E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of prolonged, excessive or frequent bleeding in women without organic pathology who desire oral contraception. |
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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 efficacy and safety of estradiol valerate (EV) / dienogest (DNG) treatment in patients with dysfunctional uterine bleeding (DUB) as compared to placebo |
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E.2.2 | Secondary objectives of the trial |
To determine the efficacy of EV/DNG in regard to individual DUB symptoms and menstrual bleeding parameters
To determine the efficacy of EV/DNG in regard to quality of life and resource use assessment
To evaluate the effect of EV/DNG on hemoglobin and serum ferritin concentrations
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
1. >/= 18 years of age and able to read and write. If over 40 years of age, must have FSH < 40 IU/mL 2. DUB defined as at least one of the following symptoms within the 90-day run-in phase: (i) Prolonged bleeding: 2 or more bleeding episodes, each lasting 8 or more days (ii) Frequent bleeding: greater than 5 bleeding episodes, with a minimum of 20 bleeding days overall (iii) Excessive bleeding: 2 or more bleeding episodes each with blood loss volume of 80 mL or more, as assessed by the alkaline hematin method 3. Willingness to use barrier contraception (e.g., condoms) from screening to study completion 4. Willingness to use and collect sanitary protection (pads and tampons) provided by the sponsor and compatible with the alkaline hematin test throughout study completion 5. Normal or clinically insignificant Pap smear results. A report within the last 6 months of visit 1 is acceptable. 6. Endometrial biopsy during the run-in phase OR a valid endometrial biopsy performed within 6 months of visit 1, without evidence of malignancy or atypical hyperplasia, with an available report. Women with simple hyperplasia can be included in the study, but will undergo an endometrial biopsy at the end of treatment. 7. Signed the Informed consent form (ICF).
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E.4 | Principal exclusion criteria |
1. Current diagnosis of organic uterine bleeding such as von Willebrand disease, chronic endometritis, adenomyosis, endometriosis, endometrial polyps, endometrial carcinomas, mixed mullerian mesenchymal tumors, leiomyomas, leiosarcomas, or endometrial stromal tumors 2. Signs of hirsutism 3. Atypical hyperplasia 4. History of endometrial ablation, or dilatation and curettage within 2 months of visit 1 5. Clinically significant abnormal TVU results 6. Clinically significant abnormal results of breast examination 7. Positive pregnancy test 8. Pregnancy, lactation, or abortion within 3 months of visit 1 9. Not willing to discontinue the use of nonsteroidal anti-inflammatory drugs during menses throughout the study 10. Use of medication intended for treatment of DUB symptoms (e.g., tranxenamic acid) 11. Hormonal contraception: Oral or intravaginal within 30 days of visit 1 Intrauterine device (IUD) still in place within 30 days of visit 1 Implants/depots still in place within 30 days of visit 1 Intramuscular: visit 1 less than 30 days from the last day of the labeled effective period of use 12. Use of steroidal OC agents during the study 13. Prohibited concomitant medication: Concomitant use of medication inhibiting or inducing cytochrome CYP 3A4 is excluded. In particular is excluded the use of additional steroid hormones, anticoagulants (e.g. heparin, Coumadin), antiepileptics (hydantoin derivatives [e.g., phenytoin] or carboxamid derivatives [e.g., carbamazepin, oxcarbamazepin], other antiepileptics [e.g., Felbamate, Topiramate]), hypnotics and sedatives (barbiturate derivatives [e.g., primidone]), tuberculostatics (e.g., rifampicin), oral antimycotics (e.g., griseofulvin, ketoconazol, itraconazol, fluoconazol), virostatic agents (e.g., ritonavir), products containing St. John's Wort, and continuous (exceeding 14 days) systemic use of antibiotics 14. Any concomitant or active disease or condition that compromises the absorption, distribution, metabolism, or excretion of the study drug (such as compromised renal function, gastrectomy, pancreatitis, renal insufficiency, hepatic dysfunction, active cholecystitis, and cholestatic jaundice) 15. Known or suspected premalignant or malignant disease including malignant melanoma (excluding other successfully treated skin cancers) or a history of these conditions 16. Abnormal laboratory values that are considered clinically significant at the discretion of the investigator and which give suspicion of a specific organ or system dysfunction 17. History of myocardial infarction or coronary heart disease requiring treatment 18. History of congestive heart failure 19. Uncontrolled hypertension; sitting systolic blood pressure >/= 140 mmHg or diastolic blood pressure >/= 90 mmHg 20. History of stroke or transient ischemic attacks 21. Thrombophlebitis or thromboembolic disorder, such as deep vein thrombosis, pulmonary embolism, myocardial infarction, or stroke, or a history of these conditions or known or suspected genetic component or positive family history of parents or a sibling or a child at an early age (</= 40 years) 22. Uncontrolled thyroid disorders 23. Known sickle cell anemia 24. Known, not adequately controlled diabetes mellitus or with vascular involvement 25. Current or history of migraines with focal neurological symptoms 26. Increased frequency or severity of headaches including migraines during previous estrogen therapy 27. History of drug addiction or alcohol abuse (within the last 2 years) 28. Current or history of clinically significant depression (hospitalization) 29. Received an investigational drug or participated in another clinical trial within 1 month prior to study entry at visit 1 30. Known allergic reactions and/or hypersensitivity to EV, or DNG, or other ingredients of the study drug 31. Known allergic reactions and/or hypersensitivity to sanitary protection 32. Heavy smoker (more than 10 cigarettes per day) over the age of 35 33. BMI >32, calculated with the following: body weight (kg)/body height (m2) 34. patient is a dependant person (e.g. relative, family member and/or member of the investigator's staff
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable is the overall success rate, which is defined by the number of patients with the absence of any DUB symptom during the 90-day efficacy phase, as compared to the number of patients having at least one DUB symptom at the end of the run-in phase. The absence of DUB symptoms is defined as: No bleeding episodes lasting more than 7 days and No more than 5 bleeding episodes and No bleeding episodes with blood loss volume of 80 mL or more In addition, No more than 1 bleeding episode increase from baseline and Total number of bleeding days not to exceed 27 days For patients enrolled with specific symptoms, the following criteria will also have to be met: If patients enrolled with prolonged bleeding, the decrease between the maximum duration during run-in phase and the maximum duration during the efficacy phase should be at least 2 days If patients enrolled with frequent bleeding, no more than 4 bleeding episodes If patients enrolled with excessive bleeding, the decrease between the maximum blood loss volume during the run-in phase and the maximum blood loss volume during the efficacy phase should be at least 20 mL
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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 | Information not present in EudraCT |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
E.8.2.3 | Other | No |
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.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
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 | 9 |
E.8.9.1 | In the Member State concerned days | |
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 | 9 |