| 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. |
|
| 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 |
|
| 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
|
|
| 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/L
2. DUB defined as at least one of the following symptoms within the 90-day run-in
phase:
- Prolonged bleeding: 2 or more bleeding episodes, each lasting 8 or more days
- Frequent bleeding: greater than 5 bleeding episodes, with a minimum of 20
bleeding days overall
- 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).
|
|
| 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. Vascular diseases: Presence or history of venous thromboembolic diseases (deep
vein thrombosis, pulmonary embolism), presence or history of arterial thrombo-
embolic diseases (myocardial infarction, stroke), and any condition which could
increase the risk to suffer from any of the above mentioned disorders, e.g. a
positive family history (event that occurred in a sibling or a parent at an early
age) or a hereditary predisposition
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
|
|
| 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 and who have met all the relevant criteria for success during the 90-day efficacy assessment phase, as compared to the number of patients having at least one qualifying DUB symptom during the run-in phase. Individual components of the Primary Efficacy Variable
Absence of DUB symptoms is defined as:
- No bleeding episodes lasting more than 7 days
and
- No more than 4 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 24 days
- No increase from baseline in an individual patient's total number of bleeding days
In addition, for patients enrolled with specific symptoms, the following criteria will 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 excessive bleeding: (1) the blood loss volume associated
with each episode will be < 80 mL and (2) the blood loss volume associated with
each bleeding episode represents a decrease of at least 50% from the average of
the qualifying bleeding episodes, where the qualifying bleeding episodes are
those with a blood loss volume > 80 mL that occurred during the run-in phase.
|
|
| 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 |
|
| 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
|
|
| 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 |
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