A Multi-center, Single-blind, Randomized Clinical Trial to Compare Two Copper IUDs: Mona Lisa NT Cu380 Mini and ParaGard
Phase: PHASE3
Conditions: Healthy Women, Female Contraception
Sponsor: FHI 360

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NICHD/FHI 360 
Clinical Research Protocol 
A multi-center, single-blind, randomized clinical trial to compare two copper IUDs:  
Mona Lisa NT Cu380 Mini and ParaGard 
 
Protocol Number: 
CCN016 
Version Date: 
Final version 03.00 19Dec2018 
Investigational Product: 
Mona Lisa® NT Cu380 Mini  
Development Phase: 
Phase III 
IND Number:  
132657 
Sponsor/IND Holder 
 
 
 
Co-Sponsor 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
 
National Institutes of Health 
Eunice Kennedy Shriver National Institute of Child Health & 
Human Development (NICHD) 
Contraceptive Clinical Trial Network (CCTN) (Female) 
6100 Executive Boulevard, Room 8B13 
Bethesda, MD 20892 USA 
Funding Organizations: 
The Bill and Melinda Gates Foundation (FHI 360 portion) 
and the Eunice Kennedy Shriver National Institute of Child 
Health & Human Development (NICHD) of the National 
Institutes of Health  

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Principal Investigators: 
FHI 360 Sites 
Courtney Schreiber, MD, MPH: Perelman School of 
Medicine at the University of Pennsylvania 
Beatrice A. Chen, MD, MPH: University of Pittsburgh 
Anita Nelson, MD: Essential Access Health 
Alisa Goldberg, MD: Planned Parenthood League of 
Massachusetts,  
Ila Dayananda, MD: Planned Parenthood New York 
 
NICHD Sites 
David Archer, MD: Eastern Virginia Medical School 
Anne Burke, MD: Johns Hopkins University 
Paula Castaño, MD, MPH: Columbia University  
Mitchell Creinin, MD: University of California, Davis 
Philip Darney, MD, MSc: University of California, San 
Francisco 
Jeffrey Jensen, MD, MPH: Oregon Health & Science 
University 
Subsite: Bliss Kaneshiro, MD, MPH: University of Hawaii 
Stephanie Teal, MD, MPH: University of Colorado Denver 
Michael A. Thomas, MD: University of Cincinnati 
David Turok, MD: University of Utah 
Katharine White, MD, MPH: Boston Medical Center 
Corporation  
Medical Monitors: 
FHI 360 
Name: Kavita Nanda, MD, MHS 
Telephone: 919-544-7040, ext.  11507 
Fax: 919-544-7261 
 
 
E-mail: knanda@fhi360.org 
 
NICHD 
Name: Jill Long, MD, MPH, MHS 
Telephone: 301-496-1662 
E-mail: jill.long@nih.gov 

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Program Directors: 
FHl360 
Name: David Hubacher, PhD 
Telephone: 919 544 7040, ext 11223 
Fax: 919 544 7261 
E-mail: dhubacher@tlli360.org 
NICHD 
Name: Diana Blithe, PhD 
Telephone: 301 435 6990 
E-mail: blithcd@nih.gov 
Coordinating Center: 
Name: Clint Dart, MS 
Health Decisions 
2510 Meridian Parkway, Suite 100 
Durham, NC 27713, USA 
Telephone: 919-967-1111 
E-mail: cdart@healthdec.com 
Approval: 
Diana L Blithe -S DigitallysignedbyDianaL.Bl,ith-5 
• 
· Date: 2018.12.20 15:13:32 -OS 00 
Diana Blithe, PhD 
Program Director, NJCHD 
i)_Mi_. 
David Huba::l( 
Senior Epidemiologist, FHI 360 
CCN016 Version#: 03.00 
Version Date: 19Dec2018 
Date 
. P-! 17 L o l i?, 
Date 
Page 3 of76 

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PROTOCOL AGREEMENT 
I, the undersigned, will conduct the clinical study as described in the Protocol and will adhere to the 
Code of Federal Regulations, Title 21 and Title 45, Part 46, Good Clinical Practices (GCP), 
International Council for Harmonisation (ICH), and the Declaration of Helsinki.  I have read and 
understood the contents of the Protocol and Investigator Brochure.  
The signature of the investigator below indicates acceptance of the protocol and a complete understanding 
of the investigator obligations as outlined in Investigator Obligations. 
Protocol Number:  CCN016 
Protocol Title:  A multi-center, single-blind, randomized clinical trial to compare two copper IUDs: 
Mona Lisa NT Cu380 Mini and ParaGard 
Protocol Date: 19Dec2018 
 
 
 
Principal Investigator Signature  
 
Date 
 
Print Name and Title 
Site # 
 
 
Site Name 
 
Address 
 
 
 
 
 
 
 
Phone Number 
 
 
 
 

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1 
BACKGROUND AND RATIONALE ............................................................................... 14 
2 
STUDY PRODUCTS .......................................................................................................... 15 
2.1 
BRIEF PRODUCT DESCRIPTIONS – STRUCTURE AND REGULATORY STATUS ............................................................... 15 
2.1.1 
ParaGard (control) ..................................................................................................................... 15 
2.1.2 
Mona Lisa NT Cu380 Mini (test product) ................................................................................... 15 
2.2 
OVERVIEW OF NON-CLINICAL STUDIES .................................................................................................. 15 
2.2.1 
Mona Lisa NT Cu380 Mini .......................................................................................................... 16 
2.3 
OVERVIEW OF CLINICAL STUDIES ........................................................................................................... 16 
3 
STUDY OBJECTIVES ....................................................................................................... 17 
3.1 
PRIMARY OBJECTIVE .............................................................................................................................. 17 
3.2 
SECONDARY OBJECTIVES ............................................................................................................................... 17 
4 
STUDY DESIGN ................................................................................................................. 17 
4.1 
STUDY OVERVIEW ....................................................................................................................................... 17 
4.2 
STUDY DURATION ....................................................................................................................................... 18 
5 
PRINCIPAL INVESTIGATORS AND RESEARCH SITES ......................................... 18 
5.1 
FHI 360 SITES ......................................................................................................................................... 18 
5.2 
NICHD SITES ......................................................................................................................................... 18 
6 
CRITERIA FOR EVALUATION ..................................................................................... 19 
6.1 
PRIMARY ENDPOINT ............................................................................................................................... 19 
6.2 
SECONDARY ENDPOINTS ......................................................................................................................... 19 
6.3 
SAFETY EVALUATIONS ........................................................................................................................... 19 
7 
SUBJECT SELECTION ..................................................................................................... 19 
7.1 
STUDY POPULATION ............................................................................................................................... 19 
7.2 
INCLUSION CRITERIA .............................................................................................................................. 20 
7.3  
EXCLUSION CRITERIA .................................................................................................................................... 20 
7.4 
ALLOWABLE CRITERIA ........................................................................................................................... 21 
7.5 
NUMBER OF SUBJECTS ................................................................................................................................. 21 
8 
CONCURRENT MEDICATIONS AND TREATMENTS .............................................. 22 
8.1 
ALLOWED MEDICATIONS AND TREATMENTS ..................................................................................................... 22 
8.2 
PROHIBITED MEDICATIONS AND TREATMENTS .................................................................................................. 22 
9 
STUDY TREATMENTS .................................................................................................... 22 
9.1 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS .................................................................. 22 
9.2 
BLINDING (PARTICIPANT ONLY) .............................................................................................................. 23 
9.3 
FORMULATION OF TEST AND CONTROL PRODUCTS ................................................................................ 23 
9.3.1 
Formulation of Test and Control Products ................................................................................ 23 
9.3.2 
Packaging and Labeling ............................................................................................................ 24 
9.4 
PROVISION OF STUDY PRODUCT TO PARTICIPANTS ............................................................................................. 24 
9.4.1 
Dosage Regimen ........................................................................................................................ 24 

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9.4.2 
Dispensing ................................................................................................................................. 24 
9.4.3 
Administration Instructions ....................................................................................................... 25 
9.5 
SUPPLY OF STUDY PRODUCT AT THE SITE ............................................................................................... 25 
9.5.1 
Storage ....................................................................................................................................... 25 
9.6 
STUDY PRODUCT ACCOUNTABILITY ....................................................................................................... 25 
9.7 
MEASURES OF TREATMENT COMPLIANCE ........................................................................................................ 26 
9.8 
STUDY PRODUCT DISPOSAL/RETURN .............................................................................................................. 26 
10 
STUDY PROCEDURES AND GUIDELINES ....................................................... 26 
10.1 
INVESTIGATOR’S MEETING AND PROTOCOL TRAINING ........................................................................................ 26 
10.2 
CLINICAL ASSESSMENTS AND PROCEDURES ........................................................................................... 26 
10.2.1 Medical, Demographic, and Reproductive Health History ....................................................... 27 
10.2.2 Vital signs and Pelvic Exam ...................................................................................................... 27 
10.2.3 Ultrasound examination ............................................................................................................ 27 
10.2.4 Pap Test ..................................................................................................................................... 28 
10.2.5 Laboratory Assessments ............................................................................................................ 28 
10.2.6 Specimen collection and Processing .......................................................................................... 28 
10.3 
SUBJECT ASSESSMENTS .......................................................................................................................... 29 
10.3.1 Follow Up Form ........................................................................................................................ 29 
10.3.2 Daily Diary ................................................................................................................................ 29 
10.3.3 Other Contraceptive Use ............................................................................................................ 29 
10.3.4 Post Placement Pain Forms ....................................................................................................... 29 
11 
EVALUATIONS BY VISIT ..................................................................................... 30 
11.1 
SCREENING AND ENROLLMENT/IUD INSERTION ..................................................................................... 30 
11.1.1 Screening Procedures ................................................................................................................. 30 
11.1.2 Visit 1 (Enrollment Procedures and IUD Insertion)..................................................................... 31 
11.2 
CLINIC-BASED FOLLOW-UP VISITS ......................................................................................................... 34 
11.2.1 Visit 2 (6-weeks post-insertion ± 5 days) ................................................................................... 34 
11.2.2 Visit 3 (3 months post-insertion ± 14 days) ................................................................................ 34 
11.2.3 Visit 4 (6 months post-insertion ± 14 days) ................................................................................ 34 
11.2.4 Visit 5 (12 months post-insertion ± 14 days) .............................................................................. 34 
11.2.5 Visit 6 (24 months post-insertion ± 14 days) .............................................................................. 34 
11.2.6 Unscheduled visits (any time the participant returns for services outside the schedule) .......... 35 
11.3 
TELEPHONE CALL 1, 2, AND 3 (9 MONTHS, 18 MONTHS, AND 30 MONTHS POST-INSERTION ± 14 DAYS) .. 36 
11.4 
EXIT (37 MONTHS POST-INSERTION ± 14 DAYS) OR EARLY DISCONTINUATION VISIT ................................................. 37 
11.5 
TELEPHONE CALL 4 FOR PREGNANCY TEST RESULT (17-DAYS POST-REMOVAL + 3 DAYS) ........................................... 39 
11.6 
EARLY DISCONTINUATION VISIT ............................................................................................................ 39 
12 
SAFETY ..................................................................................................................... 40 
12.1 
ADVERSE EVENTS ................................................................................................................................... 40 
12.2 
SERIOUS ADVERSE EXPERIENCES (SAE) ................................................................................................ 42 
12.2.1 Serious Adverse Experience Reporting ...................................................................................... 43 
12.3 
MEDICAL MONITOR ................................................................................................................................ 44 
13 
PREGNANCY DETERMINATION AND FOLLOW UP .................................... 44 
14 
MONITORING ......................................................................................................... 45 
14.1 
CLINICAL SITE MONITORING........................................................................................................................... 45 

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14.1.1 Quality control and quality assurance ....................................................................................... 46 
14.1.2 Source documents and access to source data/documents ........................................................ 46 
14.2 
REGULATORY .............................................................................................................................................. 47 
15 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS ........................ 47 
15.1 
EARLY DISCONTINUATION OF STUDY PRODUCT ..................................................................................... 47 
15.1.1 Lost to Follow-Up ....................................................................................................................... 48 
15.2 
WITHDRAWAL OF SUBJECTS FROM THE STUDY .................................................................................................. 48 
15.3 
REPLACEMENT OF SUBJECTS .......................................................................................................................... 48 
15.4 
STUDY PRODUCT ERRORS ............................................................................................................................. 48 
16 
PROTOCOL DEVIATIONS ................................................................................... 49 
17 
AMENDMENTS TO THE PROTOCOL ............................................................... 49 
18 
DATA SAFETY AND EFFICACY MONITORING ............................................ 50 
18.1 
DATA AND SAFETY MONITORING BOARD (DSMB) ............................................................................................ 50 
19 
STATISTICAL METHODS AND CONSIDERATIONS ..................................... 50 
19.1 
SAMPLE SIZE ........................................................................................................................................... 50 
19.2 
STATISTICAL ANALYSES.................................................................................................................................. 51 
19.2.1 Primary analysis ........................................................................................................................ 51 
19.2.2 Analysis of secondary endpoints ................................................................................................ 52 
20 
DATA COLLECTION, RETENTION AND MONITORING ............................. 53 
20.1 
ELECTRONIC DATA CAPTURE SYSTEM .................................................................................................... 53 
20.2 
DATA HANDLING AND PROCESSING ........................................................................................................ 53 
20.3 
CONFIDENTIALITY AND REPORTING OF RESULTS .................................................................................... 53 
20.4 
ARCHIVAL OF DATA................................................................................................................................ 53 
20.5 
AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS ........................................................... 53 
20.6 
SUBJECT CONFIDENTIALITY .................................................................................................................... 54 
21 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ........ 54 
21.1 
INSTITUTIONAL REVIEW BOARDS AND INDEPENDENT ETHICS COMMITTEES .......................................... 54 
21.2 
PROTOCOL REGISTRATION ............................................................................................................................. 54 
21.3 
RISKS AND BENEFITS .................................................................................................................................... 55 
21.3.1 Risks ........................................................................................................................................... 55 
21.3.2 Benefits ...................................................................................................................................... 56 
21.4 
INFORMED CONSENT ............................................................................................................................... 56 
21.5 
CONFLICTS OF INTEREST ......................................................................................................................... 57 
21.6 
CONFIDENTIALITY .................................................................................................................................. 57 
21.7 
PUBLICATIONS ........................................................................................................................................ 57 
21.7.1 Publication Policy ....................................................................................................................... 58 
21.7.2 Authorship eligibility .................................................................................................................. 58 
22 
REFERENCES .......................................................................................................... 59 
23 
INVESTIGATOR OBLIGATIONS ........................................................................ 60 
24 
APPENDIX 1: SCHEDULE OF ASSESSMENTS ................................................ 61 

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25 
APPENDIX 2: IUD CONFIRMATION PROCESSES ......................................... 64 
26 
APPENDIX 3: DAILY DIARY................................................................................ 65 
27 
APPENDIX 4: OTHER CONTRACEPTIVE USE FORM .................................. 66 
28 
APPENDIX 5: POST PLACEMENT PAIN FORM – CLINIC ........................... 67 
29 
APPENDIX 6: POST PLACEMENT PAIN FORM – HOME ............................. 68 
30 
APPENDIX 7: PARAGARD PRESCRIBING INFORMATION ........................ 69 
31 
APPENDIX 8: MONA LISA NT CU380 MINI PRESCRIBING 
INFORMATION ......................................................................................................................... 74 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse event 
β-hCG 
Beta-human chorionic gonadotropin 
CCTN 
CFR 
Contraceptive Clinical Trials Network 
Code of Federal Regulations 
CRF 
Case report form 
CV 
DHHS 
Curriculum Vitae 
Department of Health and Human Services 
DSMB 
eCRF 
EDC 
Data and Safety Monitoring Board 
Electronic case report form 
Electronic data capture 
EU 
European Union 
FDA 
Food and Drug Administration 
GC/CT 
Neisseria gonorrhoeae / Chlamydia trachomatis 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV/AIDS 
Human immunodeficiency virus / acquired immunodeficiency 
syndrome 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IND 
IRB 
ISO 
Investigational New Drug 
Institutional Review Board 
International Organization for Standardization 
IUD 
LTFU 
NAAT 
NICHD 
Intrauterine device  
Lost to follow-up 
Nucleic acid amplification test 
National Institute of Child Health & Human Development 
NIH 
OC 
OHRP 
National Institutes of Health 
Oral Contraceptive 
Office for Human Research Protections 
PI 
Q1,Q2,Q3,Q4 
Principal Investigator 
In the first, second, third, fourth quarter of a year 
STI/RTI 
Sexually transmitted infection / Reproductive tract infection 
SAE 
SCCC 
SOP 
TVUS 
US 
Serious adverse experience 
Statistical and Clinical Coordinating Center 
Standard Operating Procedure 
Transvaginal ultrasound 
United States  
UTI 
Urinary tract infection 

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PROTOCOL SYNOPSIS 
TITLE 
A multi-center, single-blind, randomized clinical trial to compare two 
copper IUDs: Mona Lisa NT Cu380 Mini and ParaGard 
PROTOCOL NUMBER CCN016 
PHASE 
III 
SPONSORS 
FHI 360 
NICHD 
IND NUMBER 
132657 
IND HOLDER 
FHI 360 
FUNDING 
ORGANIZATIONS 
The Bill and Melinda Gates Foundation (FHI 360) and the Eunice 
Kennedy Shriver National Institute of Child Health & Human 
Development (NICHD) of the National Institutes of Health  
NUMBER OF SITES 
Approximately 16 sites in the United States (US) 
RATIONALE 
The only currently marketed copper intrauterine device (IUD) in the 
US, first approved by the FDA in 1984, consists of a plastic T-shaped 
frame with 380 mm2 of copper surface.  Successful use of this product 
has been demonstrated in parous and nulliparous women. However, 
nulliparous women have smaller uterine cavities, and previous 
research has suggested that smaller copper IUDs may cause fewer side 
effects in nulliparous women compared to larger products.  Newer 
products available in Europe have slightly less copper, alternative 
shapes or smaller sizes.  Products that are more comfortable to use 
will increase satisfaction, retention, and protection from unintended 
pregnancy. 
STUDY DESIGN 
Randomized, single-blind, phase III controlled clinical trial 
PRIMARY 
OBJECTIVE 
To measure contraceptive efficacy of the test product (Mona Lisa NT 
Cu380 Mini) 

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SECONDARY 
OBJECTIVES 
To compare between study products: 
• continuation rates  
• the incidence of failed IUD insertion, uterine perforation, and IUD 
expulsion (complete and partial)  
• vaginal bleeding patterns 
• pelvic pain and dysmenorrhea 
• the incidence of other adverse effects  
• pain with and shortly after insertion  
• ease of IUD insertion  
• overall product satisfaction 
NUMBER OF 
SUBJECTS 
Approximately 1100 women will be randomized in a 4:1 ratio.   
Approximately 880 will receive the test product (Mona Lisa NT 
Cu380 Mini) and approximately 220 will receive the control product 
(ParaGard). 
POPULATION 
Women aged 16-40 with anticipated need for contraception of at least 
one year. 
Planned recruitment will include approximately 80% nulliparous and 
20% parous women.  Women 36-40 years old will comprise only 10% 
of the study population. We will randomize approximately 1100 
eligible participants in a 4:1 ratio to two different copper IUDs: 
approximately 880 to Mona Lisa NT Cu380 Mini and approximately 
220 to ParaGard.  
TEST PRODUCT 
Dose and Route of 
Administration 
Mona Lisa® NT Cu380 Mini containing 380mm2 of copper surface 
inserted into the uterine cavity. 
CONTROL PRODUCT 
Dose and Route of 
Administration 
ParaGard® CuT380A containing 380mm2 of copper surface inserted 
into the uterine cavity. 
 
COMPLIANCE 
Compliance will be documented by verification that the IUD is in situ 
at each visit by pelvic exam or ultrasound examination (if needed).   
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Participants will be in the study for up to 37 months or until the IUD 
is removed or expelled. 
The total duration of the study is expected to be five years: 12 months 
for subject recruitment, 37 months for subject follow-up, and sites will 
be engaged for an additional year for pre- and post-trial activities.  At 
the Exit visit, 37 months from insertion, any subject randomized to the 
ParaGard treatment arm may elect to continue use of the device under 

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care of the woman’s primary provider. The Mona Lisa NT Cu380 
Mini is to be removed at the Exit visit or 37 months following 
insertion.  
DOSAGE AND 
REGIME 
Eligible subjects will be randomly assigned to Mona Lisa NT Cu380 
Mini or ParaGard in a 4:1 ratio. The IUD will be inserted by site 
clinician and left in place for up to 37 months (study Exit). 
SAFETY 
PARAMETERS 
• 
Occurrence of adverse events (AEs) and serious adverse events 
(SAEs) 
PRIMARY ENDPOINT 
• 
Pregnancy 
SECONDARY 
ENDPOINTS 
• IUD continuation at 12, 24 and 36 months after insertion 
• Failed IUD insertion, uterine perforation, or IUD expulsion 
(complete and partial) 
• Vaginal bleeding patterns 
• Pelvic pain and dysmenorrhea 
• Other side effects  
• Pain with and shortly after insertion  
• Ease of IUD insertion  
• Overall product satisfaction 
STATISTICAL 
ANALYSIS 
Below is the original estimate for the 95% upper bound of the Pearl 
Index for the Mona Lisa Cu IUD arm if we had randomized 800 
subjects to that treatment.  Since this protocol has been amended to 
randomize approximately 880 Mona Lisa Cu IUD subjects, the 
estimated 95% upper bound of the Pearl Index would be slightly 
lower due to the larger sample size. 
Randomizing 800 women to the Mona Lisa Cu IUD will provide 
approximately 17,700 cycles for the primary efficacy analysis among 
women under 36 years old at the time of enrollment, assuming 13 
cycles of use per year with 84.3% evaluable cycles, an exponential 
discontinuation rate of 0.2 (i.e., 20% per year), and 37 months of 
prescribed follow-up per woman.1 Based on this enrollment total and 
follow-up rate, the 95% upper bound of the Pearl Index (pregnancies 
per 100 women-years of follow-up) would be ~1.0 if 6 pregnancies 
were observed.  
PLANNED DSMB 
REVIEWS  
A Data and Safety Monitoring Board (DSMB) will conduct periodic 
reviews of subject safety and pregnancy for the study.  A DSMB 
                                                          
1 Based on a recent IUD study and assuming the same yearly discontinuation rate throughout 37 months, we would 
expect to observe approximately 7,100 cycles in year 1, 5,700 cycles in year 2 and 4,900 in year 3.   

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charter will be established prior to the first DSMB meeting in order to 
detail the frequency, timing and scope of the reviews.   
In addition, the DSMB will review an interim analysis.  
 
 

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NICHD/FHI 360 
Clinical Research Protocol 
A multi-center, single-blind, randomized clinical trial to compare two copper IUDs:  
Mona Lisa NT Cu380 Mini and ParaGard 
1 
BACKGROUND AND RATIONALE 
The only copper intrauterine device (IUD) currently marketed in the United States is 
ParaGard®.1  It was approved for use in 1984 and first marketed in 1988; millions of US women 
have relied on its high safety and high efficacy for pregnancy protection.  Copper IUDs are 
unique for having three key attributes: being non-hormonal, long-acting, and reversible.  For 
many women, these features make it an indispensable option.   
Unfortunately, copper IUD users can experience increased bleeding and cramping; these side 
effects can lead up to 20% of women to discontinue use within the first year.2-5 Nulliparous 
women typically experience higher rates of side effects compared to parous women.6  Recent 
findings from the largest contemporary cohort of copper IUD users in the USA confirm that 
nulliparous women have a higher incidence of removals for side effects compared to parous 
women7. However, the current product still provides tremendous benefit to a majority of 
nulliparous users. 
Higher side effect and removal rates among nulliparous women may be due to discrepancies 
between the size/shape of the current product and the uterine cavity.  ParaGard is the largest T-
shaped product in the world (measuring 32mm x 36 mm width and length, respectively).  On 
average, nulliparous women have uterine cavities that are smaller than those of parous women. A 
recent study estimated a mean cavity volume of 57cm3 for nulliparous women versus 82cm3 and 
105cm3 for women with one and more than one live birth, respectively.8 Width of the cavity 
averaged 27mm among nulliparous women to 32mm among women with more than one live 
birth. 
Previous research in nulliparous populations suggests that smaller copper IUDs may be more 
acceptable than similarly-shaped, standard-sized products.6,9,10  The only randomized trial (of 
nulliparous women) comparing a ParaGard-sized product to a smaller, T-shaped product 
(measuring 23mm x 29mm), found that the smaller product had continuation rates that were 
more than two times higher than the larger product.11   
The American Academy of Pediatrics12 and the American College of Obstetricians and 
Gynecologists13 state that IUDs should be a first-line option for nulliparous women. Newer and 
smaller copper IUDs used in Europe may be as effective as ParaGard and may cause fewer side 
effects.  This study aims to evaluate the performance of a smaller, European-approved product 
compared with ParaGard in a predominately nulliparous population. 
The National Institute of Child Health and Human Development (NICHD) has a mission to 
develop safe and effective contraceptives for women, including obese women.  Obesity is the 
number one public health issue facing the US population and is an independent risk for venous 

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thromboembolism (VTE).  Therefore, there is a public health need to develop effective estrogen-
free contraception that does not increase the risk of VTE. A copper IUD that contains no 
hormonal contraceptives may be safer than a hormonal method, and therefore could have a direct 
benefit to obese subjects. 
2 
STUDY PRODUCTS 
2.1 
Brief Product Descriptions – Structure and Regulatory Status 
This study involves two different copper IUDs: ParaGard (the control product) and Mona Lisa 
NT Cu380 Mini (test product).  Brief descriptions of each are provided. 
2.1.1 
ParaGard (control) 
The ParaGard T 380A Intrauterine Copper Contraceptive (NDA 18-680/S-060) was approved by 
the US Food and Drug Administration (FDA) in 1984 and was first marketed in the US in 1988. 
ParaGard is approved for intrauterine contraception for up to 10 years. The pregnancy rate in 
clinical studies has been less than 1 pregnancy per 100 women each year.12 The T-framed 
product measures 32mm across the arms by 36mm in height, and is made of polyethylene with 
barium sulfate to aid in radiologic detection of the device. Copper is added to the plastic frame to 
enhance efficacy. A total of 380mm2 of copper surface is on the product (copper collars on each 
arm and a copper wire wound around the vertical stem of the T-frame). This product is currently 
marketed in the USA by Teva Pharmaceuticals. 
2.1.2 
Mona Lisa NT Cu380 Mini (test product) 
The Mona Lisa NT Cu380 Mini IUD is a T-shaped product that measures 24 mm (arm span) x 
30 mm in height (about 20% smaller than the T 380A).  Like the T380A, the Mona Lisa NT 
Cu380 Mini is made of polyethylene, has 380 mm2 of copper surface and contains barium 
sulfate.  The Mona Lisa NT Cu380 Mini was first approved in Belgium in 2014 and is indicated 
for contraception for a 5-year duration.  It is currently marketed in Canada, Germany, France, 
and six other European countries. 
The Mona Lisa NT Cu380 Mini is manufactured by Mona Lisa N.V., Graaf de Theuxlaan 25, bus 
2, 3550 Heusden-Zolder, Belgium.  The company also manufactures the NT Cu380 Standard that 
is about the same size as the T 380A.  The product insert states that the Mona Lisa NT Cu380 
Mini is “designed for women with a uterine cavity depth of less than 7 cm”, while the larger 
version is “designed for women with a uterine cavity depth of 6-9 cm.” 
Specific pharmacologic and toxicology studies have not been conducted on the NT Cu380 Mini; 
however, studies have been conducted for the larger NT Cu 380 Standard, which comprises 
identical materials and copper surface area.  There are no clinical trial data for the Mona Lisa NT 
Cu380 Mini or for the NT Standard. 
2.2 Overview of Non-Clinical Studies 
In this section, only information on the test product is presented.  Refer to the package insert 
(Appendix 4) for information on ParaGard. 

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2.2.1 
Mona Lisa NT Cu380 Mini 
The supporting nonclinical biocompatibility and toxicity studies were carried out on the NT 
Standard, which is the predecessor to the Mona Lisa NT Cu380 Mini.  The NT Standard uses the 
same manufacturing materials and processes and has the same amount of copper, and is therefore 
equivalent in essential characteristics to the Mona Lisa NT Cu380 Mini.  Since the NT Standard 
is larger than the Mini, the data may be considered “worst case” or equivalent in essential 
characteristics; the relevancy of all data will be supported by a risk analysis according to ISO 
14971:2007 Medical devices—Application of risk management to medical devices.   
The biocompatibility tests on the NT Standard were completed in 2004, however, no GLP 
certification was provided.  The tests included cytotoxicity, sensitization, in vivo irritation in 
rabbits, pyrogenicity, and systemic acute toxicity.  All of the tests were considered negative 
based on standards set by ISO 10993. 
In 2013, a GLP lab did systemic injection tests, intracutaneous injection tests, Kligman 
maximization test, reverse mutation assay tests, and cytotoxicity tests with other Mona Lisa 
copper IUDs.  The tested IUDs contained the same frame and copper materials as the Mona Lisa 
NT Cu380 Mini (the only difference in materials was polyethylene threads instead of nylon 
threads).  All the tests were considered negative based on standards set by ISO 10993.   
Genotoxicity testing was not done on the Mona Lisa NT products.  However, tests were done on 
other copper IUD designs that use the same component materials as the Mona Lisa NT products.  
In tests on these other products, involving S. typhimurium and E. coli, no mutagenic concerns 
were discovered.  
The summary of findings from nonclinical studies is presented in the separate Investigator’s 
Brochure. 
2.3 Overview of Clinical Studies 
In this section, only information on the test product is presented.  Refer to the prescribing 
information (Appendix 3 and 4) for information on ParaGard and Mona Lisa NT Cu380 Mini 
respectively. 
No clinical studies on the Mona Lisa NT Cu380 Mini have been conducted. The Mona Lisa NT 
Cu380 Mini has a CE Mark certificate, having met regulatory requirements of the EU Medical 
Devices Directive (93/42/EEC) for a Class III product, and is marketed within the EU and 
European Free Trade Association for intrauterine contraception for up to 5 years. 
Since 2014 and through August 2016, over 40,000 units of the Mona Lisa NT Cu380 Mini were 
sold in Europe with the vast majority (over 36,000 units) distributed to France and 1,200 units to 
Canada.  During this time period, no reportable incidents have come to the European 
Commission’s medical device vigilance voluntary reporting system.  No advisories, warnings, or 
safety alerts have been issued on this product since it was first marketed. 

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3 
STUDY OBJECTIVES 
3.1 Primary Objective 
To measure contraceptive efficacy of the test product (Mona Lisa NT Cu380 Mini)      
3.2 Secondary Objectives 
To compare between test products: 
• continuation rates of the products 
• the incidence of failed IUD insertion, uterine perforation, and IUD expulsion (complete and 
partial) 
• vaginal bleeding patterns 
• pelvic pain and dysmenorrhea 
• the incidence of other adverse effects  
• pain with and shortly after insertion  
• ease of IUD insertion  
• 
overall product satisfaction  
4 
STUDY DESIGN 
4.1 Study Overview 
This will be a multi-site, participant-blinded, randomized clinical trial. We will randomize 
approximately 1100 eligible participants in a 4:1 ratio to two different copper IUDs: 
approximately 880 to Mona Lisa NT Cu380 Mini and approximately 220 to ParaGard. Planned 
recruitment will include approximately 80% nulliparous and 20% parous women. A parous 
woman will be defined as having had a delivery at 6 months/24 weeks.  
The study will assign subjects to the treatments in random order. Each woman will attend a 
baseline visit, followed by visits at 6 weeks, 3 months, 6 months, 12 months, 24 months and 37 
months, with telephones calls at 9, 18 and 30 months. Each subject will participate for up to 37 
months (or earlier if the product is removed or expelled). Subjects will use a home pregnancy 
test 17 days after Exit Visit procedures or any time she suspects that she may be pregnant, and 
report the results to their respective sites via telephone. 
At the Exit visit, 37 months from insertion, subjects using ParaGard may elect to continue use 
under the care of the woman’s primary provider. The Mona Lisa NT Cu380 Mini will be 
removed at the Exit visit or 37 months following insertion. The length of elective continued use 
for Mona Lisa NT Cu380 Mini may be adjusted to allow continued use for years 4 and 5 once 
incidence of key endpoints is evaluated through interim analysis of the currently planned study. 
A separate consent document and other study requirements would still be required if such a 
decision is made.  
We will conduct this study according to CFR Title 21, CFR Title 45, Part 46, Good Clinical 
Practices (GCP) and International Council for Harmonisation (ICH) Guidelines under an IND 
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4.2 
Study Duration 
The total duration of the study for each participant is expected to be approximately 39 months: 
including screening and enrollment (up to 60 days to meet enrollment criteria), 37 months of 
participation, and a follow up telephone call 17 days post-removal. After enrollment, subject 
visits occur at 6 weeks, 3 months, 6 months, 12 months, 24 months, with telephone calls at 9, 18, 
and 30 months and seen again at 37 months for their final visit. Subjects will use a home 
pregnancy test 17 days post-removal of the IUD or Exit Visit procedures, whichever occurs first, 
and will be called by the site for the result and for safety follow-up. 
Subject recruitment began in Q2 (in the second quarter of) 2017 and is expected to continue 
through Q1 2019. However, if the enrollment rate declines or the target enrollment is not 
reached, the enrollment period may be extended beyond this date. If this enrollment timeline is 
met, all subjects should finish active treatment by approximately the end of Q1 2022. The total 
duration of the study will be approximately 57 months for each study site including pre- and 
post- trial activities. The end of the study will occur when the last subject to be enrolled has 
completed her post-removal pregnancy test telephone call. 
Total duration of the project is expected to be approximately five and a half years. Preliminary 
results of the study are expected to be available Q3 of 2022 based on the current study plan. 
5 
PRINCIPAL INVESTIGATORS AND RESEARCH SITES 
The National Institute of Child Health and Human Development (NICHD) will conduct the study 
using 11 sites from its Contraceptive Clinical Trials Network (CCTN), and FHI 360 will conduct 
the study at five additional sites. A complete list of Principal Investigators, Sub-Investigators and 
Coordinators will be maintained with the trial documentation. Listed here are the investigational 
research sites conducting this study.  
5.1 
FHI 360 Sites 
Courtney Schreiber, MD, MPH: Perelman School of Medicine at the University of Pennsylvania  
Beatrice A. Chen, MD, MPH: University of Pittsburgh 
Anita Nelson, MD: Essential Access Health 
Alisa Goldberg, MD: Planned Parenthood League of Massachusetts 
Ila Dayananda, MD: Planned Parenthood New York City 
5.2 
NICHD Sites 
David Archer, MD: Eastern Virginia Medical School 
Anne Burke, MD: Johns Hopkins University 
Paula Castaño, MD, MPH: Columbia University 
Mitchell Creinin, MD: University of California, Davis 
Philip Darney, MD, MSc: University of California, San Francisco 
Jeffrey Jensen, MD, MPH: Oregon Health & Science University 

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Subsite: Bliss Kaneshiro, MD, MPH: University of Hawaii 
Stephanie Teal, MD, MPH: University of Colorado Denver 
Michael A. Thomas, MD: University of Cincinnati 
David Turok, MD: University of Utah 
Katharine White, MD, MPH: Boston Medical Center Corporation  
6 
CRITERIA FOR EVALUATION 
6.1 
Primary Endpoint 
The primary endpoint for this study is pregnancy (contraceptive method failure).  All 
pregnancies will be dated by a combination of available clinical data according to the American 
College of Obstetricians and Gynecologists criteria for pregnancy dating.  We will review all 
pregnancies to estimate conception dates, and assess carefully whether pregnancies that are 
diagnosed soon after IUD insertion or removal should be classified as method failures. 
6.2 
Secondary Endpoints 
• IUD continuation 
• Failed IUD insertion, uterine perforation, or IUD expulsion (complete and partial)  
• Vaginal bleeding patterns 
• Pelvic pain and dysmenorrhea 
• Other side effects  
• Pain with and shortly after insertion  
• Ease of IUD insertion  
• Overall product satisfaction 
6.3 
Safety Evaluations 
The study will not require routine laboratory monitoring for safety, given that these are non-
hormonal products. At each study visit site staff will collect information on adverse events (AEs) 
and serious adverse events (SAEs).  
7 
SUBJECT SELECTION 
7.1 
Study Population 
Approximately 16 clinical sites in the US will enroll reproductive-aged women participants from 
family planning and other clinics providing gynecologic care and reproductive health services. 
Referrals from previous studies are acceptable. This study will be conducted in the US by the 
National Institute of Child Health and Human Development (NICHD) in its Contraceptive 
Clinical Trials Network (CCTN) at 11 sites and by FHI 360 at 5 sites. This study will be listed on 
the trial registration website ClinicalTrials.gov. Subject selection will occur based on the 
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7.2 
Inclusion Criteria 
• 16-40 years  
o 16 and 17 year olds, where permissible by state regulations and local Institutional 
Review Board (IRB) approval  
• Sexually active, anticipating at least one act of vaginal intercourse per menstrual cycle 
with a male partner and at risk for pregnancy  
• seeking contraception, and willing to use the study IUD as the only contraception method 
• willing to be randomized to one of the two copper IUDs 
• has an intact uterus and at least one ovary  
• has a history of regular menstrual cycles; defined as occurring every 21-35 days when not 
using hormones, and with a variation of typical cycle length of no more than 5 days 
• able and willing to provide written informed consent 
• agrees to follow all study requirements 
• not currently pregnant or at risk for luteal phase pregnancy based on history of 
unprotected intercourse 
7.3  
Exclusion Criteria 
• abnormal Pap requiring treatment after enrollment 
• known human immunodeficiency virus / acquired immunodeficiency syndrome 
(HIV/AIDS) infection 
• intending to become pregnant in the 37 months after enrollment 
• known infertility 
• history of allergy or sensitivity to copper   
• previous tubal sterilization 
• has received an injectable contraceptive in the last 9 months and has not resumed regular 
menstrual cycles (as evidenced by 2 spontaneous menses) 
• within 30 days of administration of mifepristone and/or misoprostol for medical abortion 
or for miscarriage management  
• within 30 days of first, second, or third trimester abortion or miscarriage (note: potential 
abortion/miscarriage participants can be screened and return after 30 days for 
randomization and IUD insertion) 
• within 30 days of delivery (for parous population) 
• breastfeeding or recently breastfeeding women unless two consecutive normal menstrual 
periods have occurred after delivery and prior to enrollment. 
• wants to use a copper IUD for emergency contraception 
• has previously participated in the study  
• participated in another clinical trial involving an investigational product within the last 30 
days (before screening) or planning to participate in another clinical trial involving an 
intervention or treatment during this study 
• not living in the catchment area of the study site or planning to move from the area within 
the year (unless known to be moving to the catchment area of another study site) 

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• known or suspected current alcohol or drug abuse  
• planning to undergo major surgery during study participation 
• current need for use of exogenous hormones or therapeutic anticoagulants (Note: subjects 
who start a therapeutic anticoagulant after enrolment will be allowed to continue in the 
study.)  
• at high risk for sexually-transmitted infections or pelvic infection 
• anticipated need for regular condom use (refer to Section 8.1). 
• has any condition (social or medical) which in the opinion of the Investigator would 
make study participation unsafe or complicate data interpretation 
• Reported medical contraindications (Medical Eligibility Criteria category 3 or 4)14 to 
copper IUDs, including: 
o suspicious unexplained vaginal bleeding 
o known cervical cancer 
o known endometrial cancer 
o known Wilson’s disease 
o Confirmed gestational trophoblastic disease with persistently elevated beta-hCG 
levels or malignant disease, with evidence or suspicion of intrauterine disease 
o anatomic abnormalities with distorted uterine cavity  
o current pelvic inflammatory disease (PID)  
o pelvic tuberculosis 
o immediately post-septic abortion or puerperal sepsis 
o current known purulent cervicitis or chlamydial infection or gonorrhea; Note: to 
enroll, there must be no obvious signs of infection at the time of enrollment based 
on pelvic exam.  If lab results come back for positive infection after enrollment, 
treatment should be provided but the IUD can be left in place. 
o complicated solid organ transplantation 
o systemic lupus erythematosus with severe thrombocytopenia 
7.4 
Allowable Criteria 
• 
has been using oral contraceptives, vaginal ring, or patch and is discontinuing the product 
to be enrolled 
• 
has been using a contraceptive implant or IUD, but wishes to have the device removed 
prior to enrollment 
7.5 Number of Subjects 
The study is expected to enroll approximately 1100 female subjects randomized to one of the 
two IUDs.  

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8 
CONCURRENT MEDICATIONS AND TREATMENTS 
8.1 
Allowed Medications and Treatments 
Recording of all concomitant treatments will occur on the subject’s source and electronic case 
report forms (eCRF), including the name of the drug, start and stop dates and reason for use from 
the time the informed consent form (ICF) is signed through discontinuation from the trial. Any 
other investigational product should be stopped at least 30 days before the start of screening for 
this trial. Other medications for the treatment of inter-current medical conditions will be 
permitted and recorded as detailed above unless identified on the exclusionary list of 
medications.  
Condoms are allowed for protection from sexually transmitted infection (STI).  However, 
anticipated regular use of condoms is exclusionary.  Regular use of condoms is defined as an 
anticipated need of at least one condom per month after enrollment.  
If a subject suspects that her IUD is not in place, she should return to the site as soon as possible 
for confirmation of IUD placement.  In the meantime, she should use condoms during 
intercourse until she is evaluated by the site. 
8.2 
Prohibited Medications and Treatments 
Concomitant medications that should not be used during the study include: 
• Exogenous hormones, including hormonal contraceptives, except if needed for medical 
reasons and used in a single cycle during the study  
• Therapeutic anticoagulants (at enrollment only)  
9 
STUDY TREATMENTS 
9.1 
Method of Assigning Subjects to Treatment Groups 
The study will randomly assign approximately 1100 eligible participants to Mona Lisa NT 
Cu380 Mini or ParaGard in a 4:1 ratio using a SAS-based computer-generated randomization 
scheme.   Randomization will be stratified by parity (nulliparous and parous will be the 
stratification categories with a goal of enrolling 80% nulliparous).  Enrollment will be tracked to 
ensure approximately 10% of women are 36-40 years old. 
The randomization listing will be uploaded to the HD EDC system for proper stratified 
randomization. The IUDs for each site will be provided in bulk and clinicians will pull the 
product from the existing stock based on the product identified in the EDC system at time of 
randomization. 
Health Decisions will hold the randomization listing in a secure limited access location for the 
duration of the study. 
Sites will enter the kit and randomization number provided from the EDC system on their IP 
dispensing log for each subject.  The subject identification number assigned to subjects during 
the screening visit will identify them for the duration of the study.  

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9.2 
Blinding (participant only) 
The identity of the assigned IUD will not be shared with participant from the time of insertion 
through the Exit/37-month study visit.  However, the clinicians inserting the product and 
clinicians conducting follow-up exams will know which product was assigned. Clinic staff 
completing other assessments should remain blinded as much as possible. 
Sites will ensure single-blind administration of study treatments using the following study 
procedures: 
• Once the product assignment is determined, study staff will prepare the IUD and supplies 
outside the view of the participant 
• The study staff will pull the IUD from the stock and place all identifying packing 
information out of the sight of the subject (Note: all packaging materials should be 
retained in a secure location for examination and accountability by the monitor) 
• If necessary, an overlay will cover the tray (or insertion supplies when not used on a tray) 
to prevent inadvertent unblinding to the study participant. 
When the participant returns for follow-up, the participant blinding is to be maintained. The site 
will break the blind for the study participant on completion of her study participation at the Exit 
visit after all IUD assessments have been performed. During the study, the participant blind may 
be broken only in emergencies when the patient or treating physician must know which product 
was received. When possible, the Investigator should discuss the emergency with the Medical 
Monitor prior to unblinding.  As outlined in Section 12.1, subjects should be instructed to contact 
the study site to report any untoward medical occurrence that they experience. If health care is 
received elsewhere, for any reason, the participant should inform the attending clinician of their 
study participation request that no details of their IUD be shared. 
9.3 
Formulation of Test and Control Products 
The products used in this study are the ones that are marketed in the USA and in Europe.  
9.3.1 
Formulation of Test and Control Products 
Table 01. Formulation and the Test IUDs 
 
Control Product 
Test Product 
 
ParaGard 
 Mona Lisa NT Cu380 Mini 
Manufacturer 
Teva Pharmaceutical, USA 
Mona Lisa, N.V. 
Belgium 
Active ingredient 
 
Copper 
380mm2 surface area 
Copper 
380mm2 surface area 
Copper purity 
>99.95% 
>99.95% 
Frame 
Polymer 
Polymer 
Free state shape 
“T” shape 
“T” shape 

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Control Product 
Test Product 
Frame dimensions 
32mm x 36mm 
24mm x 30mm 
 
9.3.2 
Packaging and Labeling 
All labeling of the study product will be prepared in accordance with 21CFR, Section 812.5. 
Study product will be supplied in the original manufacturer packaging containing a single use 
IUD with a study label applied on the original packaging for study purposes. The study label will 
provide the study specific information as follows: 
• Protocol Identification: CCN016  
• Sponsor Identification: NICHD/FHI 360 
• Kit Number (preprinted/space to record) 
• Subject ID (space to record) 
• Subject Initials (space to record) 
• Date Dispensed (space to record) 
• FDA Caution Statement: CAUTION -- Investigational drug. Limited by Federal (or 
United States) law to investigational use. 
• Distributor: FHI 360, 359 Blackwell Street, Suite 200, Durham, NC 27701 
• Directions: Use as Directed in CCN016 Protocol.  
• Storage:  Controlled Room Temperature (15 to 30ºC (59 to 86ºF)) 
• Keep Out of Reach of Children 
9.4 
Provision of Study Product to Participants 
At the study site, the Principal Investigator (or designee) will insert the IUD into the participant’s 
uterus during the enrollment visit. If insertion is not successful on the first attempt, a second 
attempt with the same product may be made during the enrollment visit only.  If second attempt 
is unsuccessful then the subject will be discontinued.  
Once successfully inserted, the IUD will remain in place for up to 37 months for current study 
purposes unless product expulsion occurs, safety concerns arise or the subject chooses to have 
the IUD removed prior to completion of 37 months of use for any reason. No replacement of 
study IUDs will occur should product expulsion or accidental removal occur. If expulsion or 
accidental removal occurs prior to 37 months of continuous use, subjects should contact the 
study site immediately to be scheduled for an Exit Visit. 
9.4.1 
Dosage Regimen 
Subjects will be enrolled and randomized to receive one of the copper IUDs being studied. The 
single IUD will be inserted in the uterus by delegated study staff at a subject’s enrollment visit. 
9.4.2 
Dispensing 
The Principal Investigators (or designees) have authority to retrieve the IUDs from the 
temperature controlled, secure limited access stored supply stock. 

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Prior to dispensing, the Principal Investigator or designee will record the site number, subject’s 
identification number, initials, and date dispensed on the overlay packaging. Upon dispensing, 
the original manufacture packaging should be replaced within the overlay packaging for 
monitoring accountability purposes. 
The Principal Investigator (or designee) will record the randomization number, subject 
identification number, subject initials, and date dispensed on the accountability log.  
9.4.3 
Administration Instructions  
This is a single-blinded study; the participant should not see the assigned IUD or the 
manufacturer’s product packaging. Precautions should be taken to prevent subjects from seeing 
the manufacturer’s product packaging, including but not limited to covering the IUD and 
insertion supplies with a sterile overlay to prevent inadvertent unblinding.   
Each IUD has an FDA- or European-approved product label that contains insertion instructions.  
Training will occur for Investigators on proper insertion technique for the test product.  
Investigators can also refer to the product label and Investigator’s Brochure for additional 
information.  
All pre-insertion clinical assessments are the same for all IUDs as described in Sections 11.1.1 
Screening Procedures and 11.1.2 Enrollment Procedures. 
9.5 
Supply of Study Product at the Site 
Health Decisions will oversee the shipment of Study Product to the investigational sites. 
Shipment of the initial study product will occur after site authorization (i.e., all required 
regulatory documentation has been received by the Sponsor, IRB approval has been received and 
a contract has been executed). Once a site request for resupply is received, shipment of 
subsequent study product will occur. 
9.5.1 
Storage 
Study product should be stored in a dry place at the study site at controlled room temperature, 15 
to 30ºC (59 to 86ºF) under controlled and secured conditions (in a locked storage area away from 
sunlight). A temperature log for the investigational product storage area must be maintained for 
the duration of the study. If the temperature of the study product storage area exceeds or falls 
below the allowable range, this should be reported to the Sponsor or designee and captured as a 
deviation.  
9.6 
Study Product Accountability 
An accurate and current accounting of the dispensing, insertion, and removal of study product for 
each subject will be maintained on an ongoing basis by a member of the study site staff.  
Recording of information regarding study product disposition will occur on the Investigational 
Product Accountability Log by Investigator (or designee). The study monitor will verify these 
documents and product packaging on a regular basis throughout the course of the study. Refer to 
Section 9.4.2 for some of the information that dispensing staff will capture on the Accountability 
Log. After documented accountability has been completed for a subject by the monitor, the site 
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9.7 
Measures of Treatment Compliance 
Compliance with treatment is a key endpoint of the study; this status is documented by verifying 
that the IUD is in situ. To verify the presence of the IUD, the clinician will check for the IUD 
string at each study visit (refer to Appendix 2 for confirmation process). If the IUD string is not 
visible or palpable on examination, or if there is clinical suspicion of expulsion, clinicians will 
proceed with ultrasound and x-ray examination (if appropriate) to verify that the IUD is in 
position. Should IUD be removed outside of the site, the Investigators should request release of 
medical records by subject upon notification if removal was completed by a non-study medical 
provider or proceed with verification steps in Appendix 2 to confirm removal if completed by the 
subject. For this study, we will use the following definitions: 
1. Complete expulsion: the IUD is completely outside of the uterus and cervix, as evidence by 
seeing the IUD outside the uterus or complete absence of the IUD on ultrasound examination 
with no evidence of an intraabdominal IUD by X-ray; 
2. Partial expulsion: visualization or palpation of any portion of an IUD (other than strings) at 
the cervical os, or ultrasound identification of any part of the IUD in the cervical canal, 
regardless of symptoms. 
9.8 
Study Product Disposal/Return 
At the end of the study, the monitor will complete a final accountability of all clinical supplies, 
including remaining unused product and used product overlay packaging. Remaining used (e.g., 
removed or expelled) study product destruction will occur on-site following site-specific 
destruction standard operating procedures once monitor accountability has been completed.  
Guidance for remaining unused study product return or disposal will be provided by the 
Sponsors at the end of the study.   
10 STUDY PROCEDURES AND GUIDELINES 
10.1 Investigator’s Meeting and Protocol Training 
Prior to initiating recruitment of participants, an Investigator’s Meeting will be held for the 
following purposes: 
• To train Investigators on proper insertion of the test product 
• To train Investigators on the protocol specifics and study manuals 
• To document training  
• To train on other study specific requirements 
10.2 Clinical Assessments and Procedures 
A Schedule of Assessments representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and dated 
by the subject or subject’s legal representative. If appropriate, assent must also be obtained prior 
to conducting any study-related activities. 

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10.2.1 Medical, Demographic, and Reproductive Health History 
At the screening visit, study staff will ask women about their medical and gynecologic history, 
including specific questions about any medical problems or current medications that may be 
contraindications to the use of any of the study methods. Women will also be asked about their 
past use of contraceptive methods as relevant and details about their previous pregnancies, if any. 
General subject demographic information (i.e. race, ethnicity, level of education, etc.) will also 
be collected at screening. 
10.2.2 Vital signs and Pelvic Exam 
Trained research staff will collect vital signs on all potential participants at screening to evaluate 
for contraindications to the study methods. These exams will include measurement of blood 
pressure, height, and weight, and a pelvic exam, including speculum exam. A bimanual exam 
will be done to assess for the presence of any uterine or cervical anomalies, possible pelvic 
infection, or other abnormal findings such as an adnexal mass that would preclude IUD use. An 
assessment of uterine cavity length also will be completed by sound or pipelle while speculum is 
still in place after the subject is randomized but prior to IUD insertion. Any suspected 
reproductive tract infections (RTI) identified on physical exam will be diagnosed and treated 
according to local standards of care. Enrollment will be deferred pending treatment. In addition, 
treatment will be initiated and/or adjusted as appropriate based on laboratory results when 
available and include treatment of sexual partners when indicated. If an infection is suspected or 
confirmed, treatment according to the site’s standard of care is indicated. Once treatment is 
complete, the subject may return for continued screening and may be enrolled within a month of 
the start of screening if there is no obvious sign of infection. If no infection is suspected at time 
of screening, subjects may enroll the same day. 
10.2.2.1 Suspected gonorrhoea, chlamydia, or Pelvic infection 
Clinicians diagnosing suspected gonorrhoea, chlamydia or pelvic infection on the basis of exam 
will postpone subject enrollment and prescribe appropriate treatment. In addition, treatment will 
be initiated and/or adjusted as appropriate based on laboratory results when available and include 
treatment of sexual partners when indicated. Once treatment is complete, the subject may return 
for continued screening and may be enrolled within a month of the start of screening if there is 
no obvious sign of infection per clinician judgement.  
10.2.3 Ultrasound examination 
Ultrasound examinations pre or post-enrollment are not required and should not be standard. 
Clinician judgement should be used to determine whether, when, and what type of ultrasound 
examination is needed. Potential reasons include, but are not limited to: 
• difficult insertion 
• suspected perforation 
• suspected expulsion 
• pregnancy 
Steps should be taken to ensure that the participant does not look at the ultrasound screen and 
that pictures are not shown to the subject to ensure subject blinding is maintained. 

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10.2.4 Pap Test 
A screening Pap test will be completed for subjects at screening if potential participant is not in 
compliance with normal standard of care guidelines regarding Pap testing.  ACOG guidelines 
should be used for current Pap test standard of care requirements.  Participants will need to 
provide results of previous Pap to confirm results are within ACOG Pap test standard of care 
requirements for Pap testing not completed by the site.  Participant pap test results, as required 
per ACOG guidelines, are required prior to the participant being enrolled and randomized into 
the study.  When scheduling Screening visits, sites should request subject bring Pap results with 
them to the Screening visit.  If additional testing or treatment is required based on Pap results, 
this should be completed prior to enrollment. 
10.2.5 Laboratory Assessments 
Laboratory evaluations:  
See Visit Procedures section 11. 
10.2.5.1 STI screening  
During screening visits, at the time of the pelvic exam, all participants will be screened for 
gonorrhoea and chlamydia using nucleic acid amplification testing of urine, vaginal, or 
endocervical swabs.  Asymptomatic participants do not need to wait for gonorrhoea and 
chlamydia results to receive their assigned IUD.  
For a few asymptomatic women, IUD insertion might occur before results of a positive 
gonorrhoea or chlamydia test are available. For these participants, treatment will commence as 
soon as possible once results of a positive test are received. IUDs should not be removed unless 
severe pelvic infection is suspected.  
10.2.5.2 Urine pregnancy testing 
Participants will undergo urine pregnancy testing at screening and enrollment (if enrollment 
occurs on a separate day from screening).  A negative test is required to proceed with possible 
IUD placement. In addition, urine pregnancy tests will be administered during follow-up visits. 
Each facility will use the test kits and specific laboratories normally used for routine services at 
the facility’s local laboratory. 
Note: if urine pregnancy test is positive at screening, no further action is required and subject 
will become a screen failure. If positive urine pregnancy test report is based on home 
pregnancy test result post enrollment, subject should be scheduled to come in for an 
Unscheduled visit to have quantitative blood pregnancy test performed.  If confirmatory 
quantitative blood pregnancy test comes back negative, then subject will be allowed to stay 
in the study. 
10.2.6 Specimen collection and Processing 
Each site will establish standard operating procedures, including specimen chain of custody and 
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per local laboratory requirements for sample processing in accordance with standards of good 
clinical and laboratory practice. 
10.3 Subject Assessments 
10.3.1 Follow Up Form 
Administration of a follow-up form will occur at Visit 2, Visit 3, Visit 4, Call 1, Visit 5, Call 2, 
Visit 6, Call 3 and Exit for subjects to answer questions about the desire to continue use of the 
IUD, IUD acceptability, last menstrual cycle, vaginal bleeding, pelvic pain, and use of alternative 
contraception since the preceding visit.  
10.3.2 Daily Diary  
For the first 12 months of use, participants will maintain a daily diary to record 
bleeding/spotting.  Each form will collect one cycle of information consisting of 28 days of daily 
records.  The form will also be used to record the use of any additional contraceptives (e.g. 
condoms) and coitus within that full 28-day cycle.  Site staff will review responses carefully to 
ensure there are no questions about responses provided by the subject.  The information from the 
daily diaries will be entered in the corresponding CRFs. Each site will retain originals of the 
completed diaries as source documents and certified copies will be uploaded to the study 
document repository or EDC at Health Decisions.  
10.3.3 Other Contraceptive Use  
In the second and third years, participants will record cycle-to-cycle use of any other 
contraceptive methods.  The forms will be used to capture information on other contraceptives 
used for the six month period between site visits.  The information from the forms will be 
entered in the corresponding CRFs during Visit 6, and Exit.  At Calls 2 and Call 3 the site will 
ask information relative to other contraceptives used since the previous visit in order to prompt 
subjects to continue completing the forms; however, when the forms are returned at the clinic 
visits the form responses will be the primary source which will be used for data entry rather than 
information discussed during the calls that sites may have recorded in the subject’s source.  Each 
site will retain originals of the completed forms as source documents and certified copies will be 
uploaded to the study document repository or EDC at Health Decisions. 
10.3.4 Post Placement Pain Forms  
During the enrollment visit, a Clinic Post Placement Pain Form will be completed by the subject 
to record her baseline pain measurement after speculum placement and then pain measurements 
immediately and ten minutes after IUD placement.  During the Exit Visit, the subject will 
complete a measurement of pain immediately after IUD removal on the bottom of the Clinic Post 
Placement Pain Form.   
A separate Home Post Placement Pain Form will be sent home so subjects can record their 
maximum daily pain for 6 days following IUD placement. Also on this form, the subject will 
provide information on satisfaction with the IUD and use of pain medications.  This form will be 
turned in at the 6 week visit. 

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11 EVALUATIONS BY VISIT 
11.1 Screening and Enrollment/IUD Insertion 
Visit 1 includes screening, enrollment, and IUD insertion. Screening and enrollment can occur 
on the same day provided the potential participant meets eligibility criteria at the time of 
screening, and is not at risk for luteal phase pregnancy based on history of unprotected 
intercourse within her current menstrual cycle. If the participant is at risk for pregnancy in the 
current cycle or is suspected to have gonorrhea, chlamydia, or pelvic infection, enrollment 
should be deferred.  If the subject is under 21 years of age, no Pap is required per ACOG 
guidelines. If the potential participant is unable to provide results of previous Pap, defer 
enrollment until Pap results are available confirming treatment would not be required.   
11.1.1 Screening Procedures 
At the screening visit, study staff will conduct administrative and regulatory procedures 
(including obtaining written informed consent, providing contraceptive counselling, obtaining 
medical and reproductive health history, performing pelvic examinations, and collecting 
laboratory specimens for testing). Potential participants will provide written consent before any 
screening procedures are initiated. If needed, sites will refer women who are not eligible for the 
study for further care, if relevant services are not available at the research site or clinic. If a 
subject is a screen failure on her first study participation attempt, she may be rescreened one time 
per the Investigator’s discretion. 
Table 02.   Screening Visit Procedures 
Component  
Procedures  
Administrative and Regulatory  
• 
Obtain written informed consent, HIPAA 
Authorization and Assent (if applicable)  
• 
Assign Subject Identification number 
• 
Assess eligibility  
• 
Collect participant’s contact information (e.g., 
cell phone, home phone, email, etc.).  Note: If 
the subject has a cell phone, study staff should 
call the participant’s cell phone number at least 
one time prior to enrollment to ensure number 
correctly connects to the subject. 
• 
File paper forms in a secure location 
• 
Provide reimbursement  
• 
Schedule next visit 
Contraceptive Counselling  
• 
Describe contraceptive options, study IUDs, and 
answer potential participant questions  
Clinical  
• 
Collect demographic information 
• 
Obtain medical, gynecologic, menstrual, 
contraceptive, and reproductive history 

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• 
Check vital signs and conduct pelvic 
examination  
• 
Collect concomitant medication information 
• 
Collect Pap test if subject is unable to provide 
results within ACOG standard of care 
guidelines 
Laboratory                        
      Urine 
• 
Test urine for pregnancy 
                                   
STI 
 
• 
Test endocervical or vaginal swabs or urine (per 
clinic testing standard) for Neisseria 
gonorrhoeae and Chlamydia trachomatis 
(GC/CT) to complete a Nucleic Acid 
Amplification Test (NAAT) (per clinic testing 
standard) and treat clinically suspected 
gonorrhoea, chlamydia, or pelvic infection per 
standard of care  
11.1.2 Visit 1 (Enrollment Procedures and IUD Insertion) 
Potential participants will usually proceed to enrollment procedures immediately after successful 
screening (i.e., screening and enrollment visits can occur on the same day).   
The protocol allows same-day enrollment and IUD insertion in these potential participants: 
• Women not using hormonal contraception who are in the first 7 days of the menstrual 
cycle, 
• Women who have been correctly and consistently using a reliable hormonal method of 
contraception before screening (OCs, patch, ring, implants) once these methods are 
stopped/removed, 
• Women who have been using any type of IUD (same-day removal and study enrollment 
is acceptable), 
• Women who are ≥ 30 days post uncomplicated medical abortion who have been 
consistently using a reliable hormonal method of contraception before screening (OCs, 
patch, ring) or have not had vaginal intercourse since pregnancy termination, 
• Women who are ≥ 30 days post first, second or third trimester surgical abortion who have 
been consistently using a reliable hormonal method of contraception before screening 
(OCs, patch, ring) or have not had vaginal intercourse since pregnancy termination, 
• Non-breastfeeding women who are ≥ 30 days post-delivery who have been consistently 
using a reliable hormonal method of contraception before screening (OCs, patch, ring) or 
have not had vaginal intercourse since pregnancy termination. 
 

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If enrollment cannot proceed for any reason, including a contraindicated infection or 
immediately post abortion/delivery, the potential participant should return no later than 60 days 
from the start of screening to be enrolled. If the potential participant was treated for a sexually 
transmitted infection, treatment should be complete and there should be no signs of active 
infection prior to enrollment. If the potential participant appears to have been re-infected, she 
would be considered a screen failure.  If the potential participant was screened less than 30 days 
post-abortion or delivery, confirmation of eligibility should be completed prior to randomization 
including review for any new history, review of concomitant medications and urine pregnancy 
check.  Review of cases that require a screening period longer than 60 days will occur on a case 
by case basis through a submitted waiver. If the enrollment visit occurs separately from 
screening, sites will reconfirm study eligibility prior to enrollment, including pregnancy testing. 
Study staff will collect adverse events (AEs) and any new or changed concomitant medications. 
Sites will randomize eligible women (at which point a woman will be considered enrolled) and 
women will receive one of the two study IUDs. Once enrolled, reimbursement for the women’s 
time and scheduling of their 6-week contraceptive follow-up visit will occur. 
Table 03: Enrollment Visit Procedures 
Component  
Procedures  
Administrative and Regulatory  
• 
Randomize subject in EDC system and record 
required information on study product label  
• 
Provide reimbursement  
• 
Schedule next study visit (6 weeks out ± 5 days)  
• 
Review diary cards, including proper 
completion instructions. Distribute 2 daily diary 
forms; each form covers a 1-month period 

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Clinical  
• 
If visit is separate from screening, reassess 
eligibility, including infection status, if treated, 
and risk of pregnancy 
• 
Assess for AEs and concomitant medication  
• 
Complete assessment of uterine cavity length by 
sound or pipelle.  If cavity length measures less 
than 5.5 cm, subject must be discontinued and 
insertion should not be completed. 
• 
Collect information on subject’s pain after 
speculum placement and prior to sounding of 
the uterus (baseline pain assessment) 
• 
Insert assigned IUD 
• 
Assess ease of insertion 
• 
Collect information on subject’s pain after 
insertion (immediately and 10 minutes after 
insertion) 
• 
Distribute a home pregnancy test with 
instructions to complete the test if subject has 
any suspicion that she may be pregnant. 
• 
Distribute Home Post Placement Pain Form for 
subjects to record their maximum daily pain for 
the 6 consecutive days following IUD 
placement, satisfaction with IUD and use of 
pain medications.  
Laboratory                        
     Urine 
• 
Test urine for pregnancy  
                                   
STI 
• 
Retest for STIs if needed  
Note: If enrollment does not immediately follow the screening procedure, confirmation of 
eligibility must be performed using clinical judgement to decide whether repeat pregnancy, STI 
testing, or other assessments are needed and if contact information should be reviewed. In 
addition, collection of information on AEs and concomitant medication changes will occur. 
 
Note: At the discretion of the investigator, IUD insertion may be attempted a second time on the 
day of enrollment using the same device if no contamination issues occurred. If contamination 
occurred with the initial IUD on the day of enrollment, a second product may be obtained for 
insertion on same day of enrollment only. Procedures for obtaining second IUD will be outlined in 
the Health Decisions Study Manual.  Reattempts using a different device or on a different date 
after enrollment are not allowed.  Reinsertion post enrollment insertion is also not allowed. 
 
Note: An Ultrasound does not need to be performed to confirm IUD placement. 
 
Note: No anaesthesia may be used on first insertion attempt.  Cervical anaesthesia only may be 
used if indicated per Investigator discretion for second insertion attempt on same day.  
Misoprostol is not allowed.  Tenaculum site should not be anesthetized.  

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11.2 Clinic-Based Follow-up Visits 
At 6-weeks, 3-months, 6-months, 12-months, 24-months, and 37-months post-insertion, all 
participants will return for follow-up visits (Table 04). During these visits, collection of 
information on AEs, concomitant medications, IUD acceptability, and potential concerns or side 
effects related to the study product will occur. To verify the presence of the IUD, the clinician will 
check for the IUD strings using a visual inspection, digital palpation and/or sweep for strings using a 
cytobrush. If the IUD strings are not visible or palpable, or if there is clinical suspicion of expulsion, 
clinicians will proceed with an ultrasound examination to verify that the IUD is in position (Section 
9.7, Appendix 2). Participants will be scheduled for their next follow-up visit or call. Staff will 
also encourage participants to return to the clinic for adverse events or any other concerns at any 
time. If at any visit the Investigator determines that a participant should be discontinued, follow 
Early Discontinuation Visit procedures (Section 11.5). 
11.2.1 Visit 2 (6-weeks post-insertion ± 5 days) 
Study staff will collect AEs and new or changed concomitant medications, collect and review 
diaries with the participants, ask IUD acceptability questions, and complete the follow-up 
assessment forms. Clinicians will check for IUD strings as above. Assess (and treat as 
applicable) for STIs/RTIs, as well as check for pregnancy.  Participants will be reimbursed and 
be scheduled for their 3-month follow-up visit. Reconfirm participant’s contact information. 
11.2.2 Visit 3 (3 months post-insertion ± 14 days) 
Study staff will collect AEs and new or changed concomitant medications, collect and review 
diaries with the subjects, ask IUD acceptability questions, and complete the follow-up 
assessment forms. Clinicians will check for IUD strings as above. Assess (and treat as 
applicable) for STIs/RTIs, as well as check for pregnancy.  Participants will be reimbursed and 
be scheduled for their 6-month follow-up visit. Reconfirm participant’s contact information. 
11.2.3 Visit 4 (6 months post-insertion ± 14 days) 
Study staff will collect AEs and new or changed concomitant medications, collect and review 
diaries with the subjects, ask IUD acceptability questions, and will complete the follow-up 
assessment form. Clinicians will check for IUD strings as above. Assess (and treat as applicable) 
for STIs/RTIs, as well as check for pregnancy.  Participants will be reimbursed and be scheduled 
for their 9-month phone call. Reconfirm subject’s contact information. 
11.2.4 Visit 5 (12 months post-insertion ± 14 days) 
Study staff will collect AEs and new or changed concomitant medications, collect and review 
diaries with the subjects, ask IUD acceptability questions, and will complete the follow-up 
assessment form. Clinicians will check for IUD strings as above. Assess (and treat as applicable) 
for STIs/RTIs, as well as check for pregnancy.  Participants will be reimbursed and be scheduled 
for their 18-month phone call. Reconfirm subject’s contact information. 
11.2.5 Visit 6 (24 months post-insertion ± 14 days) 
Study staff will collect AEs and new or changed concomitant medications, collect and review 
other contraceptive use forms with the subjects, ask IUD acceptability questions, and will 
complete the follow-up assessment form. Clinicians will check for IUD strings as above. Assess 

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(and treat as applicable) for STIs/RTIs, as well as check for pregnancy.  Participants will be 
reimbursed and be scheduled for their 30-month phone call. Reconfirm participant’s contact 
information. 
11.2.6 Unscheduled visits (any time the participant returns for services outside the schedule) 
Unscheduled visits can occur any time that an Investigator feels additional assessment is 
warranted. During unscheduled visits, the Investigator will perform any study assessments as 
necessary to provide appropriate treatment. Participants should be encouraged to contact the site 
for any adverse events that occur to determine if an unscheduled visit is warranted. For serious 
events, participants should always obtain appropriate immediate medical care and the site should 
request release of medical records by subject upon notification of the event.  
Based on the results of any unscheduled visit assessments, if the Investigator determines that the 
subject should be discontinued, completion of the Early Discontinuation Visit procedures (as 
detailed in Section 11.6) will occur and the subject status will change to discontinued from the 
trial. 
Table 04:  Clinic-Based Follow-up Visit Procedures (Visits 2, 3, 4, 5, and 6; Unscheduled 
Assessments as indicated) 
Component  
Procedures  
Administrative and Regulatory  
• 
Review/update contact information  
• 
Provide reimbursement  
• 
Schedule next study visit/call  
• 
File any paperwork 
• 
For Visits 2, 3, 4 and 5, collect and review daily 
diaries with subject (Visit 2 collect 2 forms, Visit 3 
collect 2 forms, Visit 4 collect 4 forms and Visit 5 
collect 7 forms).  Review proper completion 
instructions, if necessary. 
• 
For Visit 2, 3, and 4, distribute daily diary forms; 
each form covers a 1-month period (Visit 2 distribute 
2 forms, Visit 3 distribute 4 forms and Visit 4 
distribute 7 forms) 
• 
For Visit 5 and 6, distribute 2 Other Contraceptive 
Use forms; each form covers a 6-month period 
• 
For Visit 6, collect and review Other Contraceptive 
Use forms (2 forms should be collected) 

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Clinical  
• 
Ask about IUD expulsion or removal  
• 
Confirm the IUD is still in place (Section 9.7, 
Appendix 2) 
• 
Complete follow-up form 
• 
Assess for AEs and concomitant medications 
• 
Collect information related to previous full menstrual 
cycle, including subject’s pain and bleeding 
• 
Ask IUD acceptability questions 
• 
Evaluate for STIs/pelvic infection based on clinical 
judgement and treat per standard of care 
• 
Remind subject to complete the diary 
• 
Distribute additional home pregnancy tests as needed 
with instructions to complete the test if participant 
has any suspicion that they may be pregnant prior to 
their next visit. 
Laboratory                        Urine 
• 
Test urine for pregnancy (subject will become a 
screen failure if initial urine pregnancy test comes 
back positive) 
Note: 
If clinically indicated and per standard of care, conduct a pelvic exam, ultrasound, and/or test for 
chlamydia/gonorrhea. If the subject returns for an unscheduled visit, but not all assessments are required, 
perform assessments based on need and purpose of visit. 
11.3 Telephone Call 1, 2, and 3 (9 months, 18 months, and 30 months post-insertion ± 14 
days) 
The site staff will call the participant at 9-months, 18-months and 30-months post-insertion to 
administer the follow-up form, collect AEs, and to schedule the next clinic visit (or to schedule 
an earlier visit per clinician discretion). 
Table 05:  Phone Call Procedure at 9-months, 18-months, and 30-months Post-Insertion 
Component  
Procedures  
Administrative and Regulatory  
• 
Review/update contact information  
• 
Schedule next study visit  
• 
File any paperwork 

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Clinical  
• 
Ask the subject if she has noticed any evidence 
of the IUD falling out or if she thinks she may 
be pregnant 
• 
Ask about IUD removal 
• 
Collect information related to previous full 
menstrual cycle, including subject’s pain and 
bleeding 
• 
Remind subject to complete the diary form at 
Call 1 and other contraceptive use form at Calls 
2 & 3 
• 
At Calls 2 & 3, collect information from 1 
completed other contraceptive use form 
• 
Ask IUD acceptability questions  
• 
Assess for AEs  
• 
Complete Telephone Call Form 
 
11.4 Exit (37 months post-insertion ± 14 days) or Early Discontinuation Visit 
At 37 months or at any time a participant discontinues the study, she will complete Exit Visit 
procedures as defined in Table 06.   
During the Exit visit, collection of information on AEs, concomitant medications, IUD 
acceptability, and potential concerns will occur. Collection and review of diary or other 
contraceptive use forms (whichever form type was dispensed at previous visit) will occur with 
the subjects and IUD acceptability questions will be asked. Study clinicians will verify the 
presence of the IUD strings; if strings are not present, follow the procedures outlined in 
Appendix 2.   
After all IUD assessments are complete, the clinician will disclose which IUD the subject was 
using.  Those assigned to ParaGard may continue to use that product under the care of primary 
providers. Those assigned to the test IUD will have the product removed. 
All study participants wishing to continue using a different form of contraception after the study 
will be referred for ongoing contraceptive care within the routine health services, including those 
continuing use of ParaGard. Options for continued protection from unintended pregnancies 
should be discussed.  A short acting bridge contraceptive (condoms, 1 month of birth control 
pills, or 1 depo provera shot) should be provided if requested by the subject for use until referral 
to prevent any pregnancies occurring prior to Telephone Call 4. 
Site staff will provide women with a home pregnancy test and instructions to perform the test 17 
days (+ 3 days) post-removal and will be scheduled for the pregnancy test confirmation call the 
same day as testing.  During the phone call, follow up regarding ongoing AEs, if applicable, will 
also be performed. If there are study related AE or new SAEs identified during the phone call, 
they should be followed until resolution or stabilization. 

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Table 06:  Clinic-Based Exit Visit and Early Discontinuation Visit Procedures 
Component  
Procedures  
Administrative and Regulatory  
• 
Review/update contact information (Note: 
Study staff should call the participant’s main 
contact phone number prior to visit end to 
ensure number correctly connects to the 
subject.) 
• 
Provide reimbursement  
• 
Schedule telephone follow-up call to be made 
17 days (+ 3 days) after Exit Visit to document 
the pregnancy test results (completed at home 
after removal)  
• 
Complete final subject status form  
• 
File any paperwork 
Clinical  
• 
Ask about IUD expulsion or removal 
• 
Confirm the IUD is still in place as per steps in 
Appendix 2 
• 
Complete follow-up assessment form 
• 
Assess for AEs and concomitant medications 
since previous visit 
• 
Collect and review daily diary or other 
contraceptive use forms as applicable with 
subject (Collect all forms dispensed at previous 
visit)  
• 
Collect information related to previous full 
menstrual cycle, including subject’s pain and 
bleeding 
• 
Ask IUD acceptability questions, including 
information on subject’s desire to continue IUD 
use, prior to unblinding the subject  
• 
Evaluate for STIs/pelvic infection as needed 
based on clinical judgement and treat per 
standard of care 
• 
Disclose the IUD the woman is using  
• 
If the subject is using ParaGard, ask if she 
wishes to continue.  If not, remove the IUD. If 
the subject chooses to continue using ParaGard, 
she should be referred to her primary provider 
for continued IUD follow-up.   
• 
If the subject is using the Mona Lisa product, 
remove IUD 
• 
Document IUD continuation/removal 
information. 

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• 
Provide contraceptive counselling and care 
referral if applicable:  
o Options for continued protection from 
unintended pregnancy  
o Provide short acting bridge 
contraceptives as desired (e.g., until 
referral) 
• 
Distribute a home pregnancy test with 
instructions to complete the test 17 days (+ 3 
days) after removal 
Laboratory                        
Urine 
• 
Test urine for pregnancy (confirmatory 
quantitative blood pregnancy test should be 
done if initial urine pregnancy test comes back 
positive) prior to disclosing IUD 
Note: All labs and clinical IUD assessments must be done before IUD disclosure.  
11.5 Telephone Call 4 for Pregnancy Test Result (17-days post-removal + 3 days) 
The site staff will call the participant 17-days post-Exit visit to obtain the results of the home 
pregnancy test that was to be done that day and to obtain AE information.   
 
Table 08:  Phone Call Procedure at 17-days Post-Removal 
Component  
Procedures  
Administrative and Regulatory  
• 
File any paperwork 
Clinical  
• 
Record the result of the pregnancy test  
o If positive, the subject should return to 
the site for evaluation, including 
confirmatory pregnancy testing and 
ultrasound 
• 
Assess for resolution of ongoing related AEs 
and all serious adverse experiences (SAEs), if 
applicable  
• 
Collect information on new related AEs and all 
SAEs and follow until resolution 
11.6 Early Discontinuation Visit 
At any time a subject decides to discontinue her participation in the study (i.e., to remove the 
IUD) or is discontinued from the study for any other reason (e.g., product expulsion, pregnancy), 
she will be advised to return to the research site or clinic to have the Exit visit procedures 
completed as an early discontinuation visit. If the subject is willing, she also should be 
encouraged to complete the telephone call #4 (17 days after the exit visit) to provide the results 
of the home pregnancy test that was to be done that day (provided subject is not already known 
to be pregnant) and provide any AE information. 

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12 SAFETY 
12.1 Adverse Events 
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the administration of an 
investigational product, whether or not related to that investigational product.  An unexpected 
AE is one type that is not a priori identified in nature, severity, or frequency in the current 
Investigator’s Brochure or of greater severity or frequency than expected based on the 
information in the Investigator’s Brochure. 
The Investigator (or designee) will review, via direct discussion with the subject, her history 
since her previous visit in order to ascertain the occurrence of any AEs since the previous visit 
and record the information in the site’s source documents.  The history should include asking 
how she felt since her last visit or call as well as directly and indirectly asking if she has 
experienced any AEs.  A review of the subject’s diary with her should be completed at Visits 2, 
3, 4 and 5 to correct errors and inconsistencies and to identify any possible AEs reported in the 
diary. 
The reporting period for AEs is the period immediately following the subject signing the 
informed consent through Call 4/Follow-up.  All AEs must be recorded in the subject’s 
electronic CRFs and must include the following information (when applicable):  
• 
Specific condition or event.  
• 
Indication of whether the condition was preexisting and if so, whether it has 
worsened in severity or frequency in which case it is reported as an AE. 
Conditions present prior to study entry (screening) that do not worsen in severity 
are considered medical history, not AEs. Conditions identified and treated at 
screening, i.e. laboratory abnormalities, UTIs, gynecologic infections including 
Chlamydia, gonorrhea, candida, bacterial vaginosis (BV) are included in medical 
history and are not reported as AEs.  
• 
Date of occurrence.  
• 
Date of resolution. If the event has not resolved at the end of the study-reporting 
period, it will be documented as still present on the case report form.  
• 
Severity: AEs that change in intensity are recorded at the intensity level that is the 
most severe reported by the subject over consecutive days. If the intensity 
category changes over a non-consecutive period of time, then these changes 
should be recorded separately (with distinct onset dates).  
• 
Relationship to study medication as evaluated by the Investigator (causality 
assessment). 
• 
AE outcome (recovered, ongoing, etc.) 
• 
Seriousness according to the approved regulatory classification outlined in 
Section 12.2. 
 
Severity 

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The Investigator is responsible for assessing the severity of each AE using the following 
definitions for severity criteria: 
• 
Mild – events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
• 
Moderate – events result in a low level of inconvenience or concern with the 
therapeutic measures.  Moderate events may cause some interference with 
functioning. 
• 
Severe – events interrupt a subject’s usual daily activity and may require systemic 
drug therapy or other treatment.  Severe events are usually incapacitating. 
 
Relationship to Investigational Product 
The Investigator is responsible for assessing the relationship between the AE and the 
investigational product. The Investigator must determine whether there is a reasonable possibility 
that the investigational product caused or contributed to an AE. The relationship assessment, 
based on clinical judgment, often relies on the following: 
• 
A temporal relationship between the event and administration of investigational 
product; 
• 
A plausible biological mechanism for the investigational product to cause the AE; 
• 
Another possible etiology of the AE; or 
• 
Previous report of similar AEs associated with the investigational product or other 
agents in the same class. 
 
The terms used to assess the relationship of an event to the investigational product are: 
Causality Assessment 
Criteria for Assessment (note that re-challenge does not apply 
in this study) 
Definitely Related 
The experience occurs immediately following investigational 
product administration, related pharmacologically (not related to 
underlying condition/concurrent disease or other drugs or 
chemicals) 
Probably Related 
The experience follows a reasonable temporal sequence from the 
time of drug administration and follows a known response pattern 
to the suspected investigational product and cannot be reasonably 
explained by other factors such as the participant’s clinical state, 
therapeutic intervention or concomitant therapy. 
Possibly Related 
The experience follows a reasonable temporal sequence from the 
time of drug administration and/or follows a known response 
pattern to the investigational product but could have been 
produced by other factors such as the participant’s clinical state, 
therapeutic intervention or concomitant therapy. 
Unlikely Related 
Improbable temporal relationship. The experience was most 
probably produced by other factors such as the participant’s 
clinical state, therapeutic intervention or concomitant therapy and 

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does not follow a known response pattern to the investigational 
product. 
Not Related 
There is not a reasonable possibility that the AE is related to the 
investigational product; when an AE is assessed as not related to 
the investigational product, an alternative etiology, diagnosis or 
explanation for the AE should be provided. If new information 
becomes available, the relationship of any AE should be reviewed 
again and updated as required. 
Insufficient data to assess 
Selection of this rating should usually not occur in a clinical 
study because the Investigators have an obligation to obtain and 
provide this information. In exceptional instances, this rating may 
be used in order to avoid delay in initial reporting of fatal or life-
threatening SAEs from clinical studies. Such cases should include 
documentation in the comments section of the CRFs/database 
with rationale for why an assessment could not be made. 
 
Participants will be provided instructions for contacting the study site to report any untoward 
medical occurrences they may experience, except for possible life-threatening events, for which 
they will be instructed to seek immediate emergency care.  Participants will be able to seek 
evaluation at the study site, where feasible and medically appropriate. With permission of the 
participant, and whenever possible, records from all non-study medical providers related to 
untoward medical occurrences will be obtained for review. All SAEs and AEs resulting in 
method discontinuation will be recorded on study CRFs. Trained MedDRA coders will code AE 
data centrally. Participants who have on-going SAEs or related AEs at their last study visit will 
be followed until resolution or stabilization, or referred for additional care. 
12.2 Serious Adverse Experiences (SAE) 
An event is considered an SAE if in the view of either the Investigator or sponsor, it meets the 
criteria as outlined in 21 CFR 312.32 (a) as per the following:  
“any adverse drug experience occurring at any dose that results in any of the following 
outcomes: death, a life threatening adverse drug experience, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity or 
a congenital anomaly/birth defect.  Important medical events that may not result in death, 
be life-threatening or require hospitalization may be considered a serious adverse drug 
experience when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization or development of 
drug dependency or drug abuse.”  
In addition, cancer and drug overdose are included in this classification of an SAE. 

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12.2.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study product). The 
collection period for new SAEs will begin after informed consent is obtained and end at the time 
Follow-Up/Call 4 occurs. SAEs must be followed until resolution, even if this extends beyond 
the study-reporting period. Resolution of a SAE is defined as the return to baseline status or 
stabilization of the condition with the expectation that it will remain chronic.  
All SAEs will be reported promptly in accordance with the FDA and NICHD regulations and 
recorded on the appropriate forms. As the holder of this IND, FHI 360 is responsible for 
complying with the reporting requirements of SAEs to the FDA in accordance with 21 CFR 
812.40. Health Decisions will serve as the third-party monitoring body for SAEs.   
When any SAE, regardless of causality or relationship to the study product, is encountered 
during this clinical trial at an Investigator’s site, the Investigator, in accordance with 21 CFR 
812.150(a1), will notify NICHD, FHI 360, and Health Decisions within 24 hours of the 
identification/awareness of the SAE by reporting the event as specified in this protocol and via 
the electronic data capture system. The Investigator (or designee) should complete the SAE 
eCRF within the EDC system which will send the appropriate notifications to the Medical 
Monitors and Program Directors at both sponsors as well as the appropriate Health Decisions 
staff. In the event of a system outage or other complication, notification may be made to the FHI 
360 Medical Monitor at: 919-544-7040, ext. 11507. Immediately following phone 
communication, the Investigator is to follow up with the SAE Report submission by fax or email 
to both FHI 360 and Health Decisions: FHI 360 at 919-544-7261 or knanda@fhi360.org, and 
Health Decisions at 1-919-967-1145 or nichd@healthdec.com. Health Decisions will then notify 
the NICHD Medical Monitor by facsimile or email. Once the outage or complication has been 
resolved, submission of the event should promptly be done through the EDC system. 
Any additional SAE supporting documentation should be provided whenever possible (with 
subject identification information redacted) to verify the medical diagnosis. This includes 
hospital discharge summaries, lab report, death certificates/autopsy reports (where applicable), 
surgical procedure summaries, histology reports, and imaging reports. These supporting 
documents should be uploaded to the study document repository page or EDC system within 3 
days of receipt at the site.  
NOTE: Investigators should not wait to collect the additional information needed to fully 
document the event before submission of an SAE. An SAE report should be completed for any 
SAE that is experienced after the subject has signed the ICF, even if investigational product has 
not yet been administered. 
FHI 360 will be responsible for the appropriate review and compliance with regulatory reporting 
requirements to the FDA of the SAE, while Health Decisions will work with sites to ensure the 
SAE is properly recorded and will notify the Medical Monitors accordingly. If warranted, the 
study Medical Monitors will recommend if it is required to convene the DSMB or if the trial 
should be stopped prematurely, undergo modification, or be placed on hold. Health Decisions 
may also recommend to the Medical Monitors if any of these actions are warranted based on the 
SAE reports. 

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In accordance with the standard operating procedures and policies of the IRB, the Principal 
Investigator (or designee) will report SAEs to the IRB. This responsibility may be handled by 
Health Decisions in the case of central IRB reporting, if allowed. 
12.3 Medical Monitor 
Both FHI 360 and NICHD will maintain a Medical Monitor and backup Medical Monitor(s), as 
needed.   
NICHD: 
Jill Long, MD, MPH, MHS (Contraception Research Branch, 6710B Rockledge Dr., Room 
2335, Bethesda, MD 20817, Telephone: 301-496-1662; email: jill.long@nih.gov), is the NICHD 
Medical Monitor for the protocol.  Dr. Long has experience as a Medical Monitor on NIH 
clinical protocols. She is board certified in Obstetrics and Gynecology.   
FHI 360: 
Kavita Nanda, MD, MHS at FHI 360 (359 Blackwell Street, Suite 200, Durham, NC 27701, 
Office Telephone: 919 544 7040, ext. 11507, Fax 919-544-7261; email: knanda@fhi360.org) is 
the FHI 360 Medical Monitor for the protocol. Dr. Nanda is board certified in Obstetrics and 
Gynecology and has served as a Medical Monitor on FHI 360 protocols for more than 15 years. 
Each Medical Monitor will be responsible for evaluating requests for waivers and for safety 
monitoring and evaluation at their respective sites. A detailed medical monitoring plan will be 
written before the study begins.  Together the Medical Monitors will review protocol safety 
information and provide a final recommendation based on those from the DSMB, FHI 360, or 
Health Decisions.   
13 PREGNANCY DETERMINATION AND FOLLOW UP 
The incidence of pregnancy will be assessed. We will be testing study participants at study visits 
using urine pregnancy tests and a home pregnancy test 17 days (+ 3 days) after IUD removal. 
Sites will record information regarding pregnancy on all subjects becoming pregnant 
during the treatment phase of the study through 17 days after last study product use. 
If a subject becomes pregnant during the trial, the Principal Investigator (or designee) must 
inform Health Decisions of the pregnancy within 24 hours of determination. The subject must be 
discontinued from the trial, and all procedures scheduled for the Early Discontinuation Visit as 
detailed in Section 11.6 should be performed. The site will submit a Pregnancy Notification form 
and End of Study eCRF to Health Decisions within 24 hours of determination. Health Decisions 
will notify NICHD and FHI 360.  Additional pregnancy data will be submitted as it becomes 
available. 
The Investigator will estimate the date of conception based upon results of the following criteria.  
If there is uncertainty about the dating it will be reviewed with the Medical Monitors.   
• 
Transvaginal ultrasound examination 
• 
Quantitative β-hCG determination 
• 
Last menstrual period (per daily diary information through first year and patient 
report after first year) 
• 
Pelvic and/or abdominal examination  

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• 
Pregnancy outcome 
• 
Investigator estimation in the absence of above criteria 
 
Sites will counsel subjects who become pregnant during the study regarding pregnancy options 
and refer them for appropriate care. All pregnancies will be monitored until outcome (i.e. 9 
months follow-up or until outcome information is obtained through medical records). 
Information from medical records will also be collected on pregnancy outcome data including 
maternal or fetal complications, spontaneous abortions, ectopic pregnancies, stillbirths, and live 
preterm and full-term births. 
Pregnancy itself is not a SAE; however, pregnancies associated with outcomes outlined in 
Section 12.2 will be considered serious adverse events (SAEs).  Pregnancy outcome data will be 
collected for analysis.  Reports of pregnancy outcome and examinations during the pregnancy 
will be requested from the attending physician/outside clinic, if applicable. Pregnancy outcome 
data will include the rates of spontaneous abortion, stillbirth and live preterm and full-term 
births. In addition, congenital malformations and anomalies will be recorded and summarized. If 
a subject continues with her pregnancy through childbirth, every effort will be made to maintain 
contact with her so that health of the baby can be evaluated at six and twelve months and 
appropriate medical records obtained if necessary.  
14 MONITORING 
14.1 Clinical Site monitoring  
The Principal Investigator and sub-Investigators will allow representatives from Health 
Decisions, FHI 360 and NICHD direct access to all eCRFs, source documents, and 
corresponding portions of the medical records for each participant at mutually convenient times 
for periodic review before, during, and after the study has been completed. The monitoring visits 
provide the monitor with the opportunity to: 
• 
Initiate the research site. 
• 
Evaluate the progress of the study. 
• 
Verify the accuracy and completeness of the eCRFs. 
• 
Ensure that all protocol requirements, applicable FDA regulations, and 
Investigators’ obligations are being fulfilled. 
• 
Resolve any inconsistencies in the study records. 
• 
Close out the trial at the research site.  
 
Before the study begins a detailed clinical monitoring plan will be developed.  Briefly, the study 
clinical monitors will: 
• Review ICFs, procedures, and documentation 
• Assess compliance with the study protocol, Good Clinical Practices (GCP) guidelines, 
and applicable regulatory requirements  
• Verify all SAEs in source documents have been reported on CRFs and in accordance with 
regulatory guidelines 

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• Perform source document verification to ensure the accuracy and completeness of study 
data 
• Verify proper biological specimens collection  
• Verify proper storage, dispensing, and accountability of study products 
• Assess implementation and documentation of internal site quality management 
procedures 
• Verify that current license/certification is available on site for study staff listed on the 
current Statement of Investigator Form, and Delegation of Responsibilities Log/Form. 
The Principal Investigator or designee will allow study monitors to inspect study facilities and 
documentation (e.g., ICFs, clinic and laboratory records, other source documents, CRFs), as well 
as observe the performance of study procedures.  Investigators will also allow inspection of all 
study-related documentation by authorised representatives of OHRP and local and US regulatory 
authorities. Sites will maintain a site visit log to document all visits.   
14.1.1 Quality control and quality assurance 
In addition to routine monitoring, the Sponsors or its designee may, at its discretion, perform site 
audits/quality control visits.  The purpose of such visits will be to evaluate site trial conduct and 
compliance with the protocol, SOPs, GCP, the applicable regulatory requirements and discuss 
operational issues or problems.  If an audit is performed, a site must provide the auditors with 
direct access to all relevant records and documentation related to the study. All participant 
records and other study documentation must be filed and accessible on short notice (three to five 
days) during the study and subsequent retention period. Documents should be adequate to 
reconstruct the course of study events. Refer to Section 20 for requirements for data retention. 
The Investigators and sites may also be subject to a field audit by the regulatory agencies.  Such 
an audit could occur while the study is in progress, after the study is completed, or when the data 
are under review by a regulatory agency. All participant records and study documentation should 
be filed and made accessible as noted above for any regulatory agency review.  The site should 
notify NICHD, FHI 360 and Health Decisions as soon as they become aware of an audit 
scheduled by any regulatory agency. 
14.1.2 Source documents and access to source data/documents 
Sites will maintain appropriate source documents, as detailed in the study monitoring plan.  All 
investigative site records (source documents and other subject records) will be kept in a secure 
and hazard free storage area.  Access will be restricted to study personnel authorized to handle 
research documents.  These records are to be retained for at least 2 years after approval of the 
marketing application or at least 2 years have elapsed since formal discontinuation of clinical 
development for this investigational product.  NICHD and FHI 360 should be notified before 
destruction of any site records.   

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14.2 Regulatory  
Investigator will maintain and store in a secure manner complete, accurate, and current study 
records throughout the study. The Investigator will retain all study records as authorized by the 
operations team in compliance with local regulations. Study records include administrative 
documentation including protocol registration documents and all reports and correspondence 
relating to the study as well as documentation related to each participant screened for and/or 
enrolled in the study including ICFs, locator forms, case report forms, notations of all contacts 
with the participant, and all other source documents. 
The trial will be conducted in compliance with the protocol, GCP, and the applicable regulatory 
requirement(s) of the US and study site countries.  Health Decisions is responsible for assuring 
that the essential documents maintained in the trial master file at each research site for each 
Sponsor are accurate and complete. In addition, Health Decisions will be responsible for 
maintaining central documentation to demonstrate GCP compliance.  Files will be maintained 
according to written SOPs.  
15 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
A subject will be considered to have completed the clinical trial after she has completed 37 
months of using the study product and after the final procedures have been performed. 
15.1 Early Discontinuation of Study Product  
Subjects are free to request IUD removal at any time and for any reason specified or unspecified 
and without prejudice. 
Additionally, the IUD may be removed at any time if the subject, the Investigator, or the Sponsor 
feels that it is not in the subject’s best interest to continue. The following is a list of reasons that 
IUD removal may be indicated:  
• Subject withdrawal of consent (or assent) (e.g. due to personal reasons) 
• Subject is not compliant with study procedures in the opinion of the Sponsor or 
Investigator 
• Adverse event that in the opinion of the Investigator would be in the best interest of the 
subject to have the IUD removed 
• Inter-current illness or other safety concern that, in the judgment of the Investigator, 
should result in IUD removal. 
• Protocol deviation requiring IUD removal 
• Early termination of study 
• Use of prohibited medications, including any outlined in the Inclusion/Exclusion criteria 
(see Sections 7.2, 7.3, and 8.2) 
Subjects must be discontinued for the following reason: 
• Pregnancy 
• IUD expulsion  
• IUD removal 
• Failed IUD insertion (after 2 attempts on day of Enrollment) 

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• Uterine perforation 
If an Investigator determines that a subject’s IUD should be removed due to an AE, the 
Investigator or other care provider will provide appropriate treatment until the AE has resolved 
or stabilized after IUD removal.   
The Investigator will document the reason for IUD removal in the subject’s source documents 
and in the final status form. If withdrawal from the study is due to an adverse event, this 
information will also be recorded on the AE form. 
Subjects who discontinue study treatment should come in for an early discontinuation visit as 
soon as possible as outlined in Section 11.6 regardless of the reason for discontinuation with the 
exception of those subjects who have lost contact with the research site.  
15.1.1 Lost to Follow-Up 
A subject cannot be considered withdrawn due to becoming lost to follow-up (LTFU) until the 
research site performs and documents at least three (3) attempts to contact her. Documentation 
must include at least one letter sent via a method that allows a “return receipt” to be requested 
with instructions provided to the subject to call the research site. Every effort must be made to 
follow-up with subjects who terminate with product-related adverse experiences, in order to 
determine the final outcome. 
15.2 Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the Investigator, or the 
Sponsor feels that it is not in the subject’s best interest to continue, including non-compliance or 
for safety concerns.   
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the Investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in the 
subject’s source documents and the final status form.    
All efforts should be made to contact the woman when she decides to discontinue so that 
appropriate discontinuation safety procedures can be performed and data can be obtained. Such 
contact will never be used to dissuade any subject who wishes to terminate the study. 
Women who unexpectedly become pregnant during the study will be removed from further 
participation. However, their pregnancy outcome results will be ascertained as outlined in 
Section 13 and documented on the Pregnancy Outcome CRF.  
15.3 Replacement of Subjects 
Subjects who withdraw from the study treatment or withdraw from the study will not be 
replaced, regardless of the reason for discontinuation.  
15.4 Study Product Errors 
Study product will be stored according to standard procedure at each of the participating study 
sites. When a subject is randomized, the IUD will be obtained for the subject based on the 

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product identified in the EDC system (refer to Section 9.1). Product errors are unlikely as stock 
product packaging will be different between the two IUDs; however, if one occurs, the site 
should inform Health Decisions immediately upon determination. 
16 PROTOCOL DEVIATIONS 
A protocol deviation occurs when the subject, Investigator, or Sponsor fails to adhere to 
significant protocol requirements affecting the inclusion, exclusion, subject safety and primary 
endpoint criteria.  Protocol deviations for this study include, but are not limited to, the following: 
• Failure to meet inclusion/exclusion criteria 
• Enrolling a participant into the study without securing proper consent 
• Deviating from the randomization procedures 
• Informing the participant of which IUD she received prior to the exit visit 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
deviation. The Sponsor will determine if a protocol deviation will result in withdrawal of a 
subject. 
The Investigator should not deviate from the protocol without prior approval issued as a protocol 
waiver approved by the Medical Monitor, with the exception of minor visit window deviations as 
outlined for each visit/call in Section 11. In addition, all protocol deviations will be submitted 
within the EDC CRFs for the study.  
Certain protocol deviations may require the subject to be terminated early from the study. The 
Medical Monitor will review if subject termination will be required based on protocol deviation 
information at the time that the waiver is reviewed. It is the responsibility of the research sites to 
report all protocol waivers and protocol deviations to their IRB according to IRB policy. 
17 AMENDMENTS TO THE PROTOCOL 
 
Any change of the clinical trial must be written and filed as an amendment to this protocol. Such 
amendments will be made jointly by the Sponsors and the Investigators with final approval by 
the Sponsors. The Principal Investigators (or designee) must submit the protocol amendment for 
review by the IRB and shall obtain the approval of the IRB before it is implemented. 
In cases of emergency, when the protocol change or deviation is necessary in order to eliminate 
or reduce an immediate hazard or risk to human subjects, the amendment may be implemented 
before review or approval by their IRB. In such cases, the Principal Investigator (or designee) 
shall notify their IRB of the change or deviation in writing within 10 working days after 
implementation. Any protocol-related issues that pose an immediate or significant hazard to 
subjects must be reported to the Sponsors immediately.  If the protocol amendment is an 
administrative change, it will be sent to their IRB for information (updating of file). 
All modifications of the clinical trial will be written and filed with FDA as an amendment to this 
protocol, maintaining original section identification. Such modifications will be made jointly by 
the Sponsors, Health Decisions, and the Investigators with the approval of all the IRBs. 

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18 DATA SAFETY AND EFFICACY MONITORING  
18.1 Data and Safety Monitoring Board (DSMB) 
An independent, autonomous Data and Safety Monitoring Board (DSMB) has been established 
by the NIH (NICHD). The DSMB will conduct periodic reviews of study progress indicators, 
subject safety and pregnancy. It is expected that three (3) such reviews occur.  The Project 
Directors at NICHD and FHI 360 may also request additional DSMB reviews, (e.g. should any 
other findings/issues pertaining to safety or efficacy emerge requiring DSMB review outside of 
the planned periodic meeting dates).  
The DSMB charter will be prepared prior to the first DSMB meeting then modified as needed 
before the second meeting or subsequent meetings. The Charter will address the timing of each 
DSMB meeting, stopping rules relative to items including SAEs, pregnancy rates, expulsion rate, 
etc., as well as detailed blinding and unblinding procedures. Additional information about the 
DSMB composition and review procedures will be contained in the charter. As the primary 
objective of the study is non-comparative, no adjustment to confidence interval coverage error 
rates will be made to account for interim analyses when reporting for pregnancy rate data. 
Similarly, no multiplicity adjustment will be made for secondary objectives.  
The DSMB will maintain the confidentiality of its closed internal discussions and activities. 
Recommendations from the DSMB will be forwarded by the Project Directors, to the Central 
IRB, and the Principal Investigators in this Protocol for inclusion into the study TMF along with 
any DSMB open session discussion meeting minutes. 
The primary responsibilities of the DMSB are to 1) periodically review and evaluate the 
accumulated study data for participant safety, study conduct and progress, and 2) make 
recommendations to the study Investigators and the sponsor concerning the continuation, 
modification, or termination of the trial. At each review, the DSMB may recommend that the 
study proceed as designed, proceed with design modifications, or be discontinued.  
Summary results of interim data which are pooled across treatment groups may be provided to 
study sites for their information and for submission to the IRBs. 
19 STATISTICAL METHODS AND CONSIDERATIONS 
19.1 Sample Size 
Below is the original estimate for the 95% upper bound of the Pearl Index for the Mona Lisa Cu 
IUD arm if we had randomized 800 subjects to that treatment.  Since this protocol has been 
amended to randomize approximately 880 Mona Lisa Cu IUD subjects, the estimated 95% upper 
bound of the Pearl Index would be slightly lower due to the larger sample size.  In addition, the 
power to detect differences in 12-month IUD continuations rates will be slightly higher than the 
original power presented below. 
Randomizing 800 women to the Mona Lisa Cu IUD will provide approximately 17,700 cycles 
for the primary efficacy analysis among women under 36 years old at time of enrollment, 

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assuming 13 cycles of use per year with 84.3% evaluable cycles, an exponential discontinuation 
rate of 0.2 (i.e., approximately 20% per year), and 37 months of prescribed follow-up per 
woman.  Based on this enrollment total and follow-up rate, the upper bound of the Pearl Index 
(pregnancies per 100 women-years of follow-up) would be approximately 1.0 if 6 pregnancies 
were observed (see table). 
Table 09: Expected Pearl Index (pregnancies per 100 women-years of follow-up) among women 
under 36 years old at time of enrollment and 95% CI for Pearl Index as a function of observed 
number of pregnancies, assuming 800 women are randomized to Mona Lisa Cu IUD and 51.2% 
method continuation at month 37 
Observed pregnancies 
Pearl Index 
95% CI 
0 
0.0 
0.0-0.3 
1 
0.1 
0.0-0.4 
2 
0.1 
0.0-0.5 
3 
0.2 
0.0-0.6 
4 
0.3 
0.1-0.8 
5 
0.4 
0.1-0.9 
6 
0.4 
0.2-1.0 
 
In terms of estimating and comparing standard 12-month IUD continuation rates, the study will 
achieve approximately 87% power to detect a 10% greater 12-month continuation rate for the 
Mona Lisa Cu IUD using a two-sided α=0.05 level log-rank test, assuming the 12-month 
probability of continuation for ParaGard is 70% and allowing for up to 5% of women lost to 
follow-up. 
19.2 Statistical analyses  
A detailed statistical analysis plan (SAP) will be developed. The following is a summary of the 
planned analyses. Any deviations made from this summary plan will be documented in the 
detailed SAP. 
19.2.1 Primary analysis 
The primary analysis will estimate the pregnancy rate in women 35 and younger at time of 
enrollment based on the Pearl Index (pregnancies per 100 woman-years of follow-up) and its 
exact 95% confidence interval derived using a Poisson distribution assumption, after excluding 
cycles (28-day equivalents) in which women report using other contraceptive methods. Analysis 
will be done for each year of use and cumulatively through year three. Life-table methods will 
also be used to summarize the cumulative probability of pregnancy through the study follow-up 
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19.2.2 Analysis of secondary endpoints 
The standard 12-month continuation probability and its corresponding asymptotic 95% 
confidence interval for each study group will be estimated using the Kaplan-Meier method. In 
addition, a log-rank test will be used to compare early discontinuation rates between groups at 
the two-sided 0.05 significance level. Similar summaries and comparisons will also be made to 
assesses the probabilities of discontinuation by reason (e.g., IUD expulsion, failed IUD insertion, 
uterine perforation, pregnancy, personal/non-medical reasons, and other medically-related 
reasons), as well as self-reported desire to continue IUD use at the study exit but prior to 
unblinding the participant.   
We will analyze bleeding diary data using the methods described by Mishell, et al17. Statistics 
will include the mean, median, and range of the total number of heavy, moderate, light, or 
spotting days per 28-day cycle equivalent as defined on the daily diary (refer to Appendix 3). We 
will also report the per-subject mean and median number of cycles and the proportion of cycles 
that include any heavy bleeding, a prolonged bleeding episode (e.g., greater than 14 days), 
amenorrhea, or bleeding in more than 1/3 of days in the cycle. Details of the bleeding diary 
analysis will be included in the SAP, including procedures and definitions used to define 
individual cycles and to account for missing data. 
In addition to diary data, summaries of bleeding and pelvic pain experienced between study 
visits (and reported on CRFs) will be described in contingency tables and displayed graphically 
in bar charts, by study visit and overall. Chi-squared tests for ordinal repose data (e.g., less than 
normal, normal, or more than normal pelvic pain) will be used to compare treatment groups at 
each visit. Evidence of informative censoring that is differential between groups will be explored 
using competing risk analysis; in the event such effects exist then analysis methods which 
account for informative censoring will be employed when comparing secondary outcomes 
between groups over time. 
The proportions of subjects experiencing any other side effects will be calculated with 
corresponding exact confidence intervals for each group, and compared the difference between 
groups by Fisher’s exact tests or the Cochran-Mantel-Haenszel tests. Generalized linear model 
approaches for repeated occurrence side effect outcomes might be used to further assess the 
differences in the incidence of adverse events between study groups. 
Overall satisfaction with the method will be summarized and compared between groups at the 
final study visit using two-sided Mantel-Haenszel chi-square tests. Similarly, the same statistical 
analysis methods will be used to describe ease of product insertion between groups.  Changes in 
pain with and shortly after insertion from baseline will be described by the summary statistics 
(mean, median, inter-quartile, etc.) of visual analog scale measurements. The Mann-Whitney test 
or the analysis of variance method will be used to compare the changes in pain between groups. 
For all secondary objectives, comparisons between groups will be made using two-sided 0.05 
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20 DATA COLLECTION, RETENTION AND MONITORING 
20.1 Electronic Data Capture System 
All requested information should be entered in the Electronic Data Capture (EDC) system. Prior 
to the start of the clinical trial, the Principal Investigator will complete an authorized signature 
sheet showing the signatures and handwritten initials of all individuals who are authorized to 
maintain study records and submit data using the EDC system. More detailed instructions 
regarding the EDC system will be provided by Health Decisions in training and the instructions 
documents. 
20.2 Data Handling and Processing 
The study will use Electronic Data Capture (EDC) to create, modify, and maintain data generated 
for the clinical trial. The research sites will record clinical trial data in an electronic web-based 
CRF (eCRF). Health Decisions Data Management will follow written standard operating 
procedures for processing EDC data. Archiving of the EDC data will be done by the EDC 
vendor. 
20.3 Confidentiality and Reporting of Results 
Subject names will not be entered into the EDC system; instead, unique subject identifiers will 
be assigned. Medical records will be kept at the research site and will be available to study staff 
and the NICHD, Health Decisions, FHI 360, independent auditors contracted by the Sponsors, 
IRBs, local regulatory authorities or the FDA only. All data and information generated by the 
participating site as part of the trial will be kept confidential by the site principal investigator and 
other study personnel to the extent permitted by law.  This information and data will not be used 
by the site principal investigator or other study personnel for any purpose other than conducting 
the trial. 
20.4 Archival of Data. 
For archiving purposes, all eCRF information will be stored via an electronic medium at 
completion of the trial. Audit trail information will be included. eCRFs will be available for 
inspection by authorized representatives from the Sponsors, from Regulatory Authorities and/or 
IRBs. Copies of each site’s eCRF information will be supplied to each site at the completion of 
the trial.  
20.5 Availability and Retention of Investigational Records 
The Principal Investigator will maintain and store in a secure manner complete, accurate, and 
current study records throughout the study. All records are to be retained by the Principal 
Investigator for a period of at least 2 years after the latter of the following two dates: The date 
after approval of the marketing application or at least 2 years have elapsed since formal 
discontinuation of clinical development for this investigational product (per FDA CFR 812.140).  
These documents should be retained for a longer period (i.e., but never a shorter period), 
however, if required by the applicable regulatory or site-specific requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
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should be notified before destruction of any study records by their sites. For FHI 360 sites, study 
documents need to be retained for a minimum of 5 years until authorized in writing by the FHI 
360 operations team, in accordance with FHI 360 SOPs.  
Study records include administrative documentation, including protocol registration documents 
and all reports and correspondence relating to the study as well as documentation related to each 
participant screened for and/or enrolled in the study, including ICFs, locator forms, medical 
records, laboratory reports, drug disposition records, safety reports, case report forms, notations 
of all contacts with the participant, information regarding subjects who discontinued and all other 
source documents of pertinent data. 
The trial will be conducted in compliance with the protocol, GCP, and the applicable regulatory 
requirement(s) of the US.  In addition, FHI 360 and Health Decisions will be responsible for 
maintaining central documentation to demonstrate GCP compliance for the respective Sponsor 
sites. 
20.6 Subject Confidentiality 
Information on individual subjects arising from this study will be considered confidential and 
transmitted to the Sponsor and Clinical Research Organization (CRO) in a form that will not 
permit identification of individuals. Subject confidentiality will be maintained by the use of 
coded subject ID numbers.  All study records will be kept in a secure storage area with limited 
access. Coded subject numbers will identify all laboratory specimens and evaluation forms in 
order to maintain subject confidentiality. Clinical information will not be released without the 
written permission of the participant, except as necessary for monitoring by the FDA, FHI 360, 
NICHD, Health Decisions, independent auditors contracted by the Sponsors, IRBs or local 
regulatory authorities. 
21 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
21.1 Institutional Review Boards and Independent Ethics Committees 
The protocol and any amendments will be reviewed by the FDA and the designated Central IRB. 
Documented approval will be obtained from the Central IRB, which will be Chesapeake IRB for 
this study.  Each participating site will also seek approval from the appropriate local IRBs unless 
oversight is delegated to the central IRB.  Copies of the submissions and approvals should be 
retained in the site’s regulatory file and the main trial master file.  
Prior to implementation of this protocol, and any subsequent full version amendments, each site 
must have the protocol and the protocol consent forms approved, as appropriate, by their local 
IRB and any other applicable regulatory entity unless delegated to the central IRB.  
Investigators/institutions will permit trial related monitoring, audits, IRB review and regulatory 
inspection(s) providing direct access to source data/documents. 
21.2 Protocol Registration 
The study team will register this trial on ClinicalTrials.gov, a registry database of clinical studies 
of human participants conducted around the world, and updated at regular, specified intervals.   

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21.3 Risks and Benefits 
21.3.1 Risks 
Investigators will make efforts to minimise risks to participants. It is not expected that study 
procedures will expose human subjects to unreasonable risk. Pelvic examination and procedures 
may cause mild discomfort and/or vaginal bleeding or spotting. Women who learn they have a 
reproductive tract infection, in the course of the trial may experience worry, sadness or 
depression. Women who exhibit symptoms suggestive of clinical depression will be referred for 
counselling. Participation in clinical research includes the risks of loss of confidentiality and 
discomfort with the personal nature of questions when discussing sexual behaviours.  
Participants at sites requiring partner notification in response to diagnosed STI infection could 
have problems in their relationships with their sexual partners. Participants also could have 
problems in their partner relationships associated with the use of a contraceptive method. 
Site staff will make every effort to protect participant privacy while in the study. Although study 
sites make every effort to protect participant privacy and confidentiality, it is possible that 
participants' involvement in the study could become known to others, and that social harms may 
result. 
The risks of using the ParaGard IUD are low, but do exist. IUD users are at risk of uterine 
perforation (including embedment) (1/1000)15, pregnancy, PID, or expulsion of the device (5% 
in the first year of use); all of these complications are rare. If perforation or IUD embedment 
occurs, it is possible that surgery will be needed to remove the product.  Approximately 1% of 
IUD users experience PID in the three weeks after IUD insertion, then the risks decrease 
considerably thereafter.16  Approximately 50% of users experience increases in menstrual flow 
and number of days of bleeding. Approximately 20% experience intermenstrual 
spotting/bleeding, and about 35% experience painful menses.14 In addition, IUD insertion is 
uncomfortable for most women, although generally symptoms resolve within ten to fifteen 
minutes; symptoms are usually completely resolved within one day after insertion.     
The risks of using the test product has all the general risks of any IUD. However, the test product 
is not well-studied, thus it has uncertain levels of the above complications and perhaps new risks. 
Though the test product is approved and marketed in Europe, it is a novel entity from a 
regulatory perspective in the U.S.  
Contraceptive failure is possible with any of the IUDs; ParaGard has an estimated failure rate of 
less than 1% in the first year of use. If pregnancy occurs, the IUD should be removed to reduce 
the risks of spontaneous abortion, premature delivery, pelvic infection, sepsis, and other rare 
events. Failure rates for the test product are largely unknown, since they are not estimated from 
appropriately sized and regulated clinical studies in Europe. The contraceptive-related risks 
anticipated to be experienced by participants in the study are no different from those that would 
be anticipated among contraceptive users in Europe who have access to both products. 

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21.3.2 Benefits 
Participants benefit from the use of a highly effective form of contraception: one of two types of 
copper IUDs, one of which is approved for use in some countries in Europe and in Canada, and 
one of which is approved for use in the United States. 
Others may benefit in the future from information learned from this study.  Specifically, 
information learned in this study may lead to improved understanding about the benefits of 
smaller IUDs.  Participants may appreciate the opportunity to contribute to the field of 
reproductive health and contraceptive research.  
21.4 Informed Consent  
Under informed consent, the subject shall understand that she is authorizing access to medical 
records as required for monitors, auditors, IRBs and regulatory authorities.  Subjects who agree 
to participate in the study must sign the ICF prior to study-specific procedures. The principles of 
informed consent will be implemented according to the 2013 revision of the Declaration of 
Helsinki and current NIH, DHHS, and FDA regulations. The ICF will be HIPAA compliant. 
It is the Principal Investigator's responsibility to assure that each subject is provided an 
explanation of the details contained in the informed consent statement and other locally required 
documents prior to the individual signing the ICF.  This certifies voluntary participation in the 
trial and is completed prior to study participation. Under informed consent, the subject shall 
understand that she is authorizing access to medical records as required for monitors, auditors, 
IRBs and regulatory authorities. 
The subjects will be informed of their right to privacy and the fact that personal information will 
be treated as strictly confidential and will not be publicly available in accordance with HIPAA 
regulations. They will also be informed that the NICHD, Health Decisions, FHI 360, and the 
FDA have the right to inspect and possibly photocopy their medical records to verify the 
accuracy and completeness of the clinical trial results. The subject is to receive a copy of the 
signed consent form. 
 
Prior to study participation, all study candidates will: 
• 
Be informed of the nature and purpose of the study. 
• 
Be given an explanation of the procedures to be followed in the study. 
• 
Be given a description of any attendant discomforts and risks reasonably to be 
expected from the study, as well as from the study product. 
• 
Be given an opportunity to ask any questions concerning the study. 
• 
Be instructed that consent to participate in the study may be withdrawn at any 
time; and that the participant may discontinue participation in the study without 
prejudice. 
• 
Be given a copy of the ICF. 
• 
Be given the opportunity to decide to consent or not to consent to the study 
without coercion. 
• 
Be informed of alternative contraceptive methods available. 
• 
Be informed about their right to use Emergency Contraception (EC) during the 
study. 

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• 
Be given information about whom to contact if there are questions about the 
research, participant rights, or to report research-related injury. 
21.5 Conflicts of Interest 
Investigators will be affiliated with their study sites.  They will receive support for this clinical 
trial from the NICHD/NIH or FHI 360, but will not profit from results, either positive or 
negative, with regard to the product being evaluated. FHI 360, the IND holder, could profit from 
the successful development of this product. 
21.6 Confidentiality 
The information on individual subjects arising from this study is to be considered confidential 
and transmitted to the sponsor only in a form that will not permit identification of the individual.  
The information obtained from the subjects that can be identified with the subject will remain 
confidential within the research team. Regulatory and sponsoring agencies may request access to 
the study records and related medical records of each participating subject; the subject's identity 
will remain confidential to the extent permitted by the applicable laws and regulations.  The 
results of the research will be released to public agencies including regulatory agencies, 
Investigators, and research organizations without reference to items identifiable to a particular 
subject.  The results will be published such that the identity of the subjects will not be disclosed 
and cannot be ascertained. National and international agencies and sponsoring agencies may 
request access to the medical records of each participating subject, and if requested, the subject's 
identity will remain confidential. All records will be kept in a secure storage area with limited 
access. 
21.7 Publications  
A Publications Committee will be formed to write a publication policy for the trial.  Three levels 
of publications will be addressed in this policy: 
• Primary publications:  Those publications specifically reporting the results of the 
primary, secondary study, and tertiary objectives stated in the study protocol 
• Secondary publications:  Publications reporting on the study results using data from 
multiple study sites but not specifically addressing the stated objectives of the study  
• Tertiary publications:  Publications based on data from a unique study site and drafted by 
the study team at that site. 
Authorship roles will be assigned primarily according to the contributions of individual members 
as well as the likelihood that the authors will be able to complete data analysis and manuscript 
preparation in a timely manner.  All Investigators will be encouraged to participate in discussions 
regarding authorship of primary and secondary publications.  Abstracts and publications 
resulting from this study must be approved by the Publications Committee prior to submission to 
scientific meetings or journals. 

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21.7.1 Publication Policy 
Data on the use of the study product and results of all clinical and laboratory studies are 
considered private and confidential. NICHD and FHI 360 will encourage publication of the 
results of the study. Any publications or presentations that result from this study will maintain 
participant confidentiality. The IND and proprietary information about the investigational drug 
are under the supervision of the NICHD and FHI 360. The Principal Investigator agrees to 
submit all proposed publications, papers, abstracts, manuscripts, posters or other written 
materials which include data relating to the Study or the use of the Product supplied under this 
Agreement, and all outlines of any proposed oral presentations with respect thereto, to NICHD 
and FHI 360 at least thirty (30) days prior to either (a) submission of such written materials for 
publication or (b) any proposed oral disclosure to a third party outside of the NICHD CCTN and 
FHI 360 study sites. NICHD and FHI 360 shall have the right to comment on such written 
material or outline within (30) days of receipt, and such comments shall be considered in good 
faith by the Principal Investigators in determining the final form of disclosure. NICHD and FHI 
360 shall also have the right to eliminate any reference to confidential or proprietary information 
provided to Institutions and/or the Principal Investigators or the Staff pursuant to this Agreement. 
21.7.2 Authorship eligibility 
Eligibility for authorship will follow the International Committee of Medical Journal Editors 
recommendations for determining substantive contribution to a manuscript developed for 
publication. 
 
 

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22 REFERENCES 
1. 
ParaGard® T380A INTRAUTERINE COPPER CONTRACEPTIVE US Prescribing Information, 
June 2013. . http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018680s066lbl.pdf. 
(accessed January 10 2016). 
2. 
Sivin I, Stern J. Long-acting, more effective copper T IUDs: a summary of U.S. experience, 1970-
75. Studies in family planning 1979; 10(10): 263-81. 
3. 
Sivin I, Tatum HJ. Four years of experience with the TCu 380A intrauterine contraceptive device. 
Fertility and sterility 1981; 36(2): 159-63. 
4. 
Sivin I, Stern J, Coutinho E, et al. Prolonged intrauterine contraception: a seven-year randomized 
study of the levonorgestrel 20 mcg/day (LNg 20) and the Copper T380 Ag IUDS. Contraception 
1991; 44(5): 473-80. 
5. 
The TCu380A, TCu220C, multiload 250 and Nova T IUDS at 3,5 and 7 years of use--results from 
three randomized multicentre trials. World Health Organization. Special Programme of Research, 
Development and Research Training in Human Reproduction: Task Force on the Safety and 
Efficacy of Fertility Regulating Methods. Contraception 1990; 42(2): 141-58. 
6. 
Hubacher D. Copper intrauterine device use by nulliparous women: review of side effects. 
Contraception 2007; 75(6 Suppl): S8-11. 
7. 
Abraham M, Zhao Q, Peipert JF. Young Age, Nulliparity, and Continuation of Long-Acting 
Reversible Contraceptive Methods. Obstetrics and gynecology 2015; 126(4): 823-9. 
8. 
Benacerraf BR, Shipp TD, Lyons JG, Bromley B. Width of the normal uterine cavity in 
premenopausal women and effect of parity. Obstetrics and gynecology 2010; 116(2 Pt 1): 305-10. 
9. 
Koch P, Reinhardt P, Soyka E. Intrauterine contraception using the Copper Mini-Gravigard 7 IUD: 
summary of 328 case histories. Contracept Deliv Syst 1981; 2(1): 171-6. 
10. 
Petersen KR, Brooks L, Jacobsen N, Skoby SO. Clinical performance of intrauterine devices in 
nulligravidae: is the length of the endometrial cavity of significance? Acta Eur Fertil 1991; 22(4): 
225-8. 
11. 
Otero-Flores JB, Guerrero-Carreno FJ, Vazquez-Estrada LA. A comparative randomized study of 
three different IUDs in nulliparous Mexican women. Contraception 2003; 67(4): 273-6. 
12. 
Ott MA, Sucato GS. Contraception for adolescents. Pediatrics 2014; 134(4): e1257-81. 
13. 
Committee on Adolescent Health Care Long-Acting Reversible Contraception Working Group The 
American College of Obstetricians Gynecologists Committee opinion no. 539: adolescents and 
long-acting reversible contraception: implants and intrauterine devices. Obstetrics and gynecology 
2012; 120(4): 983-8. 
14. 
Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 
2016. MMWR Recommendations and reports : Morbidity and mortality weekly report 
Recommendations and reports / Centers for Disease Control 2016; 65(3): 1-103. 
15. 
Heinemann K, Reed S, Moehner S, Minh TD. Risk of uterine perforation with levonorgestrel-
releasing and copper intrauterine devices in the European Active Surveillance Study on Intrauterine 
Devices. Contraception 2015; 91(4): 274-9. 
16. 
Farley TM, Rosenberg MJ, Rowe PJ, Chen JH, Meirik O. Intrauterine devices and pelvic 
inflammatory disease: an international perspective. Lancet 1992; 339(8796): 785-8. 
17. 
Mishell DR Jr, Guillebaud J, Westhoff C, Nelson AL, Kaunitz AM, Trussell J, Davis AJ. 
Recommendations for standardization of data collection and analysis of bleeding in combined 
hormone contraceptive trials. Contraception 2007; 75(1): 11-1. 
 
 

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23 INVESTIGATOR OBLIGATIONS 
 
Clinical research studies are subject to the regulations of the FDA. Prior to beginning the study, the 
Principal Investigator will be asked to demonstrate compliance with ICH E6, 8.2 and 21 CFR 312 by 
providing the signed essential documents required for the clinical trial. The responsibilities imposed upon 
Principal Investigators by the FDA are summarized in the “Statement of Investigator Form” (Form FDA-
1572) which documents that he or she will follow the FDA regulations with respect to this study. 
 
The Principal Investigator agrees to assume the responsibilities stated on the Form FDA-1572, and 
signifies his or her agreement by signing the Form FDA-1572. These responsibilities include: 
 
• 
To conduct the study in accordance with the Study Protocol, Investigator Brochure, GCPs, ICH, 
and Declaration of Helsinki. 
• 
To secure prior approval of the study by an appropriate IRB. This board should be constituted in 
conformity with FDA regulations. 
• 
To report on the progress of the study to the IRB and to submit a final report within three (3) 
months of the conclusion of data collection. 
• 
To maintain current records of the receipt, dispensing, and disposition of study product and to 
return all unused product to the sponsor or the sponsor’s designated agent. 
• 
To obtain a valid, fully informed, freely given written consent from each subject who participates 
in the study. 
• 
To maintain adequate study documentation, hospital records, laboratory results and lab records, 
and to store these case histories for a minimum of two years following notification by the sponsor that all 
investigations have been discontinued or that the FDA has approved the study product application, or 
according to site practice only if longer than specified here. 
• 
To identify all sub-Investigators who will also supervise study product administration. 
• 
To report all Adverse Events to the sponsor or designated agent promptly. 
• 
To allow inspection or copying by the FDA, sponsor, or sponsor’s designated agent of case 
histories and records of study product distribution. 
 
Investigator Documentation required:  
 
Prior to beginning the study, the Principal Investigator will be asked to comply with ICH E6, 8.2 and 21 
CFR 312 by providing the following essential documents, including but not limited to: 
 
1. 
An original signed Investigator Agreement page of the protocol.  
2. 
An original signed acknowledgement of receipt of the Investigator’s Brochure.  
3. 
An IRB-approved Informed Consent (as described in section 21.4) in the local language.  
4. 
IRB approval of protocol and informed consent.  
5. 
Form FDA 1572, fully executed, and all updates on a new fully executed Form FDA 1572.  
6. 
Current Curriculum Vitae (CV) for the Principal Investigator and each sub-Investigator listed on 
Form FDA 1572. 
 
 

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24 APPENDIX 1: SCHEDULE OF ASSESSMENTS 
Study Procedures 
Screening 
Treatment Period 
Follow Up 
Unscheduled 
Visit Number 
SCRN 
V1 
V2 
V3 
V4 
C1 
V5 
C2 
V6 
C3 
 
EXIT9 
C4 
UNS^ 
Treatment Period* 
N/A 
Day 
1 
6 
Wks 
3 
Mos 
6 
Mos 
9 
Mos 
12 
Mos 
18 
Mos 
24 
Mos 
30 
Mos 
 
37 
Mos 
17 Days 
VAR 
Informed consent, HIPAA Authorization, 
Assent (if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Assign Subject Number 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain/Update Contact Information 
X 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Determine Eligibility (Inclusion/ Exclusion)  
X 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
Contraceptive Counselling 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, contraceptive, gynecological, 
menstrual, reproductive history 
X 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs1 
X 
X* 
 
 
 
 
 
 
 
 
 
 
 
X 
Pelvic exam2, 5 
X12 
X* 
 
 
 
 
 
 
 
 
 
 
 
X 
Assess (and treat as applicable) for STIs/RTIs  
X 
X* 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
Pregnancy test (urine)8 
X 
X* 
X 
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
Endocervical, vaginal or urine specimen 
collection for GC/CT NAAT5,7 
X 
X* 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomize subject 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Provide reimbursement 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
Schedule next visit 
X 
X 
X 
X 
X3 
X 
X3 
X 
X3 
X 
 
X6 
 
X 
Insert IUD 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Assess ease of insertion 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Collect subject insertion pain level21 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense Home Post Placement Pain Form 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Collect Home Post Placement Pain Form 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Collect IUD continuation/removal 
information20 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Collect previous menstrual cycle, bleeding, 
pain information18, 20 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Ask IUD Acceptability Questions20 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Confirm IUD placement4 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Inquire on desire for continued IUD use20 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 

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Study Procedures 
Screening 
Treatment Period 
Follow Up 
Unscheduled 
Visit Number 
SCRN 
V1 
V2 
V3 
V4 
C1 
V5 
C2 
V6 
C3 
 
EXIT9 
C4 
UNS^ 
Treatment Period* 
N/A 
Day 
1 
6 
Wks 
3 
Mos 
6 
Mos 
9 
Mos 
12 
Mos 
18 
Mos 
24 
Mos 
30 
Mos 
 
37 
Mos 
17 Days 
VAR 
Unblind IUD to subject 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Continue/Remove IUD10 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Provide bridge contraception, as desired 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Complete final subject status form 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Diary cards dispensed (n)14 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
Diary cards reviewed/discussed  
 
 
X 
X 
X 
 
X 
 
 
 
 
 
 
X 
Diary cards collected (n)15 
 
 
X 
X 
X 
 
X 
 
 
 
 
 
 
X 
Other contraceptive use forms dispensed (n)16 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
Other contraceptive use forms reviewed 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
Other contraceptive use data captured (n)17 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
Prior & concomitant medications 
X 
X* 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Home pregnancy test dispensed19 
 
X 
X 
X 
X 
 
X 
 
X 
 
 
X6 
 
X 
Blood Pregnancy Test 11  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
V = Visit; C = call; SCRN = Screening; UNS = Unscheduled; Wks = Weeks; Mos = Months; VAR = Varies; 
* If enrollment does not immediately follow the screening procedure, confirmation of eligibility must be performed and clinical judgment used to decide whether repeat pregnancy 
or other tests are needed and if contact information should be reviewed. 
* Visit Windows: If enrollment does not occur on same day as screening, subject should return no later than 60 days from start of screening to be enrolled. Post insertion: Visit 2= 
6 wks ± 5 days, Visit 3= 3 mos ± 14 days, Visit 4= 6 mos ± 14 days, Call 1 = 9 mos ± 14 days, Visit 5 = 12 mos ± 14 days, Call 2 = 18 mos ± 14 days, Visit 6 = 24 mos ± 14 days, 
Call 3 = 30 mos ± 14 days, Exit = 37 mos ± 14 days). Call 4 = 17 days (+3) post removal. 
^ During unscheduled visits, the Investigator will perform any study assessments as necessary to provide appropriate treatment. 
1 Vital signs to include measurements of blood pressure, height, and weight. 
2 Pelvic exam at screening will assess for the presence of any uterine or cervical anomalies that would preclude IUD use. 
3 Next visit to be scheduled will be a phone call instead of an in-person office visit. 
4 Confirmation of IUD placement should be done initially by visual then palpable inspection to confirm presence of the IUD string.  If the string is not present, or if there is a 
clinical suspicion of expulsion, a transvaginal ultrasound should be performed to confirm presence of IUD (Section 9.7, Appendix 2). Confirmation will be done by verbal patient 
report for the phone calls. 
5 If medically indicated, a pelvic exam, ultrasound and/or testing for chlamydia/gonorrhea can be performed at all visits. Refer to IUD Check Process outlined in Appendix 2 
6 Next visit to be scheduled during the Exit visit will be a phone call (to obtain results of in-home pregnancy test and follow up on AEs) instead of an in-person office visit. 
7 Endocervical, vaginal, or urine specimen collection is for Nucleic Acid Amplification Test (NAAT) for Neisseria gonorrhoeae and Chlamydia trachomatis (GC/CT). All subjects 
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8 Urine pregnancy test will be completed in clinic at Screening and during Enrollment prior to the subject being randomized to confirm subject is not pregnant prior to IUD 
placement if Enrollment occurs on a separate day from Screening.  
9 During the Exit visit, the clinician will disclose which IUD the subject was using only after all IUD assessments are complete.  
10 If the subject is using ParaGard, ask if she wishes to continue.  If not, remove IUD. If the subject is using the test product, remove IUD. 
11 Confirmatory quantitative blood pregnancy test should be done if initial urine pregnancy test comes back positive 
12 A screening Pap test will be completed for subjects at screening if potential subject is not in compliance with normal standard of care guidelines regarding Pap testing. If 
additional testing or treatment is required based on Pap results, this should be completed prior to enrollment. 
14 Visit 1 distribute 2 diary forms, Visit 2 distribute 2 diary forms, Visit 3 distribute 4 diary forms, and Visit 4 distribute 7 diary forms 
15 Visit 2 collect 2 diary forms, Visit 3 collect 2 diary forms, Visit 4 collect 4 diary forms and Visit 5 collect 7 diary forms 
16 Visit 5 and Visit 6 distribute 2 Other Contraceptive Use forms 
17 Call 2, Visit 6, Call 3, and Exit collect data from Other Contraceptive Use forms 
18 Includes subject’s levels for pain and bleeding 
19 Home pregnancy tests should be provided to subjects at Enrollment and then as needed at other visits with instructions for the subject to complete the test if there is any 
suspicion that they may be pregnant in between their study clinic visits. 
20 Included as part of the Follow-Up Form assessments.  At Call 1, Call 2 and Call 3, the follow up form is also referred to as the Telephone Follow Up Form since the Follow Up 
form information is collected by telephone. 
21 Pain will be assessed immediately and 10 minutes after insertion 
 
 

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25 APPENDIX 2: IUD CONFIRMATION PROCESSES 
 
In order to confirm IUD presence and placement, the following order of assessments should be completed 
until confirmation is completed.  Once IUD placement is confirmed, no further assessment is needed 
regardless of which assessment confirmed placement (i.e. stop with first assessment if IUD placement is 
confirmed): 
1. Visual inspection of cervix for presence of IUD strings or inspection with speculum 
2. Digital palpation 
3. Sweep for strings using cytobrush in endocervical canal 
4. Transvaginal ultrasound (TVUS) examination 
5. Abdominal X-ray to assess for location 
 
Note: If IUD presence confirmation is only made using TVUS, TVUS should be performed at each 
subsequent study visit unless the string becomes visible again. 
Also Note: These steps are meant to confirm IUD location at any time (not necessarily at placement). 
Additionally, either step 1 or 2 may be performed first.  Visual inspection/ inspection with speculum does 
not have to be performed prior to digital palpation and vice versa.  They can be performed 
interchangeably and not specifically in that order. 
 

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26  APPENDIX 3: DAILY DIARY 
Note: The diary includes bleeding definitions to ensure consistent assessment of bleeding amongst study subjects.  However, the definitions are 
based upon the use of tampons or pads.  Subjects using menstrual cups should be instructed to use their best judgment to assess their level of 
bleeding each day since the bleeding definitions within the diary will not apply. 
 

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27 APPENDIX 4: OTHER CONTRACEPTIVE USE FORM 
 

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28 APPENDIX 5: POST PLACEMENT PAIN FORM – CLINIC 
 

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29 APPENDIX 6: POST PLACEMENT PAIN FORM – HOME 
 

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30 APPENDIX 7: PARAGARD PRESCRIBING INFORMATION 
 
 

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CCN016 Version #: 03.00 
Version Date: 19Dec2018 
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Confidential 
 
 
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Version Date: 19Dec2018 
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Confidential 
 
 
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Confidential 
 
 
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31 APPENDIX 8: MONA LISA NT CU380 MINI PRESCRIBING INFORMATION 
 
 
 
 

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Version Date: 19Dec2018 
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Version Date: 19Dec2018 
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