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

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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 (30lg) and levonorgestrel (150lg)
in a randomized controlled trial
Peyman Hadjia, Joseph Neulenb, Katrin Schaudigc, Anneliese Schwenkhagenc, Stefanie
Grimmbacherd and Inka Wiegratze
aFrankfurter Hormon-und Osteoporosezentrum, Frankfurt am Main, Germany and Philipps-University of Marburg,

Marburg, Germany; bClinic for Gynaecological Hormone Hamburg, Endocrinology Hamburg, and Germany;
Reproductive dClinical Medicine, Science University of Aachen, Aachen, Germany; cCenter of Gynaecological
Endocrinology,
and Operations, Meda Pharma GmbH and Co. KG (A Mylan Company), Bad Homburg, Germany; eVivaNeo
Kinderwunschpraxis Frankfurt, Frankfurt am Main, Germany
ABSTRACT The objective was to assess efficacy and safety of a combined oral contraceptive containing ethinylestra-
diol (EE) and levonorgestrel (LNG) in an extended-cycle vs. a conventional-cycle regimen. This first European
randomized, active controlled, open, prospective, parallel-group trial was conducted in 48 German gynecological
centers. 1,314 healthy, sexually active women aged 18-35years were randomized. 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 bleeding days per year was significantly lower in the
extended-cycle vs. the conventional-cycle regimen. Analyses of bleeding patterns showed a reduced total number of
bleeding/spotting days per year in the extended-cycle vs. the conventional-cycle regimen. Cycle-associated
 complaints and AE were comparable in both groups. Both regimens were very well accepted. The extended-cycle
regimen of EE/LNG was effective and well tolerated resulting in a lower number of bleeding days and a favorable
bleeding pat- tern compared to the conventional-cycle regimen.
ARTICLE HISTORY Received 24 June 2019 Revised 18 December 2019 Accepted 5 January 2020 Published online 15 February 2020
KEYWORDS Oral contraceptives; extended-cycle regimen; ethinylestradiol; levonorges- trel; bleeding patterns
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 21days, 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 21þ7- regimen of 30μg ethinylestradiol/150μg 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 84þ7-regimen by the FDA in 2003 [11,12]. In Europe,
varia- tions of this regimen consist of EE30/LNG150 over 84days, but followed by 7days intake of 10 μg EE or a tailored
regime with a 3-day tablet-free interval (TFI) [13–15].
This first European clinical study of an extended-cycle (84þ7)-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 (21þ7) 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 12months (364days). The study encompassed a total of 6 clinical
visits (Appendix A; Figure A1). The extended-cycle regimen group received EE30/LNG150 for 84days followed by a 7-
day TFI (4 extended cycles). The conventionally treated group received EE30/LNG150 for 21days, 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 7days 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
Study population contraception details were recorded. Exclusion of pregnancy was
done at all visits.
Included were healthy (conformable to WHO [19]), sexually active
women aged 18–35years. They provided written consent before any
trial-related procedures.
Study endpoints
Exclusion criteria included: contraindications of study
medi- cation, presence/history of pancreatitis, severe hepatic The primary efficacy endpoint was the overall (unadjusted) Pearl
disease or liver tumors, known or suspected sex-steroid influenced Index (PI) for the extended-cycle regimen.
malig- nancies, undiagnosed vaginal bleeding, amenorrhea of The secondary endpoints were the number of bleeding
unknown cause, hypersensitivity to active substances/excipients of days per year (key secondary endpoint), method failure (adjusted
study medication, desire to become pregnant during the study, PI), cumulative pregnancy rate, bleeding patterns, cycle-associated
previ- ous/current use of medication that might have interfered withcomplaints and treatment acceptance.
(efficacy of) study medication or other contraceptive hormones,
Bleeding was defined as blood loss that requires the use
venous/arterial thrombosis (present, past, in family history).
of sanitary protection, whereas spotting does not [20].
Demographic data along with medical, gynecological
Cycle-related pelvic pain (during 7-day TFI ± 3days)
and obstetric history were documented. Bleeding
was evaluated by ranking the severity on a 6-point-rating-scale
history/characteris- tics, cycle-associated complaints and current
(01⁄4none, 51⁄4very severe).
 The highest severity of each cycle-associated complaint Primary endpoint: Unadjusted PI
on a 6-point-rating-scale (01⁄4no, 51⁄4very severe), intake of
medica- tion for each cycle-associated complaint and the number of Unadjusted PI of women in the extended-cycle group was 0.483
(upper 95% CI: 1.237). The difference between the unadjusted PI
days missed at school, work or the impairment of activities were
documented. and the upper confidence limit did not exceed 1 (4 pregnancies, 828
women-years of exposure). The result was supported by two
Acceptance of the contraceptive regimen was assessed at
sensitivity analyses (Table 1).
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 Secondary endpoints
examinations according to the EMA [10] (Appendix B).
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
Statistical analyses
test, ITT).
All efficacy analyses were based on the intention to treat (ITT) The adjusted (method failure) PI was 0.487 (upper 95% CI:
population. In the ITT population allocated to the extended cycle, 1.422). It was based on 3 pregnancies with conception dates fall-
the overall (unadjusted) PI was calculated as PI1⁄4(number of ing in the correct treatment exposure period of 7þ 2days [21] after
pregnancies/number of women-years)Â100 (methods described in the last treatment and 616 women-years of exposure.
Gerlinger et al. [21], Appendix C). The time was calculated The cumulative pregnancy rate (Kaplan–Meier estimates)
irrespective of (intercurrent) treatment interruption or was 0.004 after 4 extended cycles.
noncompliance. A two-sided 95% confidence interval (CI) for the Bleeding patterns were analyzed over 1year, considering 4
expected value of the PI was calculated (Poisson distribu- tion). separated reference periods (RP) of 91days, each corresponding to 1
One women-year was considered as 13 conventional cycles extended cycle (84þ7) or equivalent (91days conventional
(28days), respectively 4 extended cycles (91days). Kaplan–Meier treatment). There was a pronounced difference in the mean number
estimates and 95% CI were used to evaluate the cumulative preg- of bleeding days between the two regimens within each RP. A
nancy rate after 4 extended and 13 conventional cycles. Two dif- continuous decrease in mean number of bleeding days [6.8 (RP1),
ferent sensitivity analyses were carried out on the primary efficacy 6.0 (RP2), 5.5 (RP3), 5.2 (RP4)] in the extended cycle was
endpoint (Appendix C). observed. In the conventional cycle, the mean and median number
2 P. HADJI ET AL.
of bleeding days per RP remained stable around 11 to 13 days
(Figure 2(a)).
Result The total number of bleeding/spotting days per year was
s reduced [mean/median 47.5/32 (extended cycle) vs. mean/median
66.1/64 (conventional cycle)]. A continuous decrease in the mean
Study population and disposition
number of bleeding/spotting days [13.7 (RP1), 12.2 (RP2), 11.2
From 1,476 women 1,314 were randomized (Figure 1). Reasons for (RP3), 10.5 (RP4)] in the extended cycle was observed (Figure
screening failures and premature discontinuation prior to 2(b)).
randomization were protocol deviation (n1⁄489), withdrawal of The numbers of scheduled bleeding/spotting days as well as
consent (n1⁄434), nontreatment emergent AE (n1⁄422), lost to the scheduled bleeding-only or spotting-only days were consider-
follow-up (n1⁄419), at the discretion of investigator (n1⁄413) and ably lower in the extended cycle vs. the conventional cycle
others (n1⁄413). (mean/median: 19.9/20 vs. 59.5/62 scheduled bleeding/spotting
days, 14.6/15 vs. 44.6/45 scheduled bleeding-only days).
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 Cycle-associated complaints Approximately half of the subjects
baseline data (Appendix D). reported cycle-related pelvic pain (57.4% extended-cycle, 56.7%
Compliance was verified at each visit. More than 99% of the
conventional-cycle).
subjects had compliance >85%. At withdrawal visit, compliance
>85% was observed for >80% of the women.
Figure 1. Disposition flow chart (according to CONSORT).
Table 1. Unadjusted Pearl Index in the extended-cycle group (ITT).
Pregnancies (n)
Number of women years Pearl Index (PI) 2-sided 95% CI Unadjusted PI 4 828 0.483 0.132; 1.237 Sensitivity analysis
Excluding entire cycles with use of mechanical contraceptives
4 762 0.525 0.143; 1.343
Sensitivity analysis
Including all cycles with evidence of at least one non-condom protected intercourse
4 903 0.443 0.121; 1.135
ITT: intention to treat.
GYNECOLOGICAL ENDOCRINOLOGY 3
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 ( n1⁄44, 0.4% extended cycle,
n1⁄42, 0.9% conventional cycle).
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
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.
4 P. HADJI ET AL.
pregnancies occurred less than half as often as under conven- 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 84þ7-regimen with
Table 2. Patient ś 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 regimen
Conventional-cycle regimen Acceptance of treatment
(patientTs self-assessment)
n 1⁄4800 n 1⁄4 178
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 1⁄41055 n 1⁄4 231
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.
EE30/LNG150. Its use results in a lower number of bleeding days per year and offers a favorable bleeding pattern compared to the
conventional 21þ7-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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Appendice
s

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 Due to lipid parameters determination, at V1 and V6 blood samples were to
be taken after an overnight fasting period.
following was recorded at scheduled times as shown in Figure A1,
Appendix A: Safety laboratory parameters (hematology, blood The investigator had to classify each value outside normal range
chemistry); Urinalysis; Vital signs (blood pressure and pulse); into the following categories: No clinical relevance (or attributed to an
Physical examination; Gynaecological examination; Laboratory existing condition
parameters of the RFI subgroup; Return of fertility.
unrelated to study medication). Clinical relevance (e.g.
serious, causing discontinuation, or requiring therapeutic measures); a
Safety laboratory parameters The following hematology and blood respective record on the eCRF module Adverse Event (prior to study
chemistry determinations were performed for all subjects at each visit treatment: On eCRF module “Medical history”) had to be made. If the
(excluding V2) and analyzed at a central lab: Hematology: white findings contributed to a clinical diagnosis (such as hepa- titis in case of
blood cell (WBC) count and differential, red blood cell (RBC) count, increased liver enzymes), this diagnosis had to be recorded as an AE.
hemoglobin, hematocrit, plate- let count Blood Chemistry: total and Urinalysis The urine test was done at each investigational site. The
fractionated bilirubin, creatinine, serum glutamate oxalo-acetate following determinations were performed for all subjects at V1 and V6:
transaminase (GOT), serum glu- tamate pyruvate transaminase (GPT), Specific gravity, pH, ketones, total protein, glucose and blood. Vital
gamma-glutamyltransfer- ase (GGT), Ca, Na, K, total proteins. At V1
signs Vital signs, including systolic and diastolic BP (mmHg) and
and V6, in addition to the above mentioned determina- tions, the
radial pulse rate (beats per minute) were recorded at each visit. Vital
following was performed for all subjects:
signs were to be determined in a sitting position, after 5 min of rest.
Reference ranges considered normal were 90–140mmHg for
Lipid parameters (total cholesterol, high density lipoprotein [HDL] sys- tolic BP values, 90mmHg for diastolic BP values, and <90 beats
cholesterol, low density lipoprotein [LDL] cholesterol, triglycerides, very low
per minute for the heart rate. For abnormal values the investigator had
density lipoprotein [VLDL] cholesterol, lipoprotein a), fasting glucose.
6 P. HADJI ET AL. 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 þ2 days drug
free interval had to be added only if the subject had completed at least perfectly used. Therefore, correct treat- ment exposure is defined as the
21 days on the study medication. Treatment exposure after conception time period from the first day of tab- let intake to the last day of tablet
(since the subject was no longer at risk of becoming pregnant) as well intake in accordance with the intended use: thus, in addition to the
as [time periods] during which additional contraceptive methods were corrections for concomitant use of back-up contraceptive methods as
consistently used (because the risk of becoming pregnant was reduced) described for calculation of the overall PI (see above), only completed
were excluded from the calculation of the PI, as the inclusion of this extended cycles were included in the calculation of the adjusted PI.
exposure in the denominator would lead to an underestimation of the This also means that cycles in which subjects were not compliant with
PI. In particular, the following rules were applied: occa- sional use of study medication were excluded, beside those in which there was
mechanical contraceptives (condom) over one cycle led to exclusion of evidence of the intake of drugs that are known to impair COC
that 28-day period from treatment exposure in the denominator of the (Combined oral contraceptive) efficacy. However, if a subject failed to
overall PI formula; use of any other back-up contraceptive method led adhere to the correct instruc- tions for one or few cycles only, the
to exclusion of the full cycle from the calculation of treatment exposure cycle(s) with correct use, prior or afterwards, were counted in the
and of the subject from the study, unless appropriate justification was denominator of correct treatment exposure (“correct treatment
given. On the other hand, in case a woman became pregnant, despite exposure” period) [21].
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 Cumulative pregnancy rates (life table analysis) Cumulative
overall PI formula. 2. All pregnancies with dates of conception falling pregnancy rates after 13 (for the conventional cycles) and 4 (for the
in the “treatment exposure” period were included in the numerator of extended cycles) cycles of treatment were calculated using Kaplan–
the overall PI formula. If it was unclear whether conception occurred Meier estimates and 95% CI (based on the Greenwood’s formula for
during “treatment exposure” period or not, it was considered to have the standard error of the Kaplan–Meier estimate) and expressed as rates
been during treatment. A subject who dropped becoming pregnant (date in 100 subjects.
of conception) out of the “treatment exposure” period was considered as
a no pregnant subject for the Pearl Index (PI) calculation purposes. For
Number of bleeding days (“key secondary variable”) The
all post study pregnancies reported via fax it was checked whether the
conception day was within 7þ 2days after last treat- ment exposure. number of bleeding days was calculated as the total number of days
with vaginal bleeding within the study period of 364days as recorded
on the subject electronic diary. A bleeding day was defined as a day
Sensitivity analyses Two different sensitivity analyses were carried with either scheduled or unscheduled bleeding. Days with both spotting
out on the primary efficacy endpoint to support previous results. These and bleeding were considered as bleeding days. Days with spotting only
approaches were 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
based on the following as defined in the SAP (Statistical ana- lysis were compared by means of a t test.
plan): exclusion from the calculation of treatment exposure of the
entire cycle for which the use of mechanical contraceptives was
Bleeding patterns The bleeding patterns were analyzed considering
documented; inclusion in the calculation of treatment exposure of all
the following refer- ence periods (RP): One (1) year of treatment, i.e.
cycles with evidence of at least one non-condom protected intercourse.
364 days of treatment. Four (4) separate RPs of 91days (in accordance
with WHO), each corresponding to 1 extended cycle or equivalent. The
Secondary variables The following secondary efficacy first RP started on the first day of intake of study medication. In detail,
endpoints were evaluated. 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
Method failure (adjusted) PI The adjusted PI assesses the days within 4 RPs of 91 days and during 1 year of treatment.
contraceptive failure rate assuming that the contraceptive method was
Number of scheduled bleeding/spotting days and number of scheduled bleeding only days within 4 RPs of 91 days and dur- ing
1 year of treatment. A scheduled bleeding or spotting day was defined [24] as bleeding or spotting that occurred during the tablet-
free interval. For the purpose of the present study, scheduled bleeding could start on any tablet-free day and con- tinue for up to 3
days after the end of the tablet- free interval. Numbers were calculated separately, for each subject, for each of the 4 separate RPs
in both regimens. Descriptive statistics for con- tinuous variables were calculated together with the mean 95% CI.
Cycle-associated complaints Cycle-related pelvic pain and medications taken against cycle-related pelvic pain had to be
recorded daily in the subject electronic diary while other cycle-associated complaints were asked for at each visit except for V1.
Descriptive statistics of the variables were calculated together with the 95% CI for both the extended and the conventional cycles.
Subjects self-assessment of acceptance of the contracep- tive regimen Acceptance of the contraceptive regimen was
asked for at each visit except V1 and V2, by means of a 7-point subjective assessment of satisfaction.
Subject acceptance was analyzed by means of descriptive statistics.
Appendix D: Demographic characteristics and medical history
Table D1. Demographic characteristics.
Characteristics
Extended-cycle (84/7) Mean ± SD
Conventional (21/7) Mean ± SD ITT population n 1⁄41053 n 1⁄4231 Age (years) 24.6 ± 4.13 24.9 ± 4.62 Weight (kg) 64.76 ± 9.57 64.51 ±
9.28 BMI (kg/m2) 22.99 ± 2.92 22.83 ± 2.99 Ethnic origin
Caucasian 1030 (97.8%) 225 (97.4%) Asian 12 (1.1%) 3 (1.3%) Dark-Skinned 4 (0.4%) 3 (1.3%) Other 7 (0.7%) 0 Sexually active
Yes 1053 (100.0%) 231 (100.0%)
Table D2. Cycle and vaginal bleeding history at screening (SAF).
Extended Conventional SAF 1055 (100%) 231 (100%) Average duration of bleeding (days)
N 1055 231 Mean 4.2 4.4 SD 1.09 1.18 Median 4 4 Range (min, max) (1, 8) (2, 10) Average duration of cycle (days)
N 1055 231 Mean 33.6 31.3 SD 16.25 11.88 Median 28 28 Range (min, max) (21, 99) (24, 91) Current and previous bleeding abnormalities
Subjects with abnormal menstrual or pseudo-cycles
Ã
No Yes (not-CS ) 884 (83.8%) 170 (73.6%)
10 (0.9%) 0 Yes (CS) 0 0
(continued)
8 P. HADJI ET AL.
Table D2. Continued.
Extended Conventional Subjects with clinically significant conditions that may be the reason for
abnormal bleeding patterns No 894 (84.7%) 170 (73.6%) Yes 0 0 Subjects with history of contact bleeding
No 1029 (97.5%) 229 (99.1%) Yes (not-CS) 26 (2.5%) 2 (0.9%) Yes (CS) 0 0 Subjects with history of ovulation bleeding
No 1038 (98.4%) 229 (99.1%) Yes (not-CS) 17 (1.6%) 2 (0.9%) Yes (CS) 0 0 SAF: safety population; CS: clinically significant.
History of contraception
Table D3. Current contraception at screening, SAF.
Extended Conventional SAF 1055 (100%) 231 (100%) Subjects with COC use
No 161 (15.3%) 61 (26.4%) Yes 894 (84.7%) 170 (73.6%) If yes, type of COC use
Conventional cycle 764 (85.5%) 151 (88.8%) Extended cycle 130 (14.5%) 19 (11.2%) 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
protect from sexually transmitted diseases
37 (3.5%) 8 (3.5%)
Subjects with hormonal contraception in past
No 582 (55.2%) 128 (55.4%) Yes 473 (44.8%) 103 (44.6%) Subjects with concomitant condom use to
protect from sexually transmitted diseases
37 (3.5%) 8 (3.5%)
SAF: Safety population; COC: combined oral contraception.
Table D4. Gynaecological history (ITT).
Extended Conventional ITT 1053 (100%) 231 (100%) Number of subjects with previous pregnancies 236 (22.4%) 59 (25.5%) Previous
pregnancies
Mean 1.6 1.6 SD 0.93 0.91 Median 1 1 Range (min, max) (1, 6) (1, 5) Number of subjects with births 188 (17.9%) 48 (20.8%) Births
Mean 1.4 1.4 SD 0.62 0.67 Median 1 1 Range (min, max) (1, 4) (1, 3) Number of subjects with previous
spontaneous abortions
38 (3.6%) 9 (3.9%)
Previous spontaneous abortions
Mean 1.1 1 SD 0.51 0 Median 1 1 Range (min, max) (1, 4) (1, 1) Number of subjects with previous
medical abortions
69 (6.6%) 15 (6.5%)
Previous medical abortions
Mean 1.3 1.4 SD 0.50 0.83 Median 1 1 Range (min, max) (1, 3) (1, 4) Current lactation
No 1053 (100.0%) 231 (100.0%) Yes 0 0 ITT: Intention to treat.