Clinical trial NCT02985541
Conditions: Contraception
Keywords: Birth Control Heavy menstrual bleeding
Sponsor: Bayer
Start date: 2016-12-22; Completion date: 2021-05-28
Enrollment: 364 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study is performed to assess if Mirena is effective and safe as a birth control method beyond 5 years of use. Further the menstrual blood loss (in women that had Mirena inserted for the indication heavy menstrual bleeding \[HMB\]) and safety will be assessed.

Detailed description:

Arms: arm 1: Mirena during extended use (Years 6 to 8).
Interventions: intervention 1: Levonorgestrel IUS (Mirena, BAY86-5028)
Intervention descriptions: intervention 1: Levonorgestrel (LNG) intrauterine delivery system (IUS) with an initial in vitro release rate of 20 μg levonorgestrel per day.

Protocol documents:
Prot_000.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
Multi-center, open-label, uncontrolled study to assess 
contraceptive efficacy and safety of Mirena during extended 
use beyond 5 years in women 18 to 35 years of age including 
a subgroup evaluation of treatment effect on heavy menstrual 
bleeding 
NCT Number: 
NCT02985541 
Document Date: 
20-Sep-2017 
 


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Cover page of the integrated protocol
Multi-center, open-label, uncontrolled study to assess contraceptive efficacy and safety of 
Mirena during extended use beyond 5 years in women 18 to 35 years of age including a 
subgroup evaluation of treatment effect on heavy menstrual bleeding
This protocol version is an integration of the following documents / sections:
1. Original protocol, Version 1.0, dated 03 AUG 2016
2. Amendment 1 (described in Section 15.1)
forming integrated protocol Version 2.0, dated 20 SEP 2017






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Signature of principal investigator
The signatory agrees to the content of the final integrated clinical study protocol as presented.
Name:  
Affiliation:
Date:
Signature:
Signed copies of this signature page are stored in the sponsor’s study file and in the 
respective center’s investigator site file.
In the integrated protocol document, this page may remain unsigned.


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2.
Synopsis
Title
Multi-center, open-label, uncontrolled study to assess contraceptive 
efficacy and safety of Mirena during extended use beyond 5 years in 
women 18 to 35 years of age including a subgroup evaluation of treatment 
effect on heavy menstrual bleeding
Short title
Mirena Extended Trial
Acronym
MET
Clinical study phase
3
Study objectives
Primary objective of the study is to assess the contraceptive efficacy of 
Mirena beyond 5 years up to 8 years of use.
Secondary objectives for the study are the assessment of menstrual blood 
loss (in women that had Mirena inserted for the indication heavy menstrual 
bleeding [HMB]) and safety.
Further objectives are the population pharmacokinetic evaluation of LNG 
plasma concentration data and evaluation of user satisfaction.
Test drug
Mirena, levonorgestrel-releasing intrauterine system
Name of active ingredient
Levonorgestrel (LNG)
Dose
Initial release rate: 20 µg per day
Route of administration
Intrauterine
Duration of treatment
Up to 3 years (total use of the current Mirena up to 8 years)
Reference drug
None
Indication
Intrauterine contraception
Treatment of heavy menstrual bleeding for women who choose to use 
intrauterine contraception as their method of contraception.
Diagnosis and main criteria for 
inclusion /exclusion
Fertile age women (18 to 35 years at the time of the screening visit) 
currently using a Mirena for contraception or for contraception and heavy 
menstrual bleeding and who have had the Mirena in situ for at least 4 years 
and 6 months but no longer than 5 years and are willing to continue its use 
for contraception or contraception and heavy menstrual bleeding for up to 8 
years in total.
Study design
Multi-center, open-label, uncontrolled study to be conducted in the US. 
Duration of the study treatment period is up to 3 years.
Methodology
Monitoring of occurrence of pregnancies and evaluating the menstrual 
blood loss in the HMB subgroup


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Type of control
Uncontrolled study
Number of subjects
Approximately 360 subject to enter the treatment period
Primary variable
Occurrence of pregnancies
Time point/frame of 
measurement for primary 
variable(s)
Treatment period of up to 3 years (total time of Mirena use up to 8 years). 
Plan for statistical analysis
Analysis of primary variable: 
Primary Analysis: The Pearl index (PI) will be calculated as the number of 
pregnancies within years 6-8 of Mirena use per 100 women years, and the 
corresponding 2-sided 95% confidence interval will be provided. 
Secondary Analysis: The cumulative failure rate, i.e., the probability of 
getting pregnant will be calculated using the Kaplan Meier method in 
addition to the calculation of PIs.


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Table of contents
Cover page of the integrated protocol.....................................................................................1
1.
Title page ............................................................................................................................2
Signature of the sponsor’s medically responsible person......................................................3
Signature of principal investigator..........................................................................................4
2.
Synopsis...............................................................................................................................5
Table of Tables........................................................................................................................11
Table of Figures.......................................................................................................................12
List of abbreviations ...............................................................................................................13
3.
Introduction......................................................................................................................15
4.
Study objectives................................................................................................................19
5.
Study design......................................................................................................................19
6.
Study population..............................................................................................................21
6.1
Inclusion criteria.............................................................................................................22
6.2
Exclusion criteria............................................................................................................22
6.3
Justification of selection criteria.....................................................................................23
6.4
Withdrawal of subjects from study.................................................................................24
6.4.1
Withdrawal..................................................................................................................24
6.4.2
Replacement................................................................................................................26
6.5
Subject identification......................................................................................................26
7.
Treatments........................................................................................................................26
7.1
Treatments to be administered........................................................................................26
7.2
Identity of study treatment..............................................................................................26
7.3
Treatment assignment.....................................................................................................26
7.4
Dosage and administration .............................................................................................27
7.4.1
Removal of Mirena .....................................................................................................27
7.5
Blinding..........................................................................................................................27
7.6
Drug logistics and accountability...................................................................................27
7.7
Treatment compliance ....................................................................................................27
8.
Non-study therapy ...........................................................................................................28
8.1
Concomitant therapy ......................................................................................................28
8.2
Post-study therapy ..........................................................................................................28
9.
Procedures and variables................................................................................................28
9.1
Tabular schedule of evaluations .....................................................................................28
9.2
Visit description..............................................................................................................34
9.2.1
Optional pre-screening contact ...................................................................................35
9.2.2
Screening – Visit 1......................................................................................................35


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9.2.3
Baseline – Visit 2 ........................................................................................................36
9.2.4
6-month visit – Visit 3.................................................................................................36
9.2.5
12-month visit – Visit 4 (End of Year 6 of Mirena use) .............................................37
9.2.6
18-month visit – Visit 5...............................................................................................37
9.2.7
24 –month visit – Visit 6 (End of Year 7 of Mirena use) ...........................................38
9.2.8
30-month visit – Visit 7...............................................................................................38
9.2.9
36-month visit, EOT – Visit 8 (End of Year 8 of Mirena use) ...................................39
9.2.10
3-week follow-up call (EOS) ......................................................................................39
9.2.11
3-month follow-up contact for post-study pregnancies ..............................................39
9.2.12
12-month follow-up contact for return-to-fertility......................................................40
9.3
Population characteristics...............................................................................................40
9.3.1
Demographic...............................................................................................................40
9.3.2
Medical history............................................................................................................40
9.3.3
Reproductive and menstrual history............................................................................40
9.3.4
Other baseline characteristics......................................................................................40
9.3.4.1
Indication for current Mirena...................................................................................40
9.4
Efficacy...........................................................................................................................41
9.4.1
Occurrence of pregnancies..........................................................................................41
9.4.1.1
Pregnancies during the study ...................................................................................41
9.4.1.2
Pregnancies occurring after the end of study treatment...........................................41
9.4.2
Assessment of menstrual blood loss (MBL) by alkaline hematin method..................42
9.5
Pharmacokinetics / pharmacodynamics .........................................................................42
9.5.1
Sample collection........................................................................................................42
9.5.2
Drug measurements.....................................................................................................43
9.5.3
Pharmacokinetic evaluation ........................................................................................43
9.5.4
Residual LNG content analysis...................................................................................44
9.6
Safety..............................................................................................................................44
9.6.1
Adverse events ............................................................................................................44
9.6.1.1
Definitions................................................................................................................44
9.6.1.2
Classifications for adverse event assessment...........................................................46
9.6.1.3
Assessments and documentation of adverse events.................................................48
9.6.1.4
Reporting of serious adverse events.........................................................................49
9.6.1.5
Expected adverse events ..........................................................................................50
9.6.2
Pregnancies .................................................................................................................50
9.6.3
Further safety ..............................................................................................................50
9.6.3.1
Vital signs and weight..............................................................................................50
9.6.3.2
Physical examination ...............................................................................................50
9.6.3.3
Gynecological examination .....................................................................................50
9.6.3.4
Pregnancy test ..........................................................................................................51
9.6.3.5
Cervical smear .........................................................................................................51
9.6.3.6
Test for Chlamydia ..................................................................................................52
9.6.3.7
Safety laboratory tests..............................................................................................52
9.6.3.8
Presence of Mirena removal threads........................................................................53
9.6.3.9
Expulsion of Mirena ................................................................................................53
9.6.3.10
Perforation by Mirena..............................................................................................54


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9.6.3.11
Pelvic inflammatory disease ....................................................................................54
9.6.3.12
Uterine bleeding.......................................................................................................54
9.7
Other procedures and variables ......................................................................................55
9.7.1
eDiary..........................................................................................................................55
9.7.2
Continuing need of contraception ...............................................................................55
9.7.3
Mirena removal – assessment of the ease of the procedure (by investigator) and 
pain during the removal (by subject) ..........................................................................55
9.7.4
Subject satisfaction with Mirena.................................................................................56
9.7.5
Back-up contraception ................................................................................................56
9.8
Appropriateness of procedures / measurements.............................................................56
10. Statistical methods and determination of sample size..................................................56
10.1
General considerations ...................................................................................................56
10.2
Analysis sets ...................................................................................................................57
10.3
Variables and planned statistical analyses......................................................................57
10.3.1
Variables .....................................................................................................................58
10.3.1.1
Efficacy variables.....................................................................................................58
10.3.1.2
Safety variables........................................................................................................59
10.3.1.3
Other variables.........................................................................................................59
10.3.2
Statistical methods ......................................................................................................60
10.3.2.1
Analysis of the primary variable..............................................................................60
10.3.2.2
Analysis of the secondary variables.........................................................................62
10.3.2.3
Analysis of safety variables .....................................................................................64
10.3.2.4
Other variables.........................................................................................................67
10.4
Determination of sample size.........................................................................................67
10.5
Planned interim analyses ................................................................................................68
11. Data handling and quality assurance.............................................................................69
11.1
Data recording ................................................................................................................69
11.2
Monitoring......................................................................................................................70
11.3
Data processing ..............................................................................................................71
11.4
Missing data....................................................................................................................71
11.5
Audit and inspection.......................................................................................................71
11.6
Archiving........................................................................................................................72
12. Premature termination of the study...............................................................................72
13. Ethical and legal aspects..................................................................................................73
13.1
Investigators and other study personnel .........................................................................73
13.2
Funding and financial disclosure....................................................................................73
13.3
Ethical and legal conduct of the study............................................................................74
13.4
Subject information and consent ....................................................................................74
13.5
Publication policy and use of data..................................................................................75
13.6
Compensation for health damage of subjects / insurance ..............................................76
13.7
Confidentiality................................................................................................................76
14. Reference list ....................................................................................................................76


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15. Protocol amendments ......................................................................................................78
15.1
Amendment 1 – dated 20 SEP 2017...............................................................................78
15.1.1
Overview of the changes to the study .........................................................................78
15.1.1.1
Modification 1: Addition of the 6-year analysis and the required assessments 
needed for the analyses at Year 6 ............................................................................78
15.1.1.2
Modification 2: Guidance about number of 34- or 35-year old women to be 
included into the screening period...........................................................................78
15.1.1.3
Modification 3: Information on inclusion range for laboratory values added.........79
15.1.1.4
Modification 4: Revision of the criteria for mandatory withdrawal from the 
study.........................................................................................................................79
15.1.1.5
Modification 5: Clarification on counting of pregnancies with the estimated date 
of conception within 7 days after the end of Mirena treatment for the Pearl 
Index calculation......................................................................................................79
15.1.1.6
Modification 6: Clarification of the post-treatment pregnancy tracking process 
(PTPT)......................................................................................................................79
15.1.1.7
Modification 7: Clarification and correction of terms used in the definitions for 
calculation of crude exposure time ..........................................................................80
15.1.1.8
Modification 8: Clarification of excluded exposure time due to back-up 
contraception use .....................................................................................................80
15.1.1.9
Modification 9: Addition of sensitivity analysis for PI ...........................................80
15.1.1.10 Modification 10: Addition of a reference to the statistical analysis plan 
regarding handling of partial or missing data ..........................................................80
15.1.1.11 Modification 11: Clarification of the definition of clinical change in bleeding 
profile regarding HMB and of the proportion of subjects with clinical change in 
bleeding profile regarding HMB..............................................................................80
15.1.1.12 Modification 12: Change in exclusion criterion about simultaneous participation 
in other trials ............................................................................................................81
15.1.1.13 Modification 13: Withdrawal from study if heavy menstrual bleeding returns.......81
15.1.1.14 Modification 14: Reference to a local laboratory removed from the text................81
15.1.1.15 Modification 15: Revised terminology of the adverse events to be included in 
the main safety analysis, and correction of the list of other safety variables...........81
15.1.1.16 Modification 16: Improved instructions for collection of used sanitary products...82
15.1.1.17 Modification 17: Correction of the in cervical smear instructions at EOT visit......82
15.1.1.18 Modification 18: Change in the SOPs to be followed for assessing important 
deviations.................................................................................................................82
15.1.1.19 Modification 19: Definition of a bleeding/spotting episode....................................82
15.1.1.20 Modification 20: Update of the background information........................................82
15.1.1.21 Modification 21: Information on post-study contraception.....................................83
15.1.1.22 Modification 22: Mandatory TVUS if removal threads are not found ....................83
15.1.1.23 Modification 23: Clarifications................................................................................83
15.1.1.24 Modification 24: Instructions regarding bleeding irregularities detected in 
women using Mirena for contraception only...........................................................83
15.1.1.25 Modification 25: Collection of age at Baseline visit (Visit 2).................................83
15.1.1.26 Modification 26: Revision of the definition for start of treatment period for the 
primary variable.......................................................................................................84


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15.1.2
Changes to the protocol text........................................................................................84
15.1.2.1
Section 2. Synopsis..................................................................................................85
15.1.2.2
Section 3. Introduction.............................................................................................85
15.1.2.3
Section 5 Study design.............................................................................................86
15.1.2.4
Section 6 Study population......................................................................................86
15.1.2.5
Section 6.2 Exclusion criteria ..................................................................................87
15.1.2.6
Section 6.4.1 Withdrawal.........................................................................................87
15.1.2.7
Section 9.1 Tabular schedule of evaluations............................................................89
15.1.2.8
Section 9.2 Visit description....................................................................................96
15.1.2.9
Section 9.2.3 Baseline – Visit 2...............................................................................97
15.1.2.10 Section 9.2.5 12-month visit – Visit 4 (End of Year 6 of Mirena use)....................97
15.1.2.11 Section 9.2.8 30-month visit – Visit 7 .....................................................................98
15.1.2.12 Section 9.2.9 36-month visit, EOT – Visit 8 (End of Year 8 of Mirena use)..........99
15.1.2.13 Section 9.2.10 3-week follow-up call (EOS).........................................................100
15.1.2.14 Section 9.2.11 3-month follow-up contact for post-study pregnancies .................100
15.1.2.15 Section 9.2.12 12-months follow-up contact for return-to-fertility.......................101
15.1.2.16 Section 9.3.1 Demographic....................................................................................101
15.1.2.17 Section 9.4.1.1 Pregnancies during the study ........................................................102
15.1.2.18 Section 9.4.1.2 Pregnancies occurring after the end of study treatment................102
15.1.2.19 Section 9.6.3.6 Test for chlamydia ........................................................................103
15.1.2.20 Section 9.6.3.7 Safety laboratory tests...................................................................104
15.1.2.21 Section 9.6.3.8 Presence of Mirena removal threads.............................................104
15.1.2.22 Section 9.6.3.12 Uterine bleeding..........................................................................105
15.1.2.23 Section 9.7.1 eDiary...............................................................................................105
15.1.2.24 Section 9.7.4 Subject satisfaction with Mirena......................................................106
15.1.2.25 Section 10.2 Analysis sets......................................................................................106
15.1.2.26 Section 10.3 Variables and planned statistical analyses ........................................107
15.1.2.27 Section 10.3.1.1.1 Primary efficacy variable.........................................................108
15.1.2.28 Section 10.3.1.2 Safety variables...........................................................................109
15.1.2.29 Section 10.3.2.1 Analysis of the primary variable.................................................110
15.1.2.30 Section 10.3.2.2.1 Menstrual blood loss................................................................113
15.1.2.31 Section 10.3.2.2.2 Categorized menstrual blood loss (MBL) (<80ml / 30 days) ..114
15.1.2.32 Section 10.3.2.3 Analysis of safety variables ........................................................116
15.1.2.33 Section 10.3.2.3.2 Bleeding pattern.......................................................................116
15.1.2.34 Section 10.5 Planned interim analyses...................................................................118
15.1.2.35 Section 11.1 Data recording...................................................................................118
15.1.2.36 Section 13.1 Investigators and other study personnel............................................119
15.1.2.37 Section 14 Reference list .......................................................................................119
Table of Tables
Table 3–1: Prediction of in vivo release rates based on residual content data from Report 
A15942..................................................................................................................16


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Table 3–2: Comparison of average LNG serum concentrations (% CV) data of Jaydess/Skyla, 
LCS16 and Mirena................................................................................................17
Table 9–1 Schedule of activities and evaluations – amended................................................29
Table 9–2 Schedule of activities needed for the MBL evaluations – amended.....................33
Table 9–3 Uterine bleeding – bleeding intensity definitions – amended...............................55
Table 10–1 Definition of crude exposure times – amended ....................................................60
Table 10–2 Bleeding Intensity Codes and WHO Definitions for Bleeding Intensity – amended
...............................................................................................................................65
Table 10–3 Example of an Assessment of Bleeding Episodes ................................................66
Table of Figures
Figure 5—1
Overview of the study design.......................................................................... 19


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List of abbreviations
ADR
Adverse drug reaction
AE
Adverse event
AIDS
Acquired immune deficiency syndrome
ALT
Alanine aminotransferase 
ASCUS
Atypical squamous cells of undetermined significance  
AST
Aspartate aminotransferase 
BL
Baseline
CI
Confidence interval
CRA
Clinical research associate
CRF
Case report form
CRO
Contract research organization
CSR
Clinical Study Report
CV
Coefficient of variation
DNA
Deoxyribonucleic acid
eCRF
Electronic case report form
e.g.
Exempli gratia (for example)
EMA
European Medicines Agency
EOS
End of study
EOT
End of treatment
FAS
Full analysis set
FDA
Food and Drug Administration
FPFV
First patient first visit
FSH
Follicle-stimulating hormone
GCL
Global Clinical Leader
GCP
Good Clinical Practice
GLP
Good Laboratory Practices
HbA1c
Glycosylated hemoglobin
hCG
Human chorionic gonadotropin
HDL
High density lipoprotein
HIV
Human immunodeficiency virus
HMB
Heavy menstrual bleeding
HPV
Human papilloma virus
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council on Harmonization
i.e.
Id est (that is)
IEC
Independent Ethics Committee
IME
Important Medical Event
IRB
Institutional Review Board
IUD
Intrauterine device
IUS
Intrauterine system
LC-MS
Liquid chromatography-mass spectrometry
LCS
Levonorgestrel contraceptive intrauterine system
LDL
Low density lipoprotein
LNG
Levonorgestrel
LPLV
Last patient last visit
mIU
milliInternational Unit
MBL
Menstrual blood loss
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MET
Mirena Extended Trial
mg
milligram


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MI
Myocardial infarction
mL
milliliter
MRP
Medical Review Plan
MS
Mass spectrometry
NAAT
Nucleic acid amplification tests
NJ
New Jersey 
PAS
Primary analysis set
PCR
Polymerase chain reaction
PI
Pearl Index
PID
Pelvic inflammatory disease
PK
Pharmacokinetics
popPK
Population pharmacokinetic
PRO
Patient-reported outcomes
PT
Preferred term
PTPT
Post-Treatment Pregnancy Tracking
QC
Quality control
SAE
Serious adverse event
SAF
Safety analysis set
SE
Standard error
SHBG
Sex hormone binding globulin
SID
Subject identification (number)
SOC
System organ class
SOP
Standard Operating Procedure
STD
Sexually transmitted disease
STIs
Sexually transmissible infections
SUSARs
Suspected, unexpected, serious adverse reactions
TVUS
Transvaginal ultrasound
US
United States of America
WHO
World Health Organization 


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3.
Introduction
Background
Mirena, a levonorgestrel-releasing intrauterine system (LNG IUS; initial in vitro release rate 
20 g LNG / day), has been proven a safe and reliable method of contraception over the 
5 years of labeled use.  It has been on the market since mid-1990s in most European countries 
and since 2001 in the United States (US).
This section was changed in Amendment 1, see Section 15.1.1.20.
Three contraceptive efficacy studies on extended use beyond the indicated 5 years up to 7 
years (1, 2, 3) have been published. In a comparative study the effectiveness of the 
contraceptive implant and the 52-mg hormonal intrauterine device in women using the 
method for 2 years beyond the approved duration was evaluated (1). Among 496 LNG IUS 
users, 696.9 woman-years of follow-up have been completed. Two pregnancies have been 
reported. The failure rate in the sixth year of use of the LNG IUS is calculated as 0.25 
(95% CI, 0.04-1.42) per 100 woman-years; failure rate during the seventh year is 0.43 (95% 
CI 0.08-2.39) per 100 woman-years. In the recently published study by Rowe et al 2016 (2), 
the overall pregnancy rate of the TCu380A was significantly higher than that of the LNG 
IUD: at the end of the seventh year the cumulative rate was 2.45 (standard error [SE] 0.44)
per 100 for the TCu380A and 0.53 (SE 0.21) per 100 for the LNG IUD. In the earlier study 
(3), no pregnancies occurred to users of either device in years 6 and 7. Cumulative pregnancy 
rates were 1.1 per 100 at seven years for the LNG IUS and 1.4 per 100 for the copper-
releasing IUDs. Hidalgo et al (2009) (4) evaluated the serum levonorgestrel levels and 
endometrial thickness during extended use of the levonorgestrel-releasing intrauterine system
up to 8 1/2 years after insertion. During extended use of the LNG IUS, serum LNG levels 
were nearly half of those found in the first 2 months of use. Despite the very thin 
endometrium, menstrual bleeding was reinstated in many cases. The incidence of amenorrhea 
decreased from 41.8% at 84 months to 31.5% at 102 months of use (4).
The in vivo LNG release rate at the end of the 5 years of Mirena use is 10.1 µg/d which is 
higher than that for other LNG IUS, Jaydess (5.4 µg/d at 3 years) and LCS16 (7.4 µg/d at 5 
years) (see Table 3–1), suggesting that the product would be efficacious in preventing 
pregnancy for a longer period of use.  
This study will evaluate the contraceptive efficacy of Mirena during the extended use for up 
to 8 years.  The stability of the effect on heavy menstrual bleeding during the extended use 
will be studied in a subgroup of women for whom the Mirena was prescribed for heavy 
menstrual bleeding (as a secondary indication to contraception).
Further details can be found in the latest available version of the investigator's brochure, 
which contains comprehensive information on the study drug.


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Rationale of the study
Mirena has a high contraceptive efficacy resulting in a failure rate of approximately 0.2% at 
1 year and a cumulative failure rate of approximately 0.7% at 5 years.  In addition, Mirena
has been shown to reduce menstrual blood loss by more than 90% after 1 year and to 
consequently increase blood hemoglobin levels (5).  Clinical practice has shown that Mirena
often relieves dysmenorrhea and premenstrual symptoms.  
Mirena is currently indicated for use up to 5 years.  Bayer wishes to study the extended
duration of use of Mirena up to 8-years in the indication contraception. Depending on the 
results, this may allow recommendation of a longer interval between the IUS placements in 
women who may wish to continue use of Mirena for contraception beyond 5 years. The 
planned study will provide the basis for extension of Mirena use up to 8 years for 
contraception.
To support the extension of use over 8 years, a prediction of typical in vivo release rates for 
Mirena at 5, 6, 7, and 8 years after insertion of the IUD was performed using population 
pharmacokinetic (PK) methods. The prediction was based on residual content data from 
Report A15942 and a first-order release was assumed.
Table 3–1: Prediction of in vivo release rates based on residual content data from 
Report A15942
Time point 
after 
insertion
Mirena
Residual LNG 
(mg)
Mirena
Residual LNG 
(%)
Mirena
in vivo release 
rate [µg/d]
Jaydess/Skyla
in vivo release 
rate [µg/d]
LCS16
in vivo release 
rate [µg/d]
3 years
--
--
13.7
5.4
8.0
5 years
24.2
46.5%
10.1
--
7.4
6 years
20.7
39.9%
8.6
--
--
7 years
17.8
34.2%
7.4
--
--
8 years
15.3
29.3%
6.4
--
--
Table 3–1 shows the residual LNG content in the device after 5, 6, 7, and 8 years of use as 
amount in mg and in % of initial content (52 mg). Even after 8 years, about 30% of the initial 
content is still in the LNG IUS. The typical in vivo release rates for Mirena decline from 
about 10 µg/d to 6.4 µg/d after 8 years of use. Compared to Jaydess/Skyla, which is the 
LNG IUS with the lowest release rate on the market, the anticipated in vivo release rate for 
Mirena is still higher.
In support of the extended use of Mirena beyond 5 years, serum LNG concentrations (5 years 
and beyond, from Mirena in comparison with LCS16 and Jaydess/Skyla) are presented in 
Table 3–2 below:


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Table 3–2: Comparison of average LNG serum concentrations (% CV) data of 
Jaydess/Skyla, LCS16 and Mirena
Time
Jaydess/Skyla
(ng/L)
LCS16
(ng/L)
Mirena
(ng/L)
3 years
68.5 (33.0%)a
85.2 (63.9%)a
165 (40.5%)a
5 years
-
64.0 (23.0%)e
150 (35.6%)b
6.5 years
-
-
76.3 (31.8%)c
8 years
-
-
117 (50.4%)d
Abbreviations: CV=coefficient of variation; LNG=levonorgestrel
a
A46796 CSR (6)
b
B078 CSR (7)
c
B073 CSR (8)
d
Seeber B, et al. 2012 (13)
e
PH-37274 CSR (9)
The above data indicate that serum concentrations of LNG after 8 years of Mirena use are in 
a similar range compared to Jaydess/Skyla after 3 years of use as can be expected based on 
the similar in vivo release rates. 
The simulated in vivo release rates for Mirena support the extended use up to 8 years.
Benefit-risk assessment
Benefit /risk balance for Mirena in Contraception:
Mirena has a very high contraceptive efficacy which is less dependent on user-compliance 
and compares favorably to other contraceptive methods including barrier methods, combined 
oral contraceptive, progestin-only pill, injectables, and copper IUDs (eg. ParaGard). Its 
efficacy is not influenced by hepatic enzyme-inducing drugs (in contrast to other hormonal 
methods). Further non-contraceptive benefits include decreased menstrual blood loss and 
alleviation of dysmenorrhea. Some studies have also suggested that Mirena may have 
beneficial effects on pelvic pain related to endometriosis or adenomyosis. Due to its mainly 
local mechanism of action and the fact that it does not contain estrogens, Mirena is suitable 
for many women in whom combined contraceptive methods are contraindicated or not 
desirable. Mirena can be inserted immediately after a first trimester abortion, with immediate 
effect of contraceptive efficacy. Mirena does not interfere with lactation.
The majority of Mirena users experience bleeding changes. Other "very common" adverse 
drug reactions (ADRs) in clinical trials include headache and abdominal/pelvic pain. Ovarian 
cysts are observed under Mirena use but are in the vast majority, transient and asymptomatic. 
Hormonal side effects of levonorgestrel are less frequently observed.
Identified safety risks are device related complications (such as expulsions), and side effects 
caused by levonorgestrel. Important safety risks/serious events are rare (pelvic inflammatory 
disease [PID], uterine perforation) and can be managed with adequate medical or surgical 
treatment. Clinical trials and observational studies have established that the risk of PID 
associated with insertion of intrauterine contraceptives is confined to the first weeks after 
insertion. A large European active surveillance study (EURAS-IUD) (10) showed that the 


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risk of uterine perforation is increased in women who are breastfeeding at time of insertion, 
or have given birth up to 36 weeks before insertion. However, the need for reliable 
contraception is high in this population, but contraceptive options in this population are 
restricted to methods not interfering with lactation.
Although the absolute rate of ectopic pregnancies with Mirena is lower than in subjects 
without any contraceptive method, the relative risk of ectopic pregnancy in women becoming 
pregnant while using Mirena is increased.
Intrauterine pregnancy, when occurring during use of Mirena, is associated with a higher risk 
for spontaneous abortion and premature delivery. The more common risks of bleeding 
changes, ovarian cysts and expulsions are non-serious.
Extension of Mirena use for contraception to 8 years
Extended duration of use of Mirena up to 8 years offers a benefit for those women who want 
to continue the use of Mirena beyond 5 years for contraception by extending the period in 
between the two consecutive LNG IUS and thus prolonging the time interval between IUS 
placements. By prolonging the time interval between IUS placements, the risk of IUS-
insertion related complications is further reduced by reducing the number of IUS placements 
that will be necessary in women who choose to continue this method of contraception during 
a longer period of their fertile years. Reducing the number of times that a woman will have to 
expect the discomfort and the cost associated with the insertion of an intrauterine 
contraceptive may ultimately lead to increased use of a highly effective method of 
contraception. 
Contraceptive efficacy during extended duration of use of Mirena during years 6, 7 and 8 is 
expected to be high, as the lower release rate of other LNG IUS products (Skyla and LCS16) 
have been proven to provide high efficacy with a Pearl Index of less than 0.5 up to 3 years
(11) and 5 years (9). Risks associated with contraceptive failure (i.e. risk of ectopic 
pregnancy, and risk to a pregnancy with Mirena in situ) are not expected to change during 
years 6, 7 and 8 with continued high contraceptive efficacy, which will be demonstrated in 
the proposed clinical study.
The bleeding profile during the extended use of the same device is expected to remain 
favorable and similar to that observed during the use up to 5 years. The incidence of 
infrequent bleeding or absence of bleeding increase with time in users of LNG IUS, while the 
incidence of prolonged and frequent bleeding decreases. Absence of bleeding is associated 
with high overall satisfaction and continuation rates in women using a second consecutive 
Mirena (12).
The study will also analyze the removal procedure after 8 years of use to confirm the 
usability of the product for the extended duration of use. No new risks are anticipated.
In summary, a positive benefit risk balance is anticipated during the extended use of Mirena 
for contraception up to 8 years.


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4.
Study objectives
Primary objective of the study is to assess the contraceptive efficacy of Mirena beyond 5 
years up to 8 years of use.
Secondary objectives for the study are the assessment of menstrual blood loss (in women that 
had Mirena inserted for the indication heavy menstrual bleeding [HMB]) and safety.
Further objectives are the population pharmacokinetic evaluation of LNG plasma 
concentration data and evaluation of user satisfaction.
5.
Study design
Design overview
This is a multi-center, uncontrolled, single group study to be conducted in the US only.  
Study design is presented below in Figure 5—1.
Figure 5—1
Overview of the study design
The target for the total number of women to be included in the extended treatment period is
360 women (200 women to complete study treatment). To evaluate the effect of extended 
Mirena use on HMB, it is targeted that 10% of the women to be treated (i.e. 36 women out of 
360) should have Mirena prescribed for the treatment of HMB in addition to contraception.  
Please note, subjects who have Mirena prescribed for contraception and heavy menstrual 
bleeding will have to consent to the HMB subgroup procedures. 


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The study will consist of a screening, treatment, and a follow-up period. Screening can be 
started when the subject has had the Mirena in place for 4 years and 6 months.  Screening 
activities should be completed within 60 days after signed informed consent to allow enough 
time for the evaluation of the subjects’ eligibility to the study.  Baseline visit (Visit 2) will be 
scheduled to take place 0 to 14 days before the end of Year 5 of Mirena use; and this is the 
start of the treatment period. Treatment period is defined as the 3-year period following the 
Baseline visit, i.e. years 6, 7 and 8 of extended use of Mirena. 
This section was changed in Amendment 1, see Section 15.1.1.1. An analysis of the efficacy 
and safety data will be conducted after all subjects have either completed 6 years of treatment
(i.e. completed 1 year in the study), or prematurely terminated their study participation before 
this time point. Another analysis of the efficacy and safety data will be conducted after all 
subjects have either completed 7 years of treatment (i.e. completed 2 years in the study), or 
prematurely terminated their study participation before this time point.
Final analysis will be done after all subjects have either completed 8 years of treatment or 
prematurely terminated their study participation. 
All subjects will be contacted 3 weeks after the EOT to collect information on any pregnancy 
detected shortly after the removal of Mirena.  Follow-up period for the tracking of post-
treatment pregnancies will be 3 months after the end of the treatment for subjects who
prematurely discontinued study treatment. They will be contacted unless the reason for 
discontinuation is “pregnancy”, “death”, or “withdrawal by subject” where the subject has 
withdrawn main consent during study conduct and wishes to stop future contact with the site. 
For subjects that had withdrawn consent during study, but consented to post study 
participation follow-up, post treatment pregnancy tracking information is expected.
Follow-up period for the tracking of post-treatment pregnancies will be up to 12 months for 
subjects who discontinue Mirena use because of a wish for pregnancy (i.e. collection of 
return-to-fertility data). Subjects who discontinue treatment because of a wish for pregnancy 
will receive a second telephone call at 12 months after removal of the Mirena if they still 
wished for a pregnancy at the 3-month contact and had not reported a pregnancy at the time 
of the 3-month follow-up call.
Levels of LNG (plasma) and sex hormone binding globulin (SHBG) (serum) will be 
monitored by means of sparse blood sampling, and will be evaluated using a population PK 
approach. In addition, serum LNG and SHBG levels will also be determined at the Mirena
removal in all subjects discontinuing the study prematurely. Similarly, residual LNG content 
will be determined after removal at the end of the study for all subjects who had entered the 
treatment period whether they completed the study or discontinued prematurely.  The
concentration values for LNG and SHBG and residual LNG content data will be entered into 
the database at pre-planned database opening.  The results on population pharmacokinetics 
will be reported separately.
Primary variable
Primary efficacy variable is the occurrence of pregnancy.


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Justification of the design
The efficacy and safety of Mirena for contraception and HMB has been proven in a large 
clinical development program for up to 5 years, while no company sponsored study data is 
currently available for use of Mirena beyond 5 years. New clinical data is therefore needed. 
The planned study will assess the contraceptive efficacy of Mirena during extended use 
beyond 5 years up to 8 years. In addition, approximately 10% of the total number of women 
in the study will have had Mirena prescribed for contraception and heavy menstrual bleeding; 
these subjects will form the HMB subgroup to show that the efficacy in terms of menstrual 
blood loss is maintained during extended use. This study design allows access for extended 
use of Mirena in women who have already been using Mirena close to the end of the 
currently approved maximum period of use and therefore an option for longer interval 
between the IUS placements in those women, who wish to continue use of Mirena for 
contraception or contraception and heavy menstrual bleeding (HMB) beyond 5 years.
End of study
The end of the study as a whole will be reached as soon as the last visit of the last subject (i.e. 
end of study phone call at 3 weeks after Mirena removal) has been reached in all centers.
Primary completion
The primary completion event for this study is the last patient last visit (LPLV).
The primary completion date for this study according to the FDA Amendment Act is 
specified in a separate document (not part of this study protocol).
6.
Study population
This section was changed in Amendment 1, see Sections 15.1.1.2, 15.1.1.3, and 15.1.1.12.
The study will include fertile age women (18 to 35 years at the time of the screening visit) 
currently using a Mirena for contraception or for contraception and heavy menstrual bleeding 
and who have had the Mirena in situ for at least 4 years and 6 months but no longer than 5 
years and are willing to continue its use for contraception or contraception and heavy 
menstrual bleeding for up to 8 years in total. About 90% of the women included will be 18 to 
32 (inclusive) years of age at screening (visit 1)1.  In addition, the aim is that approximately 
10% of the total number of women in the study will have had Mirena prescribed for 
contraception and heavy menstrual bleeding; these subjects will form the HMB subgroup. 
Subjects who have Mirena prescribed for contraception and heavy menstrual bleeding will 
have to consent to the HMB subgroup procedures. The subjects must have a continuing need 
for contraception during the entire duration of the study (i.e. they are sexually active and at 
risk of pregnancy during the study treatment period of 3 years, i.e. up to a total of 8 years
                                                
1 Screening of women who are 34 or 35 years old will be closed, once 10 women in this age group have 
completed the baseline visit, for details see Section 10.4.


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with the current Mirena). Women who have contraindications to use Mirena according to the 
current US label will be excluded from participation in the study.
Women in need of contraception meeting all inclusion and presenting none of the exclusion 
criteria will be eligible for enrollment to the treatment phase in the study. Inclusion and 
exclusion criteria are checked at the screening visit. A re-check on eligibility is to be done at 
baseline visit.
6.1
Inclusion criteria
1. Signed and dated informed consent
2. Women, 18 to 35 years of age at the time of screening (visit 1) who are currently 
using Mirena for contraception or for contraception and heavy menstrual bleeding. 
The duration of use of the current Mirena has to be at least 4 years 6 months at the 
start of screening phase but not more than 5 years at visit 2 and the woman is willing 
to continue with its use and has a continuing need for contraception.
3. Normal or clinically insignificant cervical smear not requiring further follow up (a 
cervical smear has to be taken at screening visit or a normal result has to be 
documented within the previous 6 months). Human papilloma virus (HPV) testing in 
subjects with atypical squamous cells of undetermined significance (ASCUS) can be 
used as an adjunctive test. Subjects with ASCUS can be included provided they are 
negative for high-risk HPV strains.
6.2
Exclusion criteria
This section was changed in Amendment 1, see Sections 15.1.1.3 and 15.1.1.12.
1. Menopausal symptoms with FSH >30 mIU/ml
2. Pregnancy or suspicion of pregnancy
3. Uterine bleeding of unknown etiology
4. Untreated acute cervicitis or vaginitis or other lower genital tract infections (until 
successfully treated)
5. Increased susceptibility to pelvic infection
6. Acute pelvic inflammatory disease (PID) or a history of PID unless successfully 
treated and which, in the investigator’s opinion, has not negatively affected subject’s
fertility 
7. Congenital or acquired uterine anomaly if it distorts the uterine cavity
8. Known or suspected breast cancer or other progestin-sensitive cancer
9. History of, diagnosed or suspected genital or other malignancy (excluding treated 
squamous cell carcinoma of the skin), and untreated cervical dysplasia
10. Known or suspected uterine or cervical neoplasia
11. Any active acute liver disease or liver tumor (benign or malignant)
12. Clinically significant endometrial polyp(s), which, in the opinion of the investigator, 
will interfere with the assessment of the bleeding profile during the study.


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13. Clinically significant ovarian cyst(s).
14. Concomitant use of other sex-hormone containing preparations
15. Hypersensitivity to any component of Mirena
16. Any diseases or conditions that can compromise the function of the body systems and 
could result in altered absorption, excessive accumulation, impaired metabolism, or 
altered excretion of the study medication
17. Any diseases or conditions that might interfere with the conduct of the study or the 
interpretation of the results
18. Abuse of alcohol, drugs, or medicine (e.g., laxatives)
19. Inability to cooperate with the study procedures for any reason, including the 
following examples: language comprehension, psychiatric illness, inability to get to 
the study site
20. Known or suspected HIV infection or high risk for STD. Conditions associated with 
increased susceptibility to infection with microorganisms, including such conditions 
as leukemia, human immunodeficiency virus (HIV)-positive status, acquired immune 
deficiency syndrome (AIDS).
21. Laboratory values outside inclusion range before baseline and considered clinically 
relevant (see Section 9.6.3.7).
22. Simultaneous participation in another clinical study with investigational medicinal 
product(s). Participation in another clinical trial prior to study entry that might have 
an impact on the study objectives, at the discretion of the investigator.
23. Close affiliation with the investigational site; e.g. a close relative of the investigator, 
dependent person (e.g. employee or student of investigational site, or sponsor’s staff)
24. Previous enrollment to the study (i.e. re-screening allowed only as described in 
section 6.4.1)
6.3
Justification of selection criteria
The entry criteria defined for the study ensure selection of fertile women who are willing to 
continue with Mirena as their method of contraception.  Entry criteria are chosen to ensure 
that subjects with specific risks related to the use of the study drug and/or subjects with 
conditions which may have an effect on the study endpoints are excluded.


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6.4
Withdrawal of subjects from study
6.4.1
Withdrawal
Withdrawal criteria
This section was changed in Amendment 1, see Section 15.1.1.4 and 15.1.1.13.
Subjects must be withdrawn from the study if any of the following occurs:

At their own request. At any time during the study and without giving reasons, a 
subject may decline to participate further.  The subject will not suffer any 
disadvantage as a result.

Complete or partial expulsion of the Mirena

Removal of Mirena outside the study procedures

Pregnancy

Partial or total perforation of the uterus or cervix by Mirena

Acute pelvic inflammatory disease (PID) not responding to treatment

Genital malignancy (e.g., uterine or cervical malignancy)

Severe arterial disease such as stroke or myocardial infarction (MI)

Liver tumor (benign or malignant)

Allergic reaction to the study medication or any of its components

If, in the investigator’s opinion, continuation of the study would be harmful to the 
subject’s well-being

Should the subject, during the course of the study, develop conditions which would 
have prevented her entry into the study according to the exclusion criteria, she must 
be withdrawn immediately if safety is concerned. In other cases, the investigator will 
decide if there is a conflict with study objectives.

Participation in any other clinical study during the duration of this study
Subjects may be withdrawn from the study if any of the following occurs:

Coagulopathy or use of anticoagulant

Migraine, focal migraine with asymmetrical visual loss or other symptoms indicating 
transient cerebral ischemia

Exceptionally severe headache

Marked increase of blood pressure

Jaundice

Non-attendance of visits despite the efforts to reach the subject (i.e. if a subject does 
not attend consecutive visits without a major reason).


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o
Every effort must be made to have the subject attend these visits in-person. 
However, once all attempts have been exhausted to have the subject come to 
the study site, if the subject is unable to do so during the allotted timeframe,
the visit may be documented via phone.  In these instances, the site should 
determine the most appropriate means for excluding that a pregnancy has 
occurred (e.g. home pregnancy test kit, menstrual history, etc).  All methods 
and results regarding determination of pregnancy must be documented.

Serious adverse event, adverse event, laboratory abnormality of considerable clinical 
concern or considerable worsening of the subject's clinical symptoms

At the specific request of the sponsor and in liaison with the investigator (e.g. obvious 
non-compliance, safety concerns).

Return of heavy menstrual bleeding, if it affects the subject’s well-being, based on the 
investigator’s clinical judgment
The reasons for any withdrawal are to be fully documented on the eCRF.
End of treatment visit (Visit 8) and the end of study phone call (3 weeks after the Mirena 
removal) must be performed also for all subjects discontinuing the study prematurely. 
Depending on the time point of withdrawal, a withdrawn subject is referred to as either 
“screening failure” or “dropout” as specified below:
Screening failure
A subject who, for any reason (e.g. failure to satisfy the entry criteria), terminates the study 
before the time point used for the definition of “dropout” (i.e. before completion of the 
baseline visit, Visit 2) is regarded a “screening failure”.  
Re-starting the defined set of screening procedures to enable the “screening failure” subject’s 
participation at a later time point is not allowed – with the following exceptions:

Initial screening occurred too early, i.e. before 4 years and 6 months of the Mirena use

The in- / exclusion criteria preventing the subject’s initial attempt to participate have 
been changed (via protocol amendment).
In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the subject to an unjustifiable health risk.  Also, for re-screening, the subject has to re-
sign the informed consent form, even if it was not changed after the subject’s previous 
screening.
Dropout
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has already been deemed eligible to participate and completed the
baseline visit (visit 2).


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General procedures
In all cases, the reason for withdrawal must be recorded in the eCRF and in the subject's 
medical records. 
The subject may object to the generation and processing of post-withdrawal data as specified 
in Section 13.4.
Any subject removed from the trial will remain under medical supervision until discharge or 
transfer is medically acceptable.
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12.
6.4.2
Replacement
Subjects who have completed the baseline visit (visit 2) and thereafter terminate their study 
participation prematurely will not be replaced.
6.5
Subject identification
The subject identification (SID) number is a 9-digit number consisting of:
Digits 1 to 5 = Unique center number
Digits 6 to 9 = Current subject number within the center
Once allocated, the SID number will identify the subject throughout the study.
If subject is re-screened, she will receive a new SID.
7.
Treatments
7.1
Treatments to be administered
No study drug (Mirena) will be provided by the sponsor.  Subjects enter this study treatment 
period wearing a Mirena that was inserted 5 years earlier and will continue its use for an 
additional 3 years, i.e. up to a total of 8 years.  Subjects are required to provide 
documentation about the prescription for the Mirena (including indication) and the date of 
insertion.
Test drug is Mirena, an LNG intrauterine delivery system (IUS) with an initial in vitro release 
rate of 20 µg LNG per day, used continuously. The total LNG content in Mirena is 52 mg.
7.2
Identity of study treatment
See Section 7.1.
7.3
Treatment assignment
Not applicable, this is a single group study. A subject enters the study with a Mirena in the 
uterus.


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7.4
Dosage and administration
The initial in vitro release rate is 20 µg LNG per day. The total LNG content in Mirena is 
52 mg.  Mirena has been inserted into the uterine cavity before the study, and will remain in 
place for up to a total of 8 years.
7.4.1
Removal of Mirena
Timing of removal

Mirena should not remain in the uterus after 8 years.

If pregnancy is not desired, the removal should be carried out during menstruation, 
provided the woman is still experiencing regular menses. If removal will occur at 
other times during the cycle, start a new contraceptive method a week prior to 
removal. If removal occurs at other times during the cycle and the woman has had 
intercourse in the week prior to removal, she is at risk of pregnancy. See also section 
8.2.
7.5
Blinding
Not applicable
7.6
Drug logistics and accountability
Return of the study drug must be properly documented according to the sponsor’s agreed and 
specified procedures. Written instructions will be made available to all affected parties.
Return of the Mirenas to the sponsor’s representative
If a subject discontinues her study participation prematurely or completes the 8 years of use, 
the Mirena should be removed by gently pulling the removal thread(s) with forceps.
After removal (or if the subject returns an expelled Mirena to the study site) the Mirena is to 
be rinsed in cold water, dried carefully with a clean paper towel and packaged in a plastic 
pouch provided by the sponsor; the pouch label needs to be completed. 
The used Mirena should be stored according to the pouch label text, in the provided pouches 
in locked storage facilities until returned to sponsor’s representative.
If performing drug accountability implies a potential risk of contamination, a safety process/ 
guidance for handling returned drug will be provided.
In the event of Product Technical Complaint (e.g. technical difficulties with the IUS during 
removal, pregnancy, expulsion), the respective forms need to be completed and returned with 
the Mirena in question to sponsor´s representative for further investigation according to 
sponsor´s instructions.
7.7
Treatment compliance
Please refer to section 9.6.3.8.


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8.
Non-study therapy
8.1
Concomitant therapy
For the use of concomitant medications please refer to Section 6.2 (Exclusion criterion #14). 
All medications taken during the study (i.e. starting with the date of informed consent) will 
be recorded in the eCRF using the trade name, indication, dose, unit, frequency, route of 
administration and dates of intake (i.e. start and stop dates).
8.2
Post-study therapy
The study subject should be informed that there will be a loss of contraceptive protection 
after the end of the study treatment, i.e. after removal of the Mirena.
The investigator will counsel the subject about the contraceptive options available after the 
study treatment (at Visit 7, or before end of the study).
If pregnancy is not desired and if a woman wishes to continue using Mirena, a new system 
can be inserted immediately after removal any time during the cycle.
If a subject with regular cycles wants to start a different birth control method, time removal 
and initiation of new method to ensure continuous contraception. Either remove Mirena 
during the first 7 days of the menstrual cycle and start the new method immediately thereafter 
or consider starting the new method at least 7 days prior to removing Mirena if removal is to 
occur at other times during the cycle. If removal occurs at other times during the cycle and 
the woman has had intercourse in the week prior to removal, she is at risk of pregnancy.
If a subject with irregular cycles or amenorrhea wants to start a different birth control 
method, consider starting the new method at least 7 days before removal.
Post-study birth control counseling will be done according to standard of practice, without the 
sponsor’s involvement.
9.
Procedures and variables
9.1
Tabular schedule of evaluations
This section was changed in Amendment 1, see Sections 15.1.1.1, 15.1.1.16, 15.1.1.24 and 
15.1.1.25.
Table 9–1 presents the schedule of activities and evaluations for the study.  The additional 
activities for the subjects in the HMB subgroup are displayed in Table 9–2.


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Table 9–1
Schedule of activities and evaluations – amended
Period
Screening
(0 to 6 mo)
Treatment Period 
(3 years; Mirena years 6 thru 8)
Pregnancy Follow-up 
(up to 12 mo)
Visit
Prescreening 
contact 
(optional)
Screening 
Baseline
EOTa
EOS
All 
subjects
3-mo 
contact
b
12-mo 
contact
c
Visit number
/
1
2
3
4
5
6
7
8



Timing
within 
60 days
Day 1
6 mo
±14 d
12 mo
±14 d
18 mo
±14 d
24 mo
±14 d
30 mo
±14 d
36 mo
-14 d
3 wks 
after 
EOT
-3 d
3 mo 
after 
EOT
-7 d/+14 
d
12 mo 
after 
EOT
+7 d
Duration of Mirena use
4 y 6 mo 
to 5 
years
5 yearsd
6 years
7 years
8 years
Informative discussion about the study/ 
Distribution of subject information
X
X
Informed consent
X
Indication for Mirena and date of insertion
X
In-/exclusion criteria
X
X
Demography
X
Age at baseline
X
Substance use - Tobacco
X
Alcohol consumption
X
Reproductive and menstrual history
X
Medical history 
X
Physical examination
X
X
X
X
Vital signs, body weight
X+height
X
X
X
Gynecological exam. incl. breast palpation
X
X
X
X
Checking of Mirena threads 
X
X
X
X
X
X
X
X
Cervical smear e
X
X
Chlamydia test f
X


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Table 9–1
Schedule of activities and evaluations – amended
Period
Screening
(0 to 6 mo)
Treatment Period 
(3 years; Mirena years 6 thru 8)
Pregnancy Follow-up 
(up to 12 mo)
Visit
Prescreening 
contact 
(optional)
Screening 
Baseline
EOTa
EOS
All 
subjects
3-mo 
contact
b
12-mo 
contact
c
Visit number
/
1
2
3
4
5
6
7
8



Timing
within 
60 days
Day 1
6 mo
±14 d
12 mo
±14 d
18 mo
±14 d
24 mo
±14 d
30 mo
±14 d
36 mo
-14 d
3 wks 
after 
EOT
-3 d
3 mo 
after 
EOT
-7 d/+14 
d
12 mo 
after 
EOT
+7 d
Duration of Mirena use
4 y 6 mo 
to 5 
years
5 yearsd
6 years
7 years
8 years
Urine pregnancy test g
X
X
X
X
X
X
X
X
X g
Safety laboratory and urinalysis
X
X
X
X
FSH
X
Blood sample for PK h
X
X i
X i
X i
X i
X
Concomitant medications
X
X
X
X
X
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
Continuing need for contraception
X
X
X
X
X
X
Dispense home pregnancy test kits
X
X
X
X
X
X
X
eDiary dispensed / collected
X
X
Back-up contraception (if used; eDiary)







Record uterine bleeding (daily, eDiary)







Review of bleeding diary with subject
X
X
X
X
X
X
Subject satisfaction with Mirena
X
X
X
X
Mirena removal
X
Mirena removal: ease and pain 
assessment
X


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Table 9–1
Schedule of activities and evaluations – amended
Period
Screening
(0 to 6 mo)
Treatment Period 
(3 years; Mirena years 6 thru 8)
Pregnancy Follow-up 
(up to 12 mo)
Visit
Prescreening 
contact 
(optional)
Screening 
Baseline
EOTa
EOS
All 
subjects
3-mo 
contact
b
12-mo 
contact
c
Visit number
/
1
2
3
4
5
6
7
8



Timing
within 
60 days
Day 1
6 mo
±14 d
12 mo
±14 d
18 mo
±14 d
24 mo
±14 d
30 mo
±14 d
36 mo
-14 d
3 wks 
after 
EOT
-3 d
3 mo 
after 
EOT
-7 d/+14 
d
12 mo 
after 
EOT
+7 d
Duration of Mirena use
4 y 6 mo 
to 5 
years
5 yearsd
6 years
7 years
8 years
Documentation of pregnancy/return to 
fertility
X
X
X
Please see next page for footnotes


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Footnote Explanations:
a
An End-of-Treatment Visit must be performed also for all subjects who discontinue treatment.  If a subject prematurely discontinues treatment, all efforts 
should be made to perform all the assessments scheduled for this EOT visit (Visit 8) including the EOS phone contact 3 weeks after the removal of Mirena 
before the subject is withdrawn from the study.
b
For subjects who prematurely discontinued study treatment unless the reason for discontinuation is “pregnancy”, “death”, or “withdrawal by subject” where 
the subject has withdrawn main consent during study conduct and wishes to stop future contact with the site. Subjects that had withdrawn consent during 
study, but consented to post study participation follow-up will be contacted at this point. See also Section 9.4.1.
c
Subjects that prematurely discontinued treatment due to ‘Wish for pregnancy’ will be contacted. If a subject was not pregnant at 3 month contact and no 
longer wished to become pregnant, a 12-month contact is not required. If a subject was “Lost to Follow-up” at 3 month contact, a 12-month contact is 
required. See also Section 9.4.1.
d
The baseline visit (Visit 2) should take place 14 to 0 days before the end of Year 5 of Mirena use.
e
A cervical smear should be taken at the Screening Visit or a documented normal result must have been obtained not more than 6 months before screening.  
Subjects with ASCUS can be included if they have an HPV DNA test that, according to the standards of the central or local laboratory, is negative for high-
risk HPV strains. A single repeat test is permissible if the screening results are abnormal.
f
If Chlamydia test is positive, also test for gonorrhea.  A single repeat test is permissible if the screening results are positive 
g
In addition to the urine pregnancy tests performed by the site at each study visit, subjects will be given home urine pregnancy tests to be used whenever a 
pregnancy is suspected.  Subjects must contact the study site immediately if a pregnancy test is positive.  Home pregnancy test is to be done on the day of 
the 3-week contact.
h
PK sampling: All subjects: one sample to be taken at baseline and at EOT (or if subject prematurely discontinues prior to removal) per subject; and two 
randomized samples to be taken at two of the visits 3 – 6.
i
PK sampling for subjects randomized to this visit.
d=day, EOS=end of study, EOT=end of treatment, mo=month, PK=pharmacokinetics, wks=weeks, y=year


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Subjects in the HMB subgroup (i.e. all women who had the Mirena inserted for contraception 
and heavy menstrual bleeding) will collect their used sanitary products (provided by sponsor) 
during 4 periods of 30 days as shown in Table 9–2.  All used sanitary products have to be 
returned to the study site as instructed in Section 9.4.2 and displayed in Table 9–2.
For subjects who have the Mirena inserted for contraception only: if bleeding irregularities 
develop during prolonged treatment, appropriate diagnostic measures should be taken by the 
investigator to rule out endometrial pathology.
Table 9–2
Schedule of activities needed for the MBL evaluations – amended
HMB subgroup only – additional activities for baseline (BL) visit and treatment period. For all other 
activities and evaluations, see Table 9–1.
Period
Screening
Treatment Period (Mirena years 6 thru 8)
Collection 
time
30 days after 
baseline 
visit,
Study Days 
2 to 31 
(inclusive)
Study Days 
322 to 351 
(inclusive)
before Visit 4
Study Days 
687 to 716 
(inclusive)
before Visit 6
Study Days 
1052 to 1081 
(inclusive)
before EOT 
visit
Visit / visit 
number
Baseline (BL)
Visit 2
Return
Return
Visit 3
Return 
Visit 4
Visit 5
Return
Visit 6
Visit 7
Return
EOT
Visit 8
Dispense 
alkaline 
hematin kit 
X
X
X
X
Collection of 
used sanitary 
products








Return of 
used sanitary 
productsa
X
X
X
X
X
X
X
X
Study Day 1 = Day of the baseline visit (Visit 2)
a
Used sanitary products should not be kept at home longer than 14 days. Return required only if 
sanitary products have been used in the time periods indicated.


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9.2
Visit description
General information
Timing of the visits
If not stated otherwise, the measures listed in the following sections will be performed by or 
under the supervision of a study site investigator.
There will be 8 scheduled study visits: screening visit (Visit 1), baseline visit (Visit 2), 5 visits 
during the treatment phase (Visit 3 to 7) and the end-of-treatment visit (EOT, Visit 8).  The 
end-of-study visit (EOS) is a phone contact at 3 weeks after the EOT (all subjects).  
In addition, there will be up to 2 follow-up contacts for post-treatment pregnancy tracking.
3-month follow-up contact is for subjects who prematurely discontinued study treatment 
unless the reason for discontinuation is “pregnancy”, “death”, or “withdrawal by subject” 
where the subject has withdrawn main consent during study conduct and wishes to stop future 
contact with the site. For subjects that had withdrawn consent during study, but consented to 
post study participation follow-up, will be contacted.  If subjects could not be contacted at 3 
months, they will be considered “Lost to Follow-up” for post-study pregnancy tracking.  
12-month contact is for subjects that prematurely discontinued treatment due to ‘Wish for 
pregnancy’. If a subject was not pregnant at 3-month contact but subject no longer wished to 
become pregnant, a 12-month contact is not required.  If subject was “Lost to Follow-up” at 3 
months, a 12-month contact is required.  For details, see Section 9.4.1.2.
The screening period can start when the subject has had the Mirena in place for 4 years and 
6 months.  Screening period is up to 6 months.  Screening activities should be completed 
within 60 days after signing the informed consent. The baseline visit (Visit 2) should take 
place 14 to 0 days before the end of Year 5 of Mirena use.
The timing of the visits is based on the date of the baseline visit.  Treatment period starts at 
the baseline visit (Visit 2, defined as Study Day 1).
The following visit windows are allowed:

Visits 3 to 7 (during treatment) should be performed ±2 weeks of the scheduled day.

Visit 8 (EOT) should be performed at the earliest 2 weeks before the scheduled day 
and not later.

Follow-up contact (EOS) should take place 3 weeks after the EOT (-3 day window 
allowed.
Unscheduled visits
If deemed necessary for an individual subject, the investigator, at his/her discretion, may 
arrange visits in addition to the scheduled study visits.  Possible reasons for unscheduled 
visits include suspicion of pregnancy and a safety concern.
Informed consent
Before any screening examination takes place, potentially eligible subjects will be given a full 
explanation about what the participation in the study would involve. This will be done both 
verbally and in writing by handing out the subject information sheet and informed consent 


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form by investigator or designee. Subjects will be given sufficient time to consider their 
participation in the study and to ask any questions about the study. Subjects willing to take 
part in the study will then be asked to sign and date the informed consent form (see Section 
13.4). 
Screening examinations will only be performed after the site staff has received the subject’s 
signed and dated informed consent form.
9.2.1
Optional pre-screening contact
Before the screening visit (Visit 1), an optional pre-screening contact can be arranged and will 
typically occur via telephone or as a response to an advertisement. During this contact, the 
study candidate may be interviewed for suitability to participate in the study consistent with 
the entry criteria of the study. The pre-screening contact may be performed by the 
investigator, study nurse, or other member of the study staff specifically trained for this task.
After the pre-screening telephone discussion, the subject information form and the informed 
consent form may be sent to the subject for further information. Regardless of whether the 
subject information form is sent to the subject, the details of the study must be thoroughly 
discussed and reviewed with the subject at the screening visit (Visit 1) before obtaining the 
signed informed consent form.
9.2.2
Screening – Visit 1
At the Screening Visit (Visit 1), the following procedures and assessments will be done:

Informative discussion about the study; distribution of subject information form.  
Note: This must occur at the Screening Visit even if the subject information form
was sent to the subject following a pre-screening contact.

Obtain signed and dated ICF (Section 13.4); allocate the unique SID number (Section 
6.5)

Record the prescribed indication for Mirena and the date of Mirena insertion
(documentation required, see also Section 7.1)

Check of inclusion/exclusion criteria (Sections 6.1 and 6.2)

Interview for the following:

Demographics, alcohol consumption, and smoking habits (Section 9.3.1)

Medical history (Section 9.3.2)

Reproductive and menstrual history (Section 9.3.3)

Concomitant medications (Section 8.1)

AEs (Section 9.6.1.  The recording period of AEs begins at the signing of 
the ICF)

Perform urine pregnancy test (Section 9.6.3.4)

Assess vital signs and weight (including height; Section 9.6.3.1)

Perform general physical examination (Section 9.6.3.2)

Perform gynecological examination (with breast palpation; Section 9.6.3.3)


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
Perform pelvic examination to visualize Mirena removal threads (Section 9.6.3.8)

Perform safety laboratory tests (including FSH) and urinalysis (Section 9.6.3.7)

Test for Chlamydia; if positive, also test for gonorrhea (Section 9.6.3.6).  A single 
repeat test is permissible if the screening results are positive.

Obtain cervical smear (Section 9.6.3.5).  A cervical smear should be taken at this visit 
or a documented normal result (using the Bethesda system or a corresponding system) 
has to have been obtained within 6 months before the Screening Visit (Visit 1). 
Subjects with ASCUS can be included if they have a HPV DNA test that, according to 
the standards of the local laboratory, is negative for high-risk HPV.  A cervical smear 
may be repeated once if the screening result is abnormal.
9.2.3
Baseline – Visit 2
This section was changed in Amendment 1, see Section 15.1.1.25.
The following procedures and assessments will be done:

Re-check inclusion/exclusion criteria (Sections 6.1 and 6.2)

Age at baseline (Section 9.3.1)

Perform pelvic examination to visualize Mirena removal threads (Section 9.6.3.8)

Perform urine pregnancy test (Section 9.6.3.4)

Blood sample for PK (all subjects) (Section 9.5.1)

Subject satisfaction with Mirena (Section 9.7.4)

Interview for the following:

Concomitant medications (Section 8.1)

AEs (Section 9.6.1)

Dispense and explain the subject’s daily eDiary device (Section 9.7.1), remind the 
subject to start the eDiary at the day of the visit (i.e. recording of uterine bleeding and 
back-up contraception)

Dispense home pregnancy kits with instructions (Section 9.6.3.4)

Dispense alkaline hematin kit with instructions for subjects in HMB group
9.2.4
6-month visit – Visit 3
The following procedures and assessments will be done:

Perform pelvic examination to visualize Mirena removal threads (Section 9.6.3.8)

Perform urine pregnancy test (Section 9.6.3.4)

Blood sample for PK (Note: subjects randomized to this visit) (Section 9.5.1)

Interview for the following:

Concomitant medications (Section 8.1)

AEs (Section 9.6.1)

Continuing need for contraception (Section 9.7.1)


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
Dispense home pregnancy kits with instructions (Section 9.6.3.4)

Review completed (monthly) eDiary, including information on uterine bleeding and 
back-up contraception.

Dispense alkaline hematin kit with instructions for subjects in HMB group
9.2.5
12-month visit – Visit 4 (End of Year 6 of Mirena use)
This section was changed in Amendment 1, see Section 15.1.1.1.
The following procedures and assessments will be done:

Assess vital signs and weight (Section 9.6.3.1)

Perform general physical examination (Section 9.6.3.2)

Perform gynecological examination (with breast palpation; Section 9.6.3.3)

Perform pelvic examination to visualize Mirena removal threads (Section 9.6.3.8)

Perform urine pregnancy test (Section 9.6.3.4)

Perform safety laboratory test and urinalysis (Section 9.6.3.7)

Blood sample for PK (Note: subjects randomized to this visit) (Section 9.5.1)

Interview for the following:

Concomitant medications (Section 8.1)

AEs (Section 9.6.1)

Continuing need for contraception (Section 9.7.1)

Dispense home pregnancy kits with instructions (Section 9.6.3.4)

Review completed (monthly) eDiary, including information on uterine bleeding and 
back-up contraception.

Subject satisfaction with Mirena (Section 9.7.4).
9.2.6
18-month visit – Visit 5
The following procedures and assessments will be done:

Perform pelvic examination to visualize Mirena removal threads (Section 9.6.3.8)

Perform urine pregnancy test (Section 9.6.3.4)

Blood sample for PK (Note: subjects randomized to this visit) (Section 9.5.1)

Interview for the following:

Concomitant medications (Section 8.1)

AEs (Section 9.6.1)

Continuing need for contraception (Section 9.7.1)

Dispense home pregnancy kits with instructions (Section 9.6.3.4)

Review completed (monthly) eDiary, including information on uterine bleeding and 
back-up contraception.

Dispense alkaline hematin kit with instructions for subjects in HMB group


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9.2.7
24 –month visit – Visit 6 (End of Year 7 of Mirena use)
The following procedures and assessments will be done:

Assess vital signs and weight (Section 9.6.3.1)

Perform general physical examination (Section 9.6.3.2)

Perform gynecological examination (with breast palpation; Section 9.6.3.3)

Perform pelvic examination to visualize Mirena removal threads (Section 9.6.3.8)

Perform urine pregnancy test (Section 9.6.3.4)

Perform safety laboratory test and urinalysis (Section 9.6.3.7)

Blood sample for PK (Note: subjects randomized to this visit) (Section 9.5.1)

Interview for the following:

Concomitant medications (Section 8.1)

AEs (Section 9.6.1)

Continuing need for contraception (Section 9.7.1)

Dispense home pregnancy kits with instructions (Section 9.6.3.4)

Review completed (monthly) eDiary, including information on uterine bleeding and 
back-up contraception

Subject satisfaction with Mirena (Section 9.7.4).
9.2.8
30-month visit – Visit 7
This section was changed in Amendment 1, see Section 15.1.1.21.
The following procedures and assessments will be done:

Perform pelvic examination to visualize Mirena removal threads (Section 9.6.3.8)

Perform urine pregnancy test (Section 9.6.3.4)

Interview for the following:

Concomitant medications (Section 8.1)

AEs (Section 9.6.1)

Continuing need for contraception (Section 9.7.1)

Dispense home pregnancy kits with instructions (Section 9.6.3.4)

Review completed (monthly) eDiary, including information on uterine bleeding and 
back-up contraception.

Dispense alkaline hematin kit with instructions for subjects in HMB group.
Discuss the contraceptive options available after the study treatment with the subject (see 
Section 8.2).


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9.2.9
36-month visit, EOT – Visit 8 (End of Year 8 of Mirena use)
This section was changed in Amendment 1, see Section 15.1.1.17.
The following procedures and assessments will be done:

Assess vital signs and weight (Section 9.6.3.1)

Perform general physical examination (Section 9.6.3.2)

Perform gynecological examination (with breast palpation; Section 9.6.3.3)

Perform pelvic examination to visualize Mirena removal threads (Section 9.6.3.8)

Obtain cervical smear (Section 9.6.3.5)

Perform urine pregnancy test (Section 9.6.3.4)

Perform safety laboratory test and urinalysis (Section 9.6.3.7)

Blood sample for PK (all subjects) (Section 9.5.1)

Interview for the following:

Concomitant medications (Section 8.1)

AEs (Section 9.6.1)

Continuing need for contraception (Section 9.7.1)

Dispense home pregnancy kits with instructions (Section 9.6.3.4)

Review completed (monthly) eDiary, including information on uterine bleeding and 
back-up contraception.

Collect eDiary device (Section 9.7.1)

Subject satisfaction with Mirena (Section 9.7.4)

Remove the Mirena (Section 9.7.3)

Complete Mirena removal ease (investigator) and pain (subject) assessment
9.2.10
3-week follow-up call (EOS)
All subjects will be contacted 3 weeks after EOT (i.e. after Mirena removal) to collect 
information on any pregnancy detected shortly after the end of study treatment, see Section 
9.4.1.
9.2.11
3-month follow-up contact for post-study pregnancies
This section was changed in Amendment 1, see Section 15.1.1.6.
Subjects who prematurely discontinued study treatment will be contacted by phone unless the 
reason for discontinuation is “pregnancy”, “death”, or “withdrawal by subject” where the 
subject has withdrawn main consent during study conduct and wishes to stop future contact 
with the site. For subjects that had withdrawn consent during study, but consented to post 
study participation follow-up, post treatment pregnancy tracking information is expected.  At 
this time, subjects will be asked if they have been pregnant after the study (i.e. after the 3-
week follow-up call). This contact is part of the Post-Treatment Pregnancy Tracking (PTPT) 
process, see Section 9.4.1.


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9.2.12
12-month follow-up contact for return-to-fertility
This section was changed in Amendment 1, see Section 15.1.1.6.
Subjects that prematurely discontinued treatment due to ‘Wish for pregnancy’ will be 
contacted and asked about pregnancies that occurred within 12 months after end of treatment 
(EOT, i.e. removal of Mirena). If a subject was not pregnant at 3 month contact and no longer 
wished to become pregnant, a 12-month contact is not required.  If subject was “Lost to 
Follow-up” at 3 months, a 12-month contact is required. This contact is part of the Post-
Treatment Pregnancy Tracking (PTPT) process, see Section 9.4.1.
9.3
Population characteristics
9.3.1
Demographic
This section was changed in Amendment 1, see Section 15.1.1.25.
Demographic data [e.g. year of birth, age at the screening (Visit 1), age at baseline (Visit 2),
race, ethnic group, educational level] and other population characteristics including tobacco 
use and alcohol consumption will be collected at time points presented in Table 9–1.
9.3.2
Medical history
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the investigator:

Start before signing of the informed consent 

Considered relevant for the subject’s study eligibility

Any condition that is being stabilized by medication at the time of signing the 
informed consent form should also be documented in the eCRF.  The medication 
being used should be recorded in the concomitant medication eCRF.
All new or worsened findings after signing the informed consent should be documented on 
the Adverse Event eCRF.
Detailed instructions on the differentiation between (i) medical history and (ii) adverse events 
can be found in Section 9.6.1.1.
9.3.3
Reproductive and menstrual history
The reproductive and menstrual history includes information on menarche, number of births
and pregnancies, number of ectopic pregnancies, absence of menstrual/withdrawal bleeding, 
intracyclic bleeding and on the average length of the cycle.
9.3.4
Other baseline characteristics
9.3.4.1
Indication for current Mirena
The subject must provide written documentation from the prescribing physician on the 
indication for which the current Mirena was prescribed (contraception or contraception and 
heavy menstrual bleeding).  The indication is recorded in the eCRF.  In addition, subject must 
provide documentation of the date of Mirena insertion.


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9.4
Efficacy
This section details the procedures for collecting data on efficacy variables.  A concise listing 
of efficacy variables is given in Section 10.3.1.1. The complete list of variables to be analyzed 
for this study will be provided in the statistical analysis plan.
9.4.1
Occurrence of pregnancies
The occurrence of a pregnancy (yes/no) is the primary efficacy variable in this study.
The sponsor will closely monitor the occurrence of pregnancies (based on the expedited 
reporting of pregnancies by the investigators) throughout the study.  
9.4.1.1
Pregnancies during the study
This section was changed in Amendment 1, see Section 15.1.1.6.
If a pregnancy is detected anytime during the study, the subject is to discontinue her 
participation in the study.  
The investigator must report to the sponsor any pregnancy occurring in a study subject during 
her participation in this study including pregnancies detected at the contact 3 weeks after 
EOT.  This report is to be submitted within the same timeframe as an SAE (i.e. no later than 
24 hours of having gained knowledge of the event), although a pregnancy, per se, is not 
considered an AE/SAE. 
The subject will be instructed to contact the study site immediately if a pregnancy is suspected 
or detected.  In such a case, an unscheduled visit should be arranged for the subject as soon as 
possible and the investigator should confirm the pregnancy by a valid method (e.g. 
ultrasound, serum hCG test).  If such confirmation cannot be achieved within 24 hours of the 
subject contacting the study center, the investigator must still report the pregnancy to the 
sponsor and then follow-up with information once confirmation has been obtained.
A pregnancy will be reported on the forms provided.  The investigator is required to 
document, as far as possible, the estimated date of conception, calculated due date, the reason 
for pregnancy (e.g., Mirena failure), location of the pregnancy, and, if applicable, the location 
of the Mirena and information regarding whether the Mirena was removed during the 
pregnancy.  The investigator is required to provide any additional information (e.g. early 
termination) as soon as it becomes available.
All pregnancies occurring during the study (including those detected during the screening 
period) will be followed for the final outcome of the pregnancy for both the subject (mother) 
and fetus/child and documented on the forms provided.  Any abnormal outcome of the mother 
or the child should also be reported as an SAE (e.g., spontaneous abortion, pre-term birth, 
elective abortion triggered by medical concern).
9.4.1.2
Pregnancies occurring after the end of study treatment
This section was changed in Amendment 1, see Sections 15.1.1.5 and 15.1.1.6.
All pregnancies detected up to 3 months after the removal of the Mirena must be reported to 
the sponsor; all subjects will be instructed to contact the investigator immediately if they 


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become pregnant less than 3 months after the removal of the Mirena. If the estimated date of 
conception is suspected to have occurred during study treatment (i.e. up to 7 days after EOT),
further investigations will be conducted, and the pregnancy should be reported immediately 
and will be followed up according to the process described above for pregnancies during the 
study.
3-month follow-up contact:  In addition, subjects who prematurely discontinued study 
treatment will be contacted unless the reason for discontinuation is “pregnancy”, “death”, or 
“withdrawal by subject” where the subject has withdrawn main consent during study conduct 
and wishes to stop future contact with the site. For subjects that had withdrawn consent during 
study, but consented to post study participation follow-up, post-treatment pregnancy tracking 
information is expected and they will be contacted by phone at 3 months after the removal of 
the Mirena.  At this time, subjects will be asked if they have been pregnant after the study.  If 
subjects could not be contacted at 3 months, they will be considered “Lost to Follow-up” for 
post-study pregnancy tracking.
12-month follow-up contact:  Only subjects that prematurely discontinued treatment due to 
‘Wish for pregnancy’ will be contacted and asked about pregnancies that occur within 1 year 
after end of treatment (EOT). If a subject was not pregnant at 3 month contact and no longer 
wishes to become pregnant, a 12-month contact is not required.  If subject was “Lost to 
Follow-up” at 3 months, a 12-month contact is required.
PTPT information, i.e. data collected at the 3- and 12-month follow-up contacts, including 
information on all pregnancies identified, must be reported to the sponsor via electronic data 
collection tool (see Section 11.1).  In addition, if the estimated date of conception is suspected 
to have occurred during study treatment, the pregnancy should be reported immediately 
according to the process described under section 9.4.1.1.
9.4.2
Assessment of menstrual blood loss (MBL) by alkaline hematin method
For the subjects in the HMB subgroup, the MBL will be assessed 4 times during the study. 
The 30-day assessment periods are scheduled as the first 30 days of the treatment period 
(starting at baseline visit, Visit 2) and for the 30 days before visits 4, 6 and 8.  The subjects in 
this subgroup will be required to use the selected types of sanitary products (towels, tampons 
and panty liners) provided by the sponsor and to collect their used sanitary products during 
these 4 periods. Subjects will return the used products to the study site at two week intervals, 
and all used sanitary products will be sent to the central laboratory for analysis. Please see 
Table 9–2 for timing of the 4 periods and the required visits.
Details of the alkaline hematin method are given in the lab manual.
9.5
Pharmacokinetics / pharmacodynamics
9.5.1
Sample collection
Blood samples for the determination of LNG concentrations in plasma and sex hormone 
binding globulin (SHBG) concentrations in serum for population pharmacokinetic (popPK) 
analysis will be taken at several time points during the study according to the schedule 
presented in Table 9–1.  A blood sample is taken from all subjects at baseline (visit 2) and at 


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the EOT (visit 8; before Mirena is removed).  In addition, two blood samples per subjects will 
be taken during two of the treatment visits 3 – 6 as outlined in more detail below. 
In case a subject prematurely discontinues the study, a blood sample will be taken in addition,
even if the 2 randomized samples (visit 3 – 6) have already been taken at a previous visit. 
This sample will always be taken before Mirena is removed.  (If Mirena has been 
completely expelled, no sample is needed.)
In order to achieve an approximately equal distribution of blood samples over the whole 
treatment period, the time points at which the samples are taken from each subject will be 
randomized.  This means that the sampling time points for each subject will be allocated to 
two of the 4 treatment period visits (visits 3 – 6).  Subjects will be allocated to one of these 
sampling time points with the same probability, i.e., with the probability 1:4.  The allocation 
of subjects to sample time points for popPK will be done using a computer generated 
randomization list.  The time points at which the samples are to be taken from an individual 
subject can be found on the randomization list provided to the study site.
The pharmacokinetic calculation will be based on the actual sampling time and dosing times. 
Deviations from the specified time points will be documented and taken into account when 
calculating the PK parameters. 
Details to the collection, processing, storage and shipment of samples will be provided in a 
separate document (e.g. Sample Handling Sheets or Lab Manual).
9.5.2
Drug measurements
The bioanalytical analyses will be performed under the supervision of the function Drug 
Metabolism and Pharmacokinetics, Bayer AG.
Determination of LNG in plasma and SHBG in serum
The analyses of LNG concentrations in EDTA K2 plasma will be performed using a validated 
LC-MS/MS method. The determination of SHBG concentrations in serum samples will be 
performed using a validated immunoassay. Quality control (QC) and calibration samples will 
be analyzed concurrently with study samples.  The results of LNG and SHBG concentrations 
as well as the results of calibration samples and QC samples will be reported in the 
Bioanalytical Reports which will be included in the Clinical Study Report for this study.
Additionally, representative study samples may be used for further pharmacokinetic analyses, 
e.g. for a validation of a SHBG binding modeling compared to actual measurements.
9.5.3
Pharmacokinetic evaluation
Plasma LNG and SHBG concentration data collected during the study will be analyzed at the 
end of study by population PK analysis using nonlinear mixed effects models. Mixed effects 
models, or population type models, describe the relationship between e.g. dose, time and 
pharmacological observations such as plasma/serum drug concentrations. Both structural and 
random effects are involved in this relationship. An existing population PK model will be 
applied to the data and refined to characterize the PK of LNG over the entire treatment period 
(during years 6 to 8) using individual LNG serum (or plasma) concentrations, SHBG serum 
concentrations and residual content measurements of LNG in the IUS. Individual PK 


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parameters of total and unbound LNG and SHBG as well as in vivo release rates will be 
calculated. The details of the analysis will be described in a separate Modeling & Simulation 
(M&S) Analysis Plan and the results will be reported in a separate M&S Report.
9.5.4
Residual LNG content analysis
In order to evaluate the performance of Mirena during extended use, the residual content of 
LNG in used Mirena devices will be determined from all subjects at the end of treatment (i.e. 
from those who complete the 3 years in the study and from those who discontinue the study 
treatment prematurely).  All used Mirena devices are to be sent to the sponsor’s 
representative.
9.6
Safety
9.6.1
Adverse events
9.6.1.1
Definitions
Definition of adverse event (AE)
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject after providing written informed consent for participation in the 
study.  Therefore, an AE may or may not be temporally or causally associated with the use of 
a medicinal (investigational) product.
A surgical procedure that was planned prior to the start of the study by any physician treating 
the subject should not be recorded as an AE (however, the condition for which the surgery is 
required may be reported in the medical history or may be an AE, (see below).
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal e.g. physical examination findings, symptoms, diseases and laboratory
findings

Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical 
history (e.g. seasonal allergy without acute complaints).

Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g. allergic pollinosis).

Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events.  This includes intercurrent illnesses.


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Definition of serious adverse event (SAE)
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f):
a.
Results in death
b. Is life-threatening
The term ‘life-threatening’ in the definition refers to an event in which the subject was 
at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met:
- The admission results in a hospital stay of less than 12 hours
- The admission is pre-planned
(e.g. elective or scheduled surgery arranged prior to the start of the study; 
admission is part of the study procedures as described in Section 9.2)
- The admission is not associated with an AE 
(e.g. social hospitalization for purposes of respite care).
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
d. Results in persistent or significant disability / incapacity
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
e.
Is a congenital anomaly / birth defect
f.
Is another serious or important medical event as judged by the investigator
Important medical events and medical review
An AE may be considered serious because it may jeopardize the subject and may require 
intervention to prevent another serious condition.  As guidance for determination of important 
medical events, the List of Important Medical Events (IME) developed and published by 
European Medicines Agency (EMA) at 
(http://eudravigilance.ema.europa.eu/human/textforIME.asp) will be used in this study.  The 
list consists of terms that refer to or might be indicative of a serious disease state.  Such 
reported events warrant special attention because of their possible association with a serious 
disease state and may lead to more decisive action than reports on other terms.
All non-serious AEs reported in this study will be reviewed against the most current IME list 
periodically. Events that are contained on the IME list will be specifically reviewed by the 


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Study Medical Expert, and if necessary, may be queried. If needed, the Investigator will be 
asked to review and confirm whether or not the event meets the criteria for seriousness, in 
his/her opinion. In addition, the events listed in Section 9.6.3 will be medically reviewed. Any 
non-serious event that, upon further review, is deemed to meet the seriousness criteria (see 
SAE criteria specified below) will be reported within 24 hours of the determination that it is 
considered serious.
Further details of the medical review to be conducted during the study are provided in a 
separate document, the Medical Review Plan (MRP), which is to be finalized and signed prior 
to the First Patient First Visit (FPFV).
9.6.1.2 Classifications for adverse event assessment
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.  
9.6.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1.
9.6.1.2.2
Intensity
The intensity of an AE is classified according to the following categories:
-
Mild
-
Moderate
- Severe
9.6.1.2.3
Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment 
is a decision to be made by the investigator, who is a qualified physician, based on all 
information available at the time of the completion of the CRF.
Causality should be assessed separately for each study treatment as detailed in the CRF. If the 
investigator feels that the event cannot be firmly attributed to one of the study treatments 
(e.g. owing to a suspected underlying interaction), the same assessment will be documented 
for each study treatment.
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.
Possible answers are “yes” or “no”


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An assessment of “no” would include:
1. The existence of a highly likely alternative explanation, e.g. mechanical bleeding at 
surgical site.
or
2. Non-plausibility, e.g. the subject is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
developing a few days after the first drug administration.
An assessment of “yes” indicates that that the AE is reasonably associated with the use of the 
study treatment.
Important factors to be considered in assessing the relationship of the AE to study treatment 
include:
- The temporal sequence from drug administration:  The event should occur after the drug 
is given.  The length of time from drug exposure to event should be evaluated in the 
clinical context of the event.
- Recovery on drug discontinuation (de-challenge):  Subject’s response after de-challenge 
should be considered in view of the usual clinical course of the event in question.
- Underlying, concomitant, intercurrent diseases:  
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the subject may have.
- Concomitant medication or treatment: 
The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them might have caused the event in question.
- Known response pattern for this class of drug: Clinical/preclinical
- Exposure to physical and/or mental stresses: The exposure to stress might induce adverse 
changes in the recipient and provide a logical and better explanation for the event
- The pharmacology and pharmacokinetics of the study treatment: 
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) of 
the study treatment, coupled with the individual subject’s pharmacodynamics should be 
considered.
- The assessment is not possible
Causal relationship to protocol-required procedures
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s).
Possible answers are “yes” or “no”
9.6.1.2.4
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.


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- Drug withdrawn
- Dose not changed
- Not applicable
- Unknown
9.6.1.2.5
Other specific treatment(s) of adverse events
- None
- Remedial drug therapy
- Other
9.6.1.2.6
Outcome
The outcome of the AE is to be documented as follows: 
- Recovered/resolved
- Recovering/resolving
- Recovered/resolved with sequelae
- Not recovered/not resolved
- Fatal
- Unknown
9.6.1.3
Assessments and documentation of adverse events
The investigator has to record on the respective eCRF pages all adverse events occurring in 
the period between the signing of the informed consent and the end of study; after the end of 
the study there is no requirement to actively collect AEs including deaths.  The type of 
information that should be assessed and recorded by the investigator for each AE is listed in 
Section 9.6.1.2.  
“Death” should not be recorded as an AE on the AE page.  Instead, “death” is the outcome of 
underlying AE(s).
For all serious adverse events (SAEs) the sponsor has to carry out a separate assessment for 
expectedness, seriousness and causal relationship to study drug.
The following events should not be reported as AEs/SAEs, unless (i) they are specifically 
considered as such by the investigator, according to the following conditions, or (ii) they lead 
to withdrawal of a subject from the study.  This is to avoid redundancy and/or inconsistent 
reporting of AEs as these data may already be recorded in the CRF or subject’s eDiary.

Ovarian cysts:  An ovarian cyst should only be reported as an AE if it is felt to be 
non-physiologic (at the discretion of the investigator).  Ultrasound examinations will 
not be routinely scheduled as part of this study but may be performed by the 
investigator if thought to be necessary to evaluate symptoms of an ovarian cyst or 
other pelvic pathology.  If an ovarian cyst is diagnosed, follow-up should be in 
accordance with the investigator’s standard practice.


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
Findings on the bleeding diary:  Uterine bleeding (including intracyclic bleeding and 
absence of bleeding) should be recorded as an AE only if:

it leads to study discontinuation

it leads to therapeutic or diagnostic procedures

it is regarded as SAE

it shows a clinically significant worsening during the study that, in the 
judgment of the investigator, is not consistent with the expected clinical 
course, or are specifically reported as AEs by the subject.
9.6.1.4
Reporting of serious adverse events
The definition of serious adverse events (SAEs) is given in Section 9.6.1.1.  Each SAE must 
be followed up until resolution or stabilization by submission of updated reports to the 
designated recipient.
Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs.  This information, including all relevant contact 
details, is summarized in the investigator site file.  This information will be updated as 
needed.
The investigator must report immediately (within 24 hours of the investigator’s awareness) all 
SAEs occurring during the observation period defined in Section 9.6.1.3 to the recipient 
detailed in the instructions for SAE reporting included in the Investigator File.  For this, an 
AE page in the CRF as well as the complementary pages provided in the Investigator File 
must be completed for each SAE.  
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.
Notification of the IECs / IRBs
Notification of the IECs / IRBs about all relevant events (e.g. SAEs, suspected, unexpected, 
serious adverse reactions [SUSARs]) will be performed by the sponsor and/or by the 
investigator according to all applicable regulations.
Notification of the authorities
The processing and reporting of all relevant events (e.g. SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (e.g. SUSARs) 
according to all applicable regulations.


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9.6.1.5 Expected adverse events
For this study, the applicable reference document is the most current version of the 
investigator’s brochure (IB).
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB.  If relevant new safety information is identified, the information will 
be integrated into an update of the IB and distributed to all participating sites.
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.
9.6.2
Pregnancies
The occurrence of pregnancies is the primary efficacy variable in this study.  For further 
details, please refer to Section 9.4.1.
9.6.3
Further safety
9.6.3.1
Vital signs and weight
Vital signs and body weight will be measured according to the schedule presented in Table 9–
1.
Vital signs will include heart rate (for 1 minute, after 5 minutes in the sitting position) and 
systolic and diastolic blood pressure (after 5 minutes in the sitting position). 
In case of clinically relevant deviations in vital signs, the values are to be confirmed by 
repeated measurement before documentation.
The subject will be weighed on a scale, without shoes, and dressed with approximately 
similarly heavy clothes at each appropriate visit (see Table 9–1).
9.6.3.2
Physical examination
A general physical examination should be conducted in accordance with the investigator’s 
standard practice at the time points shown in Table 9–1.  
Any physical examination finding, symptom, or disease observed prior to signing the ICF 
should be recorded as medical history.  After signing the ICF, any deterioration or new 
physical examination finding, symptom, or disease should be recorded as an AE/SAE.
Abnormal physical examination findings are recorded either as medical history or as adverse 
events (see Section 9.6.1.1).
9.6.3.3
Gynecological examination
Gynecological examination will be performed at visits specified in Table 9–1.  During the 
gynecological examination, the investigator will examine the following: 

Breasts 

Vulva

Vagina

Cervix


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
Uterus

Ovaries
Any gynecological examination finding, symptom, or disease observed prior to signing of the 
ICF should be recorded as medical history.  After signing of the ICF, any deterioration or new 
gynecological examination finding, symptom, or disease should be recorded as an AE/SAE 
(see Section 9.6.1.1 and 9.6.1.3).
Please note that transvaginal ultrasound is not part of the gynecological examination, please 
see also Section 9.6.3.8.
9.6.3.4
Pregnancy test
A urine pregnancy test (urine hCG) will be performed at every visit as presented in Table 9–1.  
In case of a suspected pregnancy at screening or baseline visits, the subject must be 
withdrawn from the study and is considered a screening failure.  If a pregnancy occurs during 
the study treatment period (i.e. after the baseline visit), subjects should immediately contact 
the investigator for an unscheduled visit (for reporting of pregnancies, see also Section 9.4.1).  
During the course of the study, additional urine hCG testing should be performed if there is 
clinical suspicion of pregnancy at any time. 
In addition to the urine hCG tests performed by the site at each study visit, subjects will be 
provided with home urine pregnancy tests to be used whenever a pregnancy might be 
suspected.
If results of a home pregnancy test are positive or if a subject is unsure whether she is 
pregnant after performing the test, she should immediately contact the study site to schedule a 
visit and have a confirmatory test performed.
In the event of a positive urine hCG result, pregnancy should be confirmed according to the 
local standard of care (e.g., serum hCG testing).  
9.6.3.5
Cervical smear 
Cervical smear should be obtained following the standard practice of the study site at the 
screening visit (Visit 1) if there is no documented normal result available within the previous 
6 months. Samples will be sent to the central laboratory for analysis.  The cervical smear 
needs to be normal or clinically insignificant not requiring further follow up.  Any 
abnormality detected prior to signing the ICF should be recorded as medical history.  Subjects 
with ASCUS can be included in the study if they have an HPV DNA test that, according to 
the standards of the local laboratory, is negative for high-risk HPV.  Cervical smear may be 
repeated once during the screening period if screening results are abnormal.  After signing of 
the informed consent form, any deterioration or new abnormality should be recorded as an 
AE.


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9.6.3.6
Test for Chlamydia
This section was changed in Amendment 1, see Section 15.1.1.14.
The subject will be tested for Chlamydia at the screening visit.  Chlamydia tests must be 
performed using a highly accurate test method (e.g. the polymerase chain reaction [PCR] test, 
an example of nucleic acid amplification tests [NAAT]) in the central laboratory.
A single repeat test is permissible if the screening results are positive.  If the test result is 
positive, the subject must also be tested for gonorrhea.  Gonorrhea tests must also be 
performed using a highly accurate test method that meets the standards of GLP. A subject 
with an active genital infection may not be assigned to study treatment until the infection has 
been successfully treated (see Section 6.2, Exclusion criterion 4).  
During the study, if a subject is found to have cervicovaginitis but not pelvic inflammatory 
disease, she should be treated keeping Mirena in situ and according to local medical 
standards.
9.6.3.7
Safety laboratory tests
This section was changed in Amendment 1, see Section 15.1.1.3.
Only blood samples analyzed at the central laboratory will be considered for analysis.  The 
name and address for the central lab service provider can be found in the documentation 
supplied by the vendor.  For a given laboratory parameter, the acceptable values for inclusion 
would consist of values within the reference ranges, measured at baseline, as provided in the 
Covance Central Laboratory Services (CCLS) Manual for Bayer Protocol 18649 (Covance 
Project #: 518179). The safety laboratory tests may be repeated once during the screening 
period if laboratory values are outside the inclusion range and assessed as clinically relevant.
The basic safety laboratory includes:
Hematology:  leukocytes, erythrocytes, hemoglobin, hematocrit, mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), platelets, neutrophils, eosinophils, basophils, 
lymphocytes, monocytes, glycosylated hemoglobin (HbA1c)
Serum chemistry:  creatinine, chloride, potassium, sodium, calcium, total protein, albumin, 
total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) 
cholesterol, triglycerides, alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma-glutamyl transpeptidase, alkaline phosphatase, and total bilirubin.
Follicle-stimulating hormone (FSH) (only at screening)
Urinalysis includes pH, urobilinogen, blood/hemoglobin, total protein, ketone, bilirubin, 
nitrite, glucose, and leukocytes.
Repeat sampling and testing is permitted in the event the sample quality is deemed poor or 
inadequate.
In the event of implausible results, the laboratory may measure additional parameters to 
assess the quality of the sample (e.g. clotted or hemolyzed) and to verify the results.  The 
results from such additional analyses may neither be included in the clinical database of this 


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study nor evaluated further.  If the results are relevant, the investigator will be informed to 
determine follow-up activities outside of this protocol.
9.6.3.8
Presence of Mirena removal threads
This section was changed in Amendment 1, see Section 15.1.1.22.
The presence of the removal threads will be checked at each study visit and recorded in the 
eCRF.
The investigator will perform pelvic examinations at each study visit to verify the presence of 
the Mirena removal threads in the appropriate location in the cervical os. If the presence of the 
removal threads cannot be verified, transvaginal ultrasound (TVUS) is to be performed to 
verify that the Mirena is in the appropriate intrauterine location and to exclude expulsion or 
perforation.  The subject should be instructed to periodically check the threads by feeling for 
the threads at the top of the vaginal canal and if, at any time of the study, a subject suspects 
that the Mirena may have been expelled, she should contact the investigator and the 
investigator should assess the need for an unscheduled visit to evaluate the location of the 
Mirena.  The subject should be instructed to use non-hormonal back-up method of 
contraception until it is confirmed that the Mirena is in the proper location.
Subject is in compliance with Mirena when:

Threads are visible, or,

Threads are not visible (or not checked) but TVUS performed to localize the Mirena
shows Mirena to be “In situ” or “Displaced intrauterine”.
Subject is non-compliant with Mirena when:

Threads are not visible, and,

TVUS performed to localize Mirena shows that the IUS is “Partially or totally 
expelled into vagina or cervical canal”, “Cervical perforation”, “Myometrial 
perforation”, “Localization in the peritoneal cavity”, or “Absent”.

Threads are visible, but TVUS is performed for other reason(s) and Mirena
localization is recorded as “Partially or totally expelled into vagina or cervical canal”, 
“Cervical perforation”, “Myometrial perforation”, “Localization in the peritoneal 
cavity”.
Non-compliance with Mirena necessitates discontinuation of the subject from the study.  In 
case the IUS is partially expelled, it needs to be removed.  In case perforation has occurred, 
the IUS needs to be removed using appropriate procedures.
9.6.3.9
Expulsion of Mirena
Total or partial expulsion of the Mirena will be reported as an AE or SAE, as appropriate
(i.e. meets the criteria for an SAE as specified in Section 9.6.1.1).
Total expulsion is confirmed if Mirena is observed in the vagina, it is not shown in the uterine 
cavity by ultrasound, and/or the subject confirms that the system was expelled.  If, upon 
pelvic examination, the removal thread(s) cannot be seen, expulsion should be considered and 
an ultrasound must be performed.  Possibilities of cervical or uterine perforations may be 


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excluded by ultrasound, x-ray or hysteroscopy before making a final diagnosis of total 
expulsion.
Partial expulsion is diagnosed if the Mirena can be partially seen in the vagina or is displaced 
in the cervical canal.  If Mirena is partially expelled, it must be removed.  
Upon total or partial expulsion of Mirena, the subject must discontinue study treatment and 
the study.
9.6.3.10
Perforation by Mirena
All perforations (cervical or myometrial perforations or perforations resulting in Mirena 
localization in the peritoneal cavity) will be reported as SAEs.  
If a perforation is diagnosed, Mirena must be removed (this may require further intervention 
such as hysteroscopy or laparoscopy) and the subject must discontinue study treatment and 
the study. 
9.6.3.11
Pelvic inflammatory disease
All cases of pelvic inflammatory disease (PID) will be reported as an AE or SAE, as 
appropriate.
For the purposes of this study, a diagnosis of pelvic inflammatory disease will be based on the 
following criteria: 

Presence of tenderness on pelvic examination and

Current lower abdominal pain and

At least 2 of the following findings:

Purulent or abnormal vaginal discharge 

Increased serum C-reactive protein (30 mg/L) 

Increased body temperature (38°C) 

Typical findings of laparoscopy, if other clinical evidence is controversial

Evidence of causative pathogen (e.g., Chlamydia trachomatis or Neisseria 
gonorrhea) in the cervical canal
If pelvic inflammatory disease is not successfully treated, Mirena must be removed and the 
subject must discontinue the study. 
The pelvic inflammatory disease eCRF and AE eCRF will be completed in all cases of pelvic 
inflammatory disease.  If classified as an SAE, the appropriate forms will be completed and 
the sponsor’s local pharmacovigilance unit notified.  Details regarding notification to the 
Sponsor’s local pharmacovigilance unit are provided in Section 9.6.1.4.
9.6.3.12
Uterine bleeding
This section was changed in Amendment 1, see Section 15.1.1.19.
The occurrence of uterine bleeding will be recorded every day during the treatment phase 
using eDiaries provided by the sponsor.  The recording will start at the baseline visit and will 


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be continued daily until Mirena is removed.  Subjects are asked to rate their uterine bleeding 
in the past 24 hours on a daily basis according to the bleeding intensity definitions presented 
in Table 9–3.
Table 9–3
Uterine bleeding – bleeding intensity definitions – amended
Category
Intensity
Bleeding 
Intensity 
Code
Definition
None
None
1
No uterine bleeding
Spotting
Spotting
2
Less than associated with normal menstruation relative to the 
woman’s experience, with no need for sanitary protection 
except for panty liners
Bleeding
Light
3
Less than associated with normal menstruation relative to the 
woman’s experience, with need for sanitary protection
Normal
4
Like normal menstruation relative to the woman’s experience
Heavy
5
More than normal menstruation relative to the woman’s 
experience
9.7
Other procedures and variables
9.7.1
eDiary
This section was changed in Amendment 1, see Section 15.1.1.23.
Patient-reported outcomes (PROs) will be collected using an electronic diary (eDiary).  
Recording of the uterine bleeding is the main part of the eDiary. The use of back-up 
contraception will also be documented within the same eDiary.  Recall time will be 72 hours.
Subject will enter her data daily into the eDiary. The use of the eDiary will be explained in 
detail in a site manual, and the site personnel will train the subject on how to use the device at 
the baseline visit.  At all the following visits (see Table 9–1), the eDiary entries will be 
checked and documented by the study site personnel for completeness.  The investigator or 
designee and the on-site CRA will regularly review the eDiary entries via an internet-based 
application.  The eDiary device will be returned at the end-of-treatment visit (Visit 8).
9.7.2
Continuing need of contraception
During each study visit, the subject will be asked about her continuing need for contraception
since the last contact/visit.
9.7.3
Mirena removal – assessment of the ease of the procedure (by 
investigator) and pain during the removal (by subject)
The assessments described here have been developed by the sponsor specifically for use in 
sponsor’s IUS studies.  


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The purpose of this assessment is to provide a subjective evaluation of the pain, if any, on 
removal of Mirena.  The subject will assess the pain she experienced during Mirena removal 
as none, mild, moderate or severe and this will be recorded by the investigator in the eCRF.  
To avoid redundancy, any removal pain reported by the subject should not be recorded as an 
AE unless specifically considered as such by the investigator.
The ease of Mirena removal will be evaluated by the investigator as easy, slightly difficult or 
very difficult, and recorded in the eCRF.  The use of painkillers, (para)cervical blockade or 
dilation will be documented by the investigator in the eCRF as concomitant medication.
Information regarding the Mirena removal procedure will be collected on the Mirena 
Removal Ease (by investigator) and Pain (by subject) eCRFs.
Please see also Section 7.6 about reporting of technical complaints.
9.7.4
Subject satisfaction with Mirena
This section was changed in Amendment 1, see Section 15.1.1.1.
At baseline visit, visit 4, 6 and at the end of the treatment (EOT, visit 8) (see also Table 9–1), 
the subject is asked to evaluate her satisfaction with the Mirena on a 5-point scale as very 
satisfied, somewhat satisfied, neither satisfied or dissatisfied, dissatisfied or very dissatisfied. 
Information regarding the subject satisfaction will be documented by the investigator in 
eCRF.
9.7.5
Back-up contraception
Subjects will be required to record the use of any back-up contraception (e.g. use of condoms 
for protection against sexually transmissible infections [STIs]) in their diaries. The only back-
up contraception allowed during study treatment is the use of a barrier method (e.g. condoms).
Please see also Section 7.4.1
9.8
Appropriateness of procedures / measurements
The procedures chosen to measure the variables of this study are standard and/or widely used,
and generally recognized as reliable, accurate, and relevant.
10.
Statistical methods and determination of sample size
10.1
General considerations
Statistical analyses will be conducted by or under the supervision of the sponsor’s study 
statistician, except for the analysis of PK/PD data, which will be planned, performed and 
reported under the supervision of the sponsor´s pharmacometrics group. Statistical analysis 
will be performed using SAS; the version used will be specified in the statistical analysis plan.


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10.2
Analysis sets
This section was changed in Amendment 1, see Sections 15.1.1.1, 15.1.1.18 and 15.1.1.25.
The documentation of important deviations and the assignment of subjects to analysis sets 
will be performed according to the CRO’s applicable Standard Operating Procedures and/or 
Instruction Manuals.  
The following statistical analysis sets will be defined:
Full analysis set (FAS): 
All women who completed the baseline visit of the study
Primary analysis set Year 6 (PAS year 6):
All women in the FAS with an age of 35 years or younger at baseline visit (i.e. an age of 36 or 
younger at end of year 6)
Primary analysis set Year 7 (PAS year 7):
All women in the FAS with an age of 34 years or younger at baseline visit (i.e. an age of 36 or 
younger at end of year 7)
Primary analysis set Year 8 (PAS year 8): 
All women in the FAS with an age of 33 years or younger at baseline visit (i.e. an age of 36 or 
younger at end of year 8)
Safety analysis set (SAF):
All women who completed the baseline visit of the study, analyzed for the FAS.
The age at baseline (required for PAS year 6, PAS year 7 and PAS year 8) will be used as 
recorded at the baseline visit 2.  
10.3
Variables and planned statistical analyses
This section was changed in Amendment 1, see Section 15.1.1.26.
In order to allow some flexibility, the baseline visit is planned to take place 14 to 0 days 
before the end of Year 5 of Mirena use (see Table 9–1). As a consequence, it is expected there 
will be various subjects with that baseline visit taking place prior to the start of ‘extension 
treatment period’, i.e. Day 1 of Year 6 of Mirena use. 
Variables collected on an ongoing basis will primarily be analyzed for the ‘extension 
treatment period’ starting at Day 1 of Year 6 of Mirena use, i.e., data collected between the 
baseline visit and Day 1 of Year 6 of Mirena use will be excluded: 

Primary efficacy variable, i.e. occurrence of pregnancies (section 10.3.2.1)

Main safety variable, i.e. adverse events (section 10.3.2.3.1) 

Uterine bleeding / bleeding pattern (section 10.3.2.3.2) 
Variables collected at pre-specified visits/timeframes only will be analyzed per visit (unless 
otherwise stated): 

Secondary efficacy variable, i.e. menstrual blood loss (section 10.3.2.2) 


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
Other safety variables, not listed above (section 10.3.2.3.3) 

Other variables (section 10.3.2.4) 
More details will be provided in the statistical analysis plan.
10.3.1
Variables
10.3.1.1
Efficacy variables
10.3.1.1.1 Primary efficacy variable
This section was changed in Amendment 1, see Section 15.1.1.1 and 15.1.1.26.
The primary efficacy variable is the occurrence of pregnancy within years 6 thru 8 of Mirena 
use. However, for the analysis after 6 years of Mirena use, the primary efficacy variable is the 
occurrence of pregnancy within year 6 of Mirena use, and for the analysis after 7 years, the 
primary efficacy variable is the occurrence of pregnancy within years 6 thru 7 of Mirena use. 
The Pearl Index (PI) is defined as the number of pregnancies per 100 woman years. The Pearl 
Index will be analyzed for the ‘extension treatment period’ starting at Day 1 of Year 6 of 
Mirena use, i.e., exposure and pregnancies between the baseline visit and Day 1 of Year 6 of 
Mirena use will be excluded. The following PIs will be calculated:

'1-year PI’ (sixth year)', PI obtained in the sixth year of treatment, i.e., number of 
pregnancies that occurred during the sixth year of treatment divided by time the 
women were under risk of getting pregnant in the sixth year of treatment.

'2-year PI’ (sixth and seventh year)', PI obtained in the sixth and seventh year of 
treatment, i.e., number of pregnancies that occurred during the sixth and seventh year 
of treatment divided by time the women were under risk of getting pregnant in the 
sixth and seventh year of treatment.

'3-year PI’ (sixth, seventh and eighth year)', PI obtained in the sixth, seventh and 
eighth year of treatment, i.e., number of pregnancies that occurred during the sixth, 
seventh and eighth year of treatment divided by time the women were under a risk of 
getting pregnant in the sixth, seventh and eighth year of treatment.
Furthermore, the following PI will be analyzed for the entire study period starting at baseline 
visit, i.e., exposure and pregnancies between the baseline visit and Day 1 of Year 6 of Mirena 
use will be included: 

'Overall PI', PI obtained during the whole study, i.e., number of pregnancies that 
occurred during the entire study period starting at baseline visit divided by the time the 
women were under a risk of getting pregnant.
The exact rules regarding how the exposure time will be calculated are given in Section 
10.3.2.1. 


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10.3.1.1.2 Secondary efficacy variables
Secondary efficacy variables are:

Menstrual blood loss (MBL) during a 30-day period starting at the baseline visit and at 
the end of Years 6, 7 and 8.  MBL will be measured by the alkaline hematin method.
The assessment of this variable is restricted to women who had Mirena inserted for 
HMB.

Categorized menstrual blood loss (MBL) (>= 80 ml per 30 days) at end of Year 6, 7 
and 8. The assessment of this variable is restricted to women who had Mirena inserted 
for HMB.
10.3.1.2
Safety variables
This section was changed in Amendment 1, see Section 15.1.1.15 and 15.1.1.26.
The main safety variable is the incidence of treatment-emergent adverse events (both serious 
and non-serious). Treatment-emergent AEs are defined as any AEs occurring during the 
‘extension treatment period’ starting at Day 1 of Year 6 of Mirena use.
Other safety variables are: 

Uterine bleeding / Bleeding pattern 

Vital signs and weight

Cervical smear 

Test for Chlamydia

Safety laboratory parameters

Presence of Mirena removal threads

Mirena expulsion rate

Mirena perforation rate 
10.3.1.3
Other variables
Other variables are: 

Pharmacokinetic parameters 

Residual LNG content

Discontinuation rate

Subject satisfaction

Mirena removal: Ease and pain


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10.3.2
Statistical methods
10.3.2.1
Analysis of the primary variable
This section was changed in Amendment 1, see Sections 15.1.1.1, 15.1.1.5, 15.1.1.7, 15.1.1.8, 
and 15.1.1.26.
The primary variable is the occurrence of pregnancy within years 6-8 of Mirena use.
However, for the analysis after 6 years, the primary variable is the occurrence of pregnancy 
within year 6 of Mirena use, and for the analysis after 7 years, the primary variable is the 
occurrence of pregnancy within years 6 thru 7 of Mirena use.
Definitions for PIs are presented in Table 10–1. 
Table 10–1 Definition of crude exposure times – amended
PI
Reason for end of 
study/ continuation 
status
Crude exposure time
1-year PI 
(6th year)
Total expulsion
Date, when expulsion was discovered – Date of Day 1 Year 6
+1
Partial Expulsion/ 
Mirena removal
Date of Mirena removal – Date of Day 1 Year 6 +1
Pregnancy
Date of conception – Date of Day 1 Year 6 +1
Lost to Follow up
Maximum of (Date Mirena last known in situ – Date of Day 1 
Year 6 +1; 1 day)
Continues into 7th year 
of treatment
365 days
2-year PI 
(6th and 
7th year)
Total expulsion
Date, when expulsion was discovered – Date of Day 1 Year 6
+1
Partial Expulsion/ 
Mirena removal
Date of Mirena removal – Date of Day 1 Year 6 +1
Pregnancy
Date of conception – Date of Day 1 Year 6 +1
Lost to Follow up
Maximum of (Date Mirena last known in situ – Date of Day 1 
Year 6 +1; 1 day)
Continues into 8th year 
of treatment
730 days
3-year PI 
(6th, 7th 
and 8th 
year)
Total expulsion
Date, when expulsion was discovered – Date of Day 1 Year 6
+1
Partial Expulsion/ 
Mirena removal
Date of Mirena removal – Date of Day 1 Year 6 +1
Pregnancy
Date of conception – Date of Day 1 Year 6 +1
Lost to Follow up
Maximum of (Date Mirena last known in situ – Date of Day 1 
Year 6 +1; 1 day)


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PI
Reason for end of 
study/ continuation 
status
Crude exposure time
Continues into 9th year 
of treatment
Minimum of (1095 days; Date of EOT visit – Date of Day 1
Year 6 +1) 
Overall PI
Total expulsion
Date, when expulsion was discovered – Baseline visit date +1
Partial Expulsion/ 
Mirena removal
Date of Mirena removal – Baseline visit date +1
Pregnancy
Date of conception – Baseline visit date +1
Lost to Follow up
Maximum of (Date Mirena last known in situ – Baseline visit 
date +1; 1 day)
Continued until EOT
Date of EOT visit – Baseline visit date +1
A pregnancy will be allocated to the time period(s) that are relevant for the calculation of the 
PIs described above, e.g., a pregnancy that occurs on day 400 will be relevant for the 7th year 
PI, the two years PI (6th and 7th year), the three years PI (6th, 7th and 8th year), and the 
overall PI. Pregnancies that occur before Day 1 Year 6 of Mirena use will not count for the 1-
year PI, 2-year PI and 3-year PI.  Pregnancies that occur after the Mirena was removed or an 
expulsion was realized will not count for any PI. 
It should be noted that e.g., pregnancies that occur after partial expulsion, but before Mirena
removal will count for the PIs. 
Furthermore, it should be noted that pregnancies that occur within 7 days after the end of 
exposure will count for the PIs. 
Exposure times to be subtracted: 
Subjects who apply additional concomitant contraception are not in risk or are under a lower 
risk of getting pregnant than subjects who do not apply additional contraception. In case a 
subject uses concomitant contraceptive methods (e.g., condoms to prevent STD); the 
respective 28-day reference period(s) of additional contraceptive method use will be excluded 
from the exposure time, unless a pregnancy occurred in that 28-day reference period.
Primary analysis
The primary method for the evaluation of the occurrence of pregnancy is the Pearl index 
defined as the number of pregnancies per 100 women years.
The PIs and the corresponding 2-sided 95 % confidence interval (CI) will be calculated using 
the model specified below. 
Mathematical model for the calculation of the PI:
By assuming that the number of pregnancies follows a Poisson-distribution, the point estimate 
and the 95 % CI for the PI can be calculated as follows:
PI = x/E, 








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10.3.2.3.2 Bleeding pattern
This section was changed in Amendment 1, see Sections 15.1.1.10, 15.1.1.19, and 15.1.1.26.
Bleeding diary data during the ‘extension treatment period’ starting at Day 1 of Year 6 of 
Mirena use will be analyzed according to the sponsor’s Best Practice Document entitled 
“Recording and evaluation of bleeding data”. Bleeding diary data prior to the ‘extension 
treatment period’ will not be included in the analyses. The handling of partial or missing data 
and detailed imputation rules will be described in the statistical analysis plan.
Bleeding intensity will be recorded by the subject on a daily basis using the categories 
presented in Table 9–3 in section 9.6.3.12.
In addition to absolute number of bleeding days, bleeding/spotting episodes will also be 
assessed according to the sponsor’s Bleeding Intensity Codes and the World Health 
Organization (WHO) definitions as provided in Table 10–2.
Table 10–2
Bleeding Intensity Codes and WHO Definitions for Bleeding Intensity
– amended
Bleeding 
Intensity
Codes
WHO Definitions
2 - 5
Bleeding/spotting episode:
Day(s) with bleeding/spotting preceded 
and followed by at least 2 bleeding-free 
days.
2
Spotting-only episode:
Day(s) with spotting preceded and followed 
by at least 2 bleeding-free days.
1
Bleeding/spotting-free interval:
At least 2 days without bleeding/spotting 
preceded and followed by at least 1 
bleeding/spotting day.
In addition to the WHO definitions, a bleeding episode is defined as day(s) with 
bleeding/spotting of which at least one day is of intensity 3 or higher, preceded and followed 
by at least 2 bleeding-free days.
In the following example (Table 10–3) of an assessment of bleeding episodes the above 
definitions are applied to determine whether the event consisted of a single bleeding episode
or multiple bleeding episodes.  In Table 10–3, each recorded bleeding event consists of 5 
bleeding days.  However, as shown and described, the pattern of bleeding determines whether 
the 5 days are considered as one or two bleeding episodes.
Based on daily data obtained from the electronic diary, the bleeding pattern will be reported 
using reference periods of 28 and 90 days.  The first 28-day and 90-day reference period, 
respectively, will start at Day 1 of Year 6 of Mirena use.  For each subject and for each 
period, the number of bleeding/spotting days and bleeding/spotting episodes will be 
calculated.  If the bleeding intensity is recorded as light, normal or heavy, this will be 
considered as ‘bleeding’.
For each subject and for each 28-day reference period and each 90-day reference period, the 




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10.3.2.3.3 Other safety variables
All other safety variables will be analyzed descriptively using summary statistics or frequency 
tables as appropriate.
10.3.2.4
Other variables
10.3.2.4.1 Pharmacokinetic parameters
Pharmacokinetic data collected during the study will be analyzed descriptively. 
Population PK analysis will be performed as described in a separate M&S Analysis Plan and 
reported in a separate M&S Report. 
10.3.2.4.2 Residual LNG content
Residual LNG content will be analyzed descriptively. 
10.3.2.4.3 Discontinuation rate 
The discontinuation rate will be provided, calculated from the number of subjects with an 
expulsion, plus those who have Mirena removed due to partial expulsion or perforation, plus 
those who discontinue study treatment for other reasons.  The Kaplan-Meier estimate will be 
used.
10.3.2.4.4 Subject satisfaction
The subject’s satisfaction with the Mirena on a 5-point scale (very satisfied, somewhat 
satisfied, neither satisfied or dissatisfied, dissatisfied, very dissatisfied) will be summarized 
descriptively.
10.3.2.4.5 Mirena removal: ease and pain
The ease of Mirena removal (easy, slightly difficult, very difficult) will be summarized 
descriptively. 
The pain during the removal (none, mild, moderate, severe) will be summarized descriptively. 
10.4
Determination of sample size
The sample size calculation is not based on statistical considerations. It is targeted to have 200 
women completing the 8th year of treatment with Mirena. With an estimated dropout rate of 
15%, the total number of women to be enrolled into the study treatment phase would be 350.
In order to account for women excluded from the primary analysis due to age restrictions (i.e. 
women 34 years of age at baseline or older will not be included in the primary analysis set 
‘PAS year 8’ for the final analysis after 8 years)2, the total number of women to be enrolled 
into the study treatment phase is 360.
                                                
2 It is assumed about 90% of women enrolled will be 18 to 32 years of age at screening, i.e. 10% of women will 
be 33 to 35 years old and accordingly less will be 34 to 35 years old.




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11.
Data handling and quality assurance
11.1
Data recording
This section was changed in Amendment 1, see Section 15.1.1.23.
The data collection tool for this study will be eCRF; a validated electronic data capture system 
called RAVE.  Subject data necessary for analysis and reporting will be entered/transmitted 
into a validated database or data system (e.g. CIE/TOSCA; SAS).  
Data will be entered by site personnel into an internet based electronic data capture software 
system RAVE, which Covance has licensed from Medidata Solutions Worldwide. RAVE has 
been validated by Medidata Solutions Worldwide and Covance for use in its clinical studies.  
RAVE allows for the application of software logic to set-up data entry screens and data 
checks to ensure the completeness and accuracy of the data entered.  Covance extensively 
applies the logic to ensure data are complete and reflect the requirements of the study.  
Queries resulting from the application of the software logic are resolved by site personnel.  
The data are stored at a secure host facility maintained by Medidata Solutions Worldwide and 
transferred on a periodic basis to Covance's internal computer system via a secure Virtual 
Private Network.
Access to RAVE is through a password-protected security system.  All personnel are 
thoroughly trained before acquiring access to the system.  Training records are maintained.
Personnel with access to RAVE are supported by a Service Desk to answer questions and 
ensure access is maintained such that data entry can proceed in a timely manner.
RAVE contains a system-generated audit trail that captures any changes made to a data field, 
including who made the change, why it was changed, and the date and time it was made.  This 
information is available both at the investigator’s site and at Covance.  
Data entries are supported by source documents maintained for all subjects. A source 
document checklist will be used at the site to identify the source data for key data points 
collected and the monitor will work with the site to complete this.
Source documentation
The site must implement processes to ensure availability of all required source 
documentation.  A source document checklist (not part of this protocol) will be used at the 
site to identify the source data for key data points collected and the monitor will work with the 
site to complete this.
It is the expectation of the sponsor that all data entered into the CRF has source 
documentation available at the site except for the data listed below which will be entered 
directly into the CRF; thus, these CRF data will be the source and no additional source 
documentation will be available.  The data entered directly into the CRF is not needed for the 
subject’s routine medical care.

data fields to be completed directly in the eCRF: 


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
assessments on Mirena removal by subject (pain) and investigator (ease of 
removal), and 

subject’s satisfaction with Mirena.
These will be entered into eCRF by the investigator.
eDiary data
The eDiary entries will be considered as primary source data.
Data recorded from screening failures
At minimum, the following data should be recorded in the CRF:

Demographic information (subject number; year of birth / age; if applicable race / 
ethnicity)

Date for Mirena insertion

Indication for Mirena

Reproductive and menstrual history

Date of informed consent

Relevant inclusion/exclusion criteria

Reason for premature discontinuation

Date of last visit.  
These data will be transferred to the respective database.
For screening failures with an SAE or pregnancy (see also section 9.4.1), the following data 
should be collected in the CRF in addition to the data specified above:

All information related to the SAE/pregnancies such as: 

The SAE itself / pregnancy test evaluation page

Concomitant medication

Medical history

Other information needed for SAE complementary page
11.2
Monitoring
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements.  When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items.


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The sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate and complete.  
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes). 

Safety and rights of subjects are being protected

Study is conducted in accordance with the currently approved protocol 
(including study treatment being used in accordance with the protocol)

Any other study agreements, GCP, and all applicable regulatory requirements are met.
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.
11.3
Data processing
Data will be collected as described in Section 11.1.  Clinical data management will be 
performed in accordance with applicable sponsor’s/CRO’s standards and data cleaning 
procedures.  This is applicable for data recorded on eCRF as well as for data from other 
sources (e.g. laboratory, ePRO).
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used.
After its initial release for biometrical analysis, the clinical database is planned to be re-
opened for the inclusion of the following additional data: e.g. pharmacokinetic data, residual 
content data and post study pregnancy tracking data. 
11.4
Missing data
Most important is to avoid missing data, e.g. by monitoring in time for completeness (see 
Section 11.2) and investigators’ training, especially by instructing them to motivate subjects 
to be compliant with the study protocol. If the subject is unable to come to on-site visit 
during the allotted timeframe, the visit may be documented via phone as described at Section 
6.4.1 in order to collect as much data as possible. In addition, for completing the eDiary, 72-
hour recall time is implemented to allow some flexibility for eDiary completion and to avoid 
missing eDiary data.
11.5
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there.  The 
investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible.  The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 


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discuss findings and any issues.  Audits and inspections may occur at any time during or after 
completion of the study.
11.6
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution or private practice.  Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period.
The investigator/institution notifies the sponsor if the archival arrangements change 
(e.g. relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The contract with the investigator/institution will contain all regulations relevant for the study 
center.
12.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. treatment arms; dose steps; centers]) at any time, which may be due but not limited to the 
following reasons: 

If risk-benefit ratio becomes unacceptable owing to, for example,

Safety findings from this study (e.g. SAEs)

Results of any interim analysis

Results of parallel clinical studies

Results of parallel animal studies 
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity).

If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame.
The investigator has the right to close his/her center at any time.


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For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties.  Final decision 
on the closure must be in writing.

All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law.

All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor.  The investigator will retain all other documents until 
notification is given by the sponsor for destruction.

In the event of a partial study closure, ongoing subjects, including those in post study 
follow-up, must be taken care of in an ethical manner.
Details for individual subject's withdrawal can be found in Section 6.4.1.
13.
Ethical and legal aspects
13.1
Investigators and other study personnel
This section was changed in Amendment 1, see Section 15.1.1.23
The name and contact information for the Sponsor’s Study Medical Expert is provided in 
Section 1.  The co-ordinating investigator who will be responsible for signing the CSR, is 
(study center #
 All other study personnel not included in 
this section are identified in a separate personnel list (not part of this clinical study protocol) 
as appropriate.  This list will be updated as needed; an abbreviated version with personnel 
relevant for the centers will be available in each center’s investigator site file.
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site.
The principal investigator of each center must sign the protocol signature page and must 
receive all required external approvals (e.g. health authority, ethics committee, sponsor) 
before subject recruitment may start at the respective center.  Likewise, all amendments to the 
protocol must be signed by the principal investigator and must have received all required 
external approvals before coming into effect at the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file.
The global sponsor of this study is identified on the title page of this protocol.  If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages.
13.2
Funding and financial disclosure
Funding
This study will be funded by its sponsor.
PPD
PPD


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Financial disclosure 
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research subjects has to provide a financial disclosure 
according to all applicable legal requirements.  All relevant documentation will be filed in the 
trial master file.
13.3
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
Good Clinical Practice (GCP) guidelines and the guiding principles detailed in the 
Declaration of Helsinki.  The study will also be carried out in keeping with applicable local 
law(s) and regulation(s).
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations.  When necessary, an extension, amendment or renewal of the IEC/IRB 
approval must be obtained and also forwarded to the sponsor.  The responsible unit (e.g. 
IEC/IRB, head of the study center/medical institution) must supply to the sponsor, upon 
request, a list of the IEC/IRB members involved in the vote and a statement to confirm that 
the IEC/IRB is organized and operates according to GCP and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.  
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties.  However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial subjects without prior IEC/IRB/sponsor approval/favorable opinion.  As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/sponsor.  Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.
13.4
Subject information and consent
All relevant information on the study will be summarized in an integrated subject information 
sheet and informed consent form provided by the sponsor or the study center.  A sample 
subject information and informed consent form is provided as a document separate to this 
protocol.
Based on this subject information sheet, the investigator or designee will explain all relevant 
aspects of the study to each subject prior to her entry into the study (i.e. before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms).


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The investigator will also mention that written approval of the IRB/IEC has been obtained.
Each subject will be informed about the following aspects of premature withdrawal:
Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision.  
The subject’s consent covers end-of-study examinations as specified in the visit 
description described in Sections 6.4 and 9.1 to be conducted after withdrawal of consent.  
The subject’s data that have been collected until the time of withdrawal will be retained 
and statistically analyzed in accordance with the statistical analysis plan. 
Subject-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. image reading, analysis of biological specimen such as 
blood, urine or tissues); these data would also be retained and statistically analyzed in 
accordance with the statistical analysis plan.  The subject has the right to object to the 
generation and processing of this post-withdrawal data. The subject’s oral objection may 
be documented in the subject’s source data.
Each subject will have ample time and opportunity to ask questions.
Only if the subject voluntarily agrees to sign the informed consent form and has done so, may 
she enter the study.  Additionally, the investigator will personally sign and date the form.  The 
subject will receive a copy of the signed and dated form.
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution.
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject´s clinical record must clearly show that informed 
consent was obtained prior to these procedures.
The informed consent form and any other written information provided to subjects will be 
revised whenever important new information becomes available that may be relevant to the 
subject’s consent, or there is an amendment to the protocol that necessitates a change to the 
content of the subject information and / or the written informed consent form.  The 
investigator will inform the subject of changes in a timely manner and will ask the subject to 
confirm her participation in the study by signing the revised informed consent form.  Any 
revised written informed consent form and written information must receive the IEC/IRB`s 
approval / favorable opinion in advance of use.
13.5
Publication policy and use of data
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov. 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.


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Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations.  The sponsor is interested in the publication of the 
results of every study it performs.  
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study.  However, the investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission.  To this end, the investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract.  
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript.  
13.6
Compensation for health damage of subjects / insurance
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.
13.7
Confidentiality
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Subject names will not be supplied to the sponsor.  Only the subject number will be recorded 
in the CRF, and if the subject name appears on any other document (e.g. pathologist report), it 
must be obliterated before a copy of the document is supplied to the sponsor.  Study findings 
stored on a computer will be stored in accordance with local data protection laws.  As part of 
the informed consent process, the subjects will be informed in writing that representatives of 
the sponsor, IEC/IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws.
If the results of the study are published, the subject’s identity will remain confidential.
The investigator will maintain a list to enable subjects to be identified.
14.
Reference list 
This section was changed in Amendment 1, see Section 15.1.1.20.
1. McNicholas C, Swor E, Wan L, Peipert JF. Prolonged use of the etonogestrel implant and 
levonorgestrel intrauterine device: 2 years beyond Food and Drug Administration-
approved duration. Am J Obstet Gynecol. 2017 Jan 29[Epub ahead of print].
2. Rowe P, Farley T, Peregoudov A, Piaggio G, Boccard S, Landoulsi S, Meirik O; IUD 
Research Group of the UNDP/UNFPA/WHO/World Bank Special Programme of 
Research; Development and Research Training in Human Reproduction. Safety and 
efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 7-
year randomized comparative study with the TCu380A. Contraception. 2016 
Jun;93(6):498-506. doi: 10.1016/j.contraception.2016.02.024. Epub 2016 Feb 23.


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3. Sivin I, Stern J, Coutinho E, Mattos CER, El Mahgoub S, Diaz S 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;44:473-80.
4. Hidalgo MM1, Hidalgo-Regina C, Bahamondes MV, Monteiro I, Petta CA, Bahamondes 
L. Serum levonorgestrel levels and endometrial thickness during extended use of the 
levonorgestrel-releasing intrauterine system. Contraception. 2009 Jul;80(1):84-9. doi: 
10.1016/j.contraception.2009.01.004. Epub 2009 Feb 27.
5. Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) 
IUDs during five years of use: a randomized comparative trial. Contraception. 
1994;49(1):56-72. PubMed PMID: 8137626.
6. A46796 Phase 2 CSR.  Multi-center, open, randomized, dose finding phase II study to 
investigate for a maximum of three years ultra low dose levonorgestrel contraceptive 
intrauterine systems (LCS) releasing in vitro 12 µg/24 h and 16 µg/24 h of levonorgestrel 
compared to MIRENA in nulliparous and parous women in need of contraception.  Bayer 
HealthCare AG, 51368 Leverkusen, Germany.  Study No. 91412 (alias 308901), version 
2.0.  14 SEP 2011.
7. B073 Clinical Study Report. Serum levonorgestrel concentration during 78 month use of 
LNG IUD. Schering. 22 Nov 1991.
8. B078 Clinical Study Report. Five-year clinical performance of the new formulation of the 
levonorgestrel intrauterine ystem and serum levonorgestrel concentration with the new 
formulation compared to that with the original one. Leiras 18 JAN 1999.
9. PH-37274 Phase 3 CSR. Multi-center, open-label, randomized study to assess the safety 
and contraceptive efficacy of two doses (in vitro 12 µg/24 h and 16 µg/24 h) of the ultra 
low dose levonorgestrel contraceptive intrauterine systems (LCS) for a maximum of 3 
years in women 18 to 35 years of age and an extension phase of the 16 µg/24 h dose group 
(LCS16 arm) up to 5 years. Bayer HealthCare AG, 51368 Leverkusen, Germany. Study 
No. 91665 (alias 310442), version 2.0, 06 Aug 2015.
10. 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 Apr;91(4):274-9.
11. A52238 Phase 3 CSR. Multi-center, open-label, randomized study to assess the safety and 
contraceptive efficacy of two doses (in vitro 12 μg/24 h and 16 μg/24 h) of the ultra low 
dose levonorgestrel contraceptive intrauterine systems (LCS) for a maximum of 3 years in 
women 18 to 35 years of age and an extension phase of the 16 μg/24 h dose group (LCS16 
arm) up to 5 years. Bayer HealthCare AG, 51368 Leverkusen, Germany. Study No. 91665 
(alias 310442), version 2.0, 06 Aug 2015.
12. Heikinheimo O, Inki P, Schmelter T, Gemzell-Danielsson K. Bleeding pattern and user 
satisfaction in second consecutive levonorgestrel-releasing intrauterine system users: 
results of a prospective 5-year study. Hum Reprod. 2014 Jun;29(6):1182-8. doi: 
10.1093/humrep/deu063. Epub 2014 Mar 28.


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13. Seeber B, Ziehr SC, Gschlieβer A, Moser C, Mattle V, Seger C, Griesmacher A, Concin 
N, Concin H, Wildt L. Quantitative levonorgestrel plasma level measurements in patients 
with regular and prolonged use of the levonorgestrel-releasing intrauterine system. 
Contraception. 2012 Oct;86(4):345-9. doi: 10.1016/j.contraception.2012.01.015. Epub 
2012 Mar 6.
15.
Protocol amendments
15.1
Amendment 1 – dated 20 SEP 2017
Amendment 1 is the first global amendment. The following is an overview of the changes 
made to the original Protocol Version 1.0.
This amendment describes the assessments and statistical analyses needed to support a
submission with 6-year efficacy and safety data to extend the duration of Mirena use to up to 
6 years.  In addition, protocol has been revised in order to consider the comments and 
feedback from the FDA (received 31 JAN 2017 and 12 JUL 2017). Also, minor edits and 
clarifications that were not previously identified in the original protocol were included in this 
amendment.
15.1.1
Overview of the changes to the study
15.1.1.1
Modification 1: Addition of the 6-year analysis and the required
assessments needed for the analyses at Year 6
Rationale: To be able to submit the data to the FDA after 6 years of Mirena use.
List of protocol sections affected by this modification:
Section 5 Study design
Section 9.1 Tabular schedule of evaluations
Section 9.2.5 12-month visit – Visit 4 (End of Year 6 of Mirena use)
Section 9.7.4 Subject satisfaction with Mirena
Section 10.2 Analysis sets
Section 10.3.1.1.1 Primary efficacy variable
Section 10.3.2.1 Analysis of the primary variable
Section 10.3.2.2.2 Categorized menstrual blood loss (MBL) (<80ml / 30 days)
Section 10.5 Planned interim analyses
15.1.1.2
Modification 2: Guidance about number of 34- or 35-year old women 
to be included into the screening period
Rationale: In order to ensure sufficient sample size for the final Pearl Index analysis (i.e. 
targeted 350 women aged 33 years or younger at baseline visit / aged 36 years or younger at 
the end of Year 8), screening of women who are 34 or 35 years old will be closed, once 10 
women in this age group have completed the baseline visit.


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List of protocol sections affected by this modification:
Section 6 Study population  
15.1.1.3
Modification 3: Information on inclusion range for laboratory values
added
Rationale: As requested by the FDA
List of protocol sections affected by this modification:
Section 6.2 Exclusion criteria
Section 9.6.3.7 Safety laboratory tests
15.1.1.4
Modification 4: Revision of the criteria for mandatory withdrawal 
from the study
Rationale: Subject must be withdrawn if stroke, myocardial infarction, uterine malignancy 
and cervical malignancy occur during the study; requested by the FDA.
List of protocol sections affected by this modification:
Section 6.4.1 Withdrawal
15.1.1.5
Modification 5: Clarification on counting of pregnancies with the 
estimated date of conception within 7 days after the end of Mirena 
treatment for the Pearl Index calculation 
Rationale: As requested by the FDA
List of protocol sections affected by this modification:

Section 9.4.1.2 Pregnancies occurring after the end of study treatment

Section 10.3.2.1 Analysis of the primary variable.
15.1.1.6
Modification 6: Clarification of the post-treatment pregnancy tracking 
process (PTPT)
Rationale: To better distinguish the PTPT process-related data from the post-treatment 
pregnancy data collected at the 3-week FUP contact.
List of protocol sections affected by this modification:
Section 9.2.10 3-week follow-up call (EOS)
Section 9.2.11 3-month follow-up contact for post-study pregnancies
Section 9.2.12 12-months follow-up contact for return-to-fertility
Section 9.4.1.1 Pregnancies during the study
Section 9.4.1.2 Pregnancies occurring after the end of study treatment


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15.1.1.7
Modification 7: Clarification and correction of terms used in the 
definitions for calculation of crude exposure time
Rationale: As requested by the FDA.
List of protocol sections affected by this modification:
Section 10.3.2.1 Analysis of the primary variable
15.1.1.8
Modification 8: Clarification of excluded exposure time due to back-up 
contraception use
Rationale: As requested by the FDA.
List of protocol sections affected by this modification:
Section 10.3.2.1 Analysis of the primary variable.
15.1.1.9
Modification 9: Addition of sensitivity analysis for PI
Rationale: As requested by the FDA.
List of protocol sections affected by this modification:
Section 10.3.2.1 Analysis of the primary variable.
15.1.1.10 Modification 10: Addition of a reference to the statistical analysis plan 
regarding handling of partial or missing data
Rationale: To provide guidance on how to handle missing or partial data, i.e. missing 
bleeding intensities to be recorded by the subject in the eDiary and/or missing and partial data 
on sanitary products to be collected by the subject.
List of protocol sections affected by this modification:
Section 10.3.2.2.1 Menstrual blood loss
Section 10.3.2.3.2 Bleeding pattern.
15.1.1.11 Modification 11: Clarification of the definition of clinical change in 
bleeding profile regarding HMB and of the proportion of subjects with 
clinical change in bleeding profile regarding HMB
Rationale: To clarify when clinical change in bleeding profile regarding HMB will be 
concluded, to add the stricter success criterion (i.e. upper confidence limit ≤ 35%) for this 
endpoint as requested by FDA and to provide more details on the nominator and 
denominators used to calculate the proportion of subjects with clinical change in bleeding 
profile regarding HMB. 


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List of protocol sections affected by this modification:
Section 10.3.2.2.2 Categorized menstrual blood loss (MBL) (<80ml / 30 days).
15.1.1.12 Modification 12: Change in exclusion criterion about simultaneous 
participation in other trials 
Rationale: Study subjects can participate in observation trials while in the study. To allow 
this, the wording in exclusion criterion #22 is revised accordingly.
List of protocol sections affected by this modification:
Section 6.2 Exclusion criteria.
15.1.1.13 Modification 13: Withdrawal from study if heavy menstrual bleeding 
returns
Rationale: Investigator should consider if a subject should be withdrawn from the study in 
case heavy menstrual bleeding returns during the study
List of protocol sections affected by this modification:
Section 6.4.1 Withdrawal
15.1.1.14 Modification 14: Reference to a local laboratory removed from the text.
Rationale: Mistake in the original protocol.
List of protocol sections affected by this modification:
Section 9.6.3.6 Test for chlamydia.
15.1.1.15 Modification 15: Revised terminology of the adverse events to be 
included in the main safety analysis, and correction of the list of other 
safety variables.
Rationale: To ensure consistent wording across different studies, terminology of adverse 
events to be included in the main safety analysis was revised from “post-baseline” to 
“treatment-emergent”. It was a mistake in the original protocol in the list of other safety 
variables. 
List of protocol sections affected by this modification:
Section 10.3.1.2 Safety variables
Section 10.3.2.3 Analysis of safety variables.


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15.1.1.16 Modification 16: Improved instructions for collection of used sanitary 
products 
Rationale:  To provide more guidance to the investigators and site personnel.
List of protocol sections affected by this modification:
Section 9.1 Tabular schedule of evaluations.
15.1.1.17 Modification 17: Correction of the in cervical smear instructions at 
EOT visit
Rationale:  Mistake in the original protocol.
List of protocol sections affected by this modification:
Section 9.2.9 36-month visit, EOT – Visit 8 (End of Year 8 of Mirena use)
15.1.1.18 Modification 18: Change in the SOPs to be followed for assessing 
important deviations
Rationale:  CRO’s SOPs will be used for the assessment of protocol deviations
List of protocol sections affected by this modification:
Section 10.2 Analysis sets
15.1.1.19 Modification 19: Definition of a bleeding/spotting episode
Rationale:  Correction of the bleeding intensity codes for bleeding/spotting episode
List of protocol sections affected by this modification:
Section 9.6.3.12 Uterine bleeding
Section 10.3.2.3.2 Bleeding pattern
15.1.1.20 Modification 20: Update of the background information
Rationale: To include recently published data about extended use of Mirena.
List of protocol sections affected by this modification:
Section 3. Introduction 
Section 14 Reference list


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15.1.1.21 Modification 21: Information on post-study contraception
Rationale: To inform the subject about the options for contraception after the study in order 
to decrease the chances for unplanned pregnancies after the study.
List of protocol section affected by this modification:
Section 9.2.8 30-month visit – Visit 7
15.1.1.22 Modification 22: Mandatory TVUS if removal threads are not found
Rationale: To ensure that Mirena is in the appropriate intrauterine location and to exclude 
expulsion or perforation.
List of protocol section affected by this modification:
Section 9.6.3.8 Presence of Mirena removal threads
15.1.1.23 Modification 23: Clarifications
Rationale: Textual editing for clarity and consistency between sections, administrative 
changes and corrections of mistakes.
List of protocol sections affected by this modification:
Section 2. Synopsis
Section 9.2 Visit description
Section 11.1 Data recording
Section 13.1 Investigators and other study personnel.
15.1.1.24 Modification 24: Instructions regarding bleeding irregularities detected 
in women using Mirena for contraception only
Rationale: As per FDA request
List of protocol sections affected by this modification:
Section 9.1 Tabular schedule of evaluations
Section 9.2 Visit description
15.1.1.25 Modification 25: Collection of age at Baseline visit (Visit 2)
Rationale: Age at baseline will be needed for the statistical analysis. As baseline might be up 
to 6 months after screening, the age at screening should not be used as it may not reflect the 
age at baseline. 
List of protocol sections affected by this modification:
Section 9.1 Tabular schedule of evaluations
Section 9.2.3 Baseline – Visit 2
Section 9.3.1 Demographic


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Section 10.2 Analysis sets
Section 9.2 Visit description
15.1.1.26 Modification 26: Revision of the definition for start of treatment period 
for the primary variable
A new term ‘extension treatment period’ is introduced. This period starts at Day 1 of Year 6 
of Mirena. Variables collected on an ongoing basis will primarily be analyzed for the 
‘extension treatment period’ starting at Day 1 of Year 6 of Mirena use, i.e., data collected 
between the baseline visit and Day 1 of Year 6 of Mirena use will be excluded.
Rationale: This enables the calculation of the Pearl Index for the period of extended use of 
Mirena beyond the five years.  Change was requested by the FDA.
List of protocol sections affected by this modification:

Section 10.3 Variables and planned statistical analyses

Section 10.3.1.1.1 Primary efficacy variable

Section 10.3.1.2 Safety variables

Section 10.3.2.1 Analysis of the primary variable

Section 10.3.2.3 Analysis of safety variables

Section 10.3.2.3.2 Bleeding pattern
15.1.2
Changes to the protocol text
In the sections on changes to the protocol text, all protocol sections affected by the respective 
amendment are detailed; the sequence of the sections follows the structure of the original
protocol. As applicable, changes to the protocol text are highlighted as follows:
1. Addition of a whole new portion
Brief identification of the new portion
2. Removal of a whole portion
Complete display of the removed portion, formatted 
as crossed out
3. Editing of an existing portion
Comparative presentation of “old text” versus “new 
text”, with “old text” referring to the most recent 
previous protocol version. Deletions are crossed out
in the “old text”. Additions are underlined in the 
“new text”. 
Tables / figures
The term “amended” is added to the caption.


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Terminological changes
Brief specification of the terminological change
Thus, in this section, a terminological change (e.g. 
“period” versus “epoch”) is defined only once, 
without displaying “old text” versus “new text” for 
each appearance.
Correction of typos or omissions are not highlighted in this section.
15.1.2.1
Section 2. Synopsis
This section was changed as a result of Modification 15.1.1.23
Old text:
Short title
Mirena Extension study
New text:
Short title
Mirena Extended Trial
15.1.2.2
Section 3. Introduction 
This section was changed as a result of Modification 15.1.1.20.
Old text:
[…]
Two controlled contraceptive efficacy studies on extended use beyond the indicated 5 years 
up to 7 years (1, 2) have been published. In the recently published study by Rowe et al 2016, 
the overall pregnancy rate of the TCu380A was significantly higher than that of the LNG 
IUD: at the end of the seventh year the cumulative rate was 2.45 (standard error [SE] 0.44) 
per 100 for the TCu380A and 0.53 (SE 0.21) per 100 for the LNG IUD.
[…]
New text:
[…]
Three contraceptive efficacy studies on extended use beyond the indicated 5 years up to 7 
years (1, 2, 3) have been published. In a comparative study the effectiveness of the 
contraceptive implant and the 52-mg hormonal intrauterine device in women using the 
method for 2 years beyond the approved duration was evaluated (1). Among 496 LNG IUS 
users, 696.9 woman-years of follow-up have been completed. Two pregnancies have been 
reported. The failure rate in the sixth year of use of the LNG IUS is calculated as 0.25 
(95% CI, 0.04-1.42) per 100 woman-years; failure rate during the seventh year is 0.43 (95% 
CI 0.08-2.39) per 100 woman-years. In the recently published study by Rowe et al 2016 (2), 


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the overall pregnancy rate of the TCu380A was significantly higher than that of the LNG 
IUD: at the end of the seventh year the cumulative rate was 2.45 (standard error [SE] 0.44) 
per 100 for the TCu380A and 0.53 (SE 0.21) per 100 for the LNG IUD.
[…]
15.1.2.3
Section 5 Study design
This section was changed as a result of Modification 15.1.1.1.
Old text:
[…]
An analysis of the efficacy and safety data will be conducted after all subjects have either 
completed 7 years of treatment, or prematurely terminated their study participation before this 
time point. 
[…]
New text:
[…]
An analysis of the efficacy and safety data will be conducted after all subjects have either 
completed 6 years of treatment (i.e. completed 1 year in the study), or prematurely terminated 
their study participation before this time point. Another  analysis of the efficacy and safety 
data will be conducted after all subjects have either completed 7 years of treatment (i.e. 
completed 2 years in the study), or prematurely terminated their study participation before this 
time point.
[…]
15.1.2.4
Section 6 Study population
This section was changed as a result of Modification 15.1.1.2.
New text – addition of footnote 1:
[…]
The study will include fertile age women (18 to 35 years at the time of the screening visit) 
currently using a Mirena for contraception or for contraception and heavy menstrual bleeding 
and who have had the Mirena in situ for at least 4 years and 6 months but no longer than 5 
years and are willing to continue its use for contraception or contraception and heavy 
menstrual bleeding for up to 8 years in total. About 90% of the women included will be 18 to 
32 (inclusive) years of age at screening (visit 1)1.
Text for Footnote 1: Screening of women who are 34 or 35 years old will be closed, once 10 
women in this age group have completed the baseline visit, for details see Section 10.4.


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15.1.2.5
Section 6.2 Exclusion criteria
This section was changed as a result of Modification 15.1.1.3 and 15.1.1.12.
Old text:
[…]
21.
Laboratory values outside inclusion range before baseline and considered clinically 
relevant.
22.
Simultaneous participation in another clinical trial. Participation in another clinical 
trial prior to study entry that might have an impact on the study objectives, at the 
discretion of the investigator.
New text:
[…]
21.
Laboratory values outside inclusion range before baseline and considered clinically 
relevant (see Section 9.6.3.7).
22.
Simultaneous participation in another clinical study with investigational medicinal 
product(s). Participation in another clinical trial prior to study entry that might have an 
impact on the study objectives, at the discretion of the investigator.
[…]
15.1.2.6
Section 6.4.1 Withdrawal
This section was changed as a result of Modification 15.1.1.4 and 15.1.1.13.
Old text:
[…]
Subjects must be withdrawn from the study if any of the following occurs:

[…]

Acute pelvic inflammatory disease (PID) not responding to treatment

Genital malignancy

Liver tumor (benign or malignant)

Allergic reaction to the study medication or any of its components

If, in the investigator’s opinion, continuation of the study would be harmful to the 
subject’s well-being

[…]


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Subjects may be withdrawn from the study if any of the following occurs:

[…]

Marked increase of blood pressure

Severe arterial disease such as stroke or myocardial infarction

Uterine or cervical malignancy

Jaundice

[…]

Should the subject, during the course of the study, develop conditions which would 
have prevented her entry into the study according to the exclusion criteria, she must be 
withdrawn immediately if safety is concerned. In other cases, the investigator will 
decide if there is a conflict with study objectives.

At the specific request of the sponsor and in liaison with the investigator (e.g. obvious 
non-compliance, safety concerns).
The reasons for any withdrawal are to be fully documented on the eCRF.
[…]
New text:
[…]
Subjects must be withdrawn from the study if any of the following occurs:

[…]

Acute pelvic inflammatory disease (PID) not responding to treatment

Genital malignancy (e.g., uterine or cervical malignancy)

Severe arterial disease such as stroke or myocardial infarction

Liver tumor (benign or malignant)

Allergic reaction to the study medication or any of its components

If, in the investigator’s opinion, continuation of the study would be harmful to the 
subject’s well-being

Should the subject, during the course of the study, develop conditions which would 
have prevented her entry into the study according to the exclusion criteria, she must be 
withdrawn immediately if safety is concerned. In other cases, the investigator will 
decide if there is a conflict with study objectives.

[…]


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Subjects may be withdrawn from the study if any of the following occurs:

[…]

Marked increase of blood pressure

Jaundice

[…]

At the specific request of the sponsor and in liaison with the investigator (e.g. obvious 
non-compliance, safety concerns).

Return of heavy menstrual bleeding, if it affects the subject’s well-being, based on the 
investigator’s clinical judgment
The reasons for any withdrawal are to be fully documented on the eCRF.
[…]
15.1.2.7
Section 9.1 Tabular schedule of evaluations
This section was changed as a result of Modification 15.1.1.1, 15.1.1.16, 15.1.1.24, and
15.1.1.25.
Old text:


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Table 9–1
Schedule of activities and evaluations
Period
Screening
(0 to 6 mo)
Treatment Period 
(3 years; Mirena years 6 thru 8)
Pregnancy Follow-up 
(up to 12 mo)
Visit
Prescreening 
contact 
(optional)
Screening 
Baseline
EOTa
EOS
All 
subjects
3-mo 
contact
b
12-mo 
contact
c
Visit number
/
1
2
3
4
5
6
7
8



Timing
within 
60 days
Day 1
6 mo
±14 d
12 mo
±14 d
18 mo
±14 d
24 mo
±14 d
30 mo
±14 d
36 mo
-14 d
3 wks 
after 
EOT
-3 d
3 mo 
after 
EOT
-7 d/+14 
d
12 mo 
after 
EOT
+7 d
Duration of Mirena use
4 y 6 mo 
to 5 
years
5 yearsd
6 years
7 years
8 years
[…]
Demography
X
[…]
Physical examination
X
X
X
Vital signs, body weight
X+height
X
X
Gynecological exam. incl. breast palpation
X
X
X
[…]
Urine pregnancy test g
X
X
X
X
X
X
X
X
X
[…]
Dispense home pregnancy test kits
X
X
X
X
X
X
[…]
Subject satisfaction with Mirena
X
X
X
Footnote explanations:
c
For subjects that prematurely discontinued treatment due to ‘Wish for pregnancy’ will be contacted. If a subject was not pregnant at 3 month contact and no 
longer wished to become pregnant, a 12-month contact is not required. If a subject was “Lost to Follow-up” at 3 month contact, a 12-month contact is 
required. See also Section 9.4.1.
[…]
g
In addition to the urine pregnancy tests performed by the site at each study visit, subjects will be given home urine pregnancy tests to be used whenever a 


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pregnancy is suspected.  Subjects must contact the study site immediately if a pregnancy test is positive.  Home pregnancy test is to be done on the day of 
the 3-week contact.


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New text:
Table 9–1
Schedule of activities and evaluations – amended 
Period
Screening
(0 to 6 mo)
Treatment Period 
(3 years; Mirena years 6 thru 8)
Pregnancy Follow-up 
(up to 12 mo)
Visit
Prescreening 
contact 
(optional)
Screening 
Baseline
EOTa
EOS
All 
subjects
3-mo 
contact
b
12-mo 
contact
c
Visit number
/
1
2
3
4
5
6
7
8



Timing
within 
60 days
Day 1
6 mo
±14 d
12 mo
±14 d
18 mo
±14 d
24 mo
±14 d
30 mo
±14 d
36 mo
-14 d
3 wks 
after 
EOT
-3 d
3 mo 
after 
EOT
-7 d/+14 
d
12 mo 
after 
EOT
+7 d
Duration of Mirena use
4 y 6 mo 
to 5 
years
5 yearsd
6 years
7 years
8 years
[…]
Demography
X
Age at baseline
X
[…]
Physical examination
X
X
X
X
Vital signs, body weight
X+height
X
X
X
Gynecological exam. incl. breast palpation
X
X
X
X
[…]
Urine pregnancy test g
X
X
X
X
X
X
X
X
X g
[…]
Dispense home pregnancy test kits
X
X
X
X
X
X
X
[…]
Subject satisfaction with Mirena
X
X
X
X
[…]
Footnote explanations:
c
Subjects that prematurely discontinued treatment due to ‘Wish for pregnancy’ will be contacted. If a subject was not pregnant at 3 month contact and no 


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longer wished to become pregnant, a 12-month contact is not required. If a subject was “Lost to Follow-up” at 3 month contact, a 12-month contact is 
required. See also Section 9.4.1.
[…]
g
In addition to the urine pregnancy tests performed by the site at each study visit, subjects will be given home urine pregnancy tests to be used whenever a 
pregnancy is suspected.  Subjects must contact the study site immediately if a pregnancy test is positive.  Home pregnancy test is to be done on the day of 
the 3-week contact.
[…]
d=day, EOS=end of study, EOT=end of treatment, mo=month, PK=pharmacokinetics, wks=weeks, y=year


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Old text:
[…]
Subjects in the HMB subgroup (i.e. all women who had the Mirena inserted for contraception 
and heavy menstrual bleeding) will collect their used sanitary products (provided by sponsor) 
during 4 periods of 30 days as shown in Table 9-2.  All used sanitary products have to be 
returned to the study site at time points given in Table 9-2.
[…]
New text:
[…]
Subjects in the HMB subgroup (i.e. all women who had the Mirena inserted for contraception 
and heavy menstrual bleeding) will collect their used sanitary products (provided by sponsor) 
during 4 periods of 30 days as shown in Table 9-2.  All used sanitary products have to be 
returned to the study site as instructed in Section 9.4.2 and displayed in Table 9-2.
[…]


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Old text:
[…]
Table 9–2
Schedule of activities needed for the MBL evaluations
HMB subgroup only – additional activities for baseline (BL) visit and treatment period
Period
Screening
Treatment Period (Mirena years 6 thru 8)
30 days after 
baseline 
visit
30 days prior 
to visit 4
30 days prior 
to visit 6
30 days prior 
to EOT
Visit / visit 
number
Baseline (BL) 
Visit 2
Return
Return
Visit 3
Return 
Visit 4
Visit 5
Return
Visit 6
Visit 7
Return
EOT 
Visit 8
Timing
2 
weeks
2 
weeks 
after 
BL
30 
days 
after 
BL
6 mo
±2 
weeks
2 
weeks 
before 
V4
12 mo 
±2 
weeks 
18 mo
±2 
weeks
2 
weeks 
before 
V6
24 mo
±2 
weeks
30 mo
±2 
weeks
2 
weeks 
before 
EOT
36 mo
2 
week
s
Dispense 
alkaline 
hematin kit 
X
X
X
X
Collection of 
used towels 
and tampons








Return of 
used towels 
and tampons
X
X
X
X
X
X
X
X
Note:  Return required only if sanitary protection has been used in the time periods indicated.
Note:  For all other activities and evaluations, please refer to Table 9 1. 


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New text:
[…]
For subjects who have the Mirena inserted for contraception only: if bleeding irregularities 
develop during prolonged treatment, appropriate diagnostic measures should be taken by the 
investigator to rule out endometrial pathology.
Table 9–2
Schedule of activities needed for the MBL evaluations – amended 
HMB subgroup only – additional activities for baseline (BL) visit and treatment period. For all other 
activities and evaluations, see Table 9-1.
Period
Screening
Treatment Period (Mirena years 6 thru 8)
Collection 
time
30 days after 
baseline 
visit,
Study Days 
2 to 31 
(inclusive)
Study Days 
322 to 351 
(inclusive)
before Visit 4
Study Days 
687 to 716 
(inclusive)
before Visit 6
Study Days 
1052 to 1081 
(inclusive)
before EOT 
visit
Visit / visit 
number
Baseline (BL) 
Visit 2
Return
Return
Visit 3
Return 
Visit 4
Visit 5
Return
Visit 6
Visit 7
Return
EOT 
Visit 8
Dispense 
alkaline 
hematin kit 
X
X
X
X
Collection of 
used sanitary 
products








Return of 
used sanitary 
productsa
X
X
X
X
X
X
X
X
Study Day 1 = Day of the baseline visit (Visit 2)
a
Used sanitary products should not be kept at home longer than 14 days. Return required only if 
sanitary products have been used in the time periods indicated.
15.1.2.8
Section 9.2 Visit description
This section was changed as a result of Modification 15.1.1.23.
Old text:
The timing of the visits is based on the date of the baseline visit.  Treatment period starts at 
the baseline visit (Visit 2, defined as Day 1).


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New text:
The timing of the visits is based on the date of the baseline visit.  Treatment period starts at 
the baseline visit (Visit 2, defined as Study Day 1).
15.1.2.9
Section 9.2.3 Baseline – Visit 2
This section was changed as a result of Modification 15.1.1.25.
Old text:
The following procedures and assessments will be done:

Re-check inclusion/exclusion criteria (Sections 6.1 and 6.2)

Perform pelvic examination to visualize Mirena removal threads (Section 9.6.3.8)

[…]
New text:
The following procedures and assessments will be done:

Re-check inclusion/exclusion criteria (Sections 6.1 and 6.2)

Age at baseline (Section 9.3.1)

Perform pelvic examination to visualize Mirena removal threads (Section 9.6.3.8)

[…]
15.1.2.10 Section 9.2.5 12-month visit – Visit 4 (End of Year 6 of Mirena use)
This section was changed as a result of Modification 15.1.1.1.
Old text:
The following procedures and assessments will be done:

Perform pelvic examination to visualize Mirena removal threads (Section 9.6.3.8)

Perform urine pregnancy test (Section 9.6.3.4)

Perform safety laboratory test and urinalysis (Section 9.6.3.7)

Blood sample for PK (Note: subjects randomized to this visit) (Section 9.5.1)

Interview for the following:

Concomitant medications (Section 8.1)

AEs (Section 9.6.1)

Continuing need for contraception (Section 9.7.1)

Dispense home pregnancy kits with instructions (Section 9.6.3.4)

Review completed (monthly) eDiary, including information on uterine bleeding and 
back-up contraception.


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New text:
The following procedures and assessments will be done:

Assess vital signs and weight (Section 9.6.3.1)

Perform general physical examination (Section 9.6.3.2)

Perform gynecological examination (with breast palpation; Section 9.6.3.3

Perform pelvic examination to visualize Mirena removal threads (Section 9.6.3.8)

Perform urine pregnancy test (Section 9.6.3.4)

Perform safety laboratory test and urinalysis (Section 9.6.3.7)

Blood sample for PK (Note: subjects randomized to this visit) (Section 9.5.1)

Interview for the following:

Concomitant medications (Section 8.1)

AEs (Section 9.6.1)

Continuing need for contraception (Section 9.7.1)

Dispense home pregnancy kits with instructions (Section 9.6.3.4)

Review completed (monthly) eDiary, including information on uterine bleeding and 
back-up contraception.

Subject satisfaction with Mirena (Section 9.7.4).
15.1.2.11 Section 9.2.8 30-month visit – Visit 7
This section was changed as a result of Modification 15.1.1.21.
Old text:
[…]

Dispense alkaline hematin kit with instructions for subjects in HMB group.
New text:
[…]

Dispense alkaline hematin kit with instructions for subjects in HMB group.
Discuss the contraceptive options available after the study treatment with the subject (see 
Section 8.2).


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15.1.2.12 Section 9.2.9 36-month visit, EOT – Visit 8 (End of Year 8 of Mirena 
use)
This section was changed as a result of Modification 15.1.1.17.
Old text:
The following procedures and assessments will be done:
[…]

Perform pelvic examination to visualize Mirena removal threads (Section 9.6.3.8)

Obtain cervical smear (Section 9.6.3.5).  A cervical smear should be taken at this visit 
or a documented normal result (using the Bethesda system or a corresponding system) 
has to have been obtained within 6 months before the Screening Visit (Visit 1). 
Subjects with ASCUS can be included if they have a HPV DNA test that, according to 
the standards of the local laboratory, is negative for high risk HPV.  A cervical smear 
may be repeated once if the screening result is abnormal.

Perform urine pregnancy test (Section 9.6.3.4)

Perform safety laboratory test and urinalysis (Section 9.6.3.7)

Blood sample for PK (all subjects) (Section 9.5.1)

Interview for the following:

Concomitant medications (Section 8.1)

AEs (Section 9.6.1)

Continuing need for contraception (Section 9.7.1)

Review completed (monthly) eDiary, including information on uterine bleeding and 
back-up contraception.

Collect eDiary device (Section 9.7.1)

Subject satisfaction with Mirena (Section 9.7.4)

Remove the Mirena (Section 9.7.3)

Complete Mirena removal ease (investigator) and pain (subject) 
assessment
New text:
The following procedures and assessments will be done:

Assess vital signs and weight (Section 9.6.3.1)

Perform general physical examination (Section 9.6.3.2)

Perform gynecological examination (with breast palpation; Section 9.6.3.3)

Perform pelvic examination to visualize Mirena removal threads (Section 9.6.3.8)

Obtain cervical smear (Section 9.6.3.5)

Perform urine pregnancy test (Section 9.6.3.4)


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
Perform safety laboratory test and urinalysis (Section 9.6.3.7)

Blood sample for PK (all subjects) (Section 9.5.1)

Interview for the following:

Concomitant medications (Section 8.1)

AEs (Section 9.6.1)

Continuing need for contraception (Section 9.7.1)

Dispense home pregnancy kits with instructions (Section 9.6.3.4)

Review completed (monthly) eDiary, including information on uterine bleeding and 
back-up contraception.
15.1.2.13 Section 9.2.10 3-week follow-up call (EOS)
This section was changed as a result of Modification 15.1.1.6.
Old text:
All subjects will be contacted 3 weeks after EOT (i.e. after Mirena removal) to collect 
information on any pregnancy detected shortly after the end of study treatment.
New text:
All subjects will be contacted 3 weeks after EOT (i.e. after Mirena removal) to collect 
information on any pregnancy detected shortly after the end of study treatment, see Section 
9.4.1.
15.1.2.14 Section 9.2.11 3-month follow-up contact for post-study pregnancies
This section was changed as a result of Modification 15.1.1.6.
Old text:
Subjects who prematurely discontinued study treatment will be contacted by phone unless the 
reason for discontinuation is “pregnancy”, “death”, or “withdrawal by subject” where the 
subject has withdrawn main consent during study conduct and wishes to stop future contact 
with the site. For subjects that had withdrawn consent during study, but consented to post 
study participation follow-up, post treatment pregnancy tracking information is expected.  At 
this time, subjects will be asked if they have been pregnant after the study (i.e. after the 3-
week follow-up call). Please see Section 9.4.1.
New text:
Subjects who prematurely discontinued study treatment will be contacted by phone unless the 
reason for discontinuation is “pregnancy”, “death”, or “withdrawal by subject” where the 
subject has withdrawn main consent during study conduct and wishes to stop future contact 


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with the site. For subjects that had withdrawn consent during study, but consented to post 
study participation follow-up, post treatment pregnancy tracking information is expected.  At 
this time, subjects will be asked if they have been pregnant after the study (i.e. after the 3-
week follow-up call). This contact is part of the Post-Treatment Pregnancy Tracking (PTPT) 
process, see Section 9.4.1.
15.1.2.15 Section 9.2.12 12-months follow-up contact for return-to-fertility
This section was changed as a result of Modification 15.1.1.6.
Old text:
Subjects that prematurely discontinued treatment due to ‘Wish for pregnancy’ will be 
contacted and asked about pregnancies that occurred within 12 months after end of treatment
(EOT, i.e. removal of Mirena). If a subject was not pregnant at 3 month contact and no longer 
wished to become pregnant, a 12-month contact is not required.  If subject was “Lost to 
Follow-up” at 3 months, a 12-month contact is required. Please see Section 9.4.1.
New text:
Subjects that prematurely discontinued treatment due to ‘Wish for pregnancy’ will be 
contacted and asked about pregnancies that occurred within 12 months after end of treatment
(EOT, i.e. removal of Mirena). If a subject was not pregnant at 3 month contact and no longer 
wished to become pregnant, a 12-month contact is not required.  If subject was “Lost to 
Follow-up” at 3 months, a 12-month contact is required. This contact is part of the Post-
Treatment Pregnancy Tracking (PTPT) process, see Section 9.4.1.
15.1.2.16 Section 9.3.1 Demographic
This section was changed as a result of Modification 15.1.1.25.
Old text:
Demographic data [e.g. year of birth, age at the screening (Visit 1), race, ethnic group, 
educational level] and other population characteristics including tobacco use and alcohol 
consumption will be collected at time points presented in Table 9-1.
New text:
Demographic data [e.g. year of birth, age at the screening (Visit 1), age at baseline (Visit 2),
race, ethnic group, educational level] and other population characteristics including tobacco 
use and alcohol consumption will be collected at time points presented in Table 9-1.


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15.1.2.17 Section 9.4.1.1 Pregnancies during the study
This section was changed as a result of Modification 15.1.1.6.
Old text:
The investigator must report to the sponsor any pregnancy occurring in a study subject during 
her participation in this study.  This report is to be submitted within the same timeframe as an 
SAE (i.e. no later than 24 hours of having gained knowledge of the event), although a 
pregnancy, per se, is not considered an AE/SAE. 
New text:
The investigator must report to the sponsor any pregnancy occurring in a study subject during 
her participation in this study including pregnancies detected at the contact 3 weeks after 
EOT.  This report is to be submitted within the same timeframe as an SAE (i.e. no later than 
24 hours of having gained knowledge of the event), although a pregnancy, per se, is not 
considered an AE/SAE. 
15.1.2.18 Section 9.4.1.2 Pregnancies occurring after the end of study treatment
This section was changed as a result of Modification 15.1.1.5 and 15.1.1.6.
Old text:
All pregnancies detected up to 3 months after the removal of the Mirena must be reported to 
the sponsor; all subjects will be instructed to contact the investigator immediately if they 
become pregnant less than 3 months after the removal of the Mirena.  If the estimated date of 
conception is suspected to have occurred during study treatment, further investigations will be 
conducted, and the pregnancy should be reported immediately and will be followed up 
according to the process described above for pregnancies during the study.
3 weeks after EOT:  All subjects will be contacted 3 weeks after EOT to collect information 
on any pregnancy detected shortly after the end of study treatment.
New text:
All pregnancies detected up to 3 months after the removal of the Mirena must be reported to 
the sponsor; all subjects will be instructed to contact the investigator immediately if they 
become pregnant less than 3 months after the removal of the Mirena.  If the estimated date of 
conception is suspected to have occurred during study treatment (i.e. up to 7 days after EOT), 
further investigations will be conducted, and the pregnancy should be reported immediately 
and will be followed up according to the process described above for pregnancies during the 
study. 


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[…]
Old text:
Post study pregnancy tracking information, including information on all pregnancies 
identified, must be reported to the sponsor via electronic data collection tool (see 
Section 11.1).  In addition, if the estimated date of conception is suspected to have occurred 
during study treatment, the pregnancy should be reported immediately according to the 
process described under section 9.4.1.1.
New text:
PTPT information, i.e. data collected at the 3- and 12-month follow-up contacts, including 
information on all pregnancies identified, must be reported to the sponsor via electronic data 
collection tool (see Section 11.1).  In addition, if the estimated date of conception is suspected 
to have occurred during study treatment, the pregnancy should be reported immediately 
according to the process described under section 9.4.1.1.
[…]
15.1.2.19 Section 9.6.3.6 Test for chlamydia
This section was changed as a result of Modification 15.1.1.14.
Old text:
[…]
A single repeat test is permissible if the screening results are positive.  If the test result is 
positive, the subject must also be tested for gonorrhea.  Gonorrhea tests must also be 
performed using a highly accurate test method in a local laboratory that meets the standards of 
GLP. A subject with an active genital infection may not be assigned to study treatment until 
the infection has been successfully treated (see Section 6.2, Exclusion criterion 4).  
[…]
New text:
[…]
A single repeat test is permissible if the screening results are positive.  If the test result is 
positive, the subject must also be tested for gonorrhea.  Gonorrhea tests must also be 
performed using a highly accurate test method that meets the standards of GLP. A subject 
with an active genital infection may not be assigned to study treatment until the infection has 
been successfully treated (see Section 6.2, Exclusion criterion 4).  
[…]


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15.1.2.20 Section 9.6.3.7 Safety laboratory tests
This section was changed as a result of Modification 15.1.1.3.
Old text:
Only blood samples analyzed at the central laboratory will be considered for analysis.  The 
name and address for the central lab service provider can be found in the documentation 
supplied by the vendor.  The safety laboratory tests may be repeated once during the 
screening period if laboratory values are outside the inclusion range and assessed as clinically 
relevant.
New text:
Only blood samples analyzed at the central laboratory will be considered for analysis.  The 
name and address for the central lab service provider can be found in the documentation 
supplied by the vendor.  For a given laboratory parameter, the acceptable values for inclusion 
would consist of values within the reference ranges, measured at baseline, as provided in the 
Covance Central Laboratory Services (CCLS) Manual for Bayer Protocol 18649 (Covance 
Project #: 518179). The safety laboratory tests may be repeated once during the screening 
period if laboratory values are outside the inclusion range and assessed as clinically relevant.
15.1.2.21 Section 9.6.3.8 Presence of Mirena removal threads
This section was changed as a result of Modification 15.1.1.22.
Old text:
[…]
The investigator will perform pelvic examinations at each study visit to verify the presence of 
the Mirena removal threads in the appropriate location in the cervical os.  At the investigator’s 
discretion,transvaginal ultrasound (TVUS) may be performed to verify that the Mirena is in 
the appropriate intrauterine location and to exclude expulsion or perforation.  […]
New text:
[…]
The investigator will perform pelvic examinations at each study visit to verify the presence of 
the Mirena removal threads in the appropriate location in the cervical os. If the presence of 
the removal threads cannot be verified, transvaginal ultrasound (TVUS) is to be performed to 
verify that the Mirena is in the appropriate intrauterine location and to exclude expulsion or 
perforation.  […]


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15.1.2.22 Section 9.6.3.12 Uterine bleeding
This section was changed as a result of Modification 15.1.1.19.
Old text
Table 9-3
Uterine bleeding – bleeding intensity definitions
Category
Intensity
Definition
None
None
No uterine bleeding
Spotting
Spotting
Less than associated with normal menstruation relative to the woman’s 
experience, with no need for sanitary protection except for panty liners
Bleeding
Light
Less than associated with normal menstruation relative to the woman’s 
experience, with need for sanitary protection
Normal
Like normal menstruation relative to the woman’s experience
Heavy
More than normal menstruation relative to the woman’s experience
New text:
Table 9-3
Uterine bleeding – bleeding intensity definitions
Category
Intensity
Bleeding 
Intensity 
Code
Definition
None
None
1
No uterine bleeding
Spotting
Spotting
2
Less than associated with normal menstruation relative to the 
woman’s experience, with no need for sanitary protection 
except for panty liners
Bleeding
Light
3
Less than associated with normal menstruation relative to the 
woman’s experience, with need for sanitary protection
Normal
4
Like normal menstruation relative to the woman’s experience
Heavy
5
More than normal menstruation relative to the woman’s 
experience
15.1.2.23 Section 9.7.1 eDiary
This section was changed as a result of Modification 15.1.1.23.
Old text:
[…]
The use of the eDiary will be explained in detail in a site manual, and the site personnel will 
train the subject on how to use the device at the baseline visit.  At all the following visits (see
Table 9-1), the eDiary entries will be checked and documented by the study site personnel for 
completeness.  […]


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New text:
[…]
Subject will enter her data daily into the eDiary. The use of the eDiary will be explained in 
detail in a site manual, and the site personnel will train the subject on how to use the device at 
the baseline visit.  At all the following visits (see Table 9-1), the eDiary entries will be 
checked and documented by the study site personnel for completeness.  […]
15.1.2.24 Section 9.7.4 Subject satisfaction with Mirena
This section was changed as a result of Modification 15.1.1.1.
Old text:
At baseline visit, visit 6 and at the end of the treatment (EOT, visit 8) (see also Table 9-1), the 
subject is asked to evaluate her satisfaction with the Mirena on a 5-point scale as very 
satisfied, somewhat satisfied, neither satisfied or dissatisfied, dissatisfied or very dissatisfied. 
Information regarding the subject satisfaction will be documented by the investigator in 
eCRF.
New text:
At baseline visit, visit 4, 6 and at the end of the treatment (EOT, visit 8) (see also Table 9-1), 
the subject is asked to evaluate her satisfaction with the Mirena on a 5-point scale as very 
satisfied, somewhat satisfied, neither satisfied or dissatisfied, dissatisfied or very dissatisfied. 
Information regarding the subject satisfaction will be documented by the investigator in 
eCRF.
15.1.2.25 Section 10.2 Analysis sets
This section was changed as a result of Modification 15.1.1.1, 15.1.1.18 and 15.1.1.25.
Old text:
The documentation of important deviations and the assignment of subjects to analysis sets 
will be performed according to the sponsor’s applicable Standard Operating Procedures 
and/or Instruction Manuals.  
The following statistical analysis sets will be defined:
Full analysis set (FAS): 
All women who completed the baseline visit of the study
Primary analysis set Year 7 (PAS year 7):
All women in the FAS with an age of 34 years or younger at baseline visit (i.e., an age of 36 
or younger at end of year 7)
Primary analysis set Year 8 (PAS year 8): 
All women in the FAS with an age of 33 years or younger at baseline visit (i.e., an age of 36 
or younger at end of year 8)


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Safety analysis set (SAF):
All women who completed the baseline visit of the study, analyzed for the FAS
The age at baseline (required for PAS year 7 and PAS year 8) will be approximated as the 
difference between year of baseline visit and year of birth recorded at screening visit.  
New text:
The documentation of important deviations and the assignment of subjects to analysis sets 
will be performed according to the CRO´s applicable Standard Operating Procedures and/or 
Instruction Manuals.  
The following statistical analysis sets will be defined:
Full analysis set (FAS): 
All women who completed the baseline visit of the study
Primary analysis set Year 6 (PAS year 6):
All women in the FAS with an age of 35 years or younger at baseline visit (i.e., an age of 36 
or younger at end of year 6)
Primary analysis set Year 7 (PAS year 7):
All women in the FAS with an age of 34 years or younger at baseline visit (i.e., an age of 36 
or younger at end of year 7)
Primary analysis set Year 8 (PAS year 8): 
All women in the FAS with an age of 33 years or younger at baseline visit (i.e., an age of 36 
or younger at end of year 8)
Safety analysis set (SAF):
All women who completed the baseline visit of the study, analyzed for the FAS
The age at baseline (required for PAS year 6, PAS year 7 and PAS year 8) will be used as 
recorded at the baseline visit 2.  
15.1.2.26 Section 10.3 Variables and planned statistical analyses
This section was changed as a result of Modification 15.1.1.26.
New text added (no old text):
In order to allow some flexibility, the baseline visit is planned to take place 14 to 0 days 
before the end of Year 5 of Mirena use (see Table 9-1). As a consequence, it is expected there 
will be various subjects with that baseline visit taking place prior to the start of ‘extension 
treatment period’, i.e. Day 1 of Year 6 of Mirena use. 
Variables collected on an ongoing basis will primarily be analyzed for the ‘extension 
treatment period’ starting at Day 1 of Year 6 of Mirena use, i.e., data collected between the 
baseline visit and Day 1 of Year 6 of Mirena use will be excluded: 

Primary efficacy variable, i.e. occurrence of pregnancies (section 10.3.2.1) 


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
Main safety variable, i.e. adverse events (section 10.3.2.3.1) 

Uterine bleeding / bleeding pattern (section 10.3.2.3.2) 
Variables collected at pre-specified visits/timeframes only will be analyzed per visit (unless 
otherwise stated): 

Secondary efficacy variable, i.e. menstrual blood loss (section 10.3.2.2) 

Other safety variables, not listed above (section 10.3.2.3) 

Other variables (section 10.3.2.4) 
More details will be provided in the statistical analysis plan. 
15.1.2.27 Section 10.3.1.1.1 Primary efficacy variable
This section was changed as a result of Modifications 15.1.1.1 and 15.1.1.26.
Old text:
The primary efficacy variable is the occurrence of pregnancy within years 6 thru 8 of Mirena 
use. However, for the analysis after 7 years, the primary efficacy variable is the occurrence of 
pregnancy within years 6 thru 7 of Mirena use. 
The PI is defined as the number of pregnancies per 100 woman years. The following PIs will 
be calculated:

'Two years PI (sixth & seventh year)', PI obtained in the sixth and seventh year of 
treatment, i.e., number of pregnancies that occurred during the sixth and seventh year 
of treatment divided by time the women were under risk of getting pregnant in the 
sixth and seventh year of treatment.

'Three years PI (sixth, seventh & eighth year)', PI obtained in the sixth, seventh and 
eighth year of treatment, i.e., number of pregnancies that occurred during the sixth, 
seventh and eighth year of treatment divided by time the women were under a risk of 
getting pregnant in the sixth, seventh and eighth year of treatment.

'Overall PI', PI obtained during the whole study, i.e., number of pregnancies that 
occurred during the studied treatment period beyond 5 years divided by the time the 
women were under a risk of getting pregnant.
New text:
The primary efficacy variable is the occurrence of pregnancy within years 6 thru 8 of Mirena 
use. However, for the analysis after 6 years of Mirena use, the primary efficacy variable is the 
occurrence of pregnancy within year 6 of Mirena use, and for the analysis after 7 years, the 
primary efficacy variable is the occurrence of pregnancy within years 6 thru 7 of Mirena use. 
The PI is defined as the number of pregnancies per 100 woman years. The Pearl Index will be 
analyzed for the ‘extension treatment period’ starting at Day 1 of Year 6 of Mirena use, i.e., 


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exposure and pregnancies between the baseline visit and Day 1 of Year 6 of Mirena use will 
be excluded. The following PIs will be calculated:

'1-year PI’ (sixth year)', PI obtained in the sixth year of treatment, i.e., number of 
pregnancies that occurred during the sixth year of treatment divided by time the 
women were under risk of getting pregnant in the sixth year of treatment.

'2-year PI (sixth & seventh year)', PI obtained in the sixth and seventh year of 
treatment, i.e., number of pregnancies that occurred during the sixth and seventh year 
of treatment divided by time the women were under risk of getting pregnant in the 
sixth and seventh year of treatment.

'3-year PI (sixth, seventh & eighth year)', PI obtained in the sixth, seventh and eighth 
year of treatment, i.e., number of pregnancies that occurred during the sixth, seventh 
and eighth year of treatment divided by time the women were under a risk of getting 
pregnant in the sixth, seventh and eighth year of treatment.
Furthermore, the following PI will be analyzed for the entire study period starting at baseline 
visit, i.e., exposure and pregnancies between the baseline visit and Day 1 of Year 6 of Mirena 
use will be included: 

'Overall PI', PI obtained during the whole study, i.e., number of pregnancies that 
occurred during the entire study period starting at baseline visit divided by the time the 
women were under a risk of getting pregnant.
15.1.2.28 Section 10.3.1.2 Safety variables
This section was changed as a result of Modification 15.1.1.15 and 15.1.1.26.
Old text:
The main safety variable is the incidence of post baseline adverse events (both serious and 
non-serious). 
Other safety variables are: 

Uterine bleeding / Bleeding pattern 

Vital signs and weight 

Physical examination 

Gynecological examination 
[…]
New text:
The main safety variable is the incidence of treatment-emergent adverse events (both serious 
and non-serious). Treatment-emergent AEs are defined as any AEs occurring during the 
‘extension treatment period’ starting at Day 1 of Year 6 of Mirena use.


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Other safety variables are: 

Uterine bleeding / Bleeding pattern 

Vital signs and weight 
[…]
15.1.2.29 Section 10.3.2.1 Analysis of the primary variable
This section was changed as a result of Modification 15.1.1.1, 15.1.1.5, 15.1.1.7, 15.1.1.8,
15.1.1.9 and 15.1.1.26.
Old text:
The primary variable is the occurrence of pregnancy within years 6-8 of Mirena use.
However, for the analysis after 7 years, the primary variable is the occurrence of pregnancy 
within years 6 thru 7 of Mirena use.
New text:
The primary variable is the occurrence of pregnancy within years 6-8 of Mirena use.
However, for the analysis after 6 years, the primary variable is the occurrence of pregnancy 
within years 6 of Mirena use, and for the analysis after 7 years, the primary variable is the 
occurrence of pregnancy within years 6 thru 7 of Mirena use.
[…]
Old text:
Table 10–1 Definition of crude exposure times
PI
Reason for end of 
study/ continuation 
status
Crude exposure time
Two years
PI (sixth & 
seventh 
year)
Total expulsion
Date, when expulsion was realized –Baseline visit date +1
Partial Expulsion/ Mirena
removal
Date of Mirena removal – Baseline visit date +1
Pregnancy
Date of conception – Baseline visit date +1
Lost to Follow up
Max (Date Mirena last known in situ – Baseline visit date +1, 0)
Continues into 8th year of 
treatment
730 days
Three years
PI (sixth, 
seventh & 
eighth 
year)
Total expulsion
Date, when expulsion was realized –Baseline visit date +1
Partial Expulsion/ Mirena
removal
Date of Mirena removal – Baseline visit date +1
Pregnancy
Date of conception – Baseline visit date +1
Lost to Follow up
Max (Date Mirena last known in situ – Baseline visit date +1, 0)


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PI
Reason for end of 
study/ continuation 
status
Crude exposure time
Continues into 9th year of 
treatment
Min (1095 days, Date of EOT visit – Baseline visit date +1) 
Overall PI
Total expulsion
Date, when expulsion was realized –Baseline visit date +1
Partial Expulsion/ Mirena
removal
Date of Mirena removal – Baseline visit date +1
Pregnancy
Date of conception – Baseline visit date +1
Lost to Follow up
Max (Date Mirena last known in situ – Baseline visit date +1, 0)
Continued until EOT
Date of EOT visit – Baseline visit date +1
A pregnancy will be allocated to the time period(s) that are relevant for the calculation of the 
PIs described above, e.g., a pregnancy that occurs on day 400 will be relevant for the 7th year 
PI, the two years PI (6th and 7th year), the three years PI (6th, 7th and 8th year), and the 
overall PI. Pregnancies that occur after the Mirena was removed or an expulsion was realized 
will not count for any PI.
[…]
Exposure times to be subtracted:
Subjects who apply additional concomitant contraception are not in risk or are under a lower 
risk of getting pregnant than subjects who do not apply additional contraception. In case a 
subject uses concomitant contraceptive methods (e.g., condoms to prevent STD) the period of 
additional contraceptive method use will be excluded from the exposure time.
[…]
The primary analysis set will be the PAS year 7 (for the analysis after 7 years) and the PAS 
year 8 (for the final analysis after 8 years), respectively. Furthermore, analyses will be 
repeated for the FAS. 


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New text:
Table 10–1 Definition of crude exposure times – amended
PI
Reason for end of 
study/ continuation 
status
Crude exposure time
1-year PI 
(6th year)
Total expulsion
Date, when expulsion was discovered – Date of Day 1 Year 6 
+1
Partial Expulsion/ 
Mirena removal
Date of Mirena removal – Date of Day 1 Year 6 +1
Pregnancy
Date of conception – Date of Day 1 Year 6 +1
Lost to Follow up
Maximum of (Date Mirena last known in situ – Date of Day 1 
Year 6 +1; 1 day)
Continues into 7th year 
of treatment
365 days
2-year PI 
(6th and 
7th year)
Total expulsion
Date, when expulsion was discovered – Date of Day 1 Year 6
+1
Partial Expulsion/ 
Mirena removal
Date of Mirena removal – Date of Day 1 Year 6 +1
Pregnancy
Date of conception – Date of Day 1 Year 6 +1
Lost to Follow up
Maximum of (Date Mirena last known in situ – Date of Day 1 
Year 6 +1; 1 day)
Continues into 8th year 
of treatment
730 days
3-year PI 
(6th, 7th 
and 8th 
year)
Total expulsion
Date, when expulsion was discovered – Date of Day 1 Year 6
+1
Partial Expulsion/ 
Mirena removal
Date of Mirena removal – Date of Day 1 Year 6 +1
Pregnancy
Date of conception – Date of Day 1 Year 6 +1
Lost to Follow up
Maximum of (Date Mirena last known in situ – Date of Day 1 
Year 6 +1; 1 day)
Continues into 9th year 
of treatment
Minimum of (1095 days; Date of EOT visit – Date of Day 1 
Year 6 +1)
Overall PI
Total expulsion
Date, when expulsion was discovered –Baseline visit date +1
Partial Expulsion/ 
Mirena removal
Date of Mirena removal – Baseline visit date +1
Pregnancy
Date of conception – Baseline visit date +1
Lost to Follow up
Maximum of (Date Mirena last known in situ – Baseline visit 
date +1; 1 day)
Continued until EOT
Date of EOT visit – Baseline visit date +1


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A pregnancy will be allocated to the time period(s) that are relevant for the calculation of the 
PIs described above, e.g., a pregnancy that occurs on day 400 will be relevant for the 7th year 
PI, the two years PI (6th and 7th year), the three years PI (6th, 7th and 8th year), and the 
overall PI. Pregnancies that occur before Day 1 Year 6 of Mirena use will not count for the 1-
year PI, 2-year PI and 3-year PI.  Pregnancies that occur after the Mirena was removed or an 
expulsion was realized will not count for any PI.
[…]
Furthermore, it should be noted that pregnancies that occur within 7 days after the end of 
exposure will count for the PIs. 
Exposure times to be subtracted: 
Subjects who apply additional concomitant contraception are not in risk or are under a lower 
risk of getting pregnant than subjects who do not apply additional contraception. In case a 
subject uses concomitant contraceptive methods (e.g., condoms to prevent STD) the 
respective 28-day reference period(s) of additional contraceptive method use will be excluded 
from the exposure time, unless a pregnancy occurred in that 28-day reference period. 
[…]
The primary analysis set will be the PAS Year 6 (for the analysis after 6 years), the PAS Year 
7 (for the analysis after 7 years) and the PAS Year 8 (for the final analysis after 8 years), 
respectively. Furthermore, analyses will be repeated for the FAS. 
[…]
15.1.2.30 Section 10.3.2.2.1 Menstrual blood loss
This section was changed as a result of Modification 15.1.1.10.
Old text:
[…]
The basis for this analysis is the data on MBL assessed by the alkaline hematin method (see 
section 9.4.2). If a woman has documented in the eDiary (see section 9.7.1) that no bleeding 
occurred during one of the considered 30-day time periods for collection of sanitary 
protection, the MBL will be assumed to be zero in that time period.
This analysis will be conducted in the FAS in the subgroup of women who had Mirena 
inserted for HMB.
New text:
[…]
The basis for this analysis is the data on MBL assessed by the alkaline hematin method (see 
section 9.4.2). If a woman has documented in the eDiary (see section 9.7.1) that no bleeding 
occurred during one of the 30-day time periods considered for collection of sanitary products, 


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the MBL will be assumed to be zero in that time period. The handling of partial or missing 
data (i.e. data on sanitary products and/or bleeding intensities) and detailed imputation rules 
will be described in the statistical analysis plan. 
This analysis will be conducted in the FAS in the HMB subgroup, i.e. women who had 
Mirena inserted for both contraception and HMB.
[…]
15.1.2.31 Section 10.3.2.2.2 Categorized menstrual blood loss (MBL) (<80ml / 30 
days)
This section was changed as a result of Modification 15.1.1.11.
Old text:
No clinical change in bleeding profile regarding HMB will be concluded if the volume of 
blood loss remains < 80mL during the end of years 6, 7 and 8. Therefore, the proportion of 
women with an MBL <80 mL / 30 days will analyzed.  Descriptive statistics as well as 95% 
Clopper-Pearson confidence intervals will be provided for each of the time periods in which 
HMB is assessed. Success will be concluded regarding this endpoint if less than 20% of the 
women included into the study for HMB have a clinical change in bleeding profile (according 
to the definition above).
This analysis will be conducted in the FAS in the subgroup of women who had Mirena 
inserted for HMB.
New text:
No clinical change in bleeding profile regarding HMB after Year 5 until the end of Year 6, 
until the end of Year 7 and until the end of Year 8, respectively, will be concluded if the 
volume of blood loss was < 80mL at the beginning of Year 6 and remained < 80mL at the end 
of Years 6, 7 and 8, respectively. Vice versa, clinical change in bleeding profile regarding 
HMB after Year 5 until the end of Year 6, end of Year 7 and end of Year 8, respectively, will 
be concluded if the volume of blood loss was ≥ 80mL at the beginning of Year 6 or at end of 
Years 6, 7 or 8, respectively.
Therefore, the proportion of women with clinical change in bleeding profile regarding HMB 
will be analyzed.  Descriptive statistics as well as 95% Clopper-Pearson confidence intervals 
will be provided. 
For the analysis after 6 years, the proportion of women with clinical change in bleeding 
profile regarding HMB after Year 5 until the end of Year 6 will be analyzed. 
For the analysis after 6 years, the following women will constitute the denominator: 

Baseline MBL>80mL/30days, or 

Baseline MBL not >80mL/30days and 
End of Year 6 MBL assessment available. 


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That means, women with Baseline MBL not >80mL/30days and MBL assessment at the end 
of Year 6 not available will be excluded from the denominator, as they are considered lost to 
follow up without preceding clinical change in bleeding profile regarding HMB. 
For the analysis after 6 years, the following women will constitute the nominator: 

Baseline MBL>80mL/30days, or 

End of Year 6 MBL>80mL/30days. 
For the analysis after 7 years, the proportion of women with clinical change in bleeding 
profile regarding HMB after Year 5 until the end of Year 7 will be analyzed. 
For the analysis after 7 years, the following women will constitute the denominator: 

Baseline MBL>80mL/30days, or 

End of Year 6 MBL>80mL/30days, or 

Baseline MBL not >80mL/30days and 
End of Year 6 MBL not >80mL/30days and 
End of Year 7 MBL assessment available. 
That means, women with Baseline MBL not >80mL/30days, MBL at the end of Year 6 not 
>80mL/30days and MBL assessment at the end of Year 7 not available will be excluded from 
the denominator, as they are considered lost to follow up without preceding clinical change in 
bleeding profile regarding HMB. 
For the analysis after 7 years, the following women will constitute the nominator: 

Baseline MBL>80mL/30days, or 

End of Year 6 MBL>80mL/30days, or 

End of Year 7 MBL>80mL/30days.
For the final analysis after 8 years, the proportion of women with clinical change in bleeding 
profile regarding HMB after Year 5 until the end of Year 8 will be analyzed. 
For the analysis after 8 years, the following women will constitute the denominator: 

Baseline MBL>80mL/30days, or 

End of Year 6 MBL>80mL/30days, or 

End of Year 7 MBL>80mL/30days, or 

Baseline MBL not >80mL/30days and 
End of Year 6 MBL not >80mL/30days and 
End of Year 7 MBL not >80mL/30days and 
End of Year 8 MBL assessment available. 
That means, women with Baseline MBL not >80mL/30days, MBL at the end of Year 6 not 
>80mL/30days, MBL at the end of Year 7 not >80mL/30days and MBL assessment at the end 
of Year 8 not available will be excluded from the denominator, as they are considered lost to 
follow up without preceding clinical change in bleeding profile regarding HMB. 
For the analysis after 8 years, the following women will constitute the nominator: 


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
Baseline MBL>80mL/30days, or 

End of Year 6 MBL>80mL/30days, or 

End of Year 7 MBL>80mL/30days, or 

End of Year 8 MBL>80mL/30days. 
Success will be concluded regarding this endpoint if less than 20% of the women in the HMB
subgroup have a clinical change in bleeding profile regarding HMB (according to the 
definition above) and the upper limit of the corresponding 95% Clopper-Pearson confidence 
interval is equal to or less than 35%.
This analysis will be conducted in the FAS in the HMB subgroup, i.e. women who had 
Mirena inserted for both contraception and HMB.
15.1.2.32 Section 10.3.2.3 Analysis of safety variables
This section was changed as a result of Modification 15.1.1.15 and 15.1.1.26.
Old text:
All safety variables will be analyzed based on the SAF.
The main safety variable is the incidence of post baseline adverse events (both serious and 
non-serious).
New text:
All safety variables will be analyzed based on the SAF.
The main safety variable is the incidence of treatment-emergent adverse events (both serious 
and non-serious). Treatment-emergent AEs are defined as any AEs occurring during the 
‘extension treatment period’ starting at Day 1 of Year 6 of Mirena use.
15.1.2.33 Section 10.3.2.3.2 Bleeding pattern
This section was changed as a result of Modification 15.1.1.10, 15.1.1.19 and 15.1.1.26.
Old text:
Bleeding diary data will be analyzed according to the sponsor’s Best practice entitled 
“Recording and evaluation of bleeding data”.
[…]


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Table 10–2
Bleeding Intensity Codes and WHO Definitions for Bleeding Intensity
Bleeding Intensity
Codes
WHO Definitions
3 - 5
Bleeding/spotting episode:
Day(s) with bleeding/spotting preceded 
and followed by at least 2 bleeding-free 
days.
2
Spotting-only episode:
Day(s) with spotting preceded and followed 
by at least 2 bleeding-free days.
1
Bleeding/spotting-free interval:
At least 2 days without bleeding/spotting 
preceded and followed by at least 1 
bleeding/spotting day.
[…]
Based on daily data obtained from the electronic diary, the bleeding pattern will be reported 
using reference periods of 28 and 90 days.  The first 28-day and 90-day reference period, 
respectively, will start at the baseline visit (Visit 2).  For each subject and for each period, the 
number of bleeding/spotting days and bleeding/spotting episodes will be calculated.[…]
New text:
Bleeding diary data during the ‘extension treatment period’ starting at Day 1 of Year 6 of 
Mirena use will be analyzed according to the sponsor’s Best Practice Document entitled 
“Recording and evaluation of bleeding data”. Bleeding diary data prior to the ‘extension 
treatment period’ will not be included in the analyses. The handling of partial or missing data 
and detailed imputation rules will be described in the statistical analysis plan.
[…]
Table 10–2
Bleeding Intensity Codes and WHO Definitions for Bleeding Intensity –
amended 
Bleeding Intensity
Codes
WHO Definitions
2 - 5
Bleeding/spotting episode:
Day(s) with bleeding/spotting preceded 
and followed by at least 2 bleeding-free 
days.
2
Spotting-only episode:
Day(s) with spotting preceded and followed 
by at least 2 bleeding-free days.
1
Bleeding/spotting-free interval:
At least 2 days without bleeding/spotting 
preceded and followed by at least 1 
bleeding/spotting day.
[…]
Based on daily data obtained from the electronic diary, the bleeding pattern will be reported 
using reference periods of 28 and 90 days.  The first 28-day and 90-day reference period, 


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respectively, will start at Day 1 of Year 6 of Mirena use.  For each subject and for each 
period, the number of bleeding/spotting days and bleeding/spotting episodes will be 
calculated. […]
15.1.2.34 Section 10.5 Planned interim analyses
This section was changed as a result of Modification 15.1.1.1.
Old text:
No formal interim analysis in the sense of a group sequential or adaptive design is planned. 
However, an analysis of the data is planned after year 7, including all subjects who have 
prematurely discontinued or completed Visit 6, i.e. treated with Mirena for up to 7 years (2 
years in the study).
New text:
No formal interim analysis in the sense of a group sequential or adaptive design is planned. 
However, an analysis of the data is planned after Year 6, including all subjects who have 
prematurely discontinued or completed Visit 4, i.e. treated with Mirena for up to 6 years 
(1 year in the study). Another analysis of the data is planned after Year 7, including all 
subjects who have prematurely discontinued or completed Visit 6, i.e. treated with Mirena for 
up to 7 years (2 years in the study).
15.1.2.35 Section 11.1 Data recording
This section was changed as a result of Modification 15.1.1.23.
Old text:
The data collection tool for this study will be eCRF; a validated electronic data capture system 
called RAVE.  Subject data necessary for analysis and reporting will be entered/transmitted 
into a validated database or data system (CIE/TOSCA; SAS).  
Covance will perform the data entry for this study.  Data will be entered by site personnel into 
an internet based electronic data capture software system RAVE, which Covance has licensed 
from Medidata Solutions Worldwide. RAVE has been validated by Medidata Solutions 
Worldwide and Covance for use in its clinical studies.  […]
New text:
The data collection tool for this study will be eCRF; a validated electronic data capture system 
called RAVE.  Subject data necessary for analysis and reporting will be entered/transmitted 
into a validated database or data system (e.g. CIE/TOSCA; SAS).  
Data will be entered by site personnel into an internet based electronic data capture software 
system RAVE, which Covance has licensed from Medidata Solutions Worldwide. RAVE has 


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been validated by Medidata Solutions Worldwide and Covance for use in its clinical studies.  
[…]
15.1.2.36 Section 13.1 Investigators and other study personnel
New text added:
The name and contact information for the Sponsor’s Study Medical Expert is provided in 
Section 1.  The co-ordinating investigator who will be responsible for signing the CSR, is 
 (study center #
  All other study personnel not included in 
this section are identified in a separate personnel list (not part of this clinical study protocol) 
as appropriate. […]
15.1.2.37 Section 14 Reference list
This section was changed as a result of Modification 15.1.1.20.
Old text:
1.
Rowe P, Farley T, Peregoudov A, Piaggio G, Boccard S, Landoulsi S, Meirik O; IUD 
Research Group of the UNDP/UNFPA/WHO/World Bank Special Programme of 
Research; Development and Research Training in Human Reproduction. Safety and 
efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 
7-year randomized comparative study with the TCu380A. Contraception. 2016 
Jun;93(6):498-506. doi: 10.1016/j.contraception.2016.02.024. Epub 2016 Feb 23.
2.
Sivin I, Stern J, Coutinho E, Mattos CER, El Mahgoub S, Diaz S 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;44:473-80.
New text:
1.
McNicholas C, Swor E, Wan L, Peipert JF. Prolonged use of the etonogestrel implant 
and levonorgestrel intrauterine device: 2 years beyond Food and Drug Administration-
approved duration. Am J Obstet Gynecol. 2017 Jan 29[Epub ahead of print].
2.
Rowe P, Farley T, Peregoudov A, Piaggio G, Boccard S, Landoulsi S, Meirik O; IUD 
Research Group of the UNDP/UNFPA/WHO/World Bank Special Programme of 
Research; Development and Research Training in Human Reproduction. Safety and 
efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 
7-year randomized comparative study with the TCu380A. Contraception. 2016 
Jun;93(6):498-506. doi: 10.1016/j.contraception.2016.02.024. Epub 2016 Feb 23.
3.
Sivin I, Stern J, Coutinho E, Mattos CER, El Mahgoub S, Diaz S 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;44:473-80.
PPD
PPD

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
Multi-center, open-label, uncontrolled study to assess 
contraceptive efficacy and safety of Mirena during extended 
use beyond 5 years in women 18 to 35 years of age 
including a subgroup evaluation of treatment effect on 
heavy menstrual bleeding 
NCT Number: 
NCT02985541 
Document Date: 
10-Jun-2021 
 


Statistical Analysis Plan (Supplement)
Protocol No.: BAY 86-5028 / 18649
Page: 1 of 42
Multi-center, open-label, uncontrolled study to assess contraceptive efficacy 
and safety of Mirena during extended use beyond 5 years in women 18 to 35 
years of age including a subgroup evaluation of treatment effect on heavy 
menstrual bleeding
Mirena Extended Trial (MET)
Bayer study drug
Levonorgestrel BAY86-5028 / levonorgestrel-releasing intrauterine 
system, Mirena
Study purpose:
Efficacy
Clinical study 
phase:
3
Date:
10 June 2021
Study No.:
18649
Version:
5.0 (supplement, after 
Year 7 database lock, 
prior to Year 8 database 
lock)
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


Statistical Analysis Plan (Supplement)
Protocol No.: BAY 86-5028 / 18649
Page: 2 of 42
Table of Contents
Table of Tables.......................................................................................................................... 3
Table of Figures........................................................................................................................ 3
Abbreviations............................................................................................................................ 4
1.
Introduction ....................................................................................................................... 5
2.
Study Objectives................................................................................................................ 5
3.
Study Design ...................................................................................................................... 5
4.
General Statistical Considerations .................................................................................. 7
4.1
General Principles............................................................................................................ 7
4.1.1
‘Treatment Period’ versus ‘Extension Treatment Period”............................................ 7
4.2
Handling of Dropouts ...................................................................................................... 8
4.3
Handling of Missing Data................................................................................................ 8
4.4
Handling of Missing Bleeding Intensities and Censored eDiaries ................................ 10
4.5
Handling of Censored and Missing Menstrual Blood Loss (MBL) Data ...................... 10
4.6
Interim Analyses and Data Monitoring.......................................................................... 15
4.7
Data Rules...................................................................................................................... 16
4.8
Data Review................................................................................................................... 18
5.
Analysis Sets..................................................................................................................... 19
5.1
Assignment of analysis sets ........................................................................................... 19
6.
Statistical Methodology................................................................................................... 19
6.1
Population characteristics .............................................................................................. 19
6.1.1
Disposition.................................................................................................................. 19
6.1.2
Demographics............................................................................................................. 20
6.1.2.1
Baseline characteristics ........................................................................................... 20
6.1.2.2
Medical, reproductive and menstrual history.......................................................... 20
6.1.2.3
Previous and concomitant medications ................................................................... 21
6.1.3
Study drug administration and compliance ................................................................ 21
6.1.3.1
Insertion procedure.................................................................................................. 21
6.1.3.2
Removal procedure.................................................................................................. 22
6.1.3.3
Expulsion rates ........................................................................................................ 22
6.1.3.4
Discontinuation rates............................................................................................... 22
6.1.3.5
Compliance.............................................................................................................. 23
6.1.3.6
Extent of exposure................................................................................................... 24
6.2
Efficacy.......................................................................................................................... 24
6.2.1
Primary efficacy variable............................................................................................ 24
6.2.2
Secondary efficacy variables ...................................................................................... 30
6.2.2.1
Menstrual blood loss ............................................................................................... 30
6.2.2.2
Categorized menstrual blood loss (<80 mL / 30 days)............................................ 31
6.3
Pharmacokinetics/pharmacodynamics........................................................................... 33
6.3.1
Pharmacokinetics........................................................................................................ 33
6.3.2
Pharmacodynamics..................................................................................................... 34


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6.4
Safety ............................................................................................................................. 34
6.4.1
Pretreatment adverse events ....................................................................................... 35
6.4.2
Treatment-emergent adverse events ........................................................................... 35
6.4.2.1
Perforation rates ...................................................................................................... 35
6.4.2.2
Pelvic inflammatory disease.................................................................................... 36
6.4.3
Uterine bleeding / bleeding pattern............................................................................. 36
6.4.4
Safety laboratory parameters ...................................................................................... 38
6.4.5
Vital signs and body weight ....................................................................................... 38
6.4.6
Further safety variables............................................................................................... 38
6.4.6.1
Cervical smear......................................................................................................... 38
6.4.6.2
Chlamydia test......................................................................................................... 38
6.4.6.3
Gynecological ultrasound........................................................................................ 39
6.4.6.4
Pregnancy test.......................................................................................................... 39
6.4.6.5
Death ....................................................................................................................... 39
6.4.6.6
Post-treatment pregnancy and return-to-fertility tracking....................................... 39
6.5
Patient / investigator reported outcomes........................................................................ 39
6.5.1
Subject satisfaction with Mirena ................................................................................ 39
6.5.2
Ease of and pain during Mirena removal.................................................................... 39
6.5.3
Continuing need of contraception............................................................................... 39
6.6
Covid-19 pandemic........................................................................................................ 40
7.
Document history and changes in the planned statistical analysis ............................. 40
8.
References ........................................................................................................................ 42
Table of Tables
Table 4–1: Different types of (complete/ incomplete/ missing) MBL data expected .............. 12
Table 6–1: Definition of crude exposure times........................................................................ 26
Table of Figures
Figure 3–1 Overview of the Study Design ................................................................................ 6


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Abbreviations
AE
Adverse event
BPD
Best Practice Document
CI
Confidence interval
eCRF
Electronic Case Report Form
FAS
Full analysis set
HMB
Heavy menstrual bleeding
LLOQ
Lower limit of quantification
LNG 
Levonorgestrel
LNG IUS
Levonorgestrel-releasing intrauterine system
MBL
Menstrual blood loss
MedDRA
Medical Dictionary for Regulatory Activities
M&S
Modeling & Simulation
PAS
Primary analysis set
PD
Protocol deviation
PI
Pearl index
PID
Pelvic inflammatory disease
PK
Pharmacokinetic
PT
Preferred term 
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical Analysis Plan
SHBG
Sex hormone binding globulin
SOC
System organ class 
TVUS
Transvaginal ultrasound 
WHO
World Health Organization


Statistical Analysis Plan (Supplement)
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1.
Introduction
Mirena, a levonorgestrel-releasing intrauterine system (LNG IUS; initial in vitro release rate 
20 µg LNG / day), has been proven a safe and reliable method of contraception over the 5 
years of labeled use. It has been on the market since the mid-1990s in most European 
countries and since 2001 in the US. 
This study will evaluate the contraceptive efficacy of Mirena during extended use for up to 8 
years. The stability of the effect on heavy menstrual bleeding (HMB) during extended use will 
be studied in a subgroup of women for whom Mirena was prescribed for HMB (as a 
secondary indication to contraception). 
The Statistical Analysis Plan (SAP) is based on the Integrated Protocol v2.0 (dated 20 SEP
2017), and describes the analysis planned after Year 6, the analysis planned after Year 7 and 
the final analysis after 8 years of extended use of Mirena. Further details about the analysis 
planned after Year 6 and Year 7, respectively, are given in Section 4.6. 
The SAP v3.0 (supplement) describes post-hoc analyses planned after the Year 6 database 
lock. The SAP v4.0 (supplement) describes clarifications/corrections and additions, 
introduced prior to Year 7 database lock. All changes/additions are summarized in the 
document history in Section 7. 
2.
Study Objectives
Primary objective of the study is to assess the contraceptive efficacy of Mirena beyond 5 years 
and up to 8 years of use.
Secondary objectives for the study are the assessment of menstrual blood loss (in women that 
had Mirena inserted for the indication HMB) and safety.
Further objectives are the population pharmacokinetic evaluation of LNG plasma 
concentration data and evaluation of user satisfaction.
3.
Study Design
This is a multi-center, open-label, uncontrolled, single group study to be conducted in the US 
only. Study design is presented below in Figure 3–1.


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Figure 3–1
Overview of the Study Design
The target for the total number of women to be included in the extended treatment period is 
360 women (200 women to complete study treatment). To evaluate the effect of extended 
Mirena use on HMB, it is targeted that 10% of the women to be treated (i.e. 36 women out of 
360) should have Mirena prescribed for the treatment of HMB in addition to contraception. 
Please note subjects who have Mirena prescribed for contraception and HMB will have to 
consent to the HMB subgroup procedures.
The study will consist of a screening, treatment, and a follow-up period. Screening can be 
started when the subject has had the Mirena in place for 4 years and 6 months. Screening 
activities should be completed within 60 days after signed informed consent to allow enough 
time for the evaluation of the subjects’ eligibility to the study. Baseline visit (Visit 2) will be 
scheduled to take place 0 to 14 days before the end of Year 5 of Mirena use; and this is the 
start of the ‘treatment period’. The ‘treatment period’ is defined as the 3-year period following 
the baseline visit, whereas the ‘extension treatment period’ is defined as the 3-year period 
following Day 1 of Year 6 of Mirena use, i.e. Years 6, 7 and 8 of extended use of Mirena
(refer to Section 4.1.1 for further details).
Analyses of the efficacy and safety data will be conducted after all subjects have either 
completed 6 and 7 years of treatment, respectively, or prematurely terminated their study 
participation before this time point.
Final analysis will be done after all subjects have either completed 8 years of treatment or 
prematurely terminated their study participation.


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4.
General Statistical Considerations
4.1
General Principles
The statistical evaluation will be performed by using the software package SAS release 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA). All variables will be analyzed by descriptive 
statistical methods. The number of data available and missing data, mean, standard deviation, 
minimum, quartiles, median, and maximum will be calculated for metric data. Mean, standard 
deviation, quartiles and median will be presented with one more decimal place than raw data; 
minimum and maximum will be presented with the same number of decimal places like raw 
data. Frequency tables will be generated for categorical data.
Summary tables on disposition and demographics will be displayed with three columns: 

Subjects in HMB subgroup, i.e. indication “Contraception and HMB”

Subjects not in HMB subgroup, i.e. indication “Contraception” 

Total subjects 
Summary tables on study drug administration, efficacy, safety and pharmacokinetics will be 
displayed with one column: 

Total subjects 
4.1.1
‘Treatment Period’ versus ‘Extension Treatment Period”
In order to allow some flexibility, the baseline visit is planned to take place 0 to 14 days 
before the end of Year 5 of Mirena use (see Integrated Protocol Table 9–1); and this is the 
start of the ‘treatment period’. The ‘extension treatment period’ will start at Day 1 of Year 6 
of Mirena use. As a consequence of the visit window, it is expected there will be various 
subjects with this baseline visit taking place prior to the start of the ‘extension treatment 
period’. Please also refer to Section 4.7. 
The following variables, collected on an ongoing basis, will primarily be analyzed for the 
‘extension treatment period’ starting at Day 1 of Year 6 of Mirena use, i.e., data collected 
between the baseline visit and Day 1 of Year 6 of Mirena use will be excluded: 

Primary efficacy variable, i.e. occurrence of pregnancies (Section 6.2.1) 

Main safety variable, i.e. adverse events (Section 6.4.2) 

Uterine bleeding / bleeding pattern (Section 6.4.3) 
The following variables, collected at pre-specified visits/timeframes only, will be analyzed per 
visit (unless otherwise stated): 

Secondary efficacy variable, i.e. menstrual blood loss (Section 6.2.2) 

Other safety variables, not listed above (Sections 6.4.4, 6.4.5, 6.4.6) 

Other variables (Section 6.4.6.6) 


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4.2
Handling of Dropouts
Depending on the time point of withdrawal, a withdrawn subject is referred to as either a 
“screening failure” or “dropout”. A subject who discontinues study participation prematurely 
for any reason is defined as a “dropout” if the subject has already been deemed eligible to 
participate and has completed the baseline visit. A subject who terminates the study before 
completion of the baseline visit is regarded a “screening failure”.
Dropouts are not to be replaced.
4.3
Handling of Missing Data 
All missing or partial data will be presented in the subject data listing as they are recorded on 
the Case Report Form (CRF) and the Bleeding Diary, respectively. 
Date Mirena last known in situ (as defined in Section 4.7)

If the day of the month of the date when Mirena threads were visible is missing, it will 
be imputed as the 15th of that month.

If the date when Mirena threads were visible is missing (after possible imputation of a 
missing day), the date of Day 1 Year 6 will be used instead. 

If the day of the month of the date when Mirena location was found to be “In situ” or 
“Displaced, intrauterine” is missing, it will be imputed as the 15th of that month. 

If the date when Mirena location was found to be “In situ” or “Displaced, intrauterine” 
is missing (after possible imputation of a missing day), the date of Day 1 Year 6 will
be used instead.
Stop date of study drug administration (as defined in Section 4.7)

If the day of the month of the Mirena expulsion/removal date is missing and the 
subject was not pregnant during the extension treatment period, it will be imputed as 
the 15th of that month of Mirena expulsion/removal. 

If the day of the month of the Mirena expulsion/removal date is missing and the 
subject was pregnant during the extension treatment period, it will be imputed as 
follows: 
o
If the subject was confirmed to be pregnant during that month (i.e. estimated 
date of conception during that month), the day of Mirena expulsion/removal 
will be imputed by the estimated day of conception. 
o
If the subject was confirmed to be pregnant prior to that month (i.e. estimated 
date of conception prior to that month), the day of the Mirena 
expulsion/removal will be imputed by the first of that month of Mirena 
expulsion/removal. 


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o
If the subject was confirmed to be pregnant after that month (i.e. estimated date 
of conception after that month), the day of the Mirena expulsion/removal will 
be imputed by the last of that month of Mirena expulsion/removal. 

If the Mirena expulsion/removal date is missing (after possible imputation of a missing 
day), the ‘date Mirena last known in situ’ will be used instead.
eDiary data 
Missing bleeding diary data will be imputed following the sponsor’s Best Practice Document 
(BPD) on “Recording and Evaluation of Bleeding Data” (RD-SOP-1107) (1) and as described 
in Section 4.4, respectively. 
Adverse event (AE) data 
The onset date of AEs is needed to distinguish treatment-emergent and pretreatment AEs. If 
the day of the month is missing, the last day of that month will be used for the derivations of 
the treatment emergent flag. If both day and month are missing December 31st will be used. 
Using this approach, AEs will always considered to be treatment emergent unless this can be 
ruled out.
Furthermore, the onset date of AEs is needed to distinguish between AEs in 6th / 7th / 8th 
year. If the day of the month is missing, the 15th of that month will be used for calculation of 
the year of onset. If both day and month are missing, July 1st will be used. If an upper or 
lower bound for the date is available (e.g. Day 1 Year 6), this date will be taken into account.
Pregnancy data: Pearl index (PI) calculation and cumulative failure rate

Partially missing conception dates will be imputed by the minimum approach, i.e. the 
first possible on-treatment date (Day 1 Year 6) will be used.

If the day of the month of the Mirena expulsion/ removal date is missing, it will be 
imputed as the 15th of that month. 

If the Mirena expulsion/ removal date is missing (after possible imputation of a 
missing day), the ‘date Mirena last known in situ’ will be used instead.
Time to expulsion/ perforation/ non-compliance

If the day of the month of the date of expulsion/ perforation/ non-compliance is 
missing, it will be imputed as the 15th of that month. 

If the date of expulsion/ perforation/ non-compliance is missing (after possible 
imputation of a missing day), the ‘date Mirena last known in situ’ will be used instead. 
Time to premature discontinuation

If the day of the month of the date of premature discontinuation of study treatment is 
missing, it will be imputed as the 15th of that month. 

If the date of premature discontinuation of study treatment is missing (after possible 
imputation of a missing day), the date of the subject’s last scheduled or unscheduled 
visit prior to the end of treatment visit will be used. 


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4.4
Handling of Missing Bleeding Intensities and Censored eDiaries 
Uterine bleeding data will be handled according to the sponsor’s BPD “Recording and 
evaluation of bleeding data” (RD-SOP-1107) (1). 
Up to two consecutive days of missing bleeding intensities will be replaced using a worst case 
approach during the evaluations. That is, the missing bleeding intensity will be replaced by 
the maximum of the bleeding intensities of the day before and the day after the missing 
day(s). If three or more consecutive days are missing bleeding intensities, the entire reference 
period is to be considered invalid/missing for the analyses. 
Up to five days of missing bleeding intensities per 90-days reference period will be replaced. 
If more than five days are missing bleeding intensities, the entire 90-days reference period is 
to be considered invalid/missing for the analyses. 
Up to two days of missing bleeding intensities per 28-days reference period will be replaced.
If more than two days are missing bleeding intensities, the entire 28-days reference period is 
to be considered invalid/missing for the analyses. 
A diary that ends before the end of the reference period will still be evaluated if it is at least 
two thirds of the length of the reference period. The bleeding pattern indices incorporating the 
length of an event, such as mean length of the bleeding episodes, will be calculated as for a 
complete diary. However, the bleeding pattern indices incorporating the number of days or the 
number of events will be corrected in order to account for the shorter length of the diary. The 
correction factor is the length of the reference period divided by the length of the diary. For 
example, 15 days of bleeding recorded in the diary that was kept 75 days instead of the 90 
days of the entire reference period will be adjusted to 15×(90 / 75) = 18 days. This rule 
assumes that the observed average number of bleeding days (15 / 75) stays constant in the 
reference period (15 / 75 = 18 / 90). 
4.5
Handling of Censored and Missing Menstrual Blood Loss (MBL) Data 
Subjects in the HMB subgroup will collect their used sanitary products during 4 periods of 30 
days as described in Integrated Protocol Section 9.1 and Integrated Protocol Table 9–2, i.e. for 
the following study days: 

beginning of Year 6, i.e. 30 days after baseline visit = study days 2-31

end of Year 6, i.e. 30 days prior to Visit 4 (-14 days) = study days 322-351

end of Year 7, i.e. 30 days prior to Visit 6 (-14 days) = study days 687-716

end of Year 8, i.e. 30 days prior to Visit 8 (-14 days) = study days 1052-1081
MBL data will be available per HMB subject per collection period per day per sanitary 
product. 
The cumulative volume of MBL will be calculated per HMB subject per analysis period (as 
described in Section 6.2.2) which is the basis for the secondary efficacy variables. 


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Since MBL is related to the bleeding intensity (which is recorded by the subject on a daily 
basis in the eDiary): 

missing bleeding intensity data will be imputed using the same approach described in 
Section 4.4, but imputations will be based on the 30-day collection period for MBL 
data (i.e. bleeding diary data prior to the ‘extension treatment period’ will be included, 
for subjects who had their baseline visit prior to the start of the ‘extension treatment 
period’)

missing MBL data will be imputed depending on the subject’s daily (imputed) 
bleeding intensity, as described in the following paragraphs. 
Different types of (complete/ incomplete/ missing) MBL data are expected in a 30-day 
collection period, 
 
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4.6
Interim Analyses and Data Monitoring
No formal interim analysis in the sense of a group sequential or adaptive design is planned. 
However, an analysis of the data is planned after Year 6, i.e. after all subjects have 
prematurely discontinued or completed Visit 4, i.e. treated with Mirena for up to 6 years (1 
year in the study). Another analysis of the data is planned after Year 7, i.e. after all subjects 
have prematurely discontinued or completed Visit 6, i.e. treated with Mirena for up to 7 years 
(2 years in the study). These will cover the full set of analyses as described in the SAP on 
hand, unless otherwise stated. 
CCI


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For the analysis after Year 6, cumulative data will be used up to the end of Year 6; each 
subject’s data will be cut-off after she has completed Visit 4 or prematurely discontinued 
(whichever occurs first). For the analysis after Year 7, cumulative data will be used up to the 
end of Year 7; each subject’s data will be cut-off after she has completed Visit 6 or 
prematurely discontinued (whichever occurs first). Subjects who have completed Visit 4 and 
Visit 6, respectively, still wearing the Mirena will be considered ongoing subjects. 
4.7
Data Rules 
Start date of ‘treatment period’
The date of baseline visit will be considered the start date of the ‘treatment period’, i.e. study 
day 1. 
Start date of study drug administration, i.e. start date of ‘extension treatment period’ 
Day 1 of Year 6 of Mirena use will be considered the start date of study drug administration.
Date Mirena last known in situ
The ‘date Mirena last known in situ’ is referred to in Integrated Protocol Section 10.3.2.1 and 
Integrated Protocol Table 10–1 and is needed to calculate the crude exposure time for PI 
calculation for subjects who were lost to follow-up (e.g. because the woman withdrew 
consent, was lost to follow-up, or died) and for ongoing subjects (during the analyses after 
Year 6 and Year 7). 
The ‘date Mirena last known in situ’ will be the latest date when the subject was found to be 
compliant with Mirena, before the first occurrence of non-compliance (if any). 
Compliance/non-compliance is described in Section 6.1.3.5 and Integrated Protocol Section 
9.6.3.8. 
Therefore, the ‘date Mirena last known in situ’ will be the latest of the following: 

Last date (before the first occurrence of non-compliance, if any) when Mirena threads 
were visible

Last date (before the first occurrence of non-compliance, if any) when Mirena location 
was found to be “In situ” or “Displaced, intrauterine” 
If any of these dates is missing or partial, it will be imputed individually as described in 
Section 4.3. 
Stop date of study drug administration 
If the Mirena was totally expelled or removed during the study, the stop date of study drug 
administration will be the date of Mirena expulsion or removal. 
If the Mirena was not totally expelled or removed during the study (e.g. because the woman
withdrew consent, was lost to follow-up, or died), the stop date of study drug administration 
will be the ‘date Mirena last known in situ’.


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For ongoing subjects (during the analyses after Year 6 and Year 7), the stop date of study drug 
administration will be the ‘date Mirena last known in situ’. 
Woman-years 
One woman-year will comprise 365 days of study treatment exposure, unless otherwise stated. 
Treatment-emergent AEs 
The onset date of AEs will be used to distinguish between treatment-emergent and pre-
treatment AEs. If an event occurred on Day 1 of Year 6 of Mirena use or later, it will be 
considered as treatment-emergent AE. Otherwise, it will be considered as pre-treatment AE. 
AEs in 6th / 7th / 8th year
The onset date of treatment-emergent AEs will be used to distinguish between AEs in 6th, 7th 
and 8th year:

If [Day 1 Year 6 ≤ onset date ≤Day 1 Year 6 + 364 days], it will be considered an AE 
in 6th year

If [Day 1 Year 6 + 365 days ≤ onset date ≤Day 1 Year 6 + 729 days], it will be 
considered an AE in 7th year 

If [Day 1 Year 6 + 730 days ≤ onset date], it will be considered an AE in 8th year
(including any AE which may fall into the beginning of Year 9)
Mapping of selected assessments to regular study visits 
For subjects who discontinued study treatment prematurely at the timing of one of their 
regular study treatment visits (i.e. Visits 3, 4, 5, 6 or 7), data will be recorded on the electronic 
case report form (eCRF) in the End of Treatment (EOT) folder (i.e. EOT / Visit 8). 
For the statistical analysis selected assessments will be mapped to regular study treatment 
visits as described in the following paragraphs, in order to ensure meaningful presentation of 
information on a visit level, e.g. in summary tables by visit. 
The following assessments will be mapped: 

Vital signs 

Checking of Mirena threads 

Pregnancy test 

Urine Sample Collection for Central Lab

Blood Sample Collection for Central Lab

Assessment of laboratory results

Pharmacokinetic (PK) Sample Collection (single sample – blood)

Continuing Need for Contraception

Subject satisfaction with Mirena


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If study treatment was discontinued prematurely and the EOT visit was performed at the 
timing of a regular study visit and data were recorded on the eCRF in the EOT folder (i.e. 
EOT / Visit 8) but not in the regular study visits folder, then assessments will be mapped as 
follows: 

If EOT visit performed at the timing of Visit 3 / Month 6 (i.e. EOT visit date = study 
day 183±14 days), then mapping to regular study treatment Visit 3 

If EOT visit performed at the timing of Visit 4 / Month 12 (i.e. EOT visit date = study 
day 365±14 days), then mapping to regular study treatment Visit 4 

If EOT visit performed at the timing of Visit 5 / Month 18 (i.e. EOT visit date = study 
day 548±14 days), then mapping to regular study treatment Visit 5 

If EOT visit performed at the timing of Visit 6 / Month 24 (i.e. EOT visit date = study 
day 730±14 days), then mapping to regular study treatment Visit 6 

If EOT visit performed at the timing of Visit 7 / Month 30 (i.e. EOT visit date = study 
day 913±14 days), then mapping to regular study treatment Visit 7 

If EOT visit performed at the timing of Visit 8 / Month 36 (i.e. EOT visit date = study 
day 1095±14 days), then mapping to regular study treatment Visit 8 
If study treatment was discontinued prematurely and the EOT visit was performed not at the 
timing of a regular study visit and data were recorded on the eCRF in the EOT folder (i.e. 
EOT / Visit 8), then assessments will be mapped to Visit “End of Treatment”. 
For subjects who completed study treatment, data will be recorded on the eCRF in the EOT 
folder (i.e. EOT / Visit 8) and mapped to regular study treatment Visit 8. 
Presentation of assessments/results in by-visit summary tables 
In subject data listings, assessments/results from both scheduled and unscheduled visits will 
be presented. In summary tables, only assessments/results from scheduled visits will be 
presented. 
Safety laboratory parameters 
If the measured value is below the lower limit of quantification (LLOQ), half the value of 
LLOQ will be used in summary tables. A difference between two values below LLOQ will be 
assigned a value of zero. 
4.8
Data Review
Protocol deviations (PDs) will be assessed following the CRO’s processes. PDs will be 
reviewed, classified and documented as important or non-important PDs periodically, after 
Year 6 (prior to first interim database lock), after Year 7 (prior to second interim database 
lock) and at the end of the study (prior to final database lock). Assignment of subjects to 
analysis sets will be documented. Any changes to the statistical analysis prompted by the 
results of the review of study data will be documented in an SAP amendment and, if 
applicable, in a supplement to this SAP.


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5.
Analysis Sets
5.1
Assignment of analysis sets
Final decisions regarding the assignment of subjects to analysis sets will be made during the 
review of study data and documented (see Section 4.8).
The following statistical analysis sets will be defined: 
Full analysis set (FAS): 
All women who completed the baseline visit of the study 
Primary analysis set Year 6 (PAS Year 6):
All women in the FAS with an age of 35 years or younger at baseline visit (i.e., an age of 36 
or younger at end of Year 6)
Primary analysis set Year 7 (PAS Year 7):
All women in the FAS with an age of 34 years or younger at baseline visit (i.e., an age of 36 
or younger at end of Year 7)
Primary analysis set Year 8 (PAS Year 8):
All women in the FAS with an age of 33 years or younger at baseline visit (i.e., an age of 36 
or younger at end of Year 8)
The age at baseline (required for PAS Year 6, PAS Year 7 and PAS Year 8) will be used as 
recorded at baseline (Visit 2). If the age at baseline was not recorded, it will be calculated as 
the difference between year of baseline visit and year of birth recorded at screening visit. 
Safety analysis set (SAF): 
The SAF is identical with the FAS, i.e. all women who completed the baseline visit of the 
study.
6.
Statistical Methodology
6.1
Population characteristics
6.1.1
Disposition 
Subject disposition will be summarized by descriptive statistics:

End of screening period (including primary/underlying reason for premature 
discontinuation) 

Subjects included in PAS Year 6, PAS Year 7 and PAS Year 8, respectively, and in 
the FAS and SAF 

Inclusion and exclusion criteria 


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
Important PDs 

End of treatment period (including primary/underlying reason for premature 
discontinuation) 
6.1.2
Demographics 
Analyses of demographics will be performed based on the PAS Year 6 (for the analysis after 
Year 6), PAS Year 7 (for the analysis after Year 7) and the PAS Year 8 (for the final analysis 
after 8 years), respectively. Furthermore, these analyses will be repeated for the FAS.
6.1.2.1
Baseline characteristics 
Baseline characteristics will be summarized by descriptive statistics: 

Demographics 
o
Age at baseline 
o
Ethnicity
o
Race 
o
Height
o
Weight 
o
BMI 

Baseline characteristics 
o
Educational level 
o
Tobacco consumption 
o
Alcohol consumption 
6.1.2.2
Medical, reproductive and menstrual history 
Medical, reproductive and menstrual history will be summarized by descriptive statistics: 

Medical history (displayed by Medical Dictionary for Regulatory Activities 
[MedDRA] system organ class [SOC], high level term and preferred term [PT]) 

Reproductive and menstrual history
o
Age at menarche 
o
Number of pregnancies 
o
Number of ectopic pregnancies 
o
Number of births 


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o
Number of vaginal births 
o
Number of caesarean births 
o
Duration from last birth or induced/spontaneous abortion to insertion
o
Absence of menstrual/withdrawal bleeding (during last 3 months) 
o
Intracyclic bleeding (during last 3 months) 
o
Average length of cycle 
6.1.2.3
Previous and concomitant medications 
All concomitant medications taken during the study (i.e. starting with the date of informed 
consent) as well as the extended use of Mirena (i.e. the study drug) with its date of insertion 
and indication at the time of insertion (contraception, or contraception plus HMB), will be 
recorded on the eCRF. 
The extended use of Mirena (i.e. the study drug) will be summarized as described in Section 
6.1.3, whereas all concomitant medications taken during the study (excluding the extended 
use of Mirena) will be summarized by World Health Organization (WHO) Drug Dictionary
substance name. 
6.1.3
Study drug administration and compliance
As described in Integrated Protocol Section 7.1, no study drug (Mirena) will be provided by 
the sponsor. Subjects will enter the ‘treatment period’ (starting at baseline visit) and the 
‘extension treatment period’ (starting at Day 1 Year 6), respectively, wearing a Mirena that 
was inserted 5 years earlier and will continue its use for an additional 3 years, i.e. up to a total 
of 8 years. 
6.1.3.1
Insertion procedure
The original indication for Mirena insertion (contraception, or contraception plus HMB) will 
be summarized descriptively. 
The duration since Mirena insertion (at baseline visit) will be calculated as the difference 
between the Mirena insertion date and the baseline visit date. 
For subjects with Mirena insertion on Feb 29th, 2012 or earlier, two leap years of 366 days 
will be considered between 2012 and 2017, i.e. duration since Mirena insertion will be 
calculated as:
(date of baseline visit – date of Mirena insertion) / [(366×2+365×3) / 5]. 
For subjects with Mirena insertion after Feb 29th, 2012, one leap year of 366 days will be 
considered between 2012 and 2017, i.e. duration since Mirena insertion will be calculated as: 
(date of baseline visit – date of Mirena insertion) / [(366×1+365×4) / 5]. 


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The duration of Mirena use since its insertion (at baseline visit) will be summarized 
descriptively as a continuous variable as well as a categorical variable: 

< 5 years minus 2 weeks 

5 years minus 2 weeks, to 5 years 

> 5 years 
6.1.3.2
Removal procedure 
The ease of and pain during Mirena removal will be analyzed as described in Section 6.5.2. 
6.1.3.3
Expulsion rates
As described in Integrated Protocol Section 9.6.3.9, total or partial expulsion of the Mirena 
must be reported as an AE. Furthermore, expulsions must be recorded on the eCRF page 
“Intrauterine System Removal” as “Totally expelled” and “Partially expelled and removed”, 
respectively. 
The number of subjects with expulsion (at least partial, or total) of the Mirena during the 
‘extension treatment period’ (starting at Day 1 Year 6) will be summarized in a frequency 
table, overall and byparity, BMI, race and ethnicity. 
The time from Day 1 Year 6 to expulsion will be analyzed using the Kaplan-Meier estimator. 
If no expulsion occurred in a subject, this will be considered a censored observation and the 
stop date of study drug administration (as defined in Section 4.7) will be used as censoring 
date. 
The estimated proportion of subjects with expulsion of the Mirena will be reported for the 
time points 6 months (5.5 years of Mirena use), 12 months (6 years of Mirena use), 18 months
(6.5 years of Mirena use), 24 months (7 years of Mirena use), 30 months (7.5 years of Mirena 
use), and 36 months (8 years of Mirena use). The cumulative proportion will be estimated.
All subjects with partial or total expulsion of the Mirena will be listed. The listing will contain 
the parity status and the time in days after Day 1 Year 6 when the expulsion was discovered.
6.1.3.4
Discontinuation rates 
The number of subjects who discontinued study treatment prematurely during the ‘extension 
treatment period’ (starting at Day 1 Year 6) as well as the primary/ underlying reason for 
premature discontinuation will be summarized in a frequency table, overall and by parity. 
The time from Day 1 Year 6 to premature discontinuation will be analyzed using the Kaplan-
Meier estimator. If the subject completed the study treatment period, this will be considered a 
censored observation and the date of Visit 8 / Month 36 will be used as censoring date. If no 
premature discontinuation of study treatment occurred because the subject is still continuing 


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in the study, this will be considered a censored observation and the date of the last visit during 
the treatment period will be used as censoring date. 
The estimated proportion of subjects who discontinued study treatment prematurely will be 
reported for the time points 6 months (5.5 years of Mirena use), 12 months (6 years of Mirena 
use), 18 months (6.5 years of Mirena use), 24 months (7 years of Mirena use), 30 months (7.5 
years of Mirena use), and 36 months (8 years of Mirena use). The cumulative proportion will 
be estimated. 
6.1.3.5
Compliance 
The definition of compliance with Mirena is given in Integrated Protocol Section 9.6.3.8. 
The number of subjects compliant and non-compliant, respectively, during the ‘extension 
treatment period’ (starting at Day 1 Year 6) will be summarized over time in frequency tables, 
overall and by parity status (no birth vs. at least one birth). 
The time from Day 1 Year 6 to (first) non-compliance will be analyzed using the Kaplan-
Meier estimator. If no non-compliance occurred in a subject, this will be considered a 
censored observation and the stop date of study drug administration (as defined in Section
4.7) will be used as censoring date. 
The estimated proportion of subjects who are compliant will be reported for the time points 6 
months (5.5 years of Mirena use), 12 months (6 years of Mirena use), 18 months (6.5 years of 
Mirena use), 24 months (7 years of Mirena use), 30 months (7.5 years of Mirena use), and 36 
months (8 years of Mirena use). The cumulative proportion will be estimated as well.
The number of subjects in each sub-category will be summarized over time in frequency 
tables, overall and by parity, as follows: 

Compliant with Mirena 
o
Threads visible 
o
Threads not visible and  transvaginal ultrasound (TVUS) performed => 
location of Mirena: 

In situ 

Displaced, intrauterine

Non-compliant with Mirena 
o
Threads not visible and  TVUS performed => location of Mirena: 

Partially or totally expelled into vagina or cervical canal

Cervical perforation

Myometrial perforation

Migration to the peritoneal cavity


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
Absent

Other 
o
Threads visible and  TVUS performed => location of Mirena: 

Partially or totally expelled into vagina or cervical canal

Cervical perforation

Myometrial perforation

Migration to the peritoneal cavity

Other 
6.1.3.6
Extent of exposure
Data rules for derivation of the start and stop dates of study drug administration are described 
in Section 4.7. Periods of backup contraception use will not be subtracted from the exposure 
time, unless stated otherwise (refer to Section 6.2.1). 
The exposure with extension treatment (i.e. number of woman-years) will be analyzed 
descriptively, overall, by parity and by age, BMI, race, ethnicity and indication for Mirena 
use.
Completion status (introduced post-hoc after Year 6 database lock, prior to Year 7 
database lock): 
In order to show the number of “completers”, the completion status of the Month 12 visit 
(after Year 6 database lock) will be summarized. 
Similar analyses will be performed after Year 7 and Year 8 database lock, showing the 
completion status of the Month 24 and Month 36 visit (after Year 7 and 8 database lock), 
respectively. 
6.2
Efficacy
The primary analysis set will be the PAS Year 6 (for the analysis after Year 6), the PAS Year 
7 (for the analysis after Year 7) and the PAS Year 8 (for the final analysis after 8 years), 
respectively, unless stated otherwise. Analyses will be repeated for the FAS.
6.2.1
Primary efficacy variable 
The primary efficacy variable is the occurrence of pregnancy within years 6 through 8 of 
Mirena use (i.e. ‘3-year PI’, as defined below). However, for the analysis after 6 years of 
Mirena use, the primary efficacy variable is the occurrence of pregnancy within year 6 of 
Mirena use (i.e. ‘1-year PI’, as defined below), and for the analysis after Year 7, the primary 
efficacy variable is the occurrence of pregnancy within years 6 through 7 of Mirena use (i.e. 
‘2-year PI’, as defined below). 


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The PI is defined as the number of pregnancies per 100 woman-years. The Pearl Index will be 
analyzed for the ‘extension treatment period’ starting at Day 1 of Year 6 of Mirena use. That 
means, for subjects who had her baseline visit prior to Day 1 Year 6, exposure and 
pregnancies between the baseline visit and Day 1 Year 6 will be excluded; for subjects who 
had their baseline visit after Day 1 Year 6, exposure and pregnancies between Day 1 Year 6 
and baseline visit will be included. The following PIs will be calculated: 

‘1-year PI (sixth year)’, PI obtained in the sixth year of treatment, i.e., number of 
pregnancies that occurred during the sixth year of treatment divided by time the 
women were at risk of getting pregnant in the sixth year of treatment. 

‘2-year PI (sixth & seventh year)’, PI obtained in the sixth and seventh year of 
treatment, i.e., number of pregnancies that occurred during the sixth and seventh year 
of treatment divided by time the women were at risk of getting pregnant in the sixth 
and seventh year of treatment. 

‘3-year PI (sixth, seventh & eighth year)’, PI obtained in the sixth, seventh and eighth 
year of treatment, i.e., number of pregnancies that occurred during the sixth, seventh 
and eighth year of treatment divided by time the women were at risk of getting 
pregnant in the sixth, seventh and eighth year of treatment. 
Furthermore, the following PI will be analyzed for the entire study period starting at baseline 
visit, i.e., exposure and pregnancies between the baseline visit and Day 1 of Year 6 of Mirena 
use will be included:

‘Overall PI’, PI obtained during the whole study, i.e., number of pregnancies that 
occurred during the entire study period starting at baseline visit divided by the time the 
women were under a risk of getting pregnant. 
The exact rules regarding how the crude exposure time will be calculated are given in 
Integrated Protocol Section 10.3.2.1 and Integrated Protocol Table 10–1 as well as in Table 6–
1 below. 


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Table 6–1: Definition of crude exposure times
PI
Reason for end of 
study/ continuation 
status
Crude exposure time
1-year PI 
(6th year)
Total expulsion
Date, when expulsion was discovered – Date of Day 1 
Year 6 +1
Partial Expulsion/
Mirena removal
Date of Mirena removal – Date of Day 1 Year 6 +1
Pregnancy
Date of conception – Date of Day 1 Year 6 +1
Lost to Follow-up
Maximum of (Date Mirena last known in situ – Date of 
Day 1 Year 6 +1; 1 day)
Continues into 7th year 
of treatment
365 days
2-year PI 
(6th and
7th year)
Total expulsion
Date, when expulsion was discovered – Date of Day 1 
Year 6 +1
Partial Expulsion/
Mirena removal
Date of Mirena removal – Date of Day 1 Year 6 +1
Pregnancy
Date of conception – Date of Day 1 Year 6 +1
Lost to Follow-up
Maximum of (Date Mirena last known in situ – Date of 
Day 1 Year 6 +1; 1 day)
Continues into 8th year 
of treatment
730 days
3-year PI 
(6th, 7th 
and 8th
year)
Total expulsion
Date, when expulsion was discovered – Date of Day 1 
Year 6 +1
Partial Expulsion/
Mirena removal
Date of Mirena removal – Date of Day 1 Year 6 +1
Pregnancy
Date of conception – Date of Day 1 Year 6 +1
Lost to Follow-up
Maximum of (Date Mirena last known in situ – Date of 
Day 1 Year 6 +1; 1 day)
Continues into 9th year 
of treatment
Minimum of (1095 days; Date of EOT visit – Date of 
Day 1 Year 6 +1)
Overall PI
Total expulsion
Date, when expulsion was discovered – Baseline visit date 
+1
Partial Expulsion/
Mirena removal
Date of Mirena removal – Baseline visit date +1
Pregnancy
Date of conception – Baseline visit date +1
Lost to Follow-up
Maximum of (Date Mirena last known in situ – Baseline 
visit date +1; 1 day)
Continued until EOT
Date of EOT visit – Baseline visit date +1
PI=Pearl Index; EOT=End of treatment


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A pregnancy will be allocated to the time period(s) that are relevant for the calculation of the 
PIs described above, e.g., a pregnancy that occurs on day 400 will be relevant for the 7th year 
PI, the 2-year PI (6th & 7th year), the 3-year PI (6th, 7th & 8th year), and the overall PI. 
Pregnancies that occur before Day 1 Year 6 of Mirena use will not count for the 1-year PI, 2-
year PI and 3-year PI.  Pregnancies that occur after the Mirena was removed or an expulsion 
was discovered will not count for any PI calculation.
It should be noted that pregnancies that occur within 7 days after the end of exposure will 
count for the PI calculations. 
Furthermore, it should be noted that pregnancies that occur after partial expulsion or first 
occurrence of non-compliance but before Mirena removal will count for the PI calculations.
Exposure times to be subtracted for Pearl index analyses: 
Subjects who apply backup contraception are not at risk or are at lower risk of getting 
pregnant than subjects who do not apply backup contraception. In case a subject uses backup
contraception (e.g., condoms to prevent sexually transmitted disease), the respective 28-day 
reference period(s) of backup contraception use will be excluded from the exposure time, 
unless a pregnancy occurred in that 28-day reference period. In the Pearl index analyses, the 
first 28-day reference period will start at Day 1 Year 6. Missing data will be considered as no 
use of backup contraception.
Primary analysis: 
The primary method for the evaluation of the occurrence of pregnancy is the PI defined as the 
number of pregnancies per 100 woman-years.
The PIs and the corresponding 2-sided 95% confidence interval (CI) will be calculated using 
the model specified below. 
Mathematical model for the calculation of the PI:
By assuming that the number of pregnancies follows a Poisson-distribution, the point estimate 
and the 95% CI for the PI can be calculated as follows:
PI = x/E, 
lower 95% confidence limit of PI = 0.5 × 2(0.025, 2x ) /E
upper 95% confidence limit of PI = 0.5 × 2(0.975, 2(x+1) ) /E
where x = number of pregnancies,
E = exposure in 100 woman-years,
2(alpha,df ) is the alpha-quantile from 2-distribution with df degrees of freedom. 
All PIs described above will also be presented by parity (no births vs. at least one birth), BMI 
(<30 kg/m² vs. ≥30 kg/m²) and age at insertion (<18 years vs. 18-25 years vs. 26-35 years, and 
<18 years vs. 18-35 years), age at baseline (18-25 years vs. 26-35 years vs. >35 years, and 18-
35 years vs. >35 years), race and ethnicity. The age at insertion will be calculated as: age at 
baseline (recorded on the eCRF at baseline, Visit 2) minus 5 years. 


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To assess pregnancies with regard to subgroup combinations, e.g. by age and parity, a listing 
on all pregnancies providing detailed information regarding subject number, age, parity, date 
of Mirena insertion, date of baseline visit, date of Day 1 Year 6 of Mirena use, date of Mirena
removal, (estimated) date of (partial/total) expulsion, estimated date of conception, location of 
pregnancy implantation at time of diagnosis, and estimated date of conception relative to 
Mirena insertion/ relative to Day 1 Year 6 of Mirena use/ relative to stop date of study drug 
administration will be provided. 
Secondary analysis: 
In order to fulfill the European guideline EMEA-‘Guideline on clinical investigation of 
steroid contraceptives in women’ (EMEA/CPMP/EWP/519/ Rev1, July 2005.) (2), the 
cumulative failure rate, i.e. the probability of getting pregnant will be calculated using the 
Kaplan-Meier method in addition to calculation of the different PIs.
Periods of backup contraception use will not be subtracted from the exposure time. 
Sensitivity analysis: 
The usual assumption for the calculation of the PI is a constant hazard for the event of 
becoming pregnant over time. As this cannot necessarily be assumed for the study treatment 
of this study, PIs will be calculated per year, as sensitivity analyses.
Similar analyses (PIs and cumulative failure rates) will be provided for ectopic pregnancies. 
Sensitivity analysis (introduced post-hoc after Year 6 database lock, prior to Year 7 
database lock): 
The primary analysis (‘1 year PI (sixth year)’ after Year 6 database lock based on the PAS 
Year 6) was conducted using the following rules:

1 WY = 365 days

Complete and incomplete 28-day cycles are used for the exposure calculation (i.e., the 
days of the last 28-day cycle are used even if incomplete)
A sensitivity analysis will be conducted using the following rules

1 WY = 13 28-day cycles (i.e., 364 days)

Only complete 28-day cycles are used
Similar analyses will be performed after Year 7 and Year 8 database lock, i.e. ‘2 year PI (sixth 
and seventh year)’ after Year 7 database lock based on the PAS Year 7 and ‘3 year PI (sixth, 
seventh and eighth year)’ after Year 8 database lock based on the PAS Year 8, respectively. 
PIs will be also be calculated per year, i.e. ‘Year 6 PI’ and ‘Year 7 PI’ after Year 7 database 
lock based on the PAS Year 7 and ‘Year 6 PI’, ‘Year 7 PI’ and ‘Year 8 PI’ after Year 8 
database lock based on the PAS Year 8. 
As for the primary analysis, pregnancies that occur within 7 days after the end of exposure as 
well as pregnancies that occur after partial expulsion or first occurrence of non-compliance 


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but before Mirena removal will count for the PI calculations; 28-day reference period(s) of 
backup contraception use will be excluded from the exposure time. 
Repeated analysis of the primary efficacy variable (introduced prior to Year 8 database 
lock) for the PAS Year 6 and PAS Year 7 based on the final database after Year 8:
For the analysis after 6 years of Mirena use, the primary efficacy variable was the occurrence 
of pregnancy within year 6 of Mirena use (i.e. ‘1-year PI’) based on the PAS Year 6, which 
was analysed based on the interim database after Year 6 and reported in the Year 6 CSR. 
For the analysis after 7 years of Mirena use, the primary efficacy variable was the occurrence 
of pregnancy within years 6 through 7 of Mirena use (i.e. ‘2-year PI’) based on the PAS Year 
7, which was analysed based on the interim database after Year 7 and reported in the Year 7 
CSR. 
These analyses (and the corresponding sensitivity analyses) will be repeated after the final 
database lock, to provide these results based on the most accurate and complete datasource, 
i.e. the final database after Year 8: 

For the PAS Year 6, based on the final database after Year 8: 
o
‘1-year PI’ (Year 6) 
o
‘1-year PI’ (Year 6) – based on only complete 28-day cycles 
o
‘1-year PI’ (Year 6) – for ectopic pregnancies 
o
‘1-year probability of getting pregnant’ (Year 6)
o
‘1-year probability of getting pregnant’ (Year 6) – for ectopic pregnancies

For the PAS Year 7, based on the final database after Year 8: 
o
‘2-year PI’ (Years 6 and 7) and 
PIs calculated per year, i.e. ‘Year 6 PI’ and ‘Year 7 PI’
o
‘2-year PI’ (Years 6 and 7) and 
PIs calculated per year, i.e. ‘Year 6 PI’ and ‘Year 7 PI’
– based on only complete 28-day cycles
o
‘2-year PI’ (Years 6 and 7) and 
PIs calculated per year, i.e. ‘Year 6 PI’ and ‘Year 7 PI’
– for ectopic pregnancies 
o
‘2-year probability of getting pregnant’ (Years 6 and 7) and 
probabilities calculated per year, i.e. ‘Year 6 probability of getting pregnant’ 
and ‘Year 7 probability of getting pregnant’
o
‘2-year probability of getting pregnant’ (Years 6 and 7) and 
probabilities calculated per year, i.e. ‘Year 6 probability of getting pregnant’ 
and ‘Year 7 probability of getting pregnant’
– for ectopic pregnancies 


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Please note that due to a more accurate and complete exposure in the final database after Year 
8 caused by the fact that the study is no longer ongoing but all subjects have completed the 
study (or discontinued prematurely), minor changes in these PIs and probabilities of getting 
pregnant (compared to the Year 6 CSR and Year 7 CSR, respectively) are expected. 
6.2.2
Secondary efficacy variables
6.2.2.1
Menstrual blood loss 
Subjects in the HMB subgroup are requested to collect their used sanitary products during 
four periods of 30 days each, as described in Integrated Protocol Section 9.1 and Integrated 
Protocol Table 9–2, i.e. for the following study days: 

beginning of Year 6, i.e. 30 days after baseline visit = study days 2-31

end of Year 6, i.e. 30 days prior to Visit 4 (-14 days) = study days 322-351

end of Year 7, i.e. 30 days prior to Visit 6 (-14 days) = study days 687-716

end of Year 8, i.e. 30 days prior to Visit 8 (-14 days) = study days 1052-1081
MBL data will be available per HMB subject per collection period per day per sanitary 
product. MBL data from sanitary products collected during these planned 30-day collection 
periods will be included in the statistical analysis; potential additional MBL data from 
sanitary products collected outside these planned 30-day collection periods will be excluded 
from the statistical analysis. 
Since MBL is related to the bleeding intensity, missing MBL data during the planned 30-day 
collection periods will be imputed depending on the subject’s daily bleeding intensity 
recorded in the eDiary, as described in Section 4.5. 
The cumulative volume of MBL will be calculated only if a day-wise cumulative MBL 
(original or imputed value, as described in Section 4.5 and Table 4–1) is available for each 
day in the planned 30-day collection period (or until the day of premature discontinuation). 
Otherwise, the collection period will be considered invalid and the cumulative volume of 
MBL will not be calculated. 
If there are less than 20 solid observations in a planned 30-day collection period (“solid” as 
defined in Section 4.5 and Table 4–1), the collection period will be considered invalid and the 
cumulative volume of MBL will not be calculated. This rule also applies to HMB subjects 
who discontinued prematurely during a 30-day collection period, i.e. if there are less than 20 
solid observations before the subject discontinued prematurely during a 30-day collection 
period, the collection period will be considered invalid and the cumulative volume of MBL 
will not be calculated. 
The cumulative volume of MBL will be calculated per HMB subject per analysis period as the 
sum of MBL values, adjusted for the length of the analysis period (in case of early and/or late 
collection without gap, and/or in case of premature discontinuation). That means the sum of 
MBL values will be multiplied by {length of analysis period in units of days divided by 30 
days}. 


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The cumulative volume of MBL at beginning of Year 6, end of Year 6, end of Year 7, and end 
of Year 8 of Mirena treatment will be presented by descriptive statistics. Furthermore, change 
from baseline (=beginning of Year 6) will be presented. 
The basis for this analysis is the data on MBL assessed by the alkaline hematin method (see 
Integrated Protocol Section 9.4.2). If a women has sent in no sanitary products and has
documented in the eDiary (see Integrated Protocol Section 9.7.1) that no bleeding occurred 
during one of the considered 30-day time periods for collection of sanitary protection, the 
MBL will be assumed to be zero in that time period. 
This analysis will be conducted in the FAS in the HMB subgroup, i.e. women who had 
Mirena inserted for both contraception and HMB. 
Sensitivity analysis approach #1 of MBL: 
As described in Section 4.5, there might be cases when the MBL value remains missing. If 
such cases occur, a sensitivity analysis will be performed using (imputed) MBL values based 
on the extended imputation rules given in Section 4.5. 
The cumulative volume of MBL will be calculated and summarized similarly as in the above 
primary analysis approach for MBL. 
6.2.2.2
Categorized menstrual blood loss (<80 mL / 30 days)
No clinical change in bleeding profile regarding HMB after Year 5 until the end of Year 6, 
until the end of Year 7 and until the end of Year 8, respectively, will be concluded if the 
cumulative volume of MBL was < 80mL at the beginning of Year 6 and remained remains 
<80mL during the end of years 6, 7 and 8, respectively. Vice versa, clinical change in 
bleeding profile regarding HMB after Year 5 until the end of Year 6, end of Year 7 and end of 
Year 8, respectively, will be concluded if the volume of blood loss was ≥ 80mL at the 
beginning of Year 6 or at end of Years 6, 7 or 8, respectively.
Therefore, the proportion of women with clinical change in bleeding profile regarding HMB 
will be analyzed. Descriptive statistics as well as 95% Clopper-Pearson confidence intervals 
will be provided. 
For the analysis after Year 6, the proportion of women with clinical change in bleeding profile 
regarding HMB after Year 5 until the end of Year 6 will be analyzed. 
 
 
 
 
 
CCI


CCI


6.3
Pharmacokinetics/pharmacodynamics
6.3.1
Pharmacokinetics
Analyses will be performed based on the FAS.
The following will be determined at several timepoints according to Integrated Protocol Table 
9–1: 

LNG concentrations in plasma

Sex hormone binding globulin (SHBG) concentrations in serum
CCI


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Data will be analyzed descriptively (including number of measurements, geometric mean with 
geometric standard deviation and coefficient of variation, arithmetic mean with arithmetic
standard deviation and coefficient of variation, minimum, maximum and median) by time 
point (i.e. Visit 2 to Visit 8). Means at any time point will be calculated only if at least two-
thirds of the individual data were measured and were above the LLOQ. For the calculation of 
the mean value a data point below LLOQ will be imputed by one-half of this limit. In tables 
showing mean values, where values below LLOQ are included in the calculation of mean 
values, these means will be marked. 
The individual PK concentrations will be presented in the subject data listing. 
Geometric mean concentration (±geometric standard deviation) curves of LNG and SHBG 
will be plotted versus time point using a linear and semi-logarithmic scale. 
PK concentrations determined after Mirena expulsion/removal will not be included in the 
descriptive analyses and plots, but only be listed. 
Furthermore, the residual content of LNG in used Mirena devices will be determined from all 
subjects at the end of treatment (i.e. from those who complete the 3 years in the study and 
from those who discontinue the study treatment prematurely). Data will be listed per subject 
and time point and individual data will be plotted versus time post baseline using a linear 
scale. 
Residual contents with a partially missing or completely missing date of Mirena 
expulsion/removal will not be included in the plot, but only be listed. 
Population PK analysis will be performed after Year 6, after Year 7 and at the end of study by 
the Modeling & Simulation (M&S) expert. A separate M&S Analysis Plan will be provided 
prior to the beginning of the population PK analysis by the M&S expert, including details of 
the planned model development and analysis. The results will be reported in a separate M&S 
Report by the M&S expert. A summary of the results will be provided in the Clinical Study 
Report. 
6.3.2
Pharmacodynamics
Not applicable.
6.4
Safety
All safety variables will be analyzed based on the SAF, unless otherwise stated.
The main safety variable is the incidence of treatment-emergent AEs (both serious and non-
serious). Treatment-emergent AEs are defined as any AEs occurring during the ‘extension 
treatment period’ starting at Day 1 of Year 6 of Mirena use. Further data rules are described in 
Section 4.7. 
All AEs will be classified using MedDRA. The latest available version at the time of coding 
will be used. The results will be summarized on the level of SOC and PT, unless stated 
otherwise. 


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6.4.1
Pretreatment adverse events
Pretreatment AEs will be summarized by SOC and PT. 
Pretreatment serious AEs (SAEs) will only be listed. 
6.4.2
Treatment-emergent adverse events
The following treatment-emergent AEs will be summarized by SOC and PT: 

AEs, by year of occurrence (6th / 7th / 8th year) and overall

Study-drug related AEs (with causality as assessed by investigator)

AEs causing discontinuation of study drug 

Study-drug related AEs (with causality as assessed by investigator) causing 
discontinuation of study drug 

AEs by outcome 

AEs by intensity 
The overall summary tables will be displayed by year of occurrence (6th / 7th / 8th year) and 
overall, whereas AEs will be allocated to the year of occurrence as described in Section 4.7. 
For the calculation of the percentages by year of occurrence, only the number of subjects that 
were still under treatment at the beginning of the respective time interval (treatment year) will 
be used as the denominator.
The following treatment-emergent SAEs will be summarized by SOC and PT: 

SAEs 

Study-drug related SAEs (with causality as assessed by investigator) 
6.4.2.1
Perforation rates 
As described in Integrated Protocol Section 9.6.3.9, perforation by the Mirena must be 
reported as an SAE. If a perforation is diagnosed, Mirena must be removed and the subject 
must discontinue study treatment and the study.
Perforations will be identified from the AEs recorded on the eCRF coded by MedDRA as one 
of the following: 

Preferred Term “Uterine perforation”

Preferred Term “Embedded Device”, 

Preferred Term “Fallopian tube perforation”, 

Lowest Level Term “Extrauterine intra-abdominal localisation of IUD”, 

Lowest Level Term “Extrauterine intra-abdominal localization of IUD”, 


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
Lowest Level Term “IUD migration”, 

Lowest Level Term “Device migration”, 

Lowest Level Term “Device dislocation into abdominal cavity”. 
The number of subjects with perforation by the Mirena during the ‘extension treatment 
period’ (starting at Day 1 Year 6) will be summarized in a frequency table, overall and by 
parity. 
In addition, the time from Day 1 Year 6 to perforation will be analyzed using the Kaplan-
Meier estimator. If no perforation occurred in a subject, this is considered a censored 
observation and the stop date of study drug administration (as defined in Section 4.7) will be 
used as censoring date.
The estimated proportion of subjects with perforation of the Mirena will be reported for the 
time points 6 months (5.5 years of Mirena use), 12 months (6 years of Mirena use), 18 months
(6.5 years of Mirena use), 24 months (7 years of Mirena use), 30 months (7.5 years of Mirena 
use), and 36 months (8 years of Mirena use). The cumulative proportion will be estimated as 
well. 
All subjects with perforation by the Mirena will be listed. The listing will contain the parity 
status as well as the duration from last birth or induced/spontaneous abortion to insertion and 
the time in days after Day 1 Year 6 when the perforation was discovered.
6.4.2.2
Pelvic inflammatory disease 
As described in Integrated Protocol Section 9.6.3.11, any case of pelvic inflammatory disease 
(PID) will be reported as an AE or SAE on the AE eCRF as well as on the pelvic 
inflammatory disease eCRF. 
PID will be presented as part of the AE summary tables described in Section 6.4.2. 
Details recorded on the pelvic inflammatory disease eCRF will be listed only. A diagnosis of 
PID is made if response to the following questions in the eCRF is a “yes”: “Were the criteria 
for PID diagnosis met?” and/or “Laparoscopy confirmed PID?”.
6.4.3
Uterine bleeding / bleeding pattern
Recording and evaluation of bleeding data: 
The occurrence of uterine bleeding will be recorded every day during the study treatment 
phase using eDiaries provided by the sponsor. The recording will start at the baseline visit and 
will be continued daily until Mirena is removed. Subjects are asked to rate their uterine 
bleeding in the past 24 hours on a daily basis according to the bleeding intensity definitions 
presented in Integrated Protocol Section 9.6.3.12 and Integrated Protocol Table 9–3. 
Uterine bleeding data during the ‘extension treatment period’ starting at Day 1 of Year 6 of 
Mirena use will be analyzed according to the sponsor’s BPD “Recording and evaluation of 
bleeding data” (RD-SOP-1107) (1). Bleeding diary data prior to the ‘extension treatment 


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period’ will not be included in the analyses described in this section. That means, for subjects 
who had her baseline visit prior to Day 1 Year 6, bleeding diary data between the baseline 
visit and Day 1 Year 6 will be excluded; for subjects who had their baseline visit after Day 1 
Year 6, bleeding diary data between Day 1 Year 6 and baseline visit will not be recorded and 
will be considered as missing data entries. Bleeding diary data after Mirena expulsion/removal 
will not be included in the statistical analysis. Bleeding diary data after the date of premature 
discontinuation of study treatment period will not be included in the statistical analysis. 
Besides the registration of absolute number of bleeding days, bleeding/spotting episodes will 
also be assessed according to the sponsor’s bleeding intensity codes and the WHO definitions 
as provided in Integrated Protocol Section 10.3.2.3.2 and Integrated Protocol Table 10–2. This 
is possible because of the direct eDiary entry. 
In addition to the WHO definitions, a “bleeding episode” is defined as day(s) with bleeding / 
spotting of which at least one day is of intensity 3 or higher, preceded and followed by at least 
2 bleed-free days. There are examples given in the sponsor’s BPD Section 1.4.1 which 
illustrate the advantage of this procedure. Another example is given in Integrated Protocol 
Section 10.3.2.3.2. 
The bleeding patterns will be described using the reference period method recommended by 
the WHO, as given in the sponsor’s BPD Section 1.4.3. 
Based on daily uterine bleeding data obtained from the eDiary, the bleeding pattern will be 
reported using reference periods of 28 and 90 days. The first 28-day and 90-day reference 
period, respectively, will start at Day 1 of Year 6 of Mirena use. For each subject and for each 
period, the number of bleeding/spotting days and bleeding/spotting episodes will be 
calculated. If the bleeding intensity is recorded as light, normal or heavy, this will be 
considered as “bleeding”.
Handling of missing bleeding intensities and censored eDiaries: 
Details on how to handle missing bleeding intensities and censored eDiaries are given in 
Section 4.4. 
Summary of bleeding pattern indices: 
For each subject and for each 28-day reference period and each 90-day reference period, the 
following bleeding pattern indices will be calculated (compare to sponsor’s BPD Section 
1.4.3): 

number of subjects with at least one bleeding/spotting day

number of subjects with at least one bleeding (excluding spotting) day

number of bleeding / spotting days

number of bleeding days (excluding spotting-only days)

number of spotting-only days

number (mean length, maximal length) of bleeding / spotting episodes
(will only be calculated for those subjects who have at least 1 bleeding/spotting 
episode) 


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
number (mean length, maximal length) of spotting-only episodes 
(will only be calculated for those subjects who have at least 1 spotting-only episode)
Furthermore, for each 90-day reference period the following bleeding indices will be provided 
according to the WHO criteria: 

number of subjects with amenorrhea, defined as no bleeding/spotting throughout the 
reference period

number of subjects with prolonged bleeding, defined as subjects with 
bleeding/spotting episodes lasting more than 14 days

number of subjects with frequent bleeding, defined as subjects with more than 5 
bleeding/spotting episodes

number of subjects with infrequent bleeding, defined as subjects with 1 or 2 
bleeding/spotting episodes

number of subjects with irregular bleeding, defined as subjects with 3 to 5 
bleeding/spotting episodes and less than 3 bleeding/spotting-free intervals of 14 days 
or more

number of subjects with normal bleeding / none of the above
6.4.4
Safety laboratory parameters 
Safety laboratory parameters will be summarized by visit using descriptive statistics. If there 
are multiple observations per subject per scheduled visit, the last observation will be used in 
summary tables. 
6.4.5
Vital signs and body weight 
Vital signs and body weight will be summarized by visit using descriptive statistics. 
6.4.6
Further safety variables
6.4.6.1
Cervical smear 
The results of cervical smear assessment and interpretation will be summarized in frequency 
tables. 
6.4.6.2
Chlamydia test 
The results of chlamydia test assessment (chlamydia trachomatis and gonorrhea, if applicable) 
will be summarized in frequency tables. 


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6.4.6.3
Gynecological ultrasound 
Gynecological ultrasound data will be listed. 
6.4.6.4
Pregnancy test 
The performance of pregnancy tests as well as the outcome will be presented in frequency 
tables.
6.4.6.5
Death 
Death data will be listed. 
6.4.6.6
Post-treatment pregnancy and return-to-fertility tracking
Data on post-treatment pregnancies and return to fertility will be presented in frequency tables 
and a detailed listing. 
6.5
Patient / investigator reported outcomes 
Analyses will be performed based on the PAS Year 6 (for the analysis after Year 6), the PAS 
Year 7 (for the analysis after Year 7) and the PAS Year 8 (for the final analysis after 8 years), 
respectively. Furthermore, analyses will be repeated for the FAS.
6.5.1
Subject satisfaction with Mirena 
The subject’s satisfaction with the Mirena on a 5-point scale (very satisfied, somewhat
satisfied, neither satisfied or dissatisfied, dissatisfied, very dissatisfied) will be summarized in 
frequency tables, overall and by parity.
6.5.2
Ease of and pain during Mirena removal 
The investigator’s assessment of the ease of Mirena removal (easy, slightly difficult, very 
difficult) will be summarized in frequency tables, overall and by parity.
The subject’s assessment of the pain during Mirena removal (none, mild, moderate, severe) 
will be summarized in frequency tables, overall and by parity.
6.5.3
Continuing need of contraception
The subject’s continuing need for contraception since the last contact/visit will be listed. 


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6.6
Covid-19 pandemic 
Additional analyses (introduced prior to Year 7 database lock): 
After the Year 7 and Year 8 database lock, subjects affected by the Covid-19 pandemic (due 
to COVID-19 related adverse event, COVID-19 related protocol deviations or premature 
discontinuation due to COVID-19 related reason) will be listed with corresponding details. 
Furthermore, COVID-19 related protocol deviations will be summarized and listed, as well as 
premature discontinuation due to COVID-19 related reason. 
In addition, scheduled visits (physical or phone) and missed visits will be summarized and 
listed by timepoint. 
7.
Document history and changes in the planned statistical analysis

05 Oct 2017
Final SAP v1.0 

14 June 2019 Final SAP v2.0, with the following changes:
o
Section 4.1: Due to low number of subjects in HMB subgroup, only summary 
tables on disposition and demographics will be displayed with three columns 
(Contraception, Contraception and HMB, Total), but summary tables on study 
drug administration, efficacy, safety and pharmacokinetics will be displayed 
with one column (Total). 
o
Section 4.3 / Section 4.7 / Section 6.4: Terminology harmonized (“non-
treatment-emergent” changed to “pretreatment”). 
o
Section 4.3 / Section 4.4 / Section 6.4.3 / Section 8: Reference to BPD updated 
as RD-SOP-1107. 
o
Section 5.1: Derivation rule added how to calculate age at baseline, if not 
recorded on CRF. 
o
Section 6.1.1: Post treatment pregnancy and return to fertility moved to new 
Section 6.4.6.6. 
o
Section 6.1.3.3: Subgroups BMI, race and ethnicity added. Patient data listing 
to display time in days after Day 1 Year 6, rather than time in days after 
baseline visit. 
o
Section 6.1.3.6: Reference to Section 6.2.1 added. Subgroups BMI, race, 
ethnicity and indication for Mirena use added. 
o
Section 6.2.1, Table 4–1: For Overall PI, formulas to calculate the crude 
exposure time corrected (use baseline visit date, but not date of Day 1 of Year 
6). 
o
Section 6.2.1, Primary analysis: Subgroup categories for age at insertion
corrected, and subgroups age at baseline, race and ethnicity added. 


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o
Section 6.2.1, Primary efficacy variable: Analysis of ectopic pregnancies 
added. 
o
Section 6.2.2.2: Terminology corrected (“nominator” changes to “numerator”). 
o
Section 6.3.1: PK concentrations determined after Mirena expulsion/removal 
not to be included in the descriptive analyses and plots, but only to be listed. 
Residual contents with partially/completely missing date of Mirena 
expulsion/removal not to be included in the plot, but only to be listed. 
o
Section 6.3.2: Empty section (not applicable) added for sake of completeness.  
o
Section 6.4.2.1: Updated list of MedDRA codes to identify perforations. 
Patient data listing to display time in days after Day 1 Year 6, rather than time 
in days after baseline visit. 
o
Section 6.4.2.2: Data not to be summarized in a frequency table, but listed 
only. 
o
Section 6.4.3: Bleeding diary data after Mirena expulsion/removal not to be 
included in the statistical analysis. Bleeding diary data after the date of 
premature discontinuation of study treatment period not to be included in the 
statistical analysis. 

21 August 2019 
Final SAP v3.0 (supplement), with the following additions 
(post-hoc analyses after Year 6 database lock):
o
Section 6.2.1: Sensitivity analysis added, to calculate the PI using only 
complete 28-day reference periods. 
o
Section 6.1.3.6: Summary of the completion status of the Month 12 visit and 
the number of “completers” added. 

08 June 2020 Final SAP v4.0 (supplement), with the following 
clarifications/corrections and additions (prior to Year 7 database lock):
o
Section 6.1.3.4: Clarification/correction included about censoring of subject 
who completed the study treatment period (i.e. at the date of Visit 8 / Month 36 
but not at the stop date of study drug administration). Clarification added about 
censoring of subjects who are continuing in the study (i.e. at the last visit 
during the treatment period). 
o
Section 6.1.3.6: Clarification added about the timepoint when the post-hoc 
analysis of completion status was introduced (i.e. after Year 6 database lock 
but prior to Year 7 database lock). Clarification added that similar analysis 
(completion status of the Month 24 and Month 36 visit, respectively) will be 
done after Year 7 and Year 8 database lock. 
o
Section 6.2.1: Clarification added about the timepoint when the post-hoc 
analysis to calculate the PI using only complete 28-day reference periods was 
introduced (i.e. after Year 6 database lock but prior to Year 7 database lock). 


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Clarification added that similar analysis will be performed after Year 7 and 
Year 8 database lock, respectively, and the analysis sets to be used for these.
o
Section 6.4.2.2: Clarification added about the disgnosis of PID, i.e. a diagnosis 
of PID is made if response to the following questions in the eCRF is a “yes”: 
“Were the criteria for PID diagnosis met?” and/or “Laparoscopy confirmed 
PID?”. 
o
Section 6.6: New section added, introducing additional tables and listings to 
present data on Covid-19 pandemic. 

10 June 2021 Final SAP v5.0 (supplement), with the following additions (introduced 
prior to Year 8 database lock):
o
Section 4.7: Definition of AEs in 8th year updated from [Day 1 Year 6 + 730 
days ≤ onset date ≤ Day 1 Year 6 + 1094 days] to [Day 1 Year 6 + 730 days ≤ 
onset date], to include any AE which may fall into the beginning of Year 9.
o
Section 6.1.2.2: Duration from last birth or induced/spontaneous abortion to 
insertion added to the summary tables of reproductive and menstrual history. 
o
Section 6.2.1: Repeated analysis of the primary efficacy variable for the PAS 
Year 6 and PAS Year 7 based on the final database after Year 8 added. 
o
Section 6.4.2.1: Duration from last birth or induced/spontaneous abortion to 
insertion added in the listing of perforations. 
8.
References
1. Sponsor’s Best Practice Document ‘Recording and Evaluation of Bleeding Data’
(RD-SOP-1107) 
2. European guideline EMEA-‘Guideline on clinical investigation of steroid 
contraceptives in women’ (EMEA/CPMP/EWP/519/ Rev1, July 2005.)