| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Endometriosis |
| Endometrióza |
|
| E.1.1.1 | Medical condition in easily understood language |
| Endometriosis |
| Endometrióza |
|
| 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 |
1.To determine the benefit of relugolix 40 mg once daily co-administered with 24 weeks of low-dose estradiol and norethindrone acetate compared with placebo on dysmenorrhea;
2.To determine the benefit of relugolix 40 mg once daily co-administered with 24 weeks of low-dose estradiol and norethindrone acetate compared with placebo on non-menstrual pelvic pain (NMPP). |
•určit přínos léčby přípravkem relugolix v dávce 40 mg jednou denně souběžně podávaným po dobu 24 týdnů s nízkou dávkou estradiolu a norethisteron acetátu ve srovnání s placebem u dysmenorey
•určit přínos léčby přípravkem relugolix v dávce 40 mg jednou denně souběžně podávaným po dobu 24 týdnů s nízkou dávkou estradiolu a norethisteron acetátu ve srovnání s placebem u NMPP. |
|
| E.2.2 | Secondary objectives of the trial |
To determine the benefit of relugolix 40 mg once daily co-administered with 24 weeks of low-dose estradiol and norethindrone acetate compared with placebo on the following:
o Function measured by the EHP-30 Pain Domain,
o Dysmenorrhea measured by the NRS; o PGIC for dysmenorrhea;
o NMPP measured by the NRS;
o PGIC for NMPP;
o Dyspareunia measured by the NRS;
o PGIC for dyspareunia;
o Dyspareunia-related functional effects (sB&B);
o Patient Global Assessment (PGA) for pain;
o PGA for function;
o Endometriosis-associated quality of life (Control and Powerlessness,Social Support, Emotional Well-Being, and Self-Image domains of the EHP-30);
o Dysmenorrhea-related functional effects (sB&B);
o NMPP-related functional effects (sB&B).
o PGA for dysmenorrhea;
o PGA for NMPP
|
• určit přínos léčby přípravkem relugolix v dávce 40 mg jednou denně souběžně podávaným po dobu 24 týdnů s nízkou dávkou estradiolu a norethisteron acetátu ve srovnání s placebem u následujících parametrů:
o funkce měřená doménou bolesti EHP-30,
o dysmenorea měřená pomocí NRS,
o PGIC u dysmenorey,
o NMPP měřená pomocí NRS,
o PGIC u NMPP,
o dyspareunie měřená pomocí NRS,
o PGIC u dyspareunie,
o funkční dopady související s dyspareunií (sB&B),
o PGA bolesti,
o PGA funkce,
o kvalita života v souvislosti s endometriózou (domény kontroly a bezmoci, sociální podpory, emoční pohody a sebehodnocení v rámci profilu EHP-30),
o funkční dopady související s dysmenoreou (sB&B),
o funkční dopady související s NMPP (sB&B).
o PGA pro dysmenoreu;
o PGA pro NMPP
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Pharmacogenomics optional sample collection |
| Odběr volitelného farmakogenomického vzorku |
|
| E.3 | Principal inclusion criteria |
1. Has voluntarily signed and dated the informed consent form prior to initiation of any screening or study-specific procedures;
2. Is a premenopausal female aged 18 to 50 years old (inclusive) on the day of signing date of the informed consent form;
3. By the patient's report, had 2 consecutive regular menstrual cycles (ie, 21 to 35 days in duration) immediately prior to Randomization. For patients who have washed off hormonal contraceptives, the 2 regular cycles must start after the first (withdrawal) bleeding following discontinuation of contraceptives;
4. Has agreed to use only study-specified analgesic medications during the study and is not known to be intolerant to these;
5. Has a diagnosis of endometriosis and has had, within 10 years prior to signing the informed consent form, surgical or direct visualization and/or histopathologic confirmation of endometriosis, for example, during a laparoscopy or laparotomy;
6. During the Screening visit, the patient reports moderate, severe, or very severe pain during the most recent menses and for NMPP in the prior month;
7. During the Run-In Period (Days R1 through 35), has at least 24 days of completed eDiary scores;
8. During the Run-In Period (Days R1 through R35), has a dysmenorrhea NRS score >= 4.0 on at least 2 days AND
a. Mean NMPP NRS score > =2.5 OR
b. Mean NMPP NRS score >= 1.25 AND NMPP NRS score >= 5.0 on >= 4.0 days;
For patients with fewer than 3 dysmenorrhea scores during Days R1 - R35, dysmenorrhea scores from Days R36 – 70 will be included in the eligibility determination until a total of 3 dysmenorrhea scores from the Run-In Period are available.
9. Has menstruated for at least 3 days during the Run-In Period
10. Is not expected to undergo gynecological surgery or other surgical procedures for treatment of endometriosis (including ablation, shaving, or excision) during the study, including during the Follow-Up Period, and the patient does not desire such treatment during this time frame;
11. Has a negative urine pregnancy test at the Screening visit and on the Baseline Day 1 visit;
12. Agrees to use contraception during the study and for 30 days following the last dose of study drug. Specifically, agrees to use nonhormonal contraception as described in Section 4.7 consistently during the Screening Period, Run-In Period, and the Randomized Treatment Period and for 30 days following treatment discontinuation. However, the patient is not required to use the specified nonhormonal contraception if she:
a. Has a sexual partner(s) who was vasectomized at least 6 months prior to the Screening Period;
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as Essure™), at least 6 months prior to the Screening visit (patients with Essure must have prior confirmation of tubal occlusion by hysterosalpingogram and no evidence of “post-Essure syndrome” in the investigator’s opinion);
c. Is not sexually active with men; periodic sexual relationship(s) with men requires the use of nonhormonal contraception as noted above; or
d. Practices total abstinence from sexual intercourse as her preferred lifestyle. Periodic abstinence is not acceptable
13. Has an adequate endometrial (aspiration) biopsy performed during the Screening visit or Run-In Period or one that was locally performed within 6 months prior to Screening with results showing no clinically significant endometrial pathology (hyperplasia, polyp, or endometrial cancer);
Note 1: Patients for whom polyps are detected on the biopsy but are either not evident on ultrasound or < 2.0 cm by ultrasound are eligible;
Note 2: endometrial biopsies that were performed or repeated during the Run-In Period and meet criteria are
acceptable;
14. If > =39 years of age at the time of the Screening, has a normal mammogram (Breast Imaging Reporting and Data System category 1 to 2 or equivalent; see Appendix 1 of Protocol) during the Run-In Period or within 6 months prior to the Run-In Period. |
|
| E.4 | Principal exclusion criteria |
1. Has a history of chronic pelvic pain that is not caused by endometriosis
2. Has had 4 or more prior laparoscopic or open abdominal or pelvic surgical procedure for endometriosis;
3. During the Run-In Period, reports NMPP is “much better” on the PGIC for NMPP
4. Has a transvaginal ultrasound during the Screening visit demonstrating pathology other than endometriosis that could be responsible for or contributing to the patient’s chronic pelvic pain or a clinically significant gynecological disorder determined by the investigator to require further evaluation and/or treatment during the study
5. Has any chronic pain or frequently recurring pain condition, other than endometriosis, that is treated with opioids or requires analgesics for > 7 days per month
6. Has had surgical procedure for treatment of endometriosis within the 3 months prior to the Screening visit
7. Has a history of previous non-response of NMPP or dysmenorrhea to GnRH agonists, GnRH antagonists, depot medroxyprogesterone acetate, or aromatase inhibitors based on patient’s report or treating physician’s assessment of chart documentation;
8. Has unexplained vaginal bleeding outside of the patient’s regular menstrual period
9. Has a weight that exceeds the weight limit of the DXA scanner
10. Has bone mineral density z-score < -2.0 at spine, total hip, or femoral neck during the Run-In Period
11. Has a gastrointestinal disorder affecting absorption or gastrointestinal motility
12. Has used, is using or is anticipated to use prohibited medications;
13. Patients receiving selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, or tricyclic antidepressants that have been recently started or undergone recent dose changes. Patients who have been on stable doses for at least 3 months and are anticipated to remain on stable doses during the study (including the Run-In Period) may be enrolled
14. Has a history of or currently has osteoporosis, or other metabolic bone disease, hyperparathyroidism, hyperprolactinemia, hyperthyroidism, anorexia nervosa, or low traumatic or atraumatic fracture. A history of successfully treated hyperparathyroidism, hyperprolactinemia, or hyperthyroidism is allowed
15. Has a history of the use of bisphosphonates, calcitonin, calcitriol, ipriflavone, teriparatide, denosumab, or any medication other than calcium and vitamin D preparations to treat bone mineral density loss
16. Has a systemic autoimmune disease
17. Has any contraindication to treatment with low-dose estradiol and norethindrone acetate,
18. Has jaundice or known current active liver disease from any cause including hepatitis A (hepatitis A virus [HAV] immunoglobulin M [IgM]), hepatitis B (hepatitis B virus surface antigen [HBsAg]), or hepatitis C (hepatitis C virus [HCV] antibody [Ab] positive, confirmed by HCV ribonucleic acid [RNA])
19. On the most recently documented Papanicolaou test, has any of the following cervical pathology: high-grade cervical neoplasia, atypical glandular cells, atypical endocervical cells, or atypical squamous cells favoring high grade. Of note, patients with atypical squamous cells of undetermined significance and low-grade cervical neoplasia may be included in the study if high-risk human papilloma virus testing is negative or if deoxyribonucleic acid (DNA) testing for human papilloma virus 16 and 18 is negative
20. Has any clinical laboratory abnormalities during the Screening or Run-In Period
21. Has clinically significant cardiovascular disease
22. Has been a participant in an investigational drug or device study within the 1 month prior to the Screening visit
23. Has a history of clinically significant condition(s)
24. Is currently pregnant or lactating, or intends to become pregnant or to donate ova during the study period or within 2 months after the last dose of study drug
25. Has a contraindication or history of sensitivity to any of the study treatments or components thereof, including protocol-specified analgesic medications; or has a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates study participation
26. Has a prior (within 1 year of the Screening visit) or current history of drug or alcohol abuse disorder according to Diagnostic and Statistical Manual of Mental Disorders V (all patients must be questioned about their drug and alcohol use)
27. Has participated in a previous clinical study that included the use of relugolix
28. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in the conduct of this study
29. Is inappropriate for participation in this study because of conditions that may interfere with interpretation of study results or prevent the patient from complying with study requirements, as determined by the investigator, sub-investigator, or medical monitor. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Proportion of responders at the Week 24/EOT pain assessment period, based on their dysmenorrhea Numerical Rating Scale (NRS) scores recorded in a daily electronic diary (eDiary), in the relugolix
40 mg group co-administered with lowdose hormonal add-back therapy for 24 weeks versus placebo;
2.Proportion of responders at the Week 24/EOT pain assessment period, based on their NMPP NRS scores recorded in a daily eDiary, in the relugolix 40 mg group co-administered with low-dose hormonal add-back therapy for 24 weeks versus placebo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
-secondary endpoints will be assessed comparing Group A with Group C:
-Change from Baseline at Week 24 in the EHP-30 Pain Domain scores in the relugolix 40 mg group co-administered with low-dose hormonal addback therapy for 24 weeks versus placebo;
Change from Baseline to Week 24/EOT in the mean dysmenorrhea NRS
score;
- Change from Baseline to Week 24/EOT in the severity scores on the PGA for dysmenorrhea;
- Proportion of patients who are better or much better on the PGIC for dysmenorrhea at Week 24/EOT;
- Change from Baseline to Week 24/EOT in the severity scores on the PGA for NMPP;
-Proportion of patients who are better or much better on the PGIC for NMPP at Week 24/EOT.
- Change from Baseline to Week 24/EOT in the mean NMPP NRS score;
- Proportion of patients who are better or much better on the PGIC for NMPP at Week 24/EOT;
- Change from Baseline to Week 24/EOT in the mean dyspareunia NRS scores.
- Proportion of patients who are better or much better on the PGIC for dyspareunia at Week 24/EOT;
- Change from Baseline to Week 24/EOT in the mean dyspareunia functional impairment on the sB&B scale;
- Change from Baseline to Week 24/EOT in severity scores on the PGA for pain;
- Proportion of responders at Week 24/EOT based on their EHP-30 Pain Domain score;
- Change from Baseline to Week 24/EOT in function impairment on the PGA for function;
- Change from Baseline to Week 24/EOT in each of the non-pain EHP-30 domains (Control and Powerlessness, Social Support, Emotional Well- Being, and Self-Image);
- Change from Baseline to Week 24/EOT in the mean dysmenorrhea functional impairment on the sB&B scale;
- Change from Baseline to Week 24/EOT in the mean NMPP functional impairment on the sB&B scale.
-The following secondary endpoints will be assessed comparing Group B with Group C:
- Proportion of responders at the Week 24/EOT pain assessment period, based on their dysmenorrhea NRS scores recorded in a daily eDiary;
- Proportion of responders at the Week 24/EOT pain assessment period, based on their NMPP NRS scores recorded in a daily eDiary.
- Change from Baseline at Week 24/EOT in the EHP-30 Pain Domain scores.
- Proportion of responders at Week 24/EOT based on their EHP-30 Pain Domain score. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 74 |
| 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 |
| Australia |
| Brazil |
| Canada |
| Chile |
| Czech Republic |
| Georgia |
| Italy |
| New Zealand |
| Poland |
| Romania |
| Sweden |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
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