| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Investigation of ovulation inhibition for indication of contraception |
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| E.1.1.1 | Medical condition in easily understood language |
| Investigation of ovulation inhibition for indication of contraception |
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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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10073728 |
| E.1.2 | Term | Hormonal contraception |
| E.1.2 | System Organ Class | 100000004865 |
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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 |
Primary aim of the study:
• To evaluate the efficacy of different dosages of levonorgestrel in supressing follicular growth in healthy premenopausal women and to identify the lowest dose at which no ovulation occurs (lowest effective dose), if among the tested doses
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| E.2.2 | Secondary objectives of the trial |
Secondary aims of the study:
• To evaluate the endogenous sexual hormone pattern under treatment with different dosages of levonorgestrel
• To determine the approximate day of ovulation in the post-treatment cycle
• To characterize descriptively the effect of different dosages of levonorgestrel on bleeding pattern over two cycles of continuous use
• To characterize systemic exposure of levonorgestrel at different doses after multiple administrations and to evaluate dose proportionality
• To evaluate the safety and tolerability of different dosages of levonorgestrel in the study subjects |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Per treatment group 30 healthy female subjects fulfilling the following 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 45 years inclusive
4. body-mass index (BMI): ≥18.0 kg/m² (no upper limit has been set, instead at least 5 subjects per group with a BMI ≥30 kg/m² shall be enrolled)
5. good state of physical and mental health based on medical, surgical and gynaecological history, physical- and gynaecological examination at screening
6. non-smoker or ex-smoker for at least 3 months if aged > 30 years or moderate smoker (10 cigarettes or 2 cigars or 2 pipes per day) if aged ≤ 30 years only; questioned at screening examination
7. both ovaries visible upon transvaginal ultrasonography; observed at screening examination
8. ovulation in the pre-treatment cycle between Day 9±1 and Day 27±1 defined as:
-TVUS observation of follicle rupture or corpus luteum formation and
- a subsequent serum progesterone concentration of ≥ 16nmol/l and
-next menstruation does not start within 6±1 days after suspected ovulation
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|
| E.4 | Principal exclusion criteria |
Safety concerns:
1. Any known severe systemic disease that might interfere with the conduct of the study or the interpretation of the results
2. existing cardiac and/or haematological diseases or pathological findings, which might interfere with the safety or tolerability of the active ingredient
3. existing hepatic and/or renal diseases or pathological findings, which might interfere with the safety or tolerability, and/or pharmacokinetics of the active ingredient
4. existing gastrointestinal diseases or pathological findings, which might interfere with the safety, tolerability, absorption and/or pharmacokinetics of the active ingredient
5. history of relevant CNS and/or psychiatric disorders and/or currently treated CNS and/or psychiatric disorders (e.g. clinically significant depression [current or in the last year])
6. acute and chronic progressive liver diseases (e.g. disturbances of the bilirubin excretion of the bile [Dubin-Johnson and Rotor syndromes], disturbances of the bile secretion, disturbances in the bile flow, idiopathic icterus or pruritus during a previous pregnancy or estrogen-progestogen treatment)
7. presence or history of liver tumours (benign or malignant)
8. existing or previous hepatic disease as long as liver function values have not returned to normal
9. existing or history of pancreatitis, if associated with severe hypertriglyceridemia
10. presence or history of venous or arterial thromboembolic diseases (e.g. deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) or prodromal conditions (e.g. transient ischemic attack, angina pectoris), cerebrovascular accident
11. presence of any hereditary or acquired predisposition for venous or arterial thrombosis that could increase the risk of any of the conditions listed in Exclusion Criterion No. 10 (e.g. APC-resistance, Antithrombin III deficiency, Protein-C and/or Protein-S deficiency, hyperhomocysteinaemia and antiphospholipid-antibodies
12. anamnestic hints for increased risk of thrombosis events in family history (e.g. any venous thromboembolic event that occurred in a close relative at a young age [≤ 50 years])
13. specific heart diseases (e.g. valvular heart disease, atrial fibrillation)
14. cardiac dysfunction (NYHA I-IV)
15. pronounced varicose veins
16. history of phlebitis in combination with other risk factors for thromboembolic diseases
17. existing uncontrolled thyroid disorders
18. known diabetes mellitus
19. Sickle-cell anaemia
20. known severe disturbances of lipid metabolism
21. existing or history of known or suspected malignant or premalignant diseases, regardless of the hormone status
22. abnormal, clinically significant findings which, according to the assessment of the investigator, may worsen under hormonal treatment (e.g. pemphigoid gestationis during a previous pregnancy, middle-ear deafness (otosclerosis); Sydenham’s chorea, porphyria, systemic lupus erythematosus, haemolytic-uremic syndrome)
23. known hypersensitivity to any ingredients of the study medication (active ingredients used or to constituents of the pharmaceutical preparations), (e.g. subjects with rare hereditary problems or galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption)
24. subjects with severe allergies or multiple drug allergies unless it is judged as not relevant for the clinical trial by the investigator
25. systolic blood pressure < 90 or > 139 mmHg
26. diastolic blood pressure < 60 or > 89 mmHg
27. puls rate < 50 bpm or > 90 bpm
28. clinical laboratory values out of normal range at screening unless the minor deviation from normal is judged as not relevant for the clinical trial by the investigator
29. ASAT > 20 % ULN, ALAT > 10 % ULN, bilirubin > 20% ULN (except in case of existing Morbus Gilbert-Meulengracht deduced from anamnesis/medical history) and creatinine > 0.1 mg/dL ULN (limit of > 0.1 mg/dL correspondents to of > 9 µmol/l ULN).
30. positive anti-HIV-test (if positive to be verified by western blot), HBs-AG-test or anti-HCV-test
31. diagnosis of latest PAP smear: findings classified higher than score 2 (Munich Nomenclature III)
32. other diseases: migraine with neurologic symptoms (complicated migraine), undiagnosed vaginal bleeding, manifest kidney disease with impaired renal function, worsening of epilepsy or chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) under hormonal treatment
Further exclusion criteria (No. 33 to No. 52) see chapter 12.2 of clinical trial protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary pharmacodynamic parameter:
• 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 pharmacodynamic parameters:
• Maximum follicular diameter
• Bleeding pattern
• Pituitary and ovarian hormones
• Endometrial thickness
• Influence on SHBG
• Return to ovulation and timespan until return to ovulation after therapy stop
And if applicable
• Cervical mucus (Insler score)
• Evaluation of Landgren et al. criteria
Pharmacokinetic variables (PK-subgroup): AUC0-24,ss, Cmax,ss, C24,ss, Cmin,ss, PTF %, Cav, t1/2, λ, CLss
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 trial has been defined as day of discharge of last subject from the clinical 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 | |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | |
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