E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Body processes [G] - Reproductive physiologi cal processes [G08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10030970 |
E.1.2 | Term | Oral contraception |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the contraceptive efficacy of 15 mg E4/3 mg DRSP using the Pearl Index in subjects aged 18 to 35 years inclusive at the time of screening. |
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E.2.2 | Secondary objectives of the trial |
Efficacy:
1. To evaluate the contraceptive efficacy of 15 mg E4/3 mg DRSP using the method failure Pearl Index and the life-table analysis in subjects aged 18 to 35 years inclusive at the time of screening.
2. To evaluate the contraceptive efficacy of 15 mg E4/3 mg DRSP using the Pearl Index, the method failure Pearl Index and the life-table analysis in the overall study population.
Other:
3. To evaluate cycle control and bleeding pattern associated with 15 mg E4/3 mg DRSP.
4. To evaluate general safety of 15 mg E4/3 mg DRSP.
5. To evaluate the impact of 15 mg E4/4 mg DRSP on physical, psychological and social functioning and well being. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Endometrial Safety Sub-study
167 Subjects
Objective:
To evaluate the endometrial safety using histological assessment of endometrial biopsy samples in a subset of subjects aged 18 to 50 years, inclusive at the time of screening.
Endometrial biopsy slides will be re-read by new expert readers and a new vendor (LKF) will be in charge to manage and set up the re read between the expert (blinding of slides, distribution, collect of results) according to protocol V2.1 06Feb2017. No further test or other analysis than the one planned in the original signed ICF and protocol is foreseen. The diagnosis will be given on each slide based on the protocol amendment version 2.1 appendix 4.
Endpoint:
Change in endometrial histology from baseline to end of treatment in subjects having been treated for at least 10 complete cycles.
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E.3 | Principal inclusion criteria |
1. Heterosexually active female at risk for pregnancy and requesting contraception.
2. Negative serum pregnancy test at subject enrollment.
3. Aged 18 to 50 years (inclusive) at the time of signing the informed consent (IC).
4. Willing to use the investigational product as the primary method of contraception for 13 subsequent cycles.
5. Good physical and mental health on the basis of medical, surgical and gynecological history, physical examination, gynecological examination, clinical laboratory, and vital signs.
6. Body mass index (BMI) below or equal to (≤) 35.0 kg/m2.
7. Able to fulfill the requirements of the protocol and have indicated a willingness to participate in the study by providing written IC.
8. Willing and able to complete the diaries and questionnaires.
For the endometrial safety sub-study:
9. Subset of subjects from the main study willing to participate in the endometrial safety sub-study by giving their consent for the endometrial safety sub-study.
9. Endometrial biopsy taken at screening that reveals no abnormal results, i.e. presence of hyperplasia (simple or complex, with or without atypia) or presence of carcinoma. |
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E.4 | Principal exclusion criteria |
1. For subjects who are not using hormonal contraception at screening, a menstrual cycle length shorter than 21 days or longer than 35 days.
2. Clinically relevant abnormal laboratory result at screening in the opinion of the investigator with an understanding of the central laboratory normal range
3. Known hypersensitivity to any of the investigational product ingredients.
4. Currently pregnant or with the intention to become pregnant during the course of the study.
5. Currently breastfeeding or before two spontaneous menstruations have occurred after cessation of breastfeeding prior to start of trial medication
6. Less than 6 weeks since last delivery/2nd trimester of abortion and before spontaneous menstruation has occurred following a delivery or 2nd trimester of abortion
7. Smoking nicotine-containing products if >= 35 years old
8. Dyslipoproteinemia requiring active treatment with antilipidemic agent
9. Diabetes mellitus with vascular involvement or diabetes mellitus of more than 20 years duration
10. Any arterial hypertension (controlled and uncontrolled) defined by blood pressure values
11. Personal history of deep vein thrombosis or pulmonary embolism
12. Current prolonged immobilization or major surgery with prolonged immobilization planned in the next 12 months
13. Known inherited or acquired hypercoagulopathies or thrombogenic mutations
14. Current treatment with anticoagulants
15. Presence or history of arterial thromboembolism
16. Complicated valvular heart disease
17. History of pregnancy related cardiomyopathy or moderately or severely impaired cardiac function
18. Systemic lupus erythematosus
19. Presence or history of migraine with aura at any age or migraine without aura if >35 years old
20. Within the past 6 months, has had undiagnosed (unexplained) abnormal vaginal bleeding or any abnormal bleeding that is expected to recur during the trial
21. In case of Chlamydial or Gonococcal infection at screening, when no treatment initiated at subject enrollment
22. Abnormal Pap test (written documentation of prior test at screening exam) based on provided criteria
23. Presence of an undiagnosed breast mass
24. Current symptomatic gallbladder disease
25. History of COC related cholestasis
26. Presence or history of severe hepatic disease as long as liver function values have not returned to normal
27. Presence or history of pancreatitis if associated with hypertriglyceridemia
28. Porphyria
29. Presence or history of hepatocellular adenoma or malignant liver tumors
30. Renal impairment
31. Hyperkaliemia or presence of conditions that predispose to hyperkaliemia such as renal impairment, hepatic impairment, adrenal insufficiency and women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium concentration
32. History of organ transplantation within 5 years before screening or chronic disease potentially necessitating organ transplantation during the anticipated course of the study
33. Presence or history of hormone-related malignancy
34. History of non-hormone-related malignancy within 5 years before screening. Subjects with a non-melanoma skin cancer are allowed in the study
35. Current regular use or regular use within 1 month prior to subject enrollment of drugs potentially triggering interactions with COCs
36. Use of an injectable hormonal method of contraception within 10 months prior to screening of an injection with a 3-month duration, within 6 months prior to screening of an injection with a 2-month duration, within 3 months prior to screening of an injection with a 1-month duration
37. History of alcohol or drug abuse (including laxatives) within 12 months prior to screening
38. Any prior procedure, disease or condition that could result in altered absorption, excessive accumulation, impaired metabolism, or altered excretion of the investigational product
39. Uncontrolled thyroid disorders
40. Participation in another investigational drug clinical study within 1 month or have received an investigational drug within the last 3 months prior to study entry. Subjects who participated in an oral contraceptive study, using FDA/EU approved active ingredients, may be enrolled 2 months after completing the preceding study
41. Sponsor, the Contract Research Organization (CRO) or Investigator's site personnel directly affiliated with this study
42. Is judged by the Investigator to be unsuitable for any reason
For the endometrial safety sub-study:
43. Use of hormone-releasing intra-uterine system immediately prior to the study treatment
44. Acute genital infection as diagnosed at the discretion of the Investigator |
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E.5 End points |
E.5.1 | Primary end point(s) |
The number of on-treatment pregnancies as assessed by the Pearl Index in subjects aged 18 to 35 years, inclusive at the time of screening. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From day 1 of treatment until 2 days after the last intake of investigational product (whether active or inactive tablet) |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
1. The number of on-treatment pregnancies as assessed by the method failure Pearl Index and the cumulative pregnancy rate in subjects aged 18 to 35 years, inclusive at time of screening.
2. The number of on-treatment pregnancies as assessed by the Pearl Index, the method failure Pearl Index and the cumulative pregnancy rate in the overall study population.
Other secondary endpoints:
3. Cycle control and bleeding pattern evaluated based on vaginal bleeding information as recorded daily by the subjects in the diaries.
4. Safety data in the overall study population obtained from routine laboratory parameters, vital signs, and physical, gynecological and breast examinations and by number, frequency, type and intensity of adverse events (AEs) and serious adverse events (SAEs).
5. Change from baseline to end of treatment in the different items of well-established questionnaires. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From day 1 of treatment until 2 days after the last intake of investigational product (whether active or inactive tablet) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 61 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Czech Republic |
Finland |
Germany |
Hungary |
Norway |
Poland |
Russian Federation |
Sweden |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |