Clinical Trial Results:
Controlled, prospective, multicentre, open, randomized study to investigate the contraceptive efficacy, bleeding patterns, metabolic effects, cycle-associated complaints, acceptance, and safety of an oral contraceptive containing 30 µg ethinylestradiol and 150 µg levonorgestrel, in two different regimens of intake (4 extended cycles of 91 days versus 13 conventional cycles of 28 days) in healthy women

Trial information Top of page
Trial identification
Sponsor protocol code	EL20T0.01
Additional study identifiers
ISRCTN number	-
US NCT number	-
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Madaus GmbH
Sponsor organisation address	Colonia Allee 15, Cologne, Germany, 51067
Public contact	Group Leader Study Manager, Meda Pharma GmbH & Co. KG, 0049 617288801, 42b@medapharma.de
Scientific contact	Head of Clinical Affairs Meda, Meda Pharma GmbH & Co. KG, 0049 617288801, 42b@medapharma.de
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	12 Jan 2017
Is this the analysis of the primary completion data?	Yes
Primary completion date	07 Jul 2016
Global end of trial reached?	Yes
Global end of trial date	07 Jul 2016
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To demonstrate the contraceptive efficacy of the EE30/LNG150 84+7 extended-cycle regimen according to the requirements of the EMA “Guideline on clinical investigation of steroid contraceptives in women” (EMEA/CPMP/EWP/519/98 Rev 1).
Protection of trial subjects	No specific additional measures to minimise pain and distress were required. The subjects could withdraw from treatment at any time and for any reason.
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	19 Mar 2014
Long term follow-up planned	Yes
Long term follow-up rationale	Regulatory reason
Long term follow-up duration	12 Months
Independent data monitoring committee (IDMC) involvement?	Yes
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Germany: 1314
Worldwide total number of subjects	1314
EEA total number of subjects	1314
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	1314
From 65 to 84 years	0
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	-
Pre-assignment
Screening details	The study population consists of healthy eligible females aged 18-35. These subjects will be prospectively stratified into three strata with respect to previous COC use (Stratum A: new users, Stratum B: conventional-cycle users, and stratum C: extended-cycle users) and will be randomized to a treatment arm within strata.
Period 1
Period 1 title	Overall study (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Not blinded
Arms
Are arms mutually exclusive	Yes
Arm title	Lisa Lang
Arm description	-
Arm type	Experimental
Investigational medicinal product name	Ethinylestradiol and Levonorgestrel
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	Tablets containing EE 30 μg, LNG 150 μg as active ingredients and 32.57 mg lactose monohydrate as an excipient. 1 tablet per day, taken orally, for 84 consecutive days, followed by a 7-day tablet-free interval for 4 extended cycles.
Arm title	Lisa Kurz
Arm description	-
Arm type	Active comparator for secondary end-point.
Investigational medicinal product name	Ethinylestradiol and Levonorgestrel
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	Tablets containing EE 30 μg, LNG 150 μg as active ingredients and 32.57 mg lactose monohydrate as an excipient. 1 tablet per day, taken orally, for 21 consecutive days, followed by a 7-day tablet-free interval for 13 conventional cycles.
Number of subjects in period 1 Lisa Lang Lisa Kurz Started 1072 242 Completed 785 171 Not completed 287 71      Adverse event, serious fatal 1 -      Consent withdrawn by subject 80 14      Adverse event, non-fatal 70 28      Other 21 4      Not exposed 17 11      At the discretion of the Investigator 3 -      Lost to follow-up 36 6      Protocol deviation 59 8

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Overall study
Reporting group description	-
Reporting group values Overall study Total Number of subjects 1314 1314 Age categorical Units: Subjects     18-35 1314 1314 Gender categorical Units: Subjects     Female 1314 1314     Male 0 0

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Lisa Lang
Reporting group description	-
Reporting group title	Lisa Kurz
Reporting group description	-

End points Top of page

Primary: Overall (Unadjusted) Pearl Index Top of page
End point title	Overall (Unadjusted) Pearl Index [1] [2]
End point description
End point type	Primary
End point timeframe	Study duration.
Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The unadjusted Pearl Index was calculated only for the extended-cycle group as planned in the clinical trial protocol. [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The unadjusted Pearl Index was calculated only for the extended-cycle group as planned in the clinical trial protocol.
End point values Lisa Lang Number of subjects analysed 1053 Units: Pregnancies / Women years * 100     number (confidence interval 95%) 0.483 (0.132 to 1.237)
No statistical analyses for this end point

Primary: Overall (Unadjusted) Pearl Index Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	Study duration.
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	15.1
Reporting groups
Reporting group title	Lisa Lang
Reporting group description	Safety Population.
Reporting group title	Lisa Kurz
Reporting group description	Safety population.
Serious adverse events Lisa Lang Lisa Kurz Total subjects affected by serious adverse events      subjects affected / exposed 49 / 1055 (4.64%) 13 / 231 (5.63%)      number of deaths (all causes) 1 0      number of deaths resulting from adverse events Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign ovarian tumour      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Cervix carcinoma stage 0      subjects affected / exposed 1 / 1055 (0.09%) 1 / 231 (0.43%)      occurrences causally related to treatment / all 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Vascular disorders Deep vein thrombosis      subjects affected / exposed 0 / 1055 (0.00%) 1 / 231 (0.43%)      occurrences causally related to treatment / all 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Surgical and medical procedures Lipoma excision      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Pregnancy, puerperium and perinatal conditions Pregnancy on oral contraceptive      subjects affected / exposed 4 / 1055 (0.38%) 2 / 231 (0.87%)      occurrences causally related to treatment / all 0 / 4 0 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 Reproductive system and breast disorders Cervical dysplasia      subjects affected / exposed 16 / 1055 (1.52%) 1 / 231 (0.43%)      occurrences causally related to treatment / all 0 / 16 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Endometriosis      subjects affected / exposed 2 / 1055 (0.19%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Pelvic adhesions      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Respiratory, thoracic and mediastinal disorders Hyperventilation      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Psychiatric disorders Acute stress disorder      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Depression      subjects affected / exposed 1 / 1055 (0.09%) 2 / 231 (0.87%)      occurrences causally related to treatment / all 0 / 1 0 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 Insomnia      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Psychosomatic disease      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Injury, poisoning and procedural complications Alcohol poisoning      subjects affected / exposed 0 / 1055 (0.00%) 1 / 231 (0.43%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Ankle fracture      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Concussion      subjects affected / exposed 0 / 1055 (0.00%) 1 / 231 (0.43%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Ligament rupture      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Post procedural haemorrhage      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Road traffic accident      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Wrist fracture      subjects affected / exposed 2 / 1055 (0.19%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Congenital, familial and genetic disorders Thyroglossal cyst      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Nervous system disorders Multiple sclerosis      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Syncope      subjects affected / exposed 0 / 1055 (0.00%) 1 / 231 (0.43%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Gastrointestinal disorders Abdominal pain      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Abdominal pain lower      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Faecaloma      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Hepatobiliary disorders Cholecystitis acute      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Endocrine disorders Autoimmune thyroiditis      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Infections and infestations Appendicitis      subjects affected / exposed 3 / 1055 (0.28%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 3 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Chronic tonsillitis      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Enteritis infectious      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Gastroenteritis      subjects affected / exposed 0 / 1055 (0.00%) 1 / 231 (0.43%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Hepatitis viral      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Laryngitis      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Peritonitis      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Pneumonia      subjects affected / exposed 1 / 1055 (0.09%) 2 / 231 (0.87%)      occurrences causally related to treatment / all 0 / 1 0 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 Pyelonephritis      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Pyelonephritis acute      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Salpingitis      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Tonsillitis      subjects affected / exposed 1 / 1055 (0.09%) 0 / 231 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Metabolism and nutrition disorders Type 2 diabetes mellitus      subjects affected / exposed 0 / 1055 (0.00%) 1 / 231 (0.43%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0
Frequency threshold for reporting non-serious adverse events: 3.3%
Non-serious adverse events Lisa Lang Lisa Kurz Total subjects affected by non serious adverse events      subjects affected / exposed 666 / 1055 (63.13%) 136 / 231 (58.87%) Nervous system disorders Headache      subjects affected / exposed 91 / 1055 (8.63%) 19 / 231 (8.23%)      occurrences all number 91 19 Reproductive system and breast disorders Dysmenorrhoea      subjects affected / exposed 287 / 1055 (27.20%) 48 / 231 (20.78%)      occurrences all number 287 48 Pelvic pain      subjects affected / exposed 43 / 1055 (4.08%) 2 / 231 (0.87%)      occurrences all number 43 2 Gastrointestinal disorders Nausea      subjects affected / exposed 35 / 1055 (3.32%) 5 / 231 (2.16%)      occurrences all number 35 5 Skin and subcutaneous tissue disorders Acne      subjects affected / exposed 44 / 1055 (4.17%) 12 / 231 (5.19%)      occurrences all number 44 12 Psychiatric disorders Mood swings      subjects affected / exposed 50 / 1055 (4.74%) 6 / 231 (2.60%)      occurrences all number 50 6 Infections and infestations Nasopharyngitis      subjects affected / exposed 42 / 1055 (3.98%) 6 / 231 (2.60%)      occurrences all number 42 6

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
02 Dec 2014	Modifications based on update of the investigators brochure which in turn was harmonised with the current, approved SmPC for the meanwhile registered IMP. No impact on prior risk-benefit assessment.
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported

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