| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| endometriosis in reproductive-age |
|
| E.1.1.1 | Medical condition in easily understood language |
| endometriosis in reproductive-age |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10014778 |
| E.1.2 | Term | Endometriosis |
| E.1.2 | System Organ Class | 10038604 - Reproductive system and breast disorders |
|
| 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 show superiority of at least one dose of mifepristone 2.5 mg and mifepristone 5 mg relative to placebo for the treatment of endometriosis in reproductive-age women at 24 weeks in terms of the
reduction of Endometriosis Associated Pelvic Pain (EAPP) as measured by Visual Analog Scale (VAS) and considering intake of rescue medication. |
|
| E.2.2 | Secondary objectives of the trial |
• Efficacy of mifepristone 2.5 mg & 5 mg during the 1st cycle and during the 2nd cycle in terms of the reduction of EAPP measured by VAS with the intake of rescue medication
• Efficacy of mifepristone 2.5 mg & 5 mg vs. placebo during the 1st treatment cycle of the reduction of each type of pain (non-menstrual pelvic pain, dysmenorrhea and/or dyschezia and/or dyspareunia)
• Percentage of responders based on the reduction in EAPP as measured by VAS with no intake of rescue medication
• Effect of mifepristone 2.5 mg, 5 mg & placebo by the modified Biberoglu & Behrman pain scale, by the Patient Global Impression of Change scale and the Clinical Global Impressions scale, on “Quality of Life” assessed by the SF-36 Health Survey questionnaire, on fertility by the Hoogland score
• Return to fertility after the treatment with mifepristone 2.5 mg & 5 mg for two cycles by the Hoogland score
• Safety of mifepristone 2.5 mg & 5 mg during two treatment cycles and in comparison to placebo
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
[1] Premenopausal female, between 18 and 45 years of age inclusive, at the time of signing consent
[2] Patients with Endometriosis Associated Pelvic Pain (EAPP: i.e. any type of pelvic pain associated with endometriosis: non-menstrual pelvic pain, dysmenorrhea, dyschezia and dyspareunia) as measured by Visual Analogue Scale (VAS) ≥ 40 mm at least once in the previous 4 weeks from baseline visit
[3] patients with a history of EAPP for at least the past 6 months prior to the initial screening visit
[4] Endometriosis diagnosed by laparoscopy and/or surgery in the past 10 years or less or diagnosed by MRI or transvaginal ultrasound in the past 5 years
[5] Patients with a history of regular menstrual cycles (21-35 days) while not being on any pharmacological treatment that could alter the menstrual cycle (e.g. oral contraceptive pills)
[6] Patients who agree to use only ibuprofen 400 mg as rescue medication up to a total daily dose of not more than 2400 mg
[7] Patients willing and able (e.g. mental and physical condition) to participate in all aspects of the study as evidenced by providing signed written informed consent
[8] Patient agrees to use double barrier contraception birth control methods (e.g. condom with spermicide) during the entire length of participation in the study. Patient is not required to use double barrier contraception methods if:
- Sexual partner(s) is (are) vasectomized, at least 6 months prior to screening
- Patient has had a bilateral tubal occlusion (including ligation and blockage methods such as Essure®), at least 3 months prior to screening
- Patient is not sexually active with men; periodic sexual relationship(s) with men requires the use of dual non-hormonal contraception as noted above.
|
|
| E.4 | Principal exclusion criteria |
[1] History of hypersensitivity or intolerance to the active substance or any of the excipients of the study medication
[2] Subject is pregnant or breast-feeding or is planning a pregnancy within the duration of the study or is less than 6 months postpartum, post-abortion, or post-lactation at the time of entry into the screening period
[3] Previous use of hormonal agents before the Screening visit: ≤24 weeks for GnRH agonists; ≤12 weeks for depot progestogens and danazol: ≤6 weeks for oral contraceptives
[4] Patients with history of any cancer (including breast cancer) and/or histological diagnosis of endometrial atypical hyperplasia at baseline (note: the combination of endometrial thickness <5 mm determined by transvaginal ultrasound and insufficient material for histological evaluation from the endometrial biopsy will be regarded as atrophic endometrium)
[5] Other clinically significant gynaecological condition causing abnormal uterine bleeding already known or identified on Screening such as severe adenomyosis or symptomatic uterine fibroids requiring treatment
[6] Subject has current or history of abnormal genital bleeding
[7] Presence of ovarian cyst of unknown etiology
[8] Cervical smear with pathological findings: class III or higher according to Papanicolaou, class IIp or higher according to the Munich III nomenclature or ASC-US or higher according to the Bethesda system
[9] Surgical treatment of endometriosis within 3 months prior to the screening visit
[10] Presence of chronic pain other than pain due to endometriosis
[11] Hepatic insufficiency
[12] History of, or complications of, thrombosis, embolism, or serious cardiac, respiratory (severe asthma not adequately controlled by treatment), renal, hematologic, endocrine diseases
[13] Uncontrolled or inadequately controlled hypertension at the time of screening with a resting supine systolic or diastolic blood pressure > 180 mmHg or > 95 mmHg, respectively
[14] Subject with hereditary porphyria
[15] Abnormal laboratory findings considered by the investigator as clinically significant
[16] Positive results for HBs-Ag, anti-HCV and HIV-1/HIV-2-antibodies
[17] Use of drugs that could be expected to affect the release of sex hormones (e.g., antipsychotics); hypericum and CYP3A4 inductors (carbamazepine, phenobarbital, phenytoin, primidone, rifampicin) or inhibitors (such as cyclosporine, macrolide antibiotics, nefazodone, azolic antifungal agents and HIV protease inhibitors)
[18] Intake of any analgesics other than ibuprofen: both opioids and non-steroidal anti-inflammatory drugs as well as paracetamol or metamizole during the screening period
[19] History of drug or alcohol abuse within 6 months prior to screening
[20] Participation in another trial within 3 months from the screening visit date;
[21] Previous enrolment in this study
[22] Any condition that, in the judgment of the investigator, may interfere with adherence to study procedures or study assessments
[23] Legal incapacity and/or other circumstances rendering the patient unable to understand the nature, scope and possible consequences of the study
[24] Unreliability or lack of cooperation during the screening period (Note that this includes proven ability to use the e-diaries via the internet). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Co-Primary end points:
- Pre−post absolute change between baseline and final value after 24 weeks double-blind treatment in EAPP
- Final value at the end of 24 weeks of double-blind treatment in the amount of analgesic rescue medication (ibuprofen 400 mg tablets)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Pre−post absolute change between baseline and final value after 24 weeks double-blind treatment in EAPP
- Final value at the end of 24 weeks of double-blind treatment in the amount of analgesic rescue medication (ibuprofen 400 mg tablets) |
|
| E.5.2 | Secondary end point(s) |
- Pre−post absolute change for every 4 weeks of treatment in EAPP as documented on a VAS (in mm) throughout the trial by the patient in her diary
- Intake of analgesic rescue medication for each 4-week period throughout the trial (i.e., number of pills/day) as documented by patient in her diary
- Pre−post absolute change of each pain type associated with endometriosis (non-menstrual pelvic pain, dysmenorrhea, dyschezia and dyspareunia) as documented on a VAS (in mm) at each visit
- Proportion of patients responding to treatment based on change in VAS EAPP and intake of analgesic rescue medication after 12 and 24 weeks of double-blind treatment
- Pre−post absolute change in the total symptom and sign severity score calculated from the modified Biberoglu and Behrman scale
- Clinical Global Impressions (CGI) scale at Week 24 of the 1st treatment cycle and Week 24 of the 2nd and 3rd treatment cycle
- Patient Global Impression of Change (PGIC) scale at Week 24 of the 1st treatment cycle and Week 24 of the 2nd and 3rd treatment cycle
- Absolute change from baseline in Quality of Life domain scores as determined by SF-36 questionnaire at Week 24 of the 1st treatment cycle and Week 24 of the 2nd and 3rd treatment cycle
- Percent of subjects who achieve amenorrhea at Weeks 4, 8, 12, 16, 20, 24 of the 1st treatment cycle and Weeks 8, 16, and 24 of the 2nd and 3rd treatment cycle and Follow-up visit
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Pre−post change for every 4 weeks in EAPP
- Intake of analgesic rescue medication for every 4 weeks
- Pre−post change of each pain type associated with endometriosis at each visit
- Proportion of patients responding to treatment based on change in VAS EAPP and intake of rescue medication after 12 and 24 weeks of double-blind treatment
- Pre−post change in the total symptom and sign severity score by B &B scale
- CGI & PGIC scale at Week 24 of the 1st cycle and Week 24 of the 2nd and 3rd cycle
- Change from baseline in Quality of Life scores by SF-36 questionnaire at Week 24 of the 1st cycle and Week 24 of the 2nd and 3rd cycle
- Percent of subjects with amenorrhea at Weeks 4, 8, 12, 16, 20, 24 of 1st cycle and Weeks 8, 16, and 24 of 2nd and 3rd cycle and Follow-up visit |
|
| 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 | 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 | 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 | 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 51 |
| 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 |
| Bulgaria |
| Hungary |
| Moldova, Republic of |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Spain |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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