Gynecological Endocrinology

ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: https://www.tandfonline.com/loi/igye20

Extended-cycle versus conventional treatment

with a combined oral contraceptive containing
ethinylestradiol (30 µg) and levonorgestrel (150 µg)
in a randomized controlled trial

Peyman Hadji, Joseph Neulen, Katrin Schaudig, Anneliese Schwenkhagen,

Stefanie Grimmbacher & Inka Wiegratz

To cite this article: Peyman Hadji, Joseph Neulen, Katrin Schaudig, Anneliese Schwenkhagen,
Stefanie Grimmbacher & Inka Wiegratz (2020): Extended-cycle versus conventional treatment with
a combined oral contraceptive containing ethinylestradiol (30 µg) and levonorgestrel (150 µg) in a
randomized controlled trial, Gynecological Endocrinology, DOI: 10.1080/09513590.2020.1725963

To link to this article: https://doi.org/10.1080/09513590.2020.1725963

Published online: 16 Feb 2020.

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GYNECOLOGICAL ENDOCRINOLOGY
https://doi.org/10.1080/09513590.2020.1725963

ORIGINAL ARTICLE

Extended-cycle versus conventional treatment with a combined oral contraceptive

containing ethinylestradiol (30 lg) and levonorgestrel (150 lg) in a randomized
controlled trial
Peyman Hadjia, Joseph Neulenb, Katrin Schaudigc, Anneliese Schwenkhagenc, Stefanie Grimmbacherd and
Inka Wiegratze
a
Frankfurter Hormon-und Osteoporosezentrum, Frankfurt am Main, Germany and Philipps-University of Marburg, Marburg, Germany; bClinic for
Gynaecological Endocrinology and Reproductive Medicine, University of Aachen, Aachen, Germany; cCenter of Gynaecological Endocrinology,
Hormone Hamburg, Hamburg, Germany; dClinical Science and Operations, Meda Pharma GmbH and Co. KG (A Mylan Company), Bad
Homburg, Germany; eVivaNeo Kinderwunschpraxis Frankfurt, Frankfurt am Main, Germany

ABSTRACT ARTICLE HISTORY

The objective was to assess efficacy and safety of a combined oral contraceptive containing ethinylestra- Received 24 June 2019
diol (EE) and levonorgestrel (LNG) in an extended-cycle vs. a conventional-cycle regimen. This first Revised 18 December 2019
European randomized, active controlled, open, prospective, parallel-group trial was conducted in 48 Accepted 5 January 2020
German gynecological centers. 1,314 healthy, sexually active women aged 18–35 years were randomized. Published online 15 February
2020
With an unadjusted PI of 0.483 (upper 95% CI: 1.237), the extended-cycle regimen fulfilled the contracep-
tive efficacy of EE/LNG, the requirements of the European Medicines Agency. The mean total number of KEYWORDS
bleeding days per year was significantly lower in the extended-cycle vs. the conventional-cycle regimen. Oral contraceptives;
Analyses of bleeding patterns showed a reduced total number of bleeding/spotting days per year in the extended-cycle regimen;
extended-cycle vs. the conventional-cycle regimen. Cycle-associated complaints and AE were comparable ethinylestradiol; levonorges-
in both groups. Both regimens were very well accepted. The extended-cycle regimen of EE/LNG was trel; bleeding patterns
effective and well tolerated resulting in a lower number of bleeding days and a favorable bleeding pat-
tern compared to the conventional-cycle regimen.

Introduction
In Europe, the use of oral contraceptives (OC) is the most popu-
lar method to prevent pregnancy [1]. The most common regi-
men is 1 active tablet per day for 21 days, followed by a 7-day
hormone-free interval.
Numerous women use OC also for improvement/prevention
of cycle-associated disorders such as menstrual pain, menstrual-
related migraine, heavy irregular bleeding and endometriosis [2].
They prefer to avoid/change bleeding [3–7] by continuous
administration of OC for several months [2,6,8,9].
Due to its acceptable risk profile, conventionally used 21 þ 7-
regimen of 30 lg ethinylestradiol/150 lg levonorgestrel (EE30/
LNG150) is recommended as standard comparator for new contra-
ceptives studies by the European Medicines Agency (EMA) [10].
An extended-cycle use of EE30/LNG150 has been approved as
84 þ 7-regimen by the FDA in 2003 [11,12]. In Europe, varia-
tions of this regimen consist of EE30/LNG150 over 84 days, but
followed by 7 days intake of 10 mg EE or a tailored regime with a
3-day tablet-free interval (TFI) [13–15].
This first European clinical study of an extended-cycle
(84 þ 7)-regimen with EE30/LNG150 was designed according to
the EMA guideline to prove and compare efficacy, safety, bleed-
ing patterns and acceptance versus a conventional regimen of
EE30/LNG150 (21 þ 7) for approval in the EU [10].
Methods
Study design
The randomized, controlled, open, prospectively stratified, paral-
lel-group phase III-study was carried out in 48 German gyneco-
logical centers. The subjects were treated for 12 months
(364 days). The study encompassed a total of 6 clinical visits
(Appendix A; Figure A1). The extended-cycle regimen group
received EE30/LNG150 for 84 days followed by a 7-day TFI (4
extended cycles). The conventionally treated group received
EE30/LNG150 for 21 days, followed by a 7-day TFI (13 conven-
tional cycles).
The participants recorded tablet intake and occurrence/sever-
ity of bleeding/spotting daily via an electronic diary (eDiary).
Compliance with the extended-cycle regimen was defined as not
missing more than one tablet per 21-day period, with no less
than 7 days between two missed tablets, and for a conventional-
cycle regimen as not missing more than one tablet per cycle.
A tablet was considered as missed if the intake was more than
12 h late.
The study was approved by the ethic committee of the
University of Marburg and conducted in accordance with the
“Declaration of Helsinki”, the Guideline for Good Clinical
Practice, and the EU GCP directives [16–18].

CONTACT Peyman Hadji p.hadji@outlook.de Frankfurter Hormon-und Osteoporosezentrum, Frankfurt am Main, Germany and Philipps-University of Marburg,
Marburg, Germany
ß 2020 Informa UK Limited, trading as Taylor & Francis Group
2 P. HADJI ET AL.
Study population
Included were healthy (conformable to WHO [19]), sexually
active women aged 18–35 years. They provided written consent
before any trial-related procedures.
Exclusion criteria included: contraindications of study medi-
cation, presence/history of pancreatitis, severe hepatic disease or
liver tumors, known or suspected sex-steroid influenced malig-
nancies, undiagnosed vaginal bleeding, amenorrhea of unknown
cause, hypersensitivity to active substances/excipients of study
medication, desire to become pregnant during the study, previ-
ous/current use of medication that might have interfered with
(efficacy of) study medication or other contraceptive hormones,
venous/arterial thrombosis (present, past, in family history).
Demographic data along with medical, gynecological and
obstetric history were documented. Bleeding history/characteris-
tics, cycle-associated complaints and current contraception
details were recorded. Exclusion of pregnancy was done at
all visits.
Study endpoints
The primary efficacy endpoint was the overall (unadjusted) Pearl
Index (PI) for the extended-cycle regimen.
The secondary endpoints were the number of bleeding days
per year (key secondary endpoint), method failure (adjusted PI),
cumulative pregnancy rate, bleeding patterns, cycle-associated
complaints and treatment acceptance.
Bleeding was defined as blood loss that requires the use of
sanitary protection, whereas spotting does not [20].
Cycle-related pelvic pain (during 7-day TFI ± 3 days) was
evaluated by ranking the severity on a 6-point-rating-scale
(0 ¼ none, 5 ¼ very severe).
The highest severity of each cycle-associated complaint on a
6-point-rating-scale (0 ¼ no, 5 ¼ very severe), intake of medica-
tion for each cycle-associated complaint and the number of days
missed at school, work or the impairment of activities
were documented.
Acceptance of the contraceptive regimen was assessed at visits
V3–V6. Safety was determined at each visit by reports of adverse
events (AEs), pregnancy, laboratory parameters (hematology,
blood chemistry), vital signs, physical/gynecological examinations
according to the EMA [10] (Appendix B).
Statistical analyses
All efficacy analyses were based on the intention to treat (ITT)
population. In the ITT population allocated to the extended
cycle, the overall (unadjusted) PI was calculated as PI¼(number
of pregnancies/number of women-years)100 (methods
described in Gerlinger et al. [21], Appendix C). The time was
calculated irrespective of (intercurrent) treatment interruption or
noncompliance. A two-sided 95% confidence interval (CI) for
the expected value of the PI was calculated (Poisson distribu-
tion). One women-year was considered as 13 conventional cycles
(28 days), respectively 4 extended cycles (91 days). Kaplan–Meier
estimates and 95% CI were used to evaluate the cumulative preg-
nancy rate after 4 extended and 13 conventional cycles. Two dif-
ferent sensitivity analyses were carried out on the primary
efficacy endpoint (Appendix C).
Results
Study population and disposition
From 1,476 women 1,314 were randomized (Figure 1). Reasons
for screening failures and premature discontinuation prior to
randomization were protocol deviation (n ¼ 89), withdrawal of
consent (n ¼ 34), nontreatment emergent AE (n ¼ 22), lost to
follow-up (n ¼ 19), at the discretion of investigator (n ¼ 13) and
others (n ¼ 13).
1,286 participants started taking study medication. Main rea-
sons for premature discontinuation are listed in Figure 1.
Both groups were comparable regarding demographics and
baseline data (Appendix D).
Compliance was verified at each visit. More than 99% of the
subjects had compliance >85%. At withdrawal visit, compliance
>85% was observed for >80% of the women.
Primary endpoint: Unadjusted PI
Unadjusted PI of women in the extended-cycle group was 0.483
(upper 95% CI: 1.237). The difference between the unadjusted PI
and the upper confidence limit did not exceed 1 (4 pregnancies,
828 women-years of exposure). The result was supported by two
sensitivity analyses (Table 1).
Secondary endpoints
Contraceptive efficacy and bleeding patterns
The mean (median) total number of bleeding days per year was
23.6 (19) days (extended cycle) vs. 47.3 (47) days (conventional
cycle; p < 0.001, t test, ITT).
The adjusted (method failure) PI was 0.487 (upper 95% CI:
1.422). It was based on 3 pregnancies with conception dates fall-
ing in the correct treatment exposure period of 7 þ 2 days [21]
after the last treatment and 616 women-years of exposure.
The cumulative pregnancy rate (Kaplan–Meier estimates) was
0.004 after 4 extended cycles.
Bleeding patterns were analyzed over 1 year, considering 4
separated reference periods (RP) of 91 days, each corresponding
to 1 extended cycle (84 þ 7) or equivalent (91 days conventional
treatment). There was a pronounced difference in the mean
number of bleeding days between the two regimens within each
RP. A continuous decrease in mean number of bleeding days
[6.8 (RP1), 6.0 (RP2), 5.5 (RP3), 5.2 (RP4)] in the extended cycle
was observed. In the conventional cycle, the mean and median
number of bleeding days per RP remained stable around 11 to
13 days (Figure 2(a)).
The total number of bleeding/spotting days per year was
reduced [mean/median 47.5/32 (extended cycle) vs. mean/median
66.1/64 (conventional cycle)]. A continuous decrease in the
mean number of bleeding/spotting days [13.7 (RP1), 12.2 (RP2),
11.2 (RP3), 10.5 (RP4)] in the extended cycle was observed
(Figure 2(b)).
The numbers of scheduled bleeding/spotting days as well as
the scheduled bleeding-only or spotting-only days were consider-
ably lower in the extended cycle vs. the conventional cycle
(mean/median: 19.9/20 vs. 59.5/62 scheduled bleeding/spotting
days, 14.6/15 vs. 44.6/45 scheduled bleeding-only days).
Cycle-associated complaints
Approximately half of the subjects reported cycle-related
pelvic pain (57.4% extended-cycle, 56.7% conventional-cycle).
 GYNECOLOGICAL ENDOCRINOLOGY 3

Figure 1. Disposition flow chart (according to CONSORT).

Table 1. Unadjusted Pearl Index in the extended-cycle group (ITT).

Number of
Pregnancies (n) women years Pearl Index (PI) 2-sided 95% CI
Unadjusted PI 4 828 0.483 0.132; 1.237
Sensitivity analysis 4 762 0.525 0.143; 1.343
Excluding entire cycles with use of mechanical contraceptives
Sensitivity analysis 4 903 0.443 0.121; 1.135
Including all cycles with evidence of at least one non-condom protected intercourse
ITT: intention to treat.

The mean/median number of days with cycle-related pelvic pain
was 22.1/15 (extended cycle) and 30.6/25 (conventional cycle).
The intensity was generally mild/moderate. Other frequently
reported cycle-related complaints were headaches, mood changes,
and mastodynia [19.3%, 17.7%, 13.4% (extended-cycle), 17.7%,
18.2%, 12.6% (conventional cycle)]. Only few subjects reported
nausea (3.9% extended cycle vs. 3.0% conventional cycle) or
vomiting (0.5% extended cycle vs. 0% conventional cycle). The
number of days with these complaints was low (mean 10.4/
median 6 days) and similar between the treatment groups.
Acceptance of regimens and safety
Both regimens were very well accepted. The majority (>80%) of
all participants were very much or much satisfied throughout the
treatment period (Table 2).
Safety was analyzed for 1,286 subjects who had taken at least
1 tablet (safety population; SAF). During the study, a comparable
proportion of subjects experienced at least 1 treatment emergent
AE (extended cycle: 63.1%, conventional cycle: 58.9%). Most AEs
were not related to study medication and moderate/mild in
intensity. Table 2 lists most common related AEs (0.5%). None
of these were unexpected within young, healthy women receiving
a combined OC over 1 year.
Serious AEs were reported for 4.6% of the subjects in the
extended-cycle and for 5.6% in the conventional-cycle regimen
[related to study medication: 1 acute cholecystitis (extended
cycle), 1 deep vein thrombosis (conventional cycle)].
Pregnancies were considered as severe AE. 6 pregnancies were
recorded during the study (n ¼ 4, 0.4% extended cycle, n ¼ 2,
0.9% conventional cycle).
4 P. HADJI ET AL.

Table 2. Patient
s self-assessment of acceptance of the contraceptive regimen at

the end of the study (V6; ITT) and most common related adverse events
(0.5%; SAF).
Extended-cycle Conventional-cycle
regimen regimen
Acceptance of treatment n ¼ 800 n ¼ 178
(patient’s self-assessment)
Very much satisfied 158 (19.8%) 34 (19.1%)
Much satisfied 547 (68.4%) 122 (68.5%)
Minimally satisfied 58 (7.3%) 12 (6.7%)
Neither satisfied nor dissatisfied 21 (2.6%) 8 (4.5%)
Minimally dissatisfied 10 (1.3%) 1 (0.6%)
Much dissatisfied 4 (0.5%) 0
Very much dissatisfied 1 (0.1%) 0
Related adverse events (AEs) n ¼ 1055 n ¼ 231
Total number of women with AE (%) 271 (25.7%) 50 (21.6%)
Dysmenorrhoea 117 (11.1%) 15 (6.5%)
Pelvic pain 12 (1.1%) 0
Breast discomfort 27 (2.6%) 2 (0.9%)
Breast pain 10 (0.9%) 1 (0.4%)
Mood swings 32 (3.0%) 4 (1.7%)
Depressed mood 5 (0.5%) 0
Headache 39 (3.7%) 9 (3.9%)
Tension headache 4 (0.4%) 3 (1.3%)
Migraine 3 (0.3%) 3 (1.3%)
Acne 37 (3.5%) 10 (4.3%)
Nausea 10 (0.9%) 2 (0.9%)
Lower abdominal pain 9 (0.9%) 0
Alanine aminotransferase elevated 8 (0.8%) 1 (0.4%)
ITT: intent to treat; SAF: safety population; AEs were coded using the Medical
Dictionary for Regulatory Activities (MedDRA) version 19.0.

pregnancies occurred less than half as often as under conven-

Figure 2. (a) Mean number of bleeding days within four reference periods. (b)
Mean number of bleeding/spotting days within four reference periods. RP:
Reference Periods, 91 days each, ITT: intention to treat; error bars indicating
95% CI.
Abnormal PAP results (PAP IIID1) were detected in 19
subjects [17 (1.6%) extended-cycle, 2 (0.9%) conventional-cycle).
Final control of PAP smears showed inconspicuous results for all
subjects except of 2 (lost to follow-up). The proportion of
patients with study drug related AEs leading to discontinuation
was 5.0% (extended cycle) vs. 8.2% (conventional cycle).
Mean values of the vital signs and analyses of the safety
laboratory parameter (blood pressure, heart rate) gave no reasons
for safety concerns.
Discussion
This was the first European randomized, prospective, controlled
clinical study investigating efficacy and safety of the extended-
cycle regimen of EE30/LNG150. The importance of its results is
illustrated by the current widespread off-label use practiced by
many European women. They use available conventional prepa-
rations according to an extended-cycle regimen, supported by
the recommendation of gynecologists, who in majority also pre-
fer an extended-cycle regimen [2,22].
The study confirmed a good contraceptive efficacy of the
extended-cycle regimen. The unadjusted PI fulfilled the EMA
requirement [10]. With the extended-cycle (0.4%), unintended
tional-cycle regimen (0.9%).
Analysis of bleeding patterns underlined that the extended-
cycle regimen could accommodate women
s preference of
reduced bleeding. A statistically significant, clinically relevant
lower total number of bleeding days occurred under the
extended-cycle compared to the conventional-cycle regimen. The
lower number of bleeding days remained stable over time and
could be mainly attributed to the lower number of scheduled
bleeding days when extending the cycle.
Cycle-associated complaints were comparable in both treat-
ment groups.
A high acceptance of both regimens was found in the major-
ity (>80%) of women, which can be attributed to the good safety
and efficacy results.
The safety evaluation confirmed the well-known safety profile.
Obvious differences were not detected. 2 serious AEs were
assessed as related to study medication: an acute cholecystitis
(extended cycle), treated by a conservative approach, not causing
a change in the study treatment and assessed as not related by
the investigator. Due to missing justification for his assessment,
it was considered possibly drug-related as per conservative
Sponsor’s convention. A deep vein thrombosis after nearly 10
months (conventional cycle) resulted in premature study
discontinuation.
Overall, the safety results gave no indications for concerns
regarding extended-cycle use and confirmed the well-known
benefit risk ratio of EE/LNG [23]. Similar safety results
were reported before in a randomized multicenter US
study [11,13,14].
Further studies should focus on the fertility after discontinu-
ation of extended-cycle regimens with EE30/LNG150 and on
long-term safety.
In conclusion, this study confirmed the contraceptive
efficacy and safety of an extended-cycle 84 þ 7-regimen with

EE30/LNG150. Its use results in a lower number of bleeding
days per year and offers a favorable bleeding pattern compared
to the conventional 21 þ 7-regimen.
Acknowledgments
Angelika Thomas and Rhoda Wismer provided medical writing
assistance in the preparation of the manuscript, all authors critically
revised the manuscript.
Disclosure statement
JN received a grant by Meda Pharma (A Mylan Company) and
Rottapharm Madaus, KS, AS, SG, IW had support from Meda
Pharma (A Mylan Company) for the submitted work; outside the
submitted work, authors had financial relationships in the previous
three years with following organizations that might have an interest
in the submitted work: PH received lectures and advisory fees from
Rottapharm Madaus, Gedeon Richter, Exeltis, Bayer-Jenapharm,
MSD, DR. KADE/BESINS Pharma, JN received personal fees from
Gedeon Richter Pharma, DR. KADE/BESINS Pharma and MSD, KS
received support for lectures, travel expenses and publications from
KADE Besins, Gedeon Richter Pharma, Bayer-Jenapharm, MSD,
Hexal, Exeltis and Mylan and acted as a consultant for Gedeon
Richter Pharma, MSD and Exeltis, AS received support for lectures,
travel expenses from DR. KADE/BESINS Pharma, Gedeon Richter
Pharma, Bayer-Jenapharm, MSD, Exeltis and Mylan and acted as a
consultant for Gedeon Richter Pharma, MSD and Exeltis, SG is an
employee of Meda Pharma (A Mylan Company), IW received sup-
port for lectures, travel expenses from DR. KADE/BESINS Pharma,
Gedeon Richter Pharma, Bayer-Jenapharm, MSD, Exeltis; no other
relationships or activities that could appear to have influenced the
submitted work.
Trial registration: 2012-004762-18 (EudraCT No).
Funding
The study was financially supported by Madaus GmbH.
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Appendices
Appendix A: Schedules
Figure A1. Time schedule. COC: combined oral contraception, V: visit, RFI: risk factor investigation, ß-HCG: beta-human chorionic gonadotropin, CRF: case report form,
B: bleeding.
Appendix B: Safety variables
Apart from AEs (adverse events), the following was recorded at
scheduled times as shown in Figure A1, Appendix A:
 Safety laboratory parameters (hematology, blood chemistry);
 Urinalysis;
 Vital signs (blood pressure and pulse);
 Physical examination;
 Gynaecological examination;
 Laboratory parameters of the RFI subgroup;
 Return of fertility.
Safety laboratory parameters
The following hematology and blood chemistry determinations were
performed for all subjects at each visit (excluding V2) and analyzed
at a central lab:
 Hematology: white blood cell (WBC) count and differential,
red blood cell (RBC) count, hemoglobin, hematocrit, plate-
let count
 Blood Chemistry: total and fractionated bilirubin, creatinine,
serum glutamate oxalo-acetate transaminase (GOT), serum glu-
tamate pyruvate transaminase (GPT), gamma-glutamyltransfer-
ase (GGT), Ca, Na, K, total proteins.
At V1 and V6, in addition to the above mentioned determina-
tions, the following was performed for all subjects:
Lipid parameters (total cholesterol, high density lipoprotein [HDL]
cholesterol, low density lipoprotein [LDL] cholesterol, triglycerides,
very low density lipoprotein [VLDL] cholesterol, lipoprotein a),
fasting glucose.
Due to lipid parameters determination, at V1 and V6 blood samples
were to be taken after an overnight fasting period.
The investigator had to classify each value outside normal range
into the following categories:
 No clinical relevance (or attributed to an existing condition
unrelated to study medication).
 Clinical relevance (e.g. serious, causing discontinuation, or
requiring therapeutic measures); a respective record on the
eCRF module Adverse Event (prior to study treatment: On
eCRF module “Medical history”) had to be made.
If the findings contributed to a clinical diagnosis (such as hepa-
titis in case of increased liver enzymes), this diagnosis had to be
recorded as an AE.
Urinalysis
The urine test was done at each investigational site. The following
determinations were performed for all subjects at V1 and V6:
 Specific gravity, pH, ketones, total protein, glucose and blood.
Vital signs
Vital signs, including systolic and diastolic BP (mmHg) and radial
pulse rate (beats per minute) were recorded at each visit. Vital signs
were to be determined in a sitting position, after 5 min of rest.
Reference ranges considered normal were 90–140 mmHg for sys-
tolic BP values, 90 mmHg for diastolic BP values, and <90 beats
per minute for the heart rate. For abnormal values the investigator
had to indicate clinical significance.
Physical examination
A general examination was carried out (according to gynaecologist’s
skill and practice) at V1 and then verified (i.e. only changes from
the previous assessment) at each visit. Height was measured only at

the screening visit while weight was to be measured at each visit.
Clinically significant findings on the examination present at screening
were documented as concomitant diseases. New findings or worsening
at any visits following the screening were to be recorded as AEs.
Gynaecological examination
A gynaecological examination was carried out for each subject at
V1, V4 and V6. The gynaecological examination included:
 Breast examination;
 Bimanual pelvic examination;
 Transvaginal sonography of uterus, endometrium and ovaries;
 PAP test (to be performed only at V1 and V6).
Appendix C: Efficacy analyses
Primary variable
Further details on analysis the primary variable
A two-sided 95% confidence interval (CI) for the expected value of
the PI of the extended-cycle users was calculated, according to the
Poisson distribution.
To calculate the PI [21] the following definitions had to be taken
in consideration:
1. “Treatment exposure” was defined as the time period from the
first day of tablet intake to the last day of tablet intake plus the
treatment-specific drug-free interval (7 days in the investigated
regimens) and extended with þ2 days according to the definition
used in Europe. This time was calculated irrespective of [inter-
current] treatment interruption or noncompliance. The same
rule applied to subjects who dropped out prematurely: in this
case, the 7 þ 2 days drug free interval had to be added only if the
subject had completed at least 21 days on the study medication.
Treatment exposure after conception (since the subject was no
longer at risk of becoming pregnant) as well as [time periods]
during which additional contraceptive methods were consistently
used (because the risk of becoming pregnant was reduced) were
excluded from the calculation of the PI, as the inclusion of this
exposure in the denominator would lead to an underestimation
of the PI. In particular, the following rules were applied: occa-
sional use of mechanical contraceptives (condom) over one cycle
led to exclusion of that 28-day period from treatment exposure
in the denominator of the overall PI formula; use of any other
back-up contraceptive method led to exclusion of the full cycle
from the calculation of treatment exposure and of the subject
from the study, unless appropriate justification was given. On
the other hand, in case a woman became pregnant, despite con-
comitant use of both the contraceptive method tested and a
back-up contraceptive method, this pregnancy was included in
the numerator as well as the woman’s treatment exposure in the
denominator of the overall PI formula.
2. All pregnancies with dates of conception falling in the
“treatment exposure” period were included in the numerator of
the overall PI formula. If it was unclear whether conception
occurred during “treatment exposure” period or not, it was
considered to have been during treatment. A subject who
dropped becoming pregnant (date of conception) out of the
“treatment exposure” period was considered as a no pregnant
subject for the Pearl Index (PI) calculation purposes.
For all post study pregnancies reported via fax it was checked
whether the conception day was within 7 þ 2 days after last treat-
ment exposure.
Sensitivity analyses
Two different sensitivity analyses were carried out on the primary
efficacy endpoint to support previous results. These approaches were
GYNECOLOGICAL ENDOCRINOLOGY 7
based on the following as defined in the SAP (Statistical ana-
lysis plan):
 exclusion from the calculation of treatment exposure of the
entire cycle for which the use of mechanical contraceptives
was documented;
 inclusion in the calculation of treatment exposure of all cycles
with evidence of at least one non-condom protected
intercourse.
Secondary variables
The following secondary efficacy endpoints were evaluated.
Method failure (adjusted) PI
The adjusted PI assesses the contraceptive failure rate assuming that
the contraceptive method was perfectly used. Therefore, correct treat-
ment exposure is defined as the time period from the first day of tab-
let intake to the last day of tablet intake in accordance with the
intended use: thus, in addition to the corrections for concomitant use
of back-up contraceptive methods as described for calculation of the
overall PI (see above), only completed extended cycles were included
in the calculation of the adjusted PI. This also means that cycles in
which subjects were not compliant with study medication were
excluded, beside those in which there was evidence of the intake of
drugs that are known to impair COC (Combined oral contraceptive)
efficacy. However, if a subject failed to adhere to the correct instruc-
tions for one or few cycles only, the cycle(s) with correct use, prior or
afterwards, were counted in the denominator of correct treatment
exposure (“correct treatment exposure” period) [21].
Cumulative pregnancy rates (life table analysis)
Cumulative pregnancy rates after 13 (for the conventional cycles)
and 4 (for the extended cycles) cycles of treatment were calculated
using Kaplan–Meier estimates and 95% CI (based on the
Greenwood’s formula for the standard error of the Kaplan–Meier
estimate) and expressed as rates in 100 subjects.
Number of bleeding days (“key secondary variable”)
The number of bleeding days was calculated as the total number of
days with vaginal bleeding within the study period of 364 days as
recorded on the subject electronic diary. A bleeding day was defined
as a day with either scheduled or unscheduled bleeding. Days with
both spotting and bleeding were considered as bleeding days. Days
with spotting only were not considered bleeding days.
The mean number of bleeding days was calculated in both the
extended cycle and the conventional cycle groups; the two regimens
were compared by means of a t test.
Bleeding patterns
The bleeding patterns were analyzed considering the following refer-
ence periods (RP):
 One (1) year of treatment, i.e. 364 days of treatment.
 Four (4) separate RPs of 91 days (in accordance with WHO),
each corresponding to 1 extended cycle or equivalent. The first
RP started on the first day of intake of study medication.
In detail, analyses of the bleeding patterns were based on the fol-
lowing secondary endpoints:
 Number of bleedings days within 4 RPs of 91 days.
 Number of bleeding/spotting days and number of spotting only
days within 4 RPs of 91 days and during 1 year of treatment.
8 P. HADJI ET AL.

 Number of scheduled bleeding/spotting days and number of Table D2. Continued.

scheduled bleeding only days within 4 RPs of 91 days and dur- Extended Conventional
ing 1 year of treatment. A scheduled bleeding or spotting day Subjects with clinically significant conditions that may be the reason for
was defined [24] as bleeding or spotting that occurred during abnormal bleeding patterns
the tablet-free interval. For the purpose of the present study, No 894 (84.7%) 170 (73.6%)
Yes 0 0
scheduled bleeding could start on any tablet-free day and con- Subjects with history of contact bleeding
tinue for up to  3 days after the end of the tablet- No 1029 (97.5%) 229 (99.1%)
free interval. Yes (not-CS) 26 (2.5%) 2 (0.9%)
Numbers were calculated separately, for each subject, for each of Yes (CS) 0 0
Subjects with history of ovulation bleeding
the 4 separate RPs in both regimens. Descriptive statistics for con- No 1038 (98.4%) 229 (99.1%)
tinuous variables were calculated together with the mean 95% CI. Yes (not-CS) 17 (1.6%) 2 (0.9%)
Yes (CS) 0 0
Cycle-associated complaints SAF: safety population; CS: clinically significant.
Cycle-related pelvic pain and medications taken against cycle-related
pelvic pain had to be recorded daily in the subject electronic diary History of contraception
while other cycle-associated complaints were asked for at each visit
except for V1.
Table D3. Current contraception at screening, SAF.
Descriptive statistics of the variables were calculated together
with the 95% CI for both the extended and the conventional cycles. Extended Conventional
SAF 1055 (100%) 231 (100%)
Subjects self-assessment of acceptance of the contracep- Subjects with COC use
tive regimen No 161 (15.3%) 61 (26.4%)
Yes 894 (84.7%) 170 (73.6%)
Acceptance of the contraceptive regimen was asked for at each visit If yes, type of COC use
except V1 and V2, by means of a 7-point subjective assessment of Conventional cycle 764 (85.5%) 151 (88.8%)
satisfaction. Extended cycle 130 (14.5%) 19 (11.2%)
Subject acceptance was analyzed by means of descriptive statistics. Subjects with use of non-hormonal contraceptives
No 930 (88.2%) 192 (83.1%)
Yes 125 (11.8%) 39 (16.9%)
Subjects with concomitant condom use to 37 (3.5%) 8 (3.5%)
Appendix D: Demographic characteristics and protect from sexually transmitted diseases
medical history Subjects with hormonal contraception in past
No 582 (55.2%) 128 (55.4%)
Yes 473 (44.8%) 103 (44.6%)
Table D1. Demographic characteristics. Subjects with concomitant condom use to 37 (3.5%) 8 (3.5%)
protect from sexually transmitted diseases
Extended-cycle (84/7) Conventional (21/7)
Characteristics Mean ± SD Mean ± SD SAF: Safety population; COC: combined oral contraception.
ITT population n ¼ 1053 n ¼ 231
Age (years) 24.6 ± 4.13 24.9 ± 4.62 Table D4. Gynaecological history (ITT).
Weight (kg) 64.76 ± 9.57 64.51 ± 9.28 Extended Conventional
BMI (kg/m2) 22.99 ± 2.92 22.83 ± 2.99 ITT 1053 (100%) 231 (100%)
Ethnic origin
Number of subjects with previous pregnancies 236 (22.4%) 59 (25.5%)
Caucasian 1030 (97.8%) 225 (97.4%)
Previous pregnancies
Asian 12 (1.1%) 3 (1.3%) Mean 1.6 1.6
Dark-Skinned 4 (0.4%) 3 (1.3%) SD 0.93 0.91
Other 7 (0.7%) 0
Median 1 1
Sexually active
Range (min, max) (1, 6) (1, 5)
Yes 1053 (100.0%) 231 (100.0%) Number of subjects with births 188 (17.9%) 48 (20.8%)
Births
Mean 1.4 1.4
Table D2. Cycle and vaginal bleeding history at screening (SAF). SD 0.62 0.67
Median 1 1
Extended Conventional Range (min, max) (1, 4) (1, 3)
SAF 1055 (100%) 231 (100%) Number of subjects with previous 38 (3.6%) 9 (3.9%)
Average duration of bleeding (days) spontaneous abortions
N 1055 231 Previous spontaneous abortions
Mean 4.2 4.4 Mean 1.1 1
SD 1.09 1.18 SD 0.51 0
Median 4 4 Median 1 1
Range (min, max) (1, 8) (2, 10) Range (min, max) (1, 4) (1, 1)
Average duration of cycle (days) Number of subjects with previous 69 (6.6%) 15 (6.5%)
N 1055 231 medical abortions
Mean 33.6 31.3 Previous medical abortions
SD 16.25 11.88 Mean 1.3 1.4
Median 28 28 SD 0.50 0.83
Range (min, max) (21, 99) (24, 91) Median 1 1
Current and previous bleeding abnormalities Range (min, max) (1, 3) (1, 4)
Subjects with abnormal menstrual or pseudo-cycles Current lactation
No 884 (83.8%) 170 (73.6%) No 1053 (100.0%) 231 (100.0%)
Yes (not-CS) 10 (0.9%) 0 Yes 0 0
Yes (CS) 0 0 ITT: Intention to treat.
(continued)