| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Endometriosis is a disease of young women (before menopause); women suffer from pain in the pelvic/ lower abdominal area and difficulties to become pregnant |
|
| 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 | LLT |
| E.1.2 | Classification code | 10014788 |
| E.1.2 | Term | Endometriosis related pain |
| E.1.2 | System Organ Class | 10038604 - Reproductive system and breast disorders |
|
| 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 |
| Explore the dose response relationship of different doses of BAY 1128688 compared to placebo in the treatment of endometriosis-related symptoms over a 12-week treatment period |
|
| E.2.2 | Secondary objectives of the trial |
| Assessment of safety and tolerability of BAY 1128688 over a 12-week treatment period |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Women of at least 18 years of age at the time of signing of informed consent
- Women with endometriosis confirmed by at least one of the two criteria:
. Visually-confirmed endometriosis within 10 years
. Imaging-confirmed endometriosis within 12 months prior to screening
- Both criteria regarding pain symptoms have to be fulfilled:
. At Visit 1: at least a score of 40 (for subjects not on hormonal treatment) on visual analogue scale (VAS; 4-week recall period) for endometriosis-associated pelvic pain (EAPP), and at least a score of 30 for subjects on hormonal treatment. Subjects are regarded to be on hormonal treatment if hormonal contraception was used any time during the 4 weeks prior to Visit 1.
. During the screening period (before randomization):
o At least 24 daily diary entries during the 28 consecutive days starting on the first day with menstrual bleeding on or after Visit 1
o A sum of at least 98 of the available entries in the endometriosis symptom
diary (ESD) item 1 (‘worst pain’ on the daily numerical rating scale [NRS]; 24-hour recall), corresponding to an average score of ≥ 3.5 over the 28-day period
- Willingness to use only ibuprofen as rescue pain medication for EAPP, if required, according to investigator’s instruction
- Good general health (except for findings related to endometriosis) as proven by medical
history, physical and gynecological examinations and laboratory test results
- Normal or clinically insignificant cervical smear not requiring further follow up (a cervical smear has to be taken at screening visit or a normal result has to be documented within the
previous 6 months). Human papilloma virus (HPV) testing in subjects with atypical squamous cells of unknown significance (ASCUS) can be used as an adjunctive test.
Subjects with ASCUS can be included if they are negative for high-risk HPV strains.
- Willingness to use non-hormonal barrier method for contraception (here spermicide-coated
condoms) from screening visit until the end of the study. This is not required if adequate contraception is achieved by vasectomy of the partner or use of copper intrauterine device (IUD) or commitment to abstinence and refrain from using hormonal contraception.
9. Willingness to be trained/instructed in using barrier method of contraception (here
spermicide-coated condoms)
10. Willingness and ability to attend the scheduled study visits and comply with study
procedures |
|
| E.4 | Principal exclusion criteria |
- Pregnancy or lactation (less than three months since delivery, abortion, or lactation before start of treatment) OR wish for pregnancy during the study
- Hypersensitivity to any ingredient of the study drug and/or ibuprofen
- Contraindications to study drug (as described in the investigator brochure) and/or ibuprofen (based on the country-specific label)
- Presence of at least one of the following risks related to bilirubin metabolism and liver function at Visit 1:
. Total bilirubin above upper limit of normal (ULN)
. Glutamic oxaloacetic transaminase (GOT) / aspartate aminotransferase (AST) above ULN
. Glutamic pyruvic transaminase (GPT) / alanine aminotransferase (ALT) above ULN
. Alkaline phosphatase (AP) equal or above 2 times ULN
. Positive results for a) hepatitis B virus surface antigen (HBsAg) or b) hepatitis C virus antibodies and mRNA (anti-HCV and HCV-mRNA)
. Any disease influencing bilirubin values such as thalassemia, Morbus Gilbert/Meulengracht, Crigler-Najjar syndrome, Rotor syndrome or other
genetic predispositions to altered bilirubin metabolism
- Presence of at least one of the following risks related to hyperandrogenemia at Visit 1
. Total testosterone above 1.5 times ULN
. Any disease influencing testosterone metabolism such as adrenogenital syndrome Diagnosed polycystic ovary syndrome (PCOS) based on
Rotterdam criteria or suspicion of polycystic ovaries (elements of the Rotterdam criteria but insufficient for diagnosis e.g. clinical features of PCOS
like hirsutism or biochemical features of PCOS like hyperandrogenemia or oligo-/amenorrhea or polycystic ovary)
- Any diseases or conditions that can compromise the function of the body systems and could result in altered absorption, excessive accumulation, impaired metabolism, or altered excretion of the study drug, for example impaired function of kidneys and liver, chronic bowel disease
- Any diseases or conditions that might interfere with the conduct of the study or the interpretation of the results (e.g. pain caused by other diseases such as uterine fibroids, fibromyalgia, chronic bowel disease)
- Any disease or condition that may worsen under treatment according to the assessment and opinion of the investigator
- Abnormal vaginal/genital bleeding in terms of regularity or heaviness (caused by organic reasons such as uterine fibroids or uterine polyps or undiagnosed; adenomyosis-related changes in regularity or heaviness of vaginal/genital bleeding are not an exclusion criterion)
- Suspicion of menopausal transition, such as absence of regular menstrual cycles based on investigator’s judgment (absence of information regarding menstrual bleeding pattern e.g. due to long term use of hormonal contraception and elevated FSH plasma concentrations
at screening are not an exclusion criterion)
- Uncontrolled thyroid disorders (well controlled hyper- and hypothyroid disorders, as proven by thyroid-stimulating hormone [TSH] at screening are allowed)
- Any medication that could result in excessive accumulation, increased or impaired metabolism, or altered excretion of the study drug or might interfere with the conduct of the study or the interpretation of the results such as:
. Moderate or strong CYP3A4 enzyme and P-gp inducers (with an expected decrease in systemic exposure to 50% or less) (see Appendix 16.1)
. Moderate or strong CYP3A4 enzyme and P-gp inhibitors (with an expected increase in systemic exposure of greater than 2-fold) (see Appendix 16.2)
These medications should be stopped at Visit 1 and are prohibited throughout the study.
- Any drug treatments which interfere with the conduct of the study or the interpretation of the results
- Any findings that require further diagnostic procedures to avoid harm to the subject (e.g. ovarian tumors of uncertain origin or pelvic masses of unclear etiology)
- History of hysterectomy, tubal-ligation or bilateral ovariectomy
- Abuse of alcohol, drugs, or medicine (e.g. laxatives)
- Major surgery scheduled for the study period
- Non-responsiveness of EAPP to GnRH-a or an endometriosis related surgery (partial response is not exclusionary). Non-responsiveness refers to clinical judgment of the investigator i.e. no cross-site definition of threshold provided.
- Previous (within the last 3 months before screening visit) or concomitant participation in another clinical study with an investigational medicinal product(s)
- Previous assignment to treatment during this study
- Inability to comply with the study procedures for any reason, including the following examples: language comprehension, psychiatric illness, inability to get to the study site
- Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site) or sponsor’s staff |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Absolute change in mean pain of the 7 days with worst EAPP from baseline (last 28 days before SoT visit) to end of treatment (last 28 days of the treatment period, Day 57 - 84) (measured on the NRS by item 1 of the ESD). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| The secondary safety variable is the incidence of treatment-emergent adverse events |
|
| 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 | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Effects of BAY 1128688 on health-related quality of life |
|
| 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 | 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 | 6 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 91 |
| 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
|
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | 5 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 5 |
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