A Study to Assess the Efficacy and Safety of OBE2109 in Subjects With Endometriosis

The study is a prospective, dose-finding, randomized, parallel group, double-blind, placebo-controlled phase 2b study investigating the efficacy and safety of OBE2109 in the treatment of 330 women with moderate-to-severe endometriosis associated pain.

Subject will be randomized to one of 6 treatment groups in a 1:1:1:1:1:1 ratio (1 placebo group, 5 dose groups with different dosage/regimen).

Eligible subjects will be offered the opportunity to continue treatment with OBE2109 in an extension phase. Subjects who do not continue in the extension will enter the treatment-free follow-up phase of the study.

• Placebo (Drug): Placebo tablets for oral administration once daily
• OBE2109 (Drug): OBE2109 tablets for oral administration once daily

Primary outcomes

• Percentage of Subjects With 30% or Greater Reduction From Baseline to Week 12 in Mean Overall Pelvic Pain Score (0-3 VRS) [From baseline to week 12]: The primary efficacy endpoint of the study was a response at Week 12, with response defined as a reduction of 30% or greater from baseline in the mean overall pelvic pain score, defined as the mean of daily pain scores reported in electronic diary during the preceding 28 days (4-week period), assessed on a Verbal Rating Scale for pelvic pain of 0 (no pain) to 3 (severe pain). The baseline mean score was calculated as the mean of daily scores recorded in electronic diary over the two complete menstrual cycles performed during the screening period. The relevant time points are Baseline and Week 12.

Secondary outcomes

• Change From Baseline to Week 12 in the Mean Overall Pelvic Pain Score (0-10 NRS) [From baseline to week 12]: This endpoint corresponds to the change from baseline to Week 12 in the mean overall pelvic pain score, defined as the mean of daily pain scores reported in electronic diary during the preceding 28 days (4-week period), assessed on a Numerical Rating Scale (NRS) for pelvic pain of 0 (no pelvic pain) to 10 (worst pelvic pain imaginable). The baseline mean score was calculated as the mean of daily scores recorded in electronic diary over the two complete menstrual cycles performed during the screening period. The relevant time points are Baseline and Week 12.
• Percentage of Subjects With 30% or Greater Reduction From Baseline to Week 12 in Mean Pelvic Pain Scores (0-3 VRS) for Days With Uterine Bleeding [From baseline to week 12]: This endpoint corresponds to a response at Week 12, with response defined as a reduction of 30% or greater from baseline in the mean pelvic pain score for days with uterine bleeding/spotting, defined as the mean of daily pain scores on days with uterine bleeding/spotting recorded in electronic diary during the preceding 28 days (4-week period), assessed on a Verbal Rating Scale for pelvic pain of 0 (no pain) to 3 (severe pain). The baseline mean score was calculated as the mean of daily scores recorded in electronic diary over the two complete menstrual cycles performed during the screening period. The relevant time points are Baseline and Week 12.
• Percentage of Subjects With 30% or Greater Reduction From Baseline to Week 12 in Mean Pelvic Pain Scores (0-3 VRS) for Days With no Uterine Bleeding [From baseline to week 12]: This endpoint corresponds to a response at Week 12, with response defined as a reduction of 30% or greater from baseline in the mean pelvic pain score for days with no uterine bleeding, defined as the mean of daily pain scores on days with no uterine bleeding recorded in electronic diary during the preceding 28 days (4-week period) on a Verbal Rating Scale for pelvic pain of 0 (no pain) to 3 (severe pain). The baseline mean score was calculated as the mean of daily scores recorded in electronic diary over the two complete menstrual cycles performed during the screening period. The relevant time points are Baseline and Week 12.
• Change From Baseline to Week 12 in the Mean Dyspareunia Score (0-3 VRS) [From baseline to week 12]: This endpoint corresponds to the change from baseline to Week 12 in the mean dyspareunia score, defined as the mean of daily dyspareunia scores recorded in electronic diary during the preceding 28 days (4-week period), assessed on a 0-3 Verbal Rating Scale (VRS) for dyspareunia, with 0 representing "No discomfort during sexual intercourse" and 3 representing "I avoided sexual intercourse because of pain". The baseline mean score was calculated as the mean of daily scores recorded in electronic diary over the two complete menstrual cycles performed during the screening period. The dyspareunia questionnaire also included an option "not applicable: I was not sexually active for reasons other than my endometriosis or did not have sexual intercourse"; for scoring, answering "not applicable" was considered like a missing value. The relevant time points are Baseline and Week 12.
• Change From Baseline to Week 12 in the Mean Dyschezia Score (0-10 NRS) [From baseline to week 12]: This endpoint corresponds to the change from baseline to week 12 in the mean dyschezia score, defined as the mean of weekly dyschezia scores reported in electronic diary during the preceding 28 days (4-week period), assessed on a 0-10 Numerical Rating Scale for dyschezia, with 0 representing no pain and 10 representing the worst pain imaginable. The baseline mean score was calculated as the mean of weekly scores recorded in electronic diary over the two complete menstrual cycles performed during the screening period. The relevant time points are Baseline and Week 12.
• Percentage of Subjects With Any Analgesics Use at Week 12 [Up to week 12]: This endpoint corresponds to the percentage of subjects at week 12 who recorded at least one pain medication intake in electronic diary during the preceding 28 days (4-week period).
• Change From Baseline to Week 12 in the Mean Score of Endometriosis Health Profile-30 (EHP-30) Pain Domain [From baseline to week 12]: This endpoint corresponds to the change from baseline to Week 12 in the mean score of pain dimension of the EHP-30. The EHP-30 questionnaire was answered on electronic diary after activation by site staff during subject's monthly visits at site. The EHP-30 pain dimension consists of 11 items each addressing the effect of pain on various activities in the past 4 weeks and each assessed on a 5-point scale (0=Never through to 4=Always). Scaled score was equalled to total of raw score of each item in scale divided by the maximum possible raw score of all the items in the dimension, multiplied by 100, resulting in a score on a scale from 0 (best possible health status) to 100 (worst possible health status). The relevant time points are Baseline and Week 12.
• Percentage of Subjects With Improvement in the Patient Global Impression of Change (PGIC) Score at Week 12 [Up to week 12]: The PGIC questionnaire consists of one question rated on a seven point scale (1="Very Much Improved" to 7="Very Much Worse"), with which the subject had to qualify her overall status since the start of the study. The PGIC was answered on electronic diary after activation by site staff during Week 12 visit at site. This endpoint corresponds to the percentage of subjects with an "improvement" in the PGIC score, which includes all subjects who answered "Very much improved" or "Much improved" or "Minimally improved" at Week 12.
• Percentage of Subjects With an Endometriosis Severity Score of "Severe" at Week 12 [Up to week 12]: Subject was asked monthly on electronic diary to assess their impression of endometriosis severity, considering the preceding 4-weeks, with following possible answers: no symptoms, very mild, mild, moderate, severe. This question was programmed to raise automatically every 4 weeks on the subject electronic diary. Result reported here is the percentage of subjects who answered "severe" at week 12.
• Change From Baseline to Week 12 in the Difficulty in Doing Daily Activities Mean Score [From baseline to week 12]: This endpoint corresponds to the change from baseline to Week 12 in the mean of daily scores for "difficulty in doing daily activities", assessed via electronic diary during the preceding 28 days (4-week period), on a Numerical Rating Scale (NRS) of 0 (no difficulty doing daily activities) to 10 (unable to do daily activities). The baseline mean score was calculated as the mean of daily scores recorded in electronic diary over the two complete menstrual cycles performed during the screening period. The relevant time points are Baseline and Week 12.
• Percentage Change From Baseline to Week 24 in Bone Mineral Density (BMD) [From baseline up to week 24]: Change from baseline to Week 24 in BMD assessed by dual-energy X-ray absorptiometry (DXA) scan of LUMBAR SPINE.
• Number of Non Benign Endometrial Biopsies at Week 24 [Week 24]: Any pathological changes in the endometrium at week 24 were assessed from endometrial biopsies. The number of non benign biopsies at Week 24 is presented per treatment arm. Note: an isolated case of hyperplasia (without atypia) was observed at week 12 in the 200 mg group in a subject whose screening biopsy results were normal. A follow-up biopsy at week 24 revealed no abnormalities.
• Change From Baseline to Week 24 in Endometrial Thickness Measured by Transvaginal Ultrasound (TVUS) [From baseline up to week 24]: The endometrium thickness was measured by TVUS at screening and at Week 24 visit by the gynaecologist and result was recorded in mm. This endpoint reports the changes from baseline to Week 24 in the endometrial thickness.
• Percentage Change From Baseline to Week 24 in the Clinical Laboratory Assessments: LDL [From baseline up to week 24]: This endpoint reports the change from baseline up to Week 24 in the clinical laboratory assessments: LDL cholesterol.
• Percentage Change From Baseline to Week 24 in Clinical Laboratory Assessments: HDL [From Baseline up to week 24]: This endpoint reports the change from baseline to week 24 in clinical laboratory assessments: HDL cholesterol.
• Percentage Change From Baseline to Week 24 in Clinical Laboratory Assessments: Triglycerides [From baseline up to week 24]: This endpoint reports the change from baseline to week 24 in clinical laboratory assessments: triglycerides.

Sex: Female, ages: 18 Years to 45 Years

Key Inclusion Criteria:

* The subject must have had her most recent surgical and - if available - histological, diagnosis of pelvic endometriosis up to 10 years before screening.
* The subject has moderate to severe endometriosis-associated pain during the screening period.
* The subject has regular menstrual cycles.
* The subject has a BMI ≥ 18 kg/m2 at the screening visit.

Key Exclusion Criteria:

* The subject is pregnant or breast feeding or is planning a pregnancy within the duration of the treatment period of the study.
* The subject had an interventional surgery for endometriosis performed within a period of 60 days before screening.
* The subject did not respond to prior treatment with gonadotropin releasing hormone (GnRH) agonists or GnRH antagonists for endometriosis.
* The subject has a history of, or known osteoporosis or other metabolic bone disease.
* The subject has chronic pelvic pain that is not caused by endometriosis and requires chronic analgesic / therapy, or that would interfere with the assessment of endometriosis related pain.

Participant flow

Outcome results

• Percentage of Subjects With 30% or Greater Reduction From Baseline to Week 12 in Mean Overall Pelvic Pain Score (0-3 VRS) (Primary), Number, percentage of subjects: Placebo / OBE2109 100mg 34.5; OBE2109 50mg 49.4; OBE2109 75mg FD + TD 61.5; OBE2109 100mg 56.4; OBE2109 200mg 56.3
• Change From Baseline to Week 12 in the Mean Overall Pelvic Pain Score (0-10 NRS) (Secondary), Mean, score on a scale: Placebo / OBE2109 100mg -1.17 (-1.70 to -0.65); OBE2109 50mg -1.75 (-2.29 to -1.20); OBE2109 75mg FD + TD -2.15 (-2.50 to -1.80); OBE2109 100mg -2.06 (-2.60 to -1.52); OBE2109 200mg -2.14 (-2.65 to -1.63)
• Percentage of Subjects With 30% or Greater Reduction From Baseline to Week 12 in Mean Pelvic Pain Scores (0-3 VRS) for Days With Uterine Bleeding (Secondary), Number, percentage of subjects: Placebo / OBE2109 100mg 28.5; OBE2109 50mg 43.3; OBE2109 75mg FD + TD 68.2; OBE2109 100mg 68.6; OBE2109 200mg 78.9
• Percentage of Subjects With 30% or Greater Reduction From Baseline to Week 12 in Mean Pelvic Pain Scores (0-3 VRS) for Days With no Uterine Bleeding (Secondary), Number, percentage of subjects: Placebo / OBE2109 100mg 37.1; OBE2109 50mg 46.2; OBE2109 75mg FD + TD 58.5; OBE2109 100mg 61.5; OBE2109 200mg 47.7
• Change From Baseline to Week 12 in the Mean Dyspareunia Score (0-3 VRS) (Secondary), Mean, score on a scale: Placebo / OBE2109 100mg -0.39 (-0.63 to -0.16); OBE2109 50mg -0.62 (-0.87 to -0.37); OBE2109 75mg FD + TD -0.59 (-0.76 to -0.43); OBE2109 100mg -0.66 (-0.91 to -0.41); OBE2109 200mg -0.79 (-1.03 to -0.54)
• Change From Baseline to Week 12 in the Mean Dyschezia Score (0-10 NRS) (Secondary), Mean, score on a scale/week: Placebo / OBE2109 100mg -0.78 (-1.34 to -0.22); OBE2109 50mg -1.55 (-2.14 to -0.96); OBE2109 75mg FD + TD -1.87 (-2.25 to -1.49); OBE2109 100mg -1.97 (-2.55 to -1.39); OBE2109 200mg -1.7 (-2.25 to -1.15)
• Percentage of Subjects With Any Analgesics Use at Week 12 (Secondary), Number, percentage of subjects: Placebo / OBE2109 100mg 90.6 (78.6 to 96.2); OBE2109 50mg 77.1 (62.7 to 87.1); OBE2109 75mg FD + TD 74.8 (65.7 to 82.1); OBE2109 100mg 68.8 (54.1 to 80.5); OBE2109 200mg 72.1 (58.4 to 82.7)
• Change From Baseline to Week 12 in the Mean Score of Endometriosis Health Profile-30 (EHP-30) Pain Domain (Secondary), Mean, score on a scale: Placebo / OBE2109 100mg -7.4 (-12.36 to -2.41); OBE2109 50mg -18.5 (-23.44 to -13.47); OBE2109 75mg FD + TD -18.9 (-22.20 to -15.69); OBE2109 100mg -19.4 (-24.28 to -14.55); OBE2109 200mg -20.9 (-25.69 to -16.10)
• Percentage of Subjects With Improvement in the Patient Global Impression of Change (PGIC) Score at Week 12 (Secondary), Number, percentage of subjects: Placebo / OBE2109 100mg 65.1; OBE2109 50mg 78.6; OBE2109 75mg FD + TD 80.6; OBE2109 100mg 86; OBE2109 200mg 95.7
• Percentage of Subjects With an Endometriosis Severity Score of "Severe" at Week 12 (Secondary), Number, percentage of subjects: Placebo / OBE2109 100mg 20.9; OBE2109 50mg 4.5; OBE2109 75mg FD + TD 7.8; OBE2109 100mg 4.5; OBE2109 200mg 4.2
• Change From Baseline to Week 12 in the Difficulty in Doing Daily Activities Mean Score (Secondary), Mean, score on a scale: Placebo / OBE2109 100mg -1.17 (-1.68 to -0.65); OBE2109 50mg -1.65 (-2.18 to -1.12); OBE2109 75mg FD + TD -2.06 (-2.41 to -1.72); OBE2109 100mg -1.88 (-2.41 to -1.36); OBE2109 200mg -1.99 (-2.49 to -1.49)
• Percentage Change From Baseline to Week 24 in Bone Mineral Density (BMD) (Secondary), Mean, percentage change: Placebo / OBE2109 100mg -0.929 (-1.71 to -0.15); OBE2109 50mg 0.137 (-0.83 to 1.11); OBE2109 75mg FD -0.798 (-1.57 to -0.03); OBE2109 75mg TD -1.000 (-1.71 to -0.29); OBE2109 100mg -1.365 (-2.14 to -0.59); OBE2109 200mg -2.602 (-3.56 to -1.65)
• Number of Non Benign Endometrial Biopsies at Week 24 (Secondary), Number, Non benign biopsies: Placebo / OBE2109 100mg 0; OBE2109 50mg 0; OBE2109 75mg FD 0; OBE2109 75mg TD 0; OBE2109 100mg 0; OBE2109 200mg 0
• Change From Baseline to Week 24 in Endometrial Thickness Measured by Transvaginal Ultrasound (TVUS) (Secondary), Mean, mm: Placebo / OBE2109 100mg -3.1 +/- 4.64; OBE2109 50mg -1.5 +/- 4.28; OBE2109 75mg FD -2.3 +/- 4.15; OBE2109 75mg TD -1.3 +/- 3.70; OBE2109 100mg -1.6 +/- 4.56; OBE2109 200mg -4.0 +/- 3.39
• Percentage Change From Baseline to Week 24 in the Clinical Laboratory Assessments: LDL (Secondary), Mean, percent change: Placebo / OBE2109 100mg 1.7 +/- 15.7; OBE2109 50mg -0.3 +/- 16.6; OBE2109 75mg FD 7.4 +/- 55.2; OBE2109 75mg TD 7.3 +/- 21.4; OBE2109 100mg 9.7 +/- 20.7; OBE2109 200mg 10.3 +/- 21.7
• Percentage Change From Baseline to Week 24 in Clinical Laboratory Assessments: HDL (Secondary), Mean, percent change: Placebo / OBE2109 100mg 5.5 +/- 11.7; OBE2109 50mg 2.9 +/- 12.9; OBE2109 75mg FD 3.8 +/- 17.8; OBE2109 75mg TD 6.2 +/- 24.1; OBE2109 100mg 5.6 +/- 18.0; OBE2109 200mg 8.1 +/- 14.7
• Percentage Change From Baseline to Week 24 in Clinical Laboratory Assessments: Triglycerides (Secondary), Mean, percent change: Placebo / OBE2109 100mg 17.9 +/- 38.6; OBE2109 50mg 16.4 +/- 41.3; OBE2109 75mg FD 5.2 +/- 35.2; OBE2109 75mg TD 13.6 +/- 45.0; OBE2109 100mg 20.5 +/- 80.6; OBE2109 200mg 24.0 +/- 57.7

Adverse events

Time frame: From baseline up to week 24

Serious adverse events by term

Other adverse events by term

• Results publication: Donnez J, Taylor HS, Taylor RN, Akin MD, Tatarchuk TF, Wilk K, Gotteland JP, Lecomte V, Bestel E. Treatment of endometriosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone-antagonist: a randomized clinical trial. Fertil Steril. 2020 Jul;114(1):44-55. doi: 10.1016/j.fertnstert.2020.02.114. Epub 2020 Jun 4. PMID 32505383

• Study Protocol and Statistical Analysis Plan (PDF, 2016-04-25)

• ObsEva SA, Study director, Geneva