instrumentation.  Initial attempts should be performed under ultrasound 

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guidance using an Alligator forceps (or similar instrument).  If unsuccessful, attempts via 
hysteroscopy should be made before proceeding to laparoscopy. 
3. Missing Strings 
The site should check for the IUS strings by palpation or direct visualization at each study visit.  
Ultrasound examination to verify the IUS is in place cannot substitute for checking the strings.   
If the strings are not evident on exam follow these steps, moving to the next one if unsuccessful: 
• Use endobrush in cervical canal to attempt to tease down string. 
• Perform a transvaginal ultrasound examination to locate the IUS.  If the IUS is confirmed 
to be present in the uterus and the strings are missing, then transvaginal ultrasonography 
should be performed at all follow-up visits to confirm presence of the IUS. 
• Obtain a flat plate abdominal x-ray to check if the IUS is within the abdomen. 
o If it is not visible on abdominal x-ray, the case will be considered a spontaneous 
expulsion. 
o If it is visible on x-ray, but not within the uterus on ultrasound, the case will be 
considered a perforation.  The patient should then be referred, as necessary, for 
IUS removal by laparoscopy or laparotomy, and for any other necessary care. 
• Subjects who experience IUS expulsion may have another study IUS inserted; only one 
replacement IUS is allowed per subject. Replacement can occur only if all of the 
following conditions are met:  
o Reinsertion occurs no more than 14 days after the expulsion; 
o Reinsertion occurs at least 7 days prior to treatment Cycle 3 or Cycle 6; 
o Reinsertion cannot occur during treatment Cycle 3 or Cycle 6; 
o Pregnancy can reasonably be excluded. 
4. Partial Expulsion 
Defined as visual evidence of the lower portion of the IUS stem protruding through the cervical 
os OR evidence of increased bleeding and/or cramping complaints with the presence of the IUS 
in the lower uterine segment.  The system can be expelled from the uterine cavity without the 
woman noticing it, resulting in the loss of contraceptive protection. As menstrual flow typically 
decreases after the first 3 to 6 months of IUS use, an increase of menstrual flow may be 
indicative of an expulsion. 

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• The IUS should be removed as soon as possible.   
• Subjects who experience a partial IUS expulsion may have another study IUS inserted 
(see criteria in #3 above) 
5. Infection 
• Patients must be taught to recognize and report to their physician promptly any symptoms 
of pelvic inflammatory disease.  These symptoms include development of menstrual 
disorders (prolonged or heavy bleeding), unusual vaginal discharge, abdominal or pelvic 
pain or tenderness, dyspareunia, chills, and fever.  Following a diagnosis of PID, or 
suspected PID, bacteriologic specimens should be obtained and antibiotic therapy should 
be initiated promptly. 
• Any woman treated by a medical professional for uterine infection/PID will be 
considered to have that diagnosis.  At a minimum, uterine tenderness must be present.  
The IUS should not be removed when such a diagnosis is made unless the infection is 
refractory to antibiotic therapy or the subject has a pelvic abscess or sepsis. 
6. Difficult Removal 
If the IUS cannot be removed by pulling on the strings, first make sure the clinician is certain the 
IUS is still in the uterus.  Embedment can result in difficult removal and, in some cases surgical 
removal may be necessary.  An embedded IUS should be removed.  Embedment may decrease 
contraceptive effectiveness and result in pregnancy.  Once certain the IUS is in the uterus, 
consider any of the following options alone or in combination: 
• Abdominal ultrasound guidance 
• Cervical anesthesia to make manipulation more tolerable 
• IUD thread retriever 
• Alligator forceps (or comparable instrument) 
If the IUS still cannot be removed in an office setting using the above techniques, hysteroscopic 
evaluation for removal should be performed. 
After removal of the IUS, verify that the system is intact.  If the system is not intact, any missing 
parts must be located and removed.  If removal of missing parts cannot be completed in the office, 
contact the Medical Monitor before attempting any other procedures.  As a reminder, all removed 
IUSs should be collected and stored in a temperature controlled freezer. 

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APPENDIX H: PROTOCOL SUMMARY OF CHANGES 
Any administrative changes to the protocol including spelling corrections, minor clarifications, 
renumbering, and reformatting are not summarized in the following table.  Such changes are 
evident and may be reviewed in the red-lined Protocol Amendment. 
 
Section 
Change to Protocol 
Rationale 
Title Page,  
Signature Page 
Date and version # changed 
The date and version # 
changed due to this 
revision 
Synopsis 
Eligibility Criteria 
and Protocol 
Section 4.3 
Extended Planned study dates 
 
Added “approximately” to the Number of 
Investigative Sites 
 
Revised inclusion criterion #10 to add 
“regardless of subject’s age” for screening 
Pap testing requirements 
To allow for a longer 
enrollment period 
 
To allow flexibility in the 
number of investigative 
sites 
To provide clarity 
 
 
 
Protocol Sections 
3 and 6.7.3.1 
Added that the first screening phase cycle 
analysis may be repeated if the considered 
less than normal by the subject.  The first 
cycle collection is discarded. 
To allow for the variability 
in bleeding amounts 
women may experience 
Protocol Section 
4,2 
Revised inclusion criterion #10 to add 
“regardless of age” for screening Pap 
testing requirements 
To provide clarity 
Protocol Section 
5.3 
Added instruction to contact the sponsor for 
IUS storage temperature excursions 
To ensure quality of the 
investigational product 
Protocol Sections 
6 
Indicated the flow chart of study assessments 
has been split into two; one for screening and 
one for enrollment and follow-up 
To provide clarity 
Protocol Sections 
6.3, 6.7.2.3 
Added that screening bloodwork does not 
require fasting 
To provide clarity 
Protocol Sections 
6.7.1 and 6.7.3.7 
Added details about determining if the cycle 
collection is likely to be less than study 
requirements before sending feminine 
hygiene products for analysis 
To identify screen failures 
prior to feminine hygiene 
product analysis 
Protocol Section 
7.1.2 
Revised to Liletta being approved for 
contraception for up to 6 years and more 
current contraceptive efficacy data 
FDA approval received 15 
October 2019 

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Protocol Sections 
7.1.3.2, 7.1.3.6 
Revised ectopic pregnancy rate and pelvic 
infection occurrence to reflect 6 years of 
use data 
To reflect the current 
product package insert 
Protocol Section 
7.10 
Revised to indicate collection of AEs to 
start with study treatment 
To be consistent with 
other sections 
Protocol Section 
11 
Added references 
To be current and 
complete 
Appendix A 
Schedule of Events now split into Appendix 
A for screening  
 
Added additional assessments 
To provide clarity 
 
 
To be more 
comprehensive