Endometriosis
Conditions
Keywords
Dysmenorrhea, Dyspareunia, Dyschezia, Non-menstrual pelvic pain
Brief summary
The primary objective of this study is to demonstrate the efficacy and safety of linzagolix administered orally once daily for 3 months at a dose of 75 mg alone or of 200 mg in combination with add-back hormone replacement therapy (ABT: estradiol (E2) 1 mg / norethisterone acetate (NETA) 0.5 mg) versus placebo, in the management of moderate to severe endometriosis-associated pain (EAP).
Detailed description
This is a prospective, randomized, double-blind, placebo-controlled study to demonstrate the efficacy and safety of linzagolix administered orally once daily at doses of 75 mg alone and 200 mg in combination with low dose ABT (E2 1 mg/NETA 0.5 mg) versus placebo in the management of moderate to severe EAP in 450 women. Eligible subjects who have completed the 6-month treatment period may enter a separate extension study for 6 additional months of active treatment (no placebo control). Subjects who do not continue in the extension study will enter a 6 month treatment-free follow-up phase.
Interventions
For oral administration once daily
For oral administration once daily
For oral administration once daily
For oral administration once daily
For oral administration once daily
For oral administration once daily
Sponsors
Kissei Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 49 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: The subject must have: * Her most recent surgical and - if available - histological diagnosis of pelvic endometriosis up to 10 years before screening. * Moderate to severe endometriosis-associated pain during the screening period. * Regular menstrual cycles. * BMI ≥ 18 kg/m2 at the screening visit. Key
Exclusion criteria
The subject will be excluded if she: * Is pregnant or breast feeding or is planning a pregnancy within the duration of the treatment period of the study. * Is less than 6 months postpartum or 3 months postabortion/ miscarriage at the time of entry into the screening period. * Has had a surgical history of any major abdominal surgery within 6 months or any interventional surgery for endometriosis performed within a period of 2 months before screening. * Did not respond to prior treatment with GnRH agonists or GnRH antagonists for endometriosis. * Has a history of, or known, osteoporosis or other metabolic bone disease. * Has chronic pelvic pain that is not caused by endometriosis and requires chronic analgesic or other chronic therapy which would interfere with the assessment of endometriosis-associated pain.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dysmenorrhea | Baseline to Month 3 | Change at Month 3 from baseline in the mean daily assessment of dysmenorrhea (DYS) measured on a 4-point Verbal Rating Scale (VRS) using an electronicdiary * The 4-point VRS scale for DYS ranges from 0 to 3 (0: No pain; 1: Mild pain; 2: Moderate pain; 3: Severe pain). * A negative change in scores would be indicative of an improvement in the pain of DYS. |
| Non-menstrual Pelvic Pain | Baseline to Month 3 | Change at Month 3 from baseline in the mean daily assessment of non-menstrual pelvic pain (NMPP) measured on a 4-point Verbal Rating Scale (VRS) using anelectronic diary * The 4-point VRS scale for NMPP ranges from 0 to 3 (0: No pain; 1: Mild pain; 2: Moderate pain; 3: Severe pain). * A negative change in scores would be indicative of an improvement in the NMPP. |
Countries
Canada, Puerto Rico, United States
Participant flow
Recruitment details
Of the 492 subjects screened, 85 were randomized. Between randomization and Day 1 (i.e., first day of dosing), 1 subject in the placebo group discontinued due to protocol deviation. Thus, 84 randomized subjects were treated and comprised the Safety Analysis Set.
Pre-assignment details
Participants with a diagnosis of pelvic endometriosis were enrolled in a 1:1:1 ratio in one of three treatment groups: LGX 75 mg, LGX 200 mg+ABT or Placebo.
Participants by arm
| Arm | Count |
|---|---|
| LGX 75 mg One Linzagolix 75 mg tablet, one Linzagolix 200 mg matching placebo tablet and one ABT matching placebo capsule were administered once daily orally for 6 months. | 28 |
| LGX 200 mg+ABT One Linzagolix 200 mg tablet and one Linzagolix 75 mg matching placebo tablet and ABT capsules (E2 1 mg / NETA 0.5 mg) were administered once daily orally for 6 months. | 29 |
| Placebo One Linzagolix 75 mg matching placebo tablet one Linzagolix 200 mg matching placebo tablet and ABT matching placebo capsule were administered once daily orally for 6 months. | 27 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 3 |
| Overall Study | Discontinuation after moving to Follow-up Period [Study termination per Sponsor] | 1 | 0 | 0 |
| Overall Study | Discontinuation after moving to Follow-up Period [Subject's Request (Family Issue)] | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 1 |
| Overall Study | Study termination | 10 | 10 | 10 |
| Overall Study | Withdrawal by Subject | 3 | 5 | 5 |
Baseline characteristics
| Characteristic | LGX 75 mg | LGX 200 mg+ABT | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants | 29 Participants | 27 Participants | 84 Participants |
| Age, Continuous | 32.6 years STANDARD_DEVIATION 7.2 | 33.4 years STANDARD_DEVIATION 6.4 | 32.1 years STANDARD_DEVIATION 6.9 | 32.7 years STANDARD_DEVIATION 6.8 |
| Age, Customized | 32.5 years | 34.0 years | 31.0 years | 33.0 years |
| BMI | 29.08 kg/m2 STANDARD_DEVIATION 5.57 | 28.54 kg/m2 STANDARD_DEVIATION 8.48 | 26.61 kg/m2 STANDARD_DEVIATION 5.84 | 28.10 kg/m2 STANDARD_DEVIATION 6.79 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 12 Participants | 9 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 17 Participants | 18 Participants | 55 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 1 Participants | 5 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 22 Participants | 27 Participants | 20 Participants | 69 Participants |
| Region of Enrollment Canada | 1 participants | 2 participants | 0 participants | 3 participants |
| Region of Enrollment Puerto Rico | 4 participants | 2 participants | 0 participants | 6 participants |
| Region of Enrollment United States | 23 participants | 25 participants | 28 participants | 76 participants |
| Sex: Female, Male Female | 28 Participants | 29 Participants | 27 Participants | 84 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Weight | 78.130 kg STANDARD_DEVIATION 16.904 | 76.540 kg STANDARD_DEVIATION 20.207 | 71.280 kg STANDARD_DEVIATION 16.05 | 75.379 kg STANDARD_DEVIATION 17.885 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 29 | 0 / 27 |
| other Total, other adverse events | 10 / 28 | 16 / 29 | 12 / 27 |
| serious Total, serious adverse events | 0 / 28 | 0 / 29 | 0 / 27 |
Outcome results
Primary
Dysmenorrhea
Change at Month 3 from baseline in the mean daily assessment of dysmenorrhea (DYS) measured on a 4-point Verbal Rating Scale (VRS) using an electronicdiary * The 4-point VRS scale for DYS ranges from 0 to 3 (0: No pain; 1: Mild pain; 2: Moderate pain; 3: Severe pain). * A negative change in scores would be indicative of an improvement in the pain of DYS.
Time frame: Baseline to Month 3
Population: Due to the COVID-19 pandemic, the study was terminated early and only 85 out of the planned 450 subjects were randomized. As there were insufficient number of treated subjects at study termination, no analyses of efficacy were conducted. This time, we calculated mean±SD from only 6 subjects with DYS \& NMPP data on both D1 \& M3 and entered them as efficacy results in this table. There were no other subjects besides these 6 who had both data at baseline and another time point (M3, M6, M9 or M12).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LGX 75 mg | Dysmenorrhea | -0.5 score on a scale | Standard Deviation 0.5 |
| LGX 200 mg+ABT | Dysmenorrhea | 0.0 score on a scale | Standard Deviation 0 |
| Placebo | Dysmenorrhea | 0.5 score on a scale | Standard Deviation 0.5 |
Primary
Non-menstrual Pelvic Pain
Change at Month 3 from baseline in the mean daily assessment of non-menstrual pelvic pain (NMPP) measured on a 4-point Verbal Rating Scale (VRS) using anelectronic diary * The 4-point VRS scale for NMPP ranges from 0 to 3 (0: No pain; 1: Mild pain; 2: Moderate pain; 3: Severe pain). * A negative change in scores would be indicative of an improvement in the NMPP.
Time frame: Baseline to Month 3
Population: Due to the COVID-19 pandemic, the study was terminated early and only 85 out of the planned 450 subjects were randomized. As there were insufficient number of treated subjects at study termination, no analyses of efficacy were conducted. This time, we calculated mean±SD from only 6 subjects with DYS \& NMPP data on both D1 \& M3 and entered them as efficacy results in this table. There were no other subjects besides these 6 who had both data at baseline and another time point (M3, M6, M9 or M12).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LGX 75 mg | Non-menstrual Pelvic Pain | -1.0 score on a scale | Standard Deviation 0 |
| LGX 200 mg+ABT | Non-menstrual Pelvic Pain | 0.0 score on a scale | Standard Deviation 0 |
| Placebo | Non-menstrual Pelvic Pain | 0.0 score on a scale | Standard Deviation 0 |