Adv Ther

https://doi.org/10.1007/s12325-020-01331-z

STUDY PROTOCOL

Safety of Dienogest and Other Hormonal Treatments

for Endometriosis in Real-World Clinical Practice
(VIPOS): A Large Noninterventional Study
Klaas Heinemann . Bruno Imthurn . Lena Marions . Christoph Gerlinger .
Kerstin Becker . Sabine Moehner . Thomas Faustmann

Received: October 23, 2019

 The Author(s) 2020

ABSTRACT for endometriosis can be effective in controlling

symptoms, but may have clinically relevant side
Introduction: Endometriosis is a common effects that limit their long-term use. Dienogest
gynecologic disease associated with a significant 2 mg (Visanne; Bayer AG, Berlin, Germany) is a
burden on women’s health and healthcare sys- 19-nortestosterone derivative that significantly
tems. Currently approved hormonal treatments reduces menstrual bleeding, dysmenorrhea,
premenstrual pain, dyspareunia, and pelvic
pain in women with endometriosis. Although
Digital Features To view digital features for this article dienogest 2 mg has demonstrated efficacy in
go to https://doi.org/10.6084/m9.figshare.12046359.
clinical trials, data regarding long-term and real-
Electronic Supplementary Material The online world use are limited.
version of this article (https://doi.org/10.1007/s12325- Methods: To our knowledge, the Visanne Post-
020-01331-z) contains supplementary material, which is
available to authorized users.
approval Observational Study (VIPOS) is the
largest real-world, noninterventional study
performed examining the safety of dienogest
K. Heinemann (&)
K. Becker
S. Moehner
ZEG Berlin, 10115 Berlin, Germany and other hormonal treatments for the
e-mail: [email protected] management of endometriosis in routine clinical
practice. Patients self-reported medical and
B. Imthurn
Department of Reproductive Endocrinology, gynecologic history and symptoms and
University Hospital Zurich, 8091 Zurich, treatment information. Primary clinical outcomes
Switzerland were clinically validated and subject to inde-
L. Marions
pendent blinded adjudication. Loss to follow-up
Department of Clinical Science and Education, was minimized through active contact with
Karolinska Institutet, 118 83 Stockholm, Sweden participating women at 6 months post-
enrollment and annually thereafter to ensure
C. Gerlinger
Statistics and Data Insights, Bayer AG, 13553 Berlin, almost all clinically relevant outcomes were
Germany captured.
Planned Outcomes: VIPOS planned to enroll
C. Gerlinger
Gynecology, Obstetrics and Reproductive Medicine,
approximately 25,000 women initiating a new
University Medical School of Saarland, treatment for endometriosis, including those
66421 Homburg, Saar, Germany prescribed dienogest 2 mg/day and other
hormonal medications for endometriosis
T. Faustmann
Bayer AG, 13353 Berlin, Germany (approved or nonapproved), from approximately
 Adv Ther

1000 centers in six European countries. The main VIPOS assesses a large, diverse population
clinical outcomes of interest for follow-up are of women with endometriosis, which we
anemia requiring medical intervention, de novo believe is valuable to evaluate women’s
or clinically worsening depression, and and physician’s behavior, rare events, and
treatment-failure patterns that result in drug subtle safety signals associated with
discontinuation. Additional analyses will charac- endometriosis treatments.
terize the baseline risk factors of medically managed
patients with endometriosis and assess treatment
utilization patterns. VIPOS was designed to provide
real-world information on endometriosis treat- INTRODUCTION
ment and associated clinical outcomes, while not
affecting the prescribing physician’s decisions or Endometriosis is a chronic, estrogen-dependent
the classification of patient diagnoses. disease that affects 10–15% of women during
Trial Registration: European Union Electronic their reproductive years and is defined by the
Register of Post-Authorisation Studies (EU PAS) presence of endometrial-like tissue outside the
no. 1613, Clinicaltrials.gov: NCT01266421. uterus cavity that induces chronic inflammation,
ovarian cyst formation, and fibrosis [1, 2].
Keywords: Dienogest; Endometriosis; Hormo- While the pathogenesis of endometriosis is
nal treatment; Observational; Prospective; Real- unclear, inflammation is now accepted as
world evidence; Women’s health central in the development and progression of
the disease, characterized by an overproduction
of inflammatory mediators, such as
Key Summary Points
prostaglandins, metalloproteinases, cytokines,
and chemokines [3]. In fact, investigation of the
To our knowledge, the Visanne Post-
expression of inflammatory cytokines in
approval Observational Study (VIPOS) is
peritoneal fluid of women with endometriosis
the largest real-world, non-interventional
has suggested that interleukin (IL)-17A and IL-2
study evaluating the medical
are involved in inflammatory processes under-
management of endometriosis, and we
lying endometriosis [4]. Moreover, reactive
believe that data from VIPOS can provide
oxygen species and free radicals may lead to the
insights into current treatment practices
growth and adhesion of endometrial cells in the
for endometriosis in Europe, the women
peritoneal cavity and thereby disease onset [3].
who typically present to their healthcare
The symptoms of endometriosis can include
providers, and their journey as a patient
pain, bleeding disorders, and impaired fertility
with endometriosis.
and represent a significant burden on women’s
VIPOS is supported by a robust study health and healthcare systems worldwide [1].
design, characterized by sensitive and Furthermore, endometriosis is known to
regular data collection, and uses multiple compromise women’s social relationships, sex-
validation steps, which aim to minimize uality, and psychologic and mental health [5, 6].
bias and misclassification of patient- The number of licensed pharmaceutical
reported clinical outcomes. agents for the treatment of endometriosis is
currently limited. Medical treatment of
The study design of VIPOS should endometriosis-associated pain is based on
minimize loss to follow-up through direct suppression of estrogen production and induc-
contact with the women enrolled, thereby tion of amenorrhea [7], and treatments are
ensuring that the impact of different long- often accompanied by clinically relevant side
term hormonal treatments on clinical effects [8]. Gonadotropin-releasing hormone
outcomes across distinct healthcare (GnRH) agonists are an example; they are gen-
settings can be accurately assessed. erally only prescribed for 3–6 months at a time
because of symptoms of estrogen deprivation,
Adv Ther

including vaginal dryness and hot flushes, and clinical practice, treatment adherence, impact
their negative impact on bone mineral density of simultaneous treatments, and trends in
[1, 9]. Likewise, the testosterone analog danazol incidence and disease management [22–25]. In
is no longer broadly prescribed for endometrio- addition, real-world studies have indicated the
sis, in particular because of its androgenizing side role that cultural influence, specialist access,
effects [9]. Danazol has been removed from many healthcare shortcomings, and socioeconomic
markets but is still prescribed in some European status have in the well-established diagnostic
countries, including Poland, Ukraine, and delay in endometriosis [24, 26, 27]. Prior to this
Russia. Consequently, there is an unmet need for study, there had been minimal investigation
medical therapies that are suitable for the long- into the real-world management of endo-
term management of endometriosis. metriosis, and cohorts recruited have often
Dienogest is a 19-nortestosterone derivative involved small numbers of women at single
progestogen that is highly selective for centers with limited follow-up periods [28, 29].
progesterone receptors, while demonstrating Here we report the design of the Visanne
only negligible binding for estrogen, androgen, (dienogest) Post-approval Observational Study
glucocorticoid, and mineralocorticoid receptors (VIPOS), a noninterventional post-authorization
[10, 11]. Furthermore, dienogest does not cause safety study of dienogest in a real-world setting.
metabolic imbalance, and treatment with VIPOS assesses the real-world safety of dienogest
dienogest can be prescribed as a continuous and other hormonal treatments administered,
regimen [11]. Evidence has supported the characterizes the baseline demographics of
comparable efficacy of dienogest with GnRH medically managed patients with endometrio-
agonists in controlling endometriosis- sis, analyzes their treatment utilization
associated pain symptoms [12]. In 2010, patterns, and investigates the risks associated
dienogest 2 mg was approved in Europe for the with long-term medical treatment for women
treatment of endometriosis after demonstrating with endometriosis. To our knowledge, VIPOS is
efficacy in patients with endometriosis by the largest observational study evaluating
improving dysmenorrhea, premenstrual pain, the real-world management of patients
dyspareunia, and diffuse endometriosis- with endometriosis and provides a unique
associated pelvic pain as well as decreasing the opportunity to expand our understanding of
duration of menstrual bleeding and the size of endometriosis and its management across
endometriomas [9, 13–16]. Since then, Europe.
dienogest 2 mg has been further investigated in
heterogeneous populations, in which the initial
observations regarding efficacy and safety have METHODS
been confirmed for the long-term treatment of
endometriosis [9, 13–15, 17, 18]. Study Design
Nevertheless, some safety and tolerability
concerns exist over the role of progestins in VIPOS is a prospective, noninterventional,
treating endometriosis, particularly surrounding long-term active surveillance cohort study of
mood disturbances, depressive symptoms, and women using various hormonal treatments for
bleeding disturbances [19–21]. endometriosis across six European countries:
Real-world observational studies are gaining Germany, Hungary, Poland, Russia, Switzer-
credibility as a study genre, serving as an land, and Ukraine. The study was a post-
important adjunct to randomized controlled marketing authorization measure after
clinical trials by addressing clinically relevant European approval and incorporated similar
questions that cannot be answered within a methodology to the European/International
controlled setting [22]. To date, economic, Active Surveillance study, which previously
clinical, and patient-reported outcomes have established the standard for evaluation of
been investigated in the field of endometriosis, post-marketing authorization safety studies for
including patient and disease characteristics in hormonal drug treatments [30, 31].
 Adv Ther

Overall, approximately 25,000 women with discontinued endometriosis treatment during

endometriosis who were initiating a new the study continued to be followed up, provided
treatment regimen were planned for enrollment they had not withdrawn study consent.
at approximately 1000 study centers [32]. The VIPOS was initiated in Germany and Poland
enrolling physician provided details of the in late 2010 and in Hungary in early 2011. Due
newly prescribed treatment for endometriosis to recruitment challenges, Ukraine, Russia, and
and the diagnostic classification (clinical or Switzerland were included to broaden the
surgical confirmation; Fig. 1). The purpose of recruitment base, with recruitment starting in
the ‘‘noninterference’’ approach of the study late 2011 in Russia and Ukraine and in 2012 for
was to provide standardized, comprehensive, Switzerland. Women participating in the study
and reliable information on endometriosis were followed for up to 7 years, and the follow-
treatment patterns. In addition, study up period ended in late 2018 [32].
assessments were not intended to interfere with
the prescribing behavior of physicians or with Measurements
the individual needs of the participating women.
At baseline, medical and gynecologic history
Sample Selection and endometriosis-related symptoms were
directly self-reported by women with
All women initiating a new treatment regimen endometriosis, and diagnosis and treatment
for endometriosis (i.e., first-time users or were reported by physicians via extensive
treatment switchers) and who were willing to questionnaires. The additional files include
take part in the long-term observational study these detailed questionnaires (Additional Files
were eligible for inclusion. This recruitment S1 and S2). Each patient was actively followed
approach ensured that the study cohort was up every 6 months for the first year of
representative of real-world users of each treatment, then annually from the second year
prescribed endometriosis treatment. There were until the end of the study (up to 7 years after
no specific medical inclusion or exclusion study enrollment), to ensure all relevant adverse
criteria, but women with a language barrier or events were captured.
who were not cooperative/available for follow-up
were not eligible to participate. Women who

Fig. 1 VIPOS study design. NAED nonapproved hormonal medications for endometriosis, OAED other hormonal
medications approved for endometriosis
Adv Ther

PLANNED OUTCOMES the treatment of endometriosis, these addi-

tional endpoints provide further clinical insight
The primary study objectives were to assess the from a large data set encompassing data on the
safety of oral dienogest 2 mg/day compared real-world symptoms, diagnosis, and treatment
with other hormonal treatments for of endometriosis in Europe.
endometriosis in routine clinical practice. Three Overall, the study outcomes in VIPOS are
primary safety endpoints of interest were expected to reveal information about current
anemia requiring medical intervention, de novo treatment practices in Europe, the women who
or clinically worsening depression, and drug typically present to their health services, and
discontinuation due to treatment failure the journey of a patient with endometriosis.
(Table 1). Secondary study objectives included The insights gained from these outcomes have
the characterization of baseline risk factors the potential to translate into better-informed
(lifetime history of comorbidity, co-medication, treatment practices, with a greater understanding
risk markers, sociodemographic data, and of the efficacy and safety of the medical manage-
lifestyle data) and the analysis of drug utiliza- ment of endometriosis.
tion patterns. While this study was primarily
developed to evaluate the safety of dienogest for Data Collection

To minimize bias and misclassification of

Table 1 Summary of study objectives patient-reported clinical outcomes, multiple
Clinical outcomes of Secondary objectives validation steps were applied. All relevant
interest for primary clinical events (i.e., anemia and depression) were
objective reported during follow-up via a questionnaire
and sent to the clinical research organization,
Occurrence of anemia Characterize baseline risk ZEG Berlin (Berlin Center for Epidemiology and
induced by cyclical factors of real-world Health Research), which contacted the relevant
bleeding disturbances patients (sociodemographic physician and patient, as needed, to confirm the
• Noninferiority test for and lifestyle data, risk event. Missing or incomplete data for most rele-
markers, comorbidities, and vant items were clarified by contacting the
dienogest 2 mg/day vs.
co-medication) patient. In addition, all reported events of
other hormonal
anemia and depression were categorized, using a
treatments predefined validated algorithm, as ‘‘confirmed’’
Newly reported or Analyze drug-use patterns of or ‘‘not confirmed.’’ Finally, verification of these
worsening clinically endometriosis treatments in cases at the end of study was undertaken by two
relevant depression routine clinical practice blinded independent medical boards appointed
by the Safety Monitoring and Advisory Council.
• Noninferiority test for The Hematology Board consisted of three inde-
dienogest 2 mg/day vs. pendent medical experts who specialize in
other hormonal internal medicine/hematology and gynecology,
treatments while the Depressive Illness Board consisted of
specialists in psychiatry and psychologic
Discontinuation due to Investigate risks of short- and medicine.
treatment failure long-term use of dienogest
• Superiority test for 2 mg/day and of established Data Analysis
dienogest 2 mg/day vs. endometriosis treatments in
other hormonal adolescent women A noninferiority study design was chosen based
treatments on the a priori assumption that use of dienogest
is not associated with an increased risk of
anemia or depression compared with other
 Adv Ther

approved hormonal medications. Three a comparatively short follow-up period [28, 29].
hypotheses were to be tested; therefore, By following patients for a minimum of 3 years
Bonferroni-Holm correction was used to main- and for up to 7 years, VIPOS will also provide
tain the overall error rate by testing each indi- greater insight into the impact of patient
vidual hypothesis based on an a level of 0.0167 baseline characteristics on the real-world treat-
(a statistical significance level of one third of ment journey for patients with endometriosis.
that required if only one hypothesis were to be VIPOS will assess a large and diverse population
tested). so that rare events and subtle safety signals
The study was powered to exclude a two-fold associated with endometriosis treatments may
risk of anemia and clinically relevant depression also be investigated, alongside patterns of
with dienogest 2 mg compared with other patient adherence and physician behavior.
endometriosis medications, based on the Although there may be differences between
expected incidence of 1 event per 100 woman- the VIPOS cohorts and other populations of
years, with a noninferiority margin of 0.01 and women with endometriosis internationally, the
90% power. Additionally, VIPOS was powered study is also expected to identify trends in
to demonstrate the superiority of dienogest clinical practice within countries, such as
2 mg compared with other endometriosis treatment utilization and diagnostic methods,
medications in relation to treatment failure, as well as any regional differences in diagnostic
with a clinically relevant difference of 0.05, and tools and therapy. It will also provide a
90% power. description of a large cohort of women with
Power calculations based on the expected endometriosis in routine clinical practice. As
incidences of anemia and depression indicated such, VIPOS will expand our understanding of
approximately 84,000 women-years as sufficient long-term hormonal therapy, treatment
to demonstrate non-inferiority of dienogest adherence risks, and impact on patient quality
compared with other endometriosis medications of life for women with endometriosis.
for anemia and depression. It was calculated that A potential limitation of previous real-world
approximately 29,500 women-years would be observational studies of endometriosis is the
required to demonstrate the superiority of die- threat to data validity from measurement error,
nogest compared with other endometriosis unmeasured confounding, missing data,
medications regarding treatment failure. The diagnostic criteria, and selection bias
original study size was based on the 3–6-year [28, 29, 33–35]. The robust study design of
follow-up of 25,000 women, which would pro- VIPOS aims to minimize these risks through
vide approximately 89,000 documented woman- sensitive and regular collection of data using
years, assuming a 10% dropout rate and 3 years to multiple validation steps, including verification
complete recruitment. of reported anemia and depression by blinded
independent adjudication. In addition, the
study design should minimize loss to follow-up
STRENGTHS AND LIMITATIONS through direct contact with the women
enrolled. As a result, the impact of different
The VIPOS post-authorization safety study is long-term hormonal treatments on clinical
the largest real-world, noninterventional outcomes across distinct healthcare settings can
evaluation of the medical management of be accurately assessed. In addition, the com-
endometriosis and is expected to provide plexities and potential interaction among
important data regarding the long-term safety depression, endometriosis, and progestogens
and efficacy of dienogest and other hormonal have previously made it difficult to differentiate
treatments for endometriosis in clinical whether an individual’s depressive symptoms
practice. Previous real-world data sets used to are causally associated with progestin use or
investigate the medical treatment of with sequelae of the disease process. To this
endometriosis have used substantially smaller end, VIPOS is needed to evaluate the influence
cohorts, often derived from single centers, with of dienogest 2 mg on long-term safety in
Adv Ther

women with endometriosis, including mood Germany) and supervised by an independent

disturbances and depression, and to compare Safety Monitoring and Advisory Council. How-
these outcomes with those observed for other ever, Bayer (respectively Schering at that time)
hormonal treatments. had peer reviewed the study protocol. All authors
had full access to all of the data in this study and
take complete responsibility for the integrity of
ETHICS AND DISSEMINATION the data and the accuracy of its analysis. The Rapid
Service and Open Access Fees for the journal were
The VIPOS study was approved by one inde- funded by Bayer AG.
pendent ethics committee/institutional review
board at each country, where required. In Medical Writing Assistance. Medical
Germany, the Ethics Committee of the Berlin writing support was provided by Afsaneh
Medical Association approved the study, and in Khetrapal (ApotheCom, London, UK) and fun-
Hungary this was done by the Scientific and ded by Bayer AG.
Research Ethics Committee of the Medical
Research Council. In Switzerland, only one Authorship. All named authors meet the
large endometriosis center (Inselspital Bern) International Committee of Medical Journal
took part in the study, and a positive vote from Editors (ICMJE) criteria for authorship for this
Swissmedic was obtained for this hospital. No article, take responsibility for the integrity of
ethical approval for non-interventional, the work as a whole, and have given their
observational studies was required by law in approval for this version to be published.
Poland, Russia, and Ukraine. Each woman was
asked to provide written informed consent Disclosures. Klaas Heinemann, Kerstin
before participating in the study. The study was Becker, and Sabine Moehner are full-time
conducted in accordance with the Guidelines employees at ZEG Berlin. Bruno Imthurn has
for Good Pharmacoepidemiology Practices nothing to disclose. Lena Marions is a principal
issued by the International Society for investigator for trials sponsored by Bayer AG
Pharmacoepidemiology (2008), the Good and Merck Sharp & Dohme. Christoph
Epidemiological Practice-Proper Conduct in Gerlinger and Thomas Faustmann are full-time
Epidemiologic Research statement issued by the employees at Bayer AG.
International Epidemiological Association
European Federation (2007), the European Compliance with Ethics Guidelines. The
Network of Centres for Pharmacoepidemiology VIPOS study was approved by one independent
and Pharmacovigilance (ENCePP) Code of ethics committee/institutional review board at
Conduct for Scientific Independence and each country, where required. In Germany, the
Transparency (2010), and the ethical principles Ethics Committee of the Berlin Medical
based on the Declaration of Helsinki. The study Association approved the study, and in Hungary
was prospectively registered in the EU PAS as this was done by the Scientific and Research
number 1613 on October 21, 2010, and received Ethics Committee of the Medical Research
an ENCePP seal. In addition, this study was Council. In Switzerland, only one large
registered on CinicalTrials.gov (NCT01266421) endometriosis center (Inselspital Bern) took part
on December 24, 2010. in the study, and a positive vote from
Swissmedic was obtained for this hospital. No
ethical approval for non-interventional, obser-
vational studies was required by law in Poland,
ACKNOWLEDGEMENTS Russia, and Ukraine. Each woman was asked to
provide written informed consent before
participating in the study. The study was con-
Funding. The VIPOS study was independently
ducted in accordance with the Guidelines for
run by ZEG Berlin, funded by an unconditional
Good Pharmacoepidemiology Practices issued
grant from Bayer Pharmaceuticals (Berlin,
 Adv Ther

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