| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10014778 |
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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 |
| To evaluate 50 and 100 mg of sufugolix (TAK-013) administered orally twice daily versus placebo for the treatment of symptomatic endometriosis in pre-menopausal females for 12 weeks. |
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| E.2.2 | Secondary objectives of the trial |
| To evaluate the effects of sufugolix (TAK-013) on dyspareunia; to assess the effect of sufugolix (TAK-013) on serum levels of Estradiol, Progesterone, LH and FSH over the 12 week dosing period; to evaluate the effects of sufugolix (TAK-013) versus placebo on endometriosis-related quality of life parameters; to assess the duration of post-treatment pain suppression at follow-up; and to evaluate the concomitant use of analgesic rescue medication. |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. The subject is a pre-menopausal female and must be 18 to 45 years of age, inclusive.
2. Female subjects of childbearing potential must be non-pregnant and non-lactating. In addition to a negative human chorionic gonadotropin (HCG) pregnancy test at Screening, they must also have a negative urine HCG pregnancy test result on the day of randomization (Day 0), prior to receiving any dose of study medication.
From screening until Visit 9 (Week 16), subjects of child bearing potential (e.g. non-sterilized) who are sexually active, must use adequate contraception, unless the sexual partner has undergone vasectomy with proven azoospermia. All subjects will be asked to confirm that they understand the requirements for avoidance of pregnancy during the course of the study as part of the informed consent process. During the course of the study females of child-bearing potential will receive continued advice on avoidance of pregnancies as part of the study procedures.
The acceptable method for this study is double-barrier contraception. Accepted barrier contraceptive devices include; male condom, female condom, diaphragm, and cap. Double barrier contraception is defined as two different barrier devices used simultaneously, each time the subject has intercourse.
Note: contraception methods, which are not accepted include: oral contraceptive pills, natural “rhythm” methods, withdrawal and spermicides (used alone).
3. Endometriosis diagnosis has been laparoscopically or laparotomy confirmed, or has been re-confirmed in the last 3 years prior to study screening.
4. The subject has symptomatic endometriosis within one month prior to screening. A subject is considered to be symptomatic if BOTH of the dysmenorrhea and pelvic pain symptoms are present, one of which is at least moderate, and the other at least mild in severity as described in the modified Biberoglu and Behrman Pain Grading Scale, see Table 2.
5. The subject must have normal menses for at least 2 cycles prior to screening and a cycle duration of 21-35 days.
6. If the subject has had surgical reduction of their endometriosis, they must have recurrence of dysmenorrhea and pelvic pain for at least 3 months post-surgery, which in the investigator’s opinion is due to their endometriosis.
7. With the exception of endometriosis, the subject is otherwise in good health, with no clinically relevant hepatic, renal, cardiovascular, endocrine, metabolic, psychiatric, neurologic, hematologic disease, or any other significant illness or clinical condition.
8. The subject is able and willing to undertake all study-required procedures and has the ability to take oral medications.
9. The subject has given written informed consent.
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| E.4 | Principal exclusion criteria |
1. The subject has clinically significant cardiovascular disease that would preclude them from participating in the study (e.g., myocardial infarction or unstable angina).
2. The subject has a history of any form of cancer (other than adequately treated basal cell and squamous cell cancers of the skin).
3. The subject has a known history of osteoporosis, osteopenia or other metabolic bone disease.
4. The subject has a body mass index (BMI) > 40 kg/m2.
5. The subject has been treated with the following medications within 3 months prior to the administration of the first dose of study medication: Depo-Provera; medications significantly affecting bone metabolism such as bisphosphonates, raloxifene, and calcitonin.
6. The subject has been treated with the following medications within 3 months prior to Screening: oral contraceptives; sex hormone medications such as norethindrone or norethisterone acetate, provera, oestrogen preparations, other progestins, and Danazol and GnRH analogue therapy. The investigator should consider any history of prior GnRH analogue therapy with respect to possible bone mineral density loss to assess subject suitability for entry into the study.
7. The subject has a positive pregnancy test.
8. The subject is less than 3 months postpartum or post-lactation at the time of the first dose of study medication.
9. The subject has a known hypersensitivity to sufugolix (TAK-013) or rescue medication therapies.
10. The subject has abnormal menstrual bleeding unrelated to endometriosis.
11. The subject has a known history of drug abuse (defined as illicit drug use) or a history of alcohol abuse (defined as routine consumption of more than 4 alcoholic drinks per day) within the past 2 years prior to study entry.
12. The subject is currently participating in any clinical trial (marketed product or otherwise) or has done so within 30 days prior to the screening visit.
13. The subject is known to be HIV positive, Hepatitis B surface antigen (HbsAg) or Hepatitis C (HCV) positive at screening.
14. The subject has a known ALT/SGPT and/or AST/SGOT of >1.5 times ULN, a known bilirubin >1.5 mg/dL, or has any hepatic or renal impairment.
15. The subject has any disease or disease state that in the opinion of the investigator would interfere with the study (e.g., chronic depression that requires treatment).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy:
Primary Endpoint(s): The co-primary efficacy endpoints will be the symptomatic improvement rate in dysmenorrhea and pelvic pain symptoms since the subject’s last visit compared to baseline by recall using a modified Biberoglu and Behrman Pain Grading Scale during monthly visits and at Week 12.
Secondary Endpoint(s): The most important secondary efficacy endpoint is symptomatic improvement rate in symptomatic dyspareunia as defined in above. Other secondary endpoints include subject provided Global Assessment; time to onset of pain relief; post-treatment pain suppression; vaginal bleeding record and post-treatment return to menses; rescue analgesic score.
Safety: Laboratory data, vital signs, adverse events, ECG.
Pharmacodynamics: Serum concentrations of Estradiol, Progesterone, LH and FSH over the course of the study
Quality of Life: Endometriosis-specific EHP-30 Quality of Life Questionnaire at Day 0, Week 12 (or Early Termination Visit) and Week 24 |
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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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
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| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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