| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Investigation of ovulation inhibition for indication of contraception |
|
| E.1.1.1 | Medical condition in easily understood language |
| Investigation of ovulation inhibition for indication of contraception |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Reproductive physiologi cal processes [G08] |
| MedDRA Classification |
| 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 determine the lowest dose at which no ovulation occurs (lowest effective dose), as well as,
• to determine the next lower dose at which at least one ovulation occurs (dose below the lowest effective dose), if among the tested range, and
• to determine the next higher dose above the one preventing ovulation (dose above the lowest effective dose), if among the tested range. |
|
| E.2.2 | Secondary objectives of the trial |
• descriptive characterisation of the influence of test products on ovarian activity determined by means of Hoogland and Skouby score
• descriptive characterisation of the influence of test products on ovarian activity determined by means of maximum follicular diameter
• descriptive characterisation of the effect of test products on endometrial thickness as well as on the pituitary and ovarian hormones the latter determined via follicle stimulating hormone (FSH), luteinising hormone (LH), estradiol (E2) and progesterone (P)
• descriptive evaluation of corpus luteum function after suspected ovulation (TVUS) by progesterone level
• descriptive characterisation of the effect of test products on bleeding pattern
• investigation of the influence of systemic trimegestone concentrations on SHBG levels
• descriptive characterisation of overall safety and tolerability (including local tolerability) in the trial population |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. written informed consent, after having been informed about benefits and potential risks of the clinical trial, as well as details of the insurance taken out to cover the subjects participating in the clinical trial
2. sex: female
3. age: 18 years to 38 years inclusive
4. body-mass index (BMI): >= 18 kg/m² and ≤ 30.0 kg/m²
5. good state of health
6. non-smoker or ex-smoker for at least 3 months aged >30 years or moderate smoker (10 cigarettes or 2 cigars or 2 pipes per day) aged ≤ 30 years only; questioned at screening examination
7. both ovaries visible upon transvaginal ultrasonography; observed at screening examination |
|
| E.4 | Principal exclusion criteria |
1. existing cardiac and/or haematological diseases or pathological findings, which might interfere with the safety or tolerability of the active ingredient
2.existing hepatic and/or renal diseases (e.g. severe renal insufficiency or acute renal failure) or pathological findings, which might interfere with the safety or tolerability, and/or pharmacokinetics of the active ingredient
3. existing diseases or pathological findings of genital organs, which might interfere with the safety, tolerability, absorption and/or pharmacokinetics of the active ingredient
4. history of relevant CNS and/or psychiatric disorders and/or currently treated CNS and/or psychiatric disorders
5. known allergic reactions to the active ingredients used or to constituents of the pharmaceutical preparations
6. subjects with severe allergies or multiple drug allergies unless it is judged as not relevant for the clinical trial by the investigator
7. systolic blood pressure < 80 or >= 140 mmHg
8. diastolic blood pressure < 50 or >= 90 mmHg
9. pulse rate < 50 bpm or > 90 bpm
10. laboratory values out of normal range unless the deviation from normal is judged as not relevant for the clinical trial by the investigator
11. ASAT > 20 % ULN, ALAT > 10 % ULN, bilirubin > 20% ULN (except in case of existing Morbus Gilbert-Meulengracht deduced from anamnesis/medical history)
12. positive anti-HIV-test (if positive to be verified by western blot), HBs-AG-test (if positive to be verified by test for HBc-IgM) or anti-HCV-test
13. presence or history of venous or arterial thrombosis (e.g. deep venous thrombosis, pulmonary embolism, myocardial infarction or prodromal conditions (e.g. angina pectoris, transient ischaemic attack)), cerebrovascular accident, inborn or acquired predisposition for venous or arterial thrombosis
14. anamnestic hints for increased risk of thrombosis events in family history
15. known hereditary or acquired predisposition for venous thromboembolism, such as APC resistance, antithrombin-III-deficiency, protein-C or -S-deficiency
16. known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant).
17. Known medical factors coming along with an increased risk of venous and/or arterial thromboembolism as e.g. systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis), sickle cell disease, and dyslipoproteinaemia
18. Presence or history of liver tumours (benign or malignant) or known or suspected malignancies of the genital organs or breasts (mammae), regardless of the hormone status
19. Presence or history of leiomyoma, endometriosis, or endometrial hyperplasia
20. Known severe lipopathy
21. Fibrocystic mastopathy
22. Diabetes mellitus
23. Hereditary angioedema
24. Unclarified vaginal bleeding
25. Existing cervicitis, vaginitis or bleeding cervical erosions at day of randomisation
26. Diagnosis of latest PAP smear: findings classified in a group higher than PAP I
27. Prolapse of uterine cervix, cystocele and/or rectocele
28. History of severe or chronic constipation
29. Presence or history of migraine as defined by criteria of International Headache Society
30. Acute or chronic diseases, which may interfere with the aims of the clinical trial
31. history of or current drug or alcohol dependence
32. regular intake of alcoholic food or beverages of > 20 units alcohol per week (1 unit is defined as: 1 beer of 0.33 l or 1 glass of wine of 0.2 l or 1 liquor of 2 cl)
33. blood donation or other blood loss of more than 400 ml within the last 2 months prior to individual start of pre-treatment cycle of the subject
34. administration of any investigational medicinal product during the last cycle prior to individual start of the pre-treatment cycle of the subject
35. treatment with any systemically available medication during the last 2 weeks prior to start of pre-treatment cycle which might interfere with pharmacodynamics, pharmacokinetics or safety of the IMPs
36. use of any sexual hormone containing preparations within 1 cycle (oral, transdermal, vaginal, intrauterine), 2 months (intramuscularly administered depot preparations used once per month), or within 6 months (intramuscularly or subcutaneously administered depot preparations used once per 3 months) prior to individual start of pre-treatment cycle of the subject
37. In case of washout phase, if no menses started within 46 days after stop of hormonal contraceptive
38. no progesterone level >10 nmol/L on or before day 25 (±4) of pre-treatment cycle
39. subjects with known relevant cycle abnormalities without hormonal contraceptive
40. subjects, who report frequent infections of the urogenital tract (e.g. vaginitis, cervicitis)
further Exclusion criteria (No. 41 to Nr. 49) see chapter 12.2 of trial protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy parameter
• ovulation inhibition rate
• ovarian activity by means of Hoogland and Skouby score
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy parameters
• maximum follicular diameter
• endometrial thickness
• pituitary and ovarian hormones (FSH, LH, E2, P)
• evaluation of Landgren criteria (if applicable)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| End of the clinical trial is defined as the day of shipment of the last Case Report Form (CRF) to the company responsible for clinical biometrics |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
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