International Active Surveillance Study of Medication Used for the Treatment of Endometriosis: Visanne Post-approval Observational Study
Conditions: Endometriosis
Sponsor: Center for Epidemiology and Health Research, Germany

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VIPOS: Study Protocol 
Revised Version of Nov. 21, 2011  
International Active Surveillance Study of Medication Used for the Treat- 
ment of Endometriosis:  Visanne Post-approval Observational Study 
STUDY ID NUMBER:  
ZEG2010_03 
PROTOCOL DATE: 
Final version: Dec 14, 2010 
1st revision: Feb. 28, 20111  
2nd revision: Nov. 21, 20112 
PRINCIPAL  
INVESTIGATOR: 
Klaas Heinemann 
Invalidenstrasse 115 
10115 Berlin 
Germany 
STUDY CONDUCT: 
ZEG –  Berlin Center for Epidemiology and 
Health Research 
Invalidenstrasse 115 
10115 Berlin  
Germany 
SAFETY MONITORING  
AND ADVISORY COUNCIL: 
1  On request of the MEB (Dutch Health Authority) a total of 3 sentences (p. 4 and 13) were 
added compared to the version of Dec. 14, 2010. 
2  On request of the Safety Monitoring and Advisory Board a total of 2 definitions given in 
Appendix 1 were modified. 
ClinicalTrials.gov Identifier: NCT01266421

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FUNDING: 
Bayer Schering Pharma AG 
13342 Berlin  
Germany 
PROTOCOL APPROVAL 
DATE: 
December 2010 
START OF PATIENT 
ENROLLMENT: 
December 2010 
LAST FOLLOW-UP: 
December 2016 
FINAL REPORT 
mid-2017 

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Table of Contents 
 
ABBREVIATIONS........................................................................................................4 
1. 
INTRODUCTION.................................................................................................5 
2. 
STUDY OBJECTIVES.........................................................................................7 
3. 
STUDY DESIGN .................................................................................................7 
4. 
STUDY CENTERS..............................................................................................8 
5. 
STUDY PARTICIPANTS.....................................................................................9 
6. 
BASELINE SURVEY...........................................................................................9 
7. 
FOLLOW-UP.....................................................................................................10 
8. 
VALIDATION OF SELF-REPORTED EVENTS.................................................11 
9. 
REPORTING OF SERIOUS AND/OR UNEXPECTED ADVERSE EVENTS ....12 
10. DATA MANAGEMENT......................................................................................13 
11.  DATA ANALYSES.............................................................................................13 
12. SIZE OF THE STUDY AND EVALUTION .........................................................15 
13. SAFETY MONITORING AND ADVISORY COUNCIL.......................................19 
14. STUDY MANAGEMENT ...................................................................................19 
15. ETHICS AND PRIVACY....................................................................................19 
16.  STUDY FEASIBILITY........................................................................................20 
17.  MILESTONES...................................................................................................21 
18. PUBLICATIONS................................................................................................21 
19. REFERENCES ....................................................................................................21 
APPENDIX 1: VALIDATION OF SELF-REPORTED EVENTS..................................23 
APPENDIX 2: BLINDED ADJUDICATION.................................................................25 
APPENDIX 3: CAUSALITY ASSESSMENT ..............................................................26 
 
 

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ABBREVIATIONS  
 
 
Abbreviation 
Definition 
AMI 
Acute Myocardial Infarction 
AT 
As Treated 
ATE 
Arterial Thromboembolism 
BMI 
Body Mass Index 
COC 
Combined Oral Contraceptive 
CVA 
Cerebrovascular Accident 
DNG 
Dienogest 
DVT 
Deep Venous Thrombosis 
EURAS 
European Active Surveillance Study 
FU 
Follow-Up 
GnRH 
Gonadotropin-releasing hormone 
HR 
Hazard Ratio 
INAS 
International Active Surveillance (study) 
ITT 
Intention To Treat 
LA 
Leuprolide acetate 
MPA 
Medroxyprogesterone acetate 
PASS 
Post-Authorization Safety Study 
PE 
Pulmonary Embolism 
SAE 
Serious Adverse Event 
SMAC 
Safety Monitoring and Advisory Council 
VIPOS 
Visanne Post-approval Observational Study 
VTE 
Venous Thromboembolism 
WY 
Women-years  
ZEG 
Berlin Center for Epidemiology & Health Research (acronym for 
the German term ‘Zentrum für Epidemiologie & Gesundheits-
forschung Berlin’) 
 
 

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1. 
INTRODUCTION 
Endometriosis is a common, chronic, gynecological disease characterized by pain 
and impaired fertility. Prevalence estimates vary widely, however, the proportion of 
premenopausal women living with endometriosis is thought to be approximately 10% 
[1].  Endometriosis causes chronic inflammation, ovarian cyst formation, fibrosis and 
adhesions [1].  There seems to be little correlation between the extent of the disease 
and severity of pain experienced [2].  However, symptoms seem to respond to 
decreased circulating estrogen [3] and the mainstay of medical treatment is hormonal 
induced anovulation and a reduction in endogenous estrogen production.  
While currently approved medications for endometriosis have proven to be effective 
in decreasing pelvic pain, many have clinically relevant side-effects. Danazol, a 
testosterone analogue, can cause androgenization and GnRH agonists are known to 
decrease bone mineral density. Consequently, treatment for endometriosis with 
these medications needs to be stopped after 6-12 months. Post-treatment 
endometrial lesions tend to regenerate, with many women’s symptoms reoccurring 1-
2 months after the cessation of treatment. Some countries in Europe also allow the 
use of progestogens for the treatment of endometriosis, however, there is currently 
no pharmaceutical preparation licensed for the treatment of endometriosis in all 
member states of the European Union.3 
Dienogest (DNG) is a 19-nortestosterone derivative progestogen that is highly 
selective for progesterone receptors [4]. DNG has been available as part of a low-
dose combined oral contraceptive containing 2mg of dienogest and 30μg of 
ethinylestradiol (DNG/EE) in Germany since 1995. As a progestin in DNG/EE, DNG 
is known for having strong endometrial effects that improve dysmenorrhoea and 
decrease the duration of menstrual bleeding [5]. In addition, progestogens may also 
modulate pain associated with endometriosis by dampening neuronal activity [3]. As 
a monotherapy for the treatment of endometriosis DNG 2mg/day has been available 
in Japan since 2008. In Japan it has been found to be a reliable and effective 
treatment for dysmenorrhea, premenstrual pain, dyspareunia and diffuse pelvic pain 
associated with endometriosis [6]. Clinical trials in Europe have shown 2mg/day DNG 
to be effective in decreasing endometriosis associated pelvic pain with improved 
tolerability compared with 3.75mg leuprolide acetate (LA) [7-8]. Unlike LA, DNG has 
minimal effects on bone density and may offer women a new option for the long-term 
control of endometriosis symptoms.  
A well-known class effect of progestogens is the induction of bleeding disturbances. 
72% of women reported inter-menstrual spotting or bleeding as a side-effect of DNG 
use in a 52-week open-label study in Japan [9]. Metorrhagia symptoms tended to 
decrease towards the end of this trial and consequently it is not known what influence 
DNG will have on bleeding disturbances associated with endometriosis over a longer 
                                                          
3 Sentence was added on request of the MEB (revised study protocol of February 28, 2011) 

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time frame. Given the initial increased incidence of metorrhagia in the Japan study 
and the overall increased risk of menorrhagia in women with endometriosis, a study 
assessing the incidence of anemia induced by bleeding disturbances in women 
receiving medical treatment for endometriosis is needed.  
An ongoing concern associated with progestogens has been their potential role in 
influencing mood disturbances and, in particular, exacerbating depressive symptoms. 
In 2004, the European Health Authorities requested a desk review of newly 
diagnosed depression cases from the EURAS-OC study and found no increased risk 
for women using oral contraceptives compared to non-users [10]. Despite this 
reassurance, concerns remain. In addition, women who suffer from endometriosis are 
at high risk of developing depressive symptoms. Sepulcri et al assessed depressive 
symptoms amongst women with a surgical diagnosis of endometriosis and found 
86.5% met SF-36 diagnostic criteria for depression, with 32.7% of women meeting 
the criteria for a severe depressive disorder [11]. Depressive symptoms may be 
correlated with the degree of chronic pelvic pain associated with the disease. 
Lorençatto C, found depressive symptoms in 86% of women with chronic pelvic pain 
associated with endometriosis while only 38% of women without pelvic pain met the 
diagnostic criteria for depression [12]. The complexities and potential interaction 
between depression, endometriosis and progestogens make it difficult to differentiate 
whether an individual’s depressive symptoms are causally associated with progestin 
use or sequela of the disease process.  Consequently, a population-based post-
authorization safety study is needed to assess the potential influence of DNG on 
mood disturbance and depression in endometriosis patients.  
To further investigate the impact that DNG will have on bleeding and mood 
disturbances associated with endometriosis, a non-interventional post-authorization 
safety study (PASS) is planned to investigate the safety of this medication for 
endometriosis with regard to medical interventions for anemia and worsening of 
depressive symptoms associated with the disease.  The VIPOS study is part of a 
post-authorization safety and risk minimization commitment by Bayer Schering 
Pharmaceuticals.  It will have a similar study design to the EURAS/INAS study design 
[13]. The EURAS/INAS study design has now been used in several post-
authorization safety studies including EURAS-HRT, EURAS-IUD, INAS-OC and 
INAS-SCORE. It has been clearly demonstrated that a large, prospective, controlled, 
non-interventional, long-term cohort study is suitable for  
1. Safety monitoring of hormonal preparations 
2. Reliable identification of relevant clinical outcomes and  
3. Providing robust estimates of their incidence.  
The procedures for recruitment, informed consent and follow-up have been modified 
slightly to comply with European regulations, and to ensure good recruitment rates 
and low loss to follow-up. The study should provide early information and regular 

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updates on relevant clinical outcomes, which will contribute to a continuous risk - 
benefit assessment during long-term follow up (up to 6 years). 
 
2. 
STUDY OBJECTIVES 
 
The primary objective of the study is to assess safety aspects of Dienogest 2 mg/day 
(Visanne®) used as endometriosis therapy and of other hormonal treatments for 
endometriosis in a study population that is representative for the actual users of the 
individual preparations. This includes an estimate of the absolute risk of rare serious 
adverse outcomes.  
The main clinical outcomes of interest for the short and long-term follow-up are: 
 Medical intervention for anemia induced by cyclical bleeding disturbances 
(anemia)4 
 First time occurrence of clinically relevant depression, or worsening of 
existing depression  
 To analyze discontinuation patterns of DNG and other endometriosis 
treatments due to treatment failure (e.g. re-occurrence of pain, adverse drug 
reaction) 
 
Secondary objectives are:  
 To characterize the baseline risk of users of the individual formulations 
(lifetime history of co-morbidity, risk markers, co-medication, socio-
demographic and lifestyle data). 
 To analyze the drug utilization pattern of DNG and other endometriosis 
treatments in a study population that is representative for typical use of the 
individual preparations under routine medical conditions.  
 To investigate risks of short and long-term use of DNG and of established 
endometriosis treatments in adolescent women. 
 
 
3. 
STUDY DESIGN 
This is a large, prospective, controlled, non-interventional, long-term cohort study 
which follows two cohorts, users of DNG and users of other medications used for the 
                                                          
4 For the purposes of this protocol, this will be referred to as “anemia” for the remainder of 
the document. The algorithms for validation of ‘anemia’ is given in Appendix 1.  

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treatment of endometriosis. A “non-interference” approach5 will be used to provide 
standardized, comprehensive, reliable information on endometriosis treatment 
patterns. In this study, regular, active contacts with the cohort members (active 
surveillance) should provide all necessary information on health-related events or 
changes in health status after a new treatment for endometriosis is prescribed.  
There will be active contacts with all study participants at baseline, six monthly for the 
first year and annually from years 2 until end of study. By means of these contacts, 
almost all relevant clinical outcomes will be captured. All clinically relevant serious 
adverse events will be verified by ZEG through contact with the relevant physicians 
and by reviewing pertinent source documentation. People without formal medical 
training often misclassify adverse events (feeling ‘down’ as clinical depression, 
tiredness and palor as anemia) even if modern diagnostic procedures or careful 
clinical examination do not provide any indication of the perceived event. This type of 
inaccuracy in patient reports therefore requires careful validation. A standard 
algorithm will be used to classify ‘clinically relevant depression’ and medically treated 
anemia as “confirmed” or “not confirmed”. At the end of the study this classification 
will be verified by blinded independent adjudication (cf. Appendix 2).  
 
4. 
STUDY CENTERS 
Recruitment of the cohort members will be conducted via a network of approximately 
1,000 physicians (study centers) managing women with a diagnosis of 
endometriosis. The combined cohort will include 25,000 women.  
The study will be implemented in several European countries including, but not 
necessarily limited to, Germany, Austria, France and Poland. The sequence for 
starting the study in individual countries will depend upon the sequence of Visanne 
launches. Study participants should undergo follow-up for 3-6 years.  
Study measures should not interfere with the prescribing behavior of physicians or 
with the individual needs of the participating women. Influence on the preference for 
specific endometriosis treatments is to be avoided but significant efforts are to be 
undertaken to ensure standardized, comprehensive and reliable documentation of all 
baseline characteristics and adverse events during the follow-up period.  
 
                                                          
5  i.e., 1) all patients who are new users of endometrial medication - regardless of the type of 
estrogen or progestin - are eligible for enrollment if they give their informed consent and 2) 
the recruitment of patients should not (significantly) influence the physician’s prescribing 
behavior. 

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5. 
STUDY PARTICIPANTS 
The study participants are women who  
 are users of a newly prescribed regimen for endometriosis (first-time users or 
switchers)  
 are willing to participate in this long-term follow-up study 
There are no specific medical inclusion or exclusion criteria. However, women  
 who are not cooperative/available for follow-up may be excluded from study 
participation 
 with a language barrier will not be eligible for study inclusion 
At the participating centers, all women prescribed a new treatment for endometriosis 
are to be asked by their physician if they are willing to participate. The physician is to 
explain the nature of the study, its purpose and associated procedures, and the 
expected duration of follow-up for each woman prior to her study entry. Each woman 
is to have ample opportunity to ask questions and must be informed about her right 
to withdraw from the study at any time without disadvantage and without having to 
provide reasons for her decision. This information will be provided on an informed 
consent and data privacy form which must be signed by all study participants. These 
documents are to be approved by the relevant local Ethics Committees and the 
relevant Data Privacy Office, if applicable. 
Once enrolled, a subject may discontinue use of the relevant medication at any time. 
However, subjects will continue to be followed whether or not they remain on their 
treatment for endometriosis, provided that they do not withdraw their consent. During 
the follow-up phase, subjects will be asked whether they have discontinued their 
treatment or whether they have switched to another medication or received surgical 
treatment to manage their endometriosis. Information on the date and reason for 
discontinuation or switching during the follow-up phase will also be collected. 
 
6. 
BASELINE SURVEY 
Each physician’s office will be provided with simple case report forms 
(questionnaires) for collecting data at baseline. The baseline visit will take place at 
the participating physician’s office. All women who receive a new prescription for the 
treatment of endometriosis are to be asked if they are willing to participate. Only after 
the endometriosis medication has been prescribed will the physician discuss the 
study with the subject. This ensures that participation in the study is not considered a 
requirement for treatment. After discussing the study details (including follow-up 
procedures and intervals, content and duration of follow-up contacts, use of data 
collected, etc.), each subject will be asked to provide written informed consent to 

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participate in the study. If the subject needs time to consider participation, she will be 
permitted to leave the physician’s office with her prescription and take an appropriate 
period to decide whether to participate. 
The informed consent will include permission for study data to be collected and 
analyzed and for contacts to be made by the study team at intervals during the 
follow-up phase for collection of study information. Each subject will also be asked to 
provide information regarding alternative contacts (a close relative or friend, or 
primary care physician) if the study team cannot reach the subject after several 
attempts. Permission for the study team to contact a subject’s primary care physician/ 
attending physician(s) and to review relevant source data (e.g., medical reports for 
validation of reported serious clinical outcomes) will also be sought. Follow-up 
frequency by the study team will be explained, and the content of follow-up contacts 
will be described. 
Confidentiality will be maintained throughout the study and no personal information 
will be shared with alternative contacts. The funder - Bayer Schering Pharma AG - 
will not have access to names, addresses, or alternative contact information for the 
subjects and all individual subject data will remain anonymous. Personal and medical 
information will be recorded on separate documents. ZEG will ensure that access to 
personal information is restricted in accordance with data privacy rules.  
Baseline data will be recorded on a self-administered questionnaire containing 
queries relating to the participant’s state of health and potential risk factors. 
Demographic data, medical and gynecological history, detailed history of previous 
treatments for endometriosis, anemia and psychiatric illnesses, medication history 
and family history of depression and anemia/hematological problems as well as the 
addresses, e-mail addresses and phone numbers of the patient, relatives or friends, 
and the primary care physician are to be provided. In compliance with data protection 
regulations names, addresses and phone numbers are to be documented on a 
separate sheet and stored separately in a locked cabinet. 
 
7. 
FOLLOW-UP 
A follow-up assessment for each woman is scheduled 6, 12, 24, 36 and depending 
on the date of enrollment 48, 60 and 72 months after baseline. Women will be 
followed-up for at least 3 years. Women recruited in the early phase of the study will 
be followed-up until study endpoint [max. 6 years].  
Follow-up questionnaires will be mailed to the participating women, who often know 
more about potentially relevant health issues than the physician who made the initial 
prescription. This is especially true for potential adverse events treated by other 
physicians. Occasionally, events may be reported by the participant or by a 
participant’s relatives, friends or attending physicians between the regular follow-ups. 

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These reports will be documented and validated in the same way as regular reports 
(see section 8).  
The follow-up questionnaires will address the occurrence of adverse events. If the 
woman reports a change in treatment, reasons for switching to another 
endometriosis treatment or discontinuation of treatment will be requested. In case the 
regimen was changed or stopped due to a wish to conceive, or due to unintended 
pregnancy, a follow-up questionnaire requesting data on pregnancy related out-
comes (abortions, stillbirths and congenital abnormalities) will be sent to the study 
participant.  
A low “loss to follow-up rate” will be essential for the validity of the study. In order to 
minimize loss to follow-up a multi-faceted, four-level follow-up process will be estab-
lished. Level 1 activities include mailing of the follow-up questionnaire and – in case 
of no response – reminder letter(s). If level 1 activities do not lead to a response, 
multiple attempts are to be made to contact the woman, friends, relatives and the 
gynecologist/primary care physician per phone. In parallel to these level 2 activities 
searches in national and international telephone and e-mail address directories are 
started (level 3 activities). If this is not successful, an official address search via the 
respective governmental administration will be conducted. This level 4 activity can 
provide information on new addresses, emigration or death. If necessary, a search in 
the national death registers is started at the end of the study to clarify the vital status 
of patients who are lost to follow-up after level 4 activities. Specific follow-up 
procedures will be governed by local peculiarities. Overall, the loss to follow-up of the 
combined cohort should be kept at less than 5%. 
 
8. 
VALIDATION OF SELF-REPORTED EVENTS 
A self-administered questionnaire used by study participants is a very sensitive tool 
which captures almost all serious clinical outcomes. From a methodological point of 
view, it captures a much higher proportion of relevant outcomes than methods relying 
on events reporting by the prescribing physician (e.g. gynecologist). However, 
laypersons can misinterpret diagnostic treatments leading to a significant difference 
between the number of events reported and the number that are validated and 
confirmed by the ZEG team. Therefore, validation of the self-reported events is of 
utmost importance. 
Validation of self-reported events begins at the level of the national field organization 
with a review of all subjective “events.” Potential serious outcomes are reported to 
ZEG on a continuing basis and validated by ZEG. 
If an event is reported by a woman, the woman’s symptoms and signs of disease 
and, if possible, the diagnosis as perceived by the patient is recorded. The name and 
address of the relevant physician (attending physician, physician responsible for the 

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follow-up treatment on discharge from hospital or primary care physician) should be 
provided by the participant.  
Follow-up questionnaires containing information on such an event are immediately 
passed on to the Medical Review group at ZEG. If information is unclear or missing, 
the woman will be contacted via phone, e-mail or other means. For many serious 
outcomes it will be necessary to contact the diagnosing and/or treating physician for 
clarification and validation of the information received from the patient. This proce-
dure is mandatory for all serious clinical outcomes (incl. anemia and depression).  
Under routine medical conditions, diagnosis of an SAE is not always confirmed by a 
diagnostic method with high specificity. Therefore, SAEs are classified by the 
investigators as “confirmed” or “not confirmed” according to a predefined algorithm 
(cf. Appendix 1). 
In order to minimize classification bias - particularly if it selectively affects an individ-
ual exposure cohort - classification of self-reported serious events into confirmed and 
not confirmed cases will be adjudicated by two blinded medical boards. The 
‘Hematology Board’ consists of three independent medical experts specialized in 
internal medicine/hematology and gynecology. The ‘Depressive Illness Board’ 
consists of specialists in psychiatry/psychological medicine. Blinded adjudication of 
both anemia and depressive illnesses are scheduled at the conclusion of the study 
(Beginning of 2017). The Safety Monitoring and Advisory Council (see section 13) will 
appoint these experts who will review all available information on the reported 
anemia and depression cases. However, brand names, dose, regimen and 
composition of the endometriosis medication used by the reporting woman will be 
rendered anonymous. The adjudicators will perform the review independently of each 
other and without knowing the judgment of the other adjudicators. If at least one 
adjudicator classifies a report as a confirmed case of anemia or depression, the 
reported event will be considered ‘confirmed’. More details on the blinded 
adjudication procedure are given in Appendix 2. 
 
9. 
REPORTING OF SERIOUS AND/OR UNEXPECTED ADVERSE EVENTS 
ZEG will report all serious6 and/or unexpected events that are possibly related to the 
use of any endometriosis treatment to the relevant pharmaceutical companies. A 
physician on the ZEG study team will assess the likelihood of a causal relationship to 
the medication use for each serious adverse event in accordance with a predefined 
algorithm (cf. Appendix 3). Overall, the handling of adverse events will follow Volume 
                                                          
6  Serious adverse event means any adverse event that results in death, a life-threatening 
experience, inpatient hospitalization, persistent or significant disability/incapacity, or 
requires medical/surgical intervention to prevent one of said outcomes. 

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9A of ‘The Rules Governing Medicinal Products in the European Union (part I, 
section 7). 
ZEG will not monitor whether the pharmaceutical companies meet their obligation to 
report these events to the Health Authorities according to (inter)national rules.  
 
10. 
DATA MANAGEMENT 
When questionnaires are received from study participants, all pages are counted and 
the questionnaire is date-stamped. Questionnaires are to be checked for correct 
subject identification number, missing pages, legibility, and incomplete information on 
the questionnaires (cf. section 6 ‘Baseline survey’ and 7 ‘Follow-Up’). Missing pages, 
illegible or missing information are requested from the study participants prior to data 
entry of the respective questionnaire.  
Data are entered by double data entry via formatted entry screens designed to reflect 
the appearance of the questionnaire. Discrepancies between first and second data 
entry are identified by comparison of the two entry files within the statistical software 
SAS. The decision on the true entry is done by the responsible data manager at 
ZEG. This may require direct contact with the study participant who filled in the 
questionnaire. Corrections will be made to the questionnaire only after contact with 
the study participant or her treating physician (cf. section 8 ‘Validation of Self-
Reported Events’). All corrections are dated and initialed by the data manager who re-
ceived the relevant new information (e.g., via direct contact or by a copy of medical 
reports/documents). The incorrect CRF entry will be crossed out; however, it must 
remain legible, and the correct entry will be placed next to it. The reason for any 
correction of medical data on the questionnaire must be documented. 
Quality control of entered data will be supported by SAS plausibility programs which 
include range, coding, missing and date checks as well as cross-reference 
(consistency) checks between variables. 
 
11.  
DATA ANALYSES 
Three primary outcomes of interest, anemia, depression and treatment failure7, will 
be analyzed for inferential statistics.  
Based on available data and pharmacological/pharmacokinetic considerations the a 
priori assumption is that use of DNG is not associated with an increased risk of 
                                                          
7  ‘Treatment failure’ is defined as cessation of treatment caused by lack of efficacy, loss of 
efficacy or an adverse drug reaction and does not include women who stop treatment 
after pre-defined treatment periods (eg. after six months for GnRH agonists). 

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anemia compared to approved hormonal medications used in the treatment of endo-
metriosis (“endometriosis medications”).  It is probable that statistical comparisons of 
DNG vs. other endometriosis medications will not show a difference. Therefore, a 
non-inferiority design to investigate the anemia risk of DNG had been chosen. The 
analysis will be based on the comparison of the upper confidence limit for the point 
estimate of the anemia hazard ratio with the predefined non-inferiority margin (cf. 
section 12).  
The null hypothesis to be tested is: HRanemia > 2 (i.e., the anemia hazard ratio for 
DNG vs. other endometriosis medications is higher or equal to 2). The alternative 
hypotheses are: HRanemia< 2.  
For clinically relevant depression (first episode or worsening), the a priori assumption 
is that no approved treatment for endometriosis is associated with a higher risk of 
depression compared with untreated endometriosis. A non-inferiority design has 
been chosen, with primary analysis based on the comparison of the upper 
confidence limit for the point estimate of the depression hazard ratio with the 
predefined non-inferiority limit (cf. section 12).  
The null hypothesis to be tested is: HRdepression > 2 (i.e., the depression hazard ratio 
for DNG vs. other endometriosis medications is higher or equal to 2). The alternative 
hypothesis is: HRdepression< 2. 
There are both pharmacological and clinical indications that suggest that DNG may 
be superior to other endometriosis medications as a long-term treatment for 
endometriosis. That is, a statistical comparison of DNG vs. other endometriosis 
medications may show a difference in ‘treatment failure’, with DNG users continuing 
on treatment for longer periods of time. ‘Treatment failure’ is defined as cessation of 
treatment caused by lack of efficacy, loss of efficacy or an adverse drug reaction and 
does not include women who stop treatment after pre-defined treatment periods (eg. 
after six months for GnRH agonists). In addition, combined treatment with GnRH, an 
estrogen and/or a progestogen (add-back therapy) will be considered as a single 
treatment regimen. In cases where add-back therapy is used the predefined end-
point is the cessation of the add-back therapy.8 A superiority design to investigate 
‘treatment failure’ for DNG has been chosen. The analysis will be based on a 5% 
point difference (difference of 0.05) of DNG vs. other endometriosis medications. 
Safety monitoring during study conduct will be based primarily on the ITT analysis of 
crude data. The final analyses will include both an “as treated” (AT) and an intention-
to-treat (ITT) analysis using Cox regression models. The safety conclusions of the 
                                                          
8 The two sentences in italics were was added on request of the MEB (revised study protocol 
of February 28, 2011) 

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study, however, will be based on the AT analyses because the ITT approach 
potentially dilutes differences between treatments.  
Crude as well as adjusted hazard ratios will be calculated. The appropriate con-
founding variables will be built into the statistical model. Based on the expectation of 
a small absolute number of serious outcomes of interest the number of confounding 
variables will be limited to established risk factors for these outcomes. For anemia 
these will include age, duration of current use, and family history of bleeding dis-
orders and a past history of anemia. For depression, age, chronic pelvic pain, anxiety 
disorder and a family history of depression are proposed. For ‘treatment failure’ 
chronic pelvic pain, age and previous surgical treatment will be included. The final 
decision on and the addition of other confounding variables (e.g. country) will be 
made by the Safety Monitoring and Advisory Council before the first interim analysis 
of follow-up data. In addition, alternative analysis will be performed with other 
potential baseline risks to check the appropriateness of this decision.  
A detailed statistical analysis plan will be developed by the Principal Investigator 
during the first year after study start. The final analysis plan will be approved by the 
Safety Monitoring and Advisory Council before the first interim analysis of follow-up 
data. 
Biannual interim reports will be provided to the funder following release of the interim 
analyses results by the independent Safety Monitoring and Advisory Council (cf. 
section 13). 
  
12. 
SIZE OF THE STUDY AND EVALUTION 
The 3 to 6 year follow-up of 25,000 women should result in approximately 89,000 
documented women-years. This estimate is based on the assumptions that (1) ZEG’s 
physicians’ network could recruit 25,000 women within three years, and (2) the 
annual drop-out rate is 10% (based on the EURAS-OC [1] and LASS studies). 
Details are provided in Table 1 and are based on the assumption that the follow-up 
period is a maximum of 6 years.  

VIPOS Study Protocol, 2nd revision of Nov. 21, 2011  
 
p. 17 of 26  
Overall, 3 hypotheses will be tested (cf. section 11). The problem of multiple 
comparisons is addressed by using Bonferroni-Holm correction to maintain the 
overall error rate by testing each individual hypothesis at a statistical significance 
level of 1/3 times what it would be if only one hypothesis were tested (i.e., the 
individual tests will be based on an α level of 0.0167 instead of 0.05).  
Power calculations based on the incidences given above showed that approximately 
84,000 women-years would be needed to show non-inferiority of DNG versus other 
endometriosis medications for anemia. The calculations for anemia are based on the 
assumptions given in Table 2. In essence, the study is powered to exclude a two-fold 
risk of anemia for the DNG with at least 10% of the total exposure – if the true risk of 
anemia is not different for the relevant sub-cohorts.  
Table 2:  Power calculation[15] for anemia based on the assumption that the true incidence of 
DNG cohort is not different from other endometriosis medications  (reference cohort) 
Test significance level, α (one-sided) 
0.0083 (= 0.0167 two-sided) 
Anemia Incidence for reference cohort  
0.01 
Non-inferiority margin 
 
0.01 (equal to the anemia 
incidence for the reference 
cohort)  
Expected anemia incidence for DNG cohort 
0.01  
Power (%) 
90 
Proportion of DNG users (% of study population) 
10 
Proportion of reference users (% of study population) 
5 
Required women years in DNG cohort 
8,400 
Required women years in reference cohort  
4,200 
Total women years 
84,000 
 
Furthermore, 84,000 WY would be sufficient to also exclude a two-fold risk of 
clinically relevant depression (cf. Table 3), assuming that DNG accounts for at least 
10% of the total exposure.  
For ‘treatment failure’ approximately 29,500WY will be required to show that DNG is 
superior to other endometriosis medications (cf. Table 4), assuming that the 
proportion of DNG, danazol and GnRH agonists users each account for 10% of the 
total exposure.  
 

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p. 18 of 26  
Table 3: Power calculation[15] for depression based on the assumption that the true incidence 
in the DNG cohort is not different from the reference cohort 
 
Test significance level, α (one-sided) 
0.0083 (= 0.0167 two-sided) 
Depression Incidence for reference cohort  
0.01  
Non-inferiority margin 
 
0.01 (equal to the 
depression incidence for the 
reference cohort)  
Expected depression incidence for DNG cohort 
0.01 
Power (%) 
90 
Proportion of DNG users (% of study population) 
10 
Proportion of reference users (% of study population) 
5 
Required women years in DNG cohort 
8,400 
Required women years in reference cohort  
4,200 
Total women years 
84,000 
 
Table 4:  Power calculation[15] for ‘treatment failure’ based on the assumption that the true 
incidence in the DNG cohort is ~ 2,500/10,000 compared to ~ 3,000/10,000 in the 
other endometriosis medications cohort. 
 
Test significance level, α (one-sided) 
0.0167  
Incidence of treatment failure for other endometriosis 
medications cohort  
0.30  
Clinically relevant difference  
 
0.05 
Expected incidence of treatment failure for DNG cohort 
0.25 
Power (%) 
90 
Proportion of DNG users (% of study population) 
10 
Proportion of reference users (% of study population) 
5 
Required women years in DNG cohort 
2,950 
Required 
women 
years 
in 
other 
endometriosis 
medications cohort  
1,475 
Total women years 
29,500 
 

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p. 19 of 26  
These power calculations suggest that this study is sufficiently powered to show non-
inferiority of DNG compared to established endometriosis treatments with regard to 
anemia and clinically relevant depression, as well as superiority with regards to 
‘treatment failure’. However, exact power calculations based on actual incidences 
and drop-out rates should be done on the basis of two years follow-up data. If these 
calculations do not confirm the assumed incidences and drop-out rates, the 
independent Safety Monitoring and Advisory Council (SMAC) may discuss the need 
for adapting patient numbers and follow-up times. 
 
13. 
SAFETY MONITORING AND ADVISORY COUNCIL 
This study will maintain scientific independence and will be governed by an inde-
pendent Safety Monitoring and Advisory Council (SMAC). Bayer Schering Pharma 
AG Berlin will provide an unconditional grant. The Berlin Center for Epidemiology and 
Health Research (ZEG), Germany and its research team will be accountable to 
SMAC in all scientific matters.  
The SMAC members will be international experts in relevant scientific fields (e.g., 
epidemiology, gynecology, psychiatry and internal medicine. The members will 
receive remuneration of expenses and an honorarium to compensate for loss of 
potential earnings during their work for SMAC. The members will not be involved in or 
paid for the operational conduct of the study. 
 
14. 
STUDY MANAGEMENT 
This study will be conducted in accordance with  
 ‘Guidelines for Good Pharmacoepidemiology Practices (GPP)’ issued by the 
International Society for Pharmacoepidemiology in 2007  
  ‘Good Epidemiological Practice (GEP) – Proper Conduct in Epidemiologic 
Research’ issued by the International Epidemiological Association (IEA) European 
Federation in 2007  
 EnCEPP code of conduct for scientific independence and transparency in the 
conduct of pharmacoepidemiological and pharmacovigilance studies, 2010 
 The ethical principles that have their origin in the Declaration of Helsinki. 
 
15. 
ETHICS AND PRIVACY 
The study will only start after all relevant legal, administrative and ethical require-
ments (including all requirements regarding the enrollment of minors) have been 
fulfilled. Information on the identity of the patients and treating physicians will be kept 

VIPOS Study Protocol, 2nd revision of Nov. 21, 2011  
 
p. 20 of 26  
separated from the clinical information throughout the study. All relevant national 
data protection laws will be followed. The study protocol will be submitted to the 
relevant Ethics Committees, Institutional Review Boards and regulatory authorities for 
comments and approval. 
Subjects will sign informed consent forms at baseline after reading a subject 
information sheet and discussing the study with the participating physician. The 
physician will describe the purpose of the study, the non-interventional character of 
the study, timing and expected content of follow-up phase contacts, and collection of 
alternative contact information. Consent will include permission to contact any 
treating physician to follow up on specific safety outcomes. Subjects will be informed 
that ZEG’s study team will contact them during the follow-up phase to ask a 
predefined set of safety related questions or to update alternative contact 
information. Answers to these questions will remain anonymous when forwarded to 
Bayer Schering Pharma AG or the Safety Monitoring and Advisory Council. 
Subjects will be asked to provide personal contact information (e.g., telephone 
number, home and e-mail address) and information regarding alternative contacts 
(e.g., relative, friend, general practitioner) in case they cannot be reached. In the 
event that a subject cannot be reached during the follow-up phase, local 
organizations will attempt to reach an alternative contact to re-establish contact with 
the subject. Subjects may be contacted between two follow-up points to confirm that 
their personal contact information is correct. 
 
Subjects retain the right to withdraw their consent at any time during the study. 
 
16.  
STUDY FEASIBILITY 
 
ZEG’s study team has performed large, multi-national, observational studies on 
pharmacoepidemiological issues for more than 30 years – in particular in the area of 
women’s health care. Many of these studies have prospectively followed-up patients 
for 5-10 years. In addition ZEG developed the EURAS/INAS study design. ZEG has 
established a broad network of several thousands gynecologists in Europe who are 
currently recruiting women for INAS-like studies. With this established international 
network no major problems are expected for the recruitment of study participants. 
Furthermore, the drop-out and follow-up rates presented in this study protocol are 
based on comprehensive experience from similar studies. Therefore the conduct of 
the VIPOS study according to this study protocol has a high probability of success.  
 
 

VIPOS Study Protocol, 2nd revision of Nov. 21, 2011  
 
p. 21 of 26  
17.  
MILESTONES 
 
Precise recruitment and follow-up milestones will depend on the specific launch 
dates of Visanne in Europe. However, we anticipate the first patient to be recruited in 
November 2010. The first Safety and Medical Advisory Council (SMAC) will take 
place in the second quarter of 2011, and 6-monthly thereafter, unless otherwise 
agreed upon by SMAC members. Written reports up-dating regulatory authorities of 
the study progress and important SMAC decisions will follow these meetings. The 
final evaluation and analysis of anemia and depression (with blinded adjudication) 
will take place at the conclusion of the study follow-up period. A comprehensive study 
report will be made available after the completion of the study. 
 
18. 
PUBLICATIONS 
The results of this study will be published. In accordance with the International 
Committee of Medical Journal Editors (ICMJE) initiative requiring prior entry of clinical 
studies in a public registry as a condition for publication, the study will be registered 
in the U.S. National Institutes of Health’s protocol registration database 
(http://ClinicalTrials.gov). 
 
19. REFERENCES 
 
[1] Wills H, Demetriou C, May K et al; NHS Evidence – women’s health Endometriosis Annual 
Evidence Update. March 2010. Nuffield Dept. of Obstetrics and Gynaecology 
[2] Sinaii N, Plumb K, Cotton L et al: Differences in characteristics among 1,000 women with 
endometriosis based on extent of disease. Am. Soc of Reproductive Medicine. 2008;89:538-545 
[3] Practice Committee for the ASRM: Treatment of Pelvic Pain Associated with Endometriosis. 
Fertility and Sterility 2008; 90(3):S260-S269 
[4] Nobukata H, Katsuki Y, Ishikawa T et al; Effect of dienogest on bleeding time, coagulation, 
fibrinolysis and platelet aggregation in female rats. Toxicol Lett. 1999, 104(1-2):93-10 
[5] Pérez-Campos EF; Ethinylestradiol/dienogest in oral contraception; Drugs. 2010 16;70(6):681-689. 
[6] Harada T, Taniguchi F; Dienogest: a new therapeutic agent for the treatment of endometriosis. 
Womens Health (Lond Engl) 2010, 6(1):27-35. 
[7] Strowitski T, Marr J, Gerlinger G et al; Dienogest is as effective as leuprolide acetate in treating the 
painful symptoms of endometriosis: a 24-week, randomized, multi-centre, open-label trial. Hum 
Reprod 2010, 25(3):633-41 
[8] Strowitzki T, Faustmann T, Gerlinger C, Seitz C; Dienogest in the treatment of endometriosis-
assoicated pelvic pain: a 12-week randomized, double-blind, placebo-controlled study. Eur J Obstet 
Gynecol Reprod Biol 2010, 151(2):193-8 
[9] Momoeda M, Harada T, Terakawa N et al; Long-term Use of Dienogest for the Treatment of 
Endometriosis. J Obstet Gyanecol Res. 2009, 25(6):1069-76 

VIPOS Study Protocol, 2nd revision of Nov. 21, 2011  
 
p. 22 of 26  
[10] Dinger JC, Heinemann LAJ, Kühl-Habich D. The safety of a drospirenone-containing oral 
contraceptive: Final results from the European Active Surveillance study on Oral Contraceptives 
(EURAS-OC) based on 142,475 women-years of observation. Contraception 2007;75:344–54.  
[11] Sepulcri Rde P, do Amaral VF; Depressive symptoms, anxiety and quality of life in women with 
pelvic endometriosis. Eur J Obstet Gynecol Reprod Biol 2009, 142(1): 53-6 
[12] Lorencatto C, Petta CA, Navarro MJ, Bahamondes L, Matos, A; Depression in women with 
endometriosis with and without chronic pelvic pain. Acta Obstet Gynecol Scand. 2006, 85(1) 88-92 
[13] Heinemann L, The European Active Surveillance Study on Oral Contraceptive Prescribing 
Practice, Benefits and Safety (EURAS) – The Study Protocol. LAMSO 2001; 2:1-10 
[14] Fischbacker C et al. Anemia in Chinese, South Asian, European populations in Newcastle upon 
Tyne: a cross-sectional study. BMJ 2001; 322: 958-959  
[15] Colett, D. Modelling Survival Data in Medical Research. Chapman and Hall 1994, Section 9.2 
 
Background references 
Halis G, Mechsner S, Ebert AD; The diagnosis and treatment of deep infiltrating endometriosis. Dtsch 
Arztebl Int 2010; 107(25)446-456. 
Harada T, Momoeda M, Taketani Y et al; Dienogest is as effective as intranasal buserelin acetate for 
the relief of pain symptoms associated with endometriosis – a randomized, double-blind, multicenter, 
controlled trial. Fertil Steril 2009, 91(3):675-81 
Kusumi E, Shoji M, Endou S et al; Prevalence of Anemia among Healthy Women in 2 Metropolitan 
Areas of Japan. Int J of Hematology 2006, 84:217-219. 
Kennedy S, Bergqvist A, Chapron C et al. ESHRE guideline for the diagnosis and treatment of 
endometriosis. Human Reproduction 2005; 20(10);2698-2704 
Siedentopf F; Chronic pelvic pain in women from a gynecologic viewpoint. Urologe A 2009, 10:1193-
1198. 
Siedentopf F, Tariverdian N, Ruecke M et al; Immune status, psychosocial distress and reduced 
quality of life in infertile patients with endometriosis. Am J Reprod UImmunol 2008, 5:449-61 

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APPENDIX 1: VALIDATION OF SELF-REPORTED EVENTS 
 
Anemia 
 
Definite Event:  
 Confirmed by repeated reliable laboratory test (e.g. hemoglobin, packed 
cell volume), plus pertinent therapy (blood or iron transfusion, iron 
tablets) and 
 No obvious explanation (such as gastrointestinal bleeding, trauma, 
major surgery) or no explanation other than endometriosis related 
bleeding9 
 
Probable Event: 
 No reliable laboratory data available, but clinical diagnosis stated by a 
physician, followed by pertinent therapy (see above)  and  
 No obvious explanation (such as gastrointestinal bleeding, trauma, 
major surgery) or no explanation other than endometriosis related 
bleeding9 
 
Event not confirmed: 
 Diagnosis reported by the patient is excluded by diagnostic procedures 
 A different medical condition is diagnosed by the attending physician 
 The woman did not contact a health professional to clarify her 
symptoms and no diagnostic measures were performed that could have 
clarified the diagnosis 
 
Definite and probable events will be classified as ‘confirmed events’. 
 
 
Clinically relevant Depression 
 
Definite Event:  
 Diagnosis is confirmed by a physician specialized in psychiatry using 
validated instruments (e.g. HAM-D, BECK depression inventory)10 
 Confirmed suicide or attempted suicide in a participant with a past 
history of depression 
 
Probable Event: 
 Clinical diagnosis confirmed by physician specialized in psychiatry 
without the use of validated instruments (see above)10 
 Confirmed (attempted) suicide without a previous psychiatric diagnosis 
                                                          
9  Original wording: “Anemia is associated with prolonged, excessive or irregular bleeding”. 
Revised on request of the Safety Monitoring and Advisory Council. 
10 Bipolar disorders and schizoaffective disorders are excluded. This specification was added 
on request of the Safety Monitoring and Advisory Council. 

VIPOS Study Protocol, 2nd revision of Nov. 21, 2011  
 
p. 24 of 26  
 
Event not confirmed: 
 Diagnosis reported by the patient is excluded by diagnostic procedures  
 Diagnosis is confirmed by a physician without specialized training in 
psychiatric diseases 
 A different medical condition is diagnosed by the attending physician 
 The woman did not contact a health professional to clarify her 
symptoms and no diagnostic measures were performed that could have 
clarified the diagnosis 
 
Definite and probable events will be classified as ‘confirmed events’. 
 
 
Other Serious Adverse Events 
 
Definite Event:  
Diagnostic measures with high specificity (e.g., ultrasound diagnosis of VTE, 
ECG with typical ST segment elevation for acute myocardial infarction, histology 
for cancers, two-sided blood pressure measurement with diastolic blood 
pressure of more than 120 mmHG for hypertensive crisis)  
 
Probable Event: 
Absence of confirmation by a diagnostic measure with high specificity, but 
clinical diagnosis confirmed by a health professional or supported by diagnostic 
tests with low specificity (D-dimer for VTE, typical ECG/blood gas tests for PE 
or confirmation of diagnosis by the treating physician for cancer). These cases 
are usually characterized by a subsequent specific therapy (such as fibrinolysis, 
long-term anticoagulant therapy or chemotherapy/radiotherapy). However, if the 
attending physician confirms that the diagnosis is correct, the event will be 
classified as a probable event even if specific treatment was not given.  
 
Event not confirmed: 
 Diagnosis reported by the patient is excluded by diagnostic procedures 
 A different medical condition is diagnosed by the attending physician 
 The woman did not contact a health professional to clarify her 
symptoms and no diagnostic measures were performed that could have 
clarified the diagnosis 
 
Definite and probable events will be classified as ‘confirmed events’. 
 
 
 
 

VIPOS Study Protocol, 2nd revision of Nov. 21, 2011  
 
p. 25 of 26  
 
APPENDIX 2: BLINDED ADJUDICATION 
 
 
The following adjudication procedure will be established: 
1) Independent adjudication by the individual specialists  
2) Documentation of the individual assessments 
3) Comparison of the individual assessments 
4) Discussion of “split decisions” among the adjudicators without enforcement of 
a unanimous decision 
5) Independent re-adjudication of the discussed cases by the individual 
adjudicators 
6) Documentation of the individual assessments 
 
Based on this procedure four different classification strategies will be possible 
I. Classification of the reported event according to the assessment of the 
majority of adjudicators before the discussion of “split decisions” takes place 
(i.e., “majority vote” based on step 2 of the six-step procedure described 
above) 
II. Classification of the reported event according to the assessment of the 
majority of adjudicators after discussion of “split decisions” takes place (i.e., 
majority classification based on step 6 of the six step procedure described 
above) 
III. Classification of the reported event as confirmed if at least one adjudicator had 
classified the event as confirmed before the discussion of split decisions took 
place (i.e., “worst case decision” based on step 2 of the six-step procedure 
described above) 
IV. Classification of the reported event as confirmed if at least one adjudicator had 
classified the event as confirmed after the discussion of split decisions took 
place (i.e., “worst case decision” based on step 6 of the six-step procedure 
described above) 
The final analysis will be based on strategy III (worst case decision without 
discussion of split decisions) because it represents the most conservative approach. 
Alternative analyses will be possible on request of the Safety Monitoring and 
Advisory Council or regulatory authorities. 
 

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p. 26 of 26  
 
APPENDIX 3: CAUSALITY ASSESSMENT 
 
 
Categories (Code)
Definition 
no (1) 
The time course between administration of the study drug and occurrence or 
worsening of the adverse event rules out a causal relationship 
and/or 
another cause is confirmed and no indication of involvement of the study drug 
in the occurrence/worsening of the adverse event exists. 
unlikely (2) 
The time course between administration of the study drug and occurrence or 
worsening of the adverse event makes a causal relationship unlikely 
and/or 
the known effects of the study drug or of the substance class provide no 
indication of involvement in occurrence/worsening of the adverse event and 
another cause adequately explaining the adverse event is known 
and/or 
regarding the occurrence/worsening of the adverse event a plausible causal 
chain may be deduced from the known effects of the study drug or the 
substance class, but another cause is much more probable 
and/or 
another cause is confirmed and involvement of the study drug in the 
occurrence/worsening of the adverse event is unlikely. 
possible (3) 
Regarding the occurrence/worsening of the adverse event, a plausible causal 
chain may be deduced from the pharmacological properties of the study drug 
or the substance class, but another cause just as likely to be involved is also 
known 
or 
although the pharmacological properties of the study drug or the substance 
class provide no indication of involvement in the occurrence/worsening of the 
adverse event, no other cause gives adequate explanation. 
probable (4) 
The pharmacological properties of the study drug or of the substance class 
and/or 
the course of the adverse event after dechallenge and, if applicable, after 
rechallenge 
and/or 
specific tests (e.g. positive allergy test, antibodies against study 
drug/metabolites) suggest involvement of the study drug in the 
occurrence/worsening of the adverse event, although another cause cannot 
be ruled out. 
definite (5) 
The pharmacological properties of the study drug or of the substance class 
and 
the course of the adverse event after dechallenge and, if applicable, after 
rechallenge 
and 
specific tests (e.g. positive allergy test, antibodies against study 
drug/metabolites) indicate involvement of the study drug in the 
occurrence/worsening of the adverse event and no indication of other causes 
exists.