Efficacy and Safety of Linzagolix for the Treatment of Endometriosis-associated Pain.

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.

• 75 mg linzagolix tablet (Drug): For oral administration once daily
• 200 mg linzagolix tablet (Drug): For oral administration once daily
• Add-back capsule (E2 1 mg / NETA 0.5 mg) (Drug): For oral administration once daily
• Placebo tablet to match 75 mg linzagolix tablet (Drug): For oral administration once daily
• Placebo tablet to match 200 mg linzagolix tablet (Drug): For oral administration once daily
• Placebo capsule to match Add-back capsule (Drug): For oral administration once daily

Primary outcomes

• Reduction of Dysmenorrhea (DYS) at Month 3 - Proportion of Responders [Baseline to Month 3]: Percentage of subjects with reduction of 1.1 for DYS in mean pelvic pain score within last 28 days prior to Month 3 or discontinuation, and stable or decreased use of analgesics for Endometriosis-associated pain (=EAP) within the same calendar days.
• Reduction of Non-menstrual Pelvic Pain (NMPP) at Month 3 - Proportion of Responders [Baseline to Month 3]: Percentage of subjects with reduction of 0.8 for NMPP in mean pelvic pain score within last 28 days prior to Month 3 or discontinuation, and stable or decreased use of analgesics for Endometriosis-associated pain (=EAP) within the same calendar days.

Sex: Female, ages: 18 Years to 49 Years

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. -

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.

Participant flow

Outcome results

• Reduction of Dysmenorrhea (DYS) at Month 3 - Proportion of Responders (Primary), Number, Percentage of responders: LGX 75 mg 44.0 (36.3 to 52.0); LGX 200 mg+ABT 72.9 (65.3 to 79.4); Placebo 23.5 (17.5 to 30.7) (p <0.001)
• Reduction of Non-menstrual Pelvic Pain (NMPP) at Month 3 - Proportion of Responders (Primary), Number, Percentage of responders: LGX 75 mg 38.9 (31.5 to 46.9); LGX 200 mg+ABT 47.3 (39.5 to 55.3); Placebo 30.9 (24.1 to 38.6) (p 0.279)

Adverse events

Time frame: Day 1 to Month 6 of the treatment period

Serious adverse events by term

Other adverse events by term

• Results publication: Donnez J, Becker C, Taylor H, Carmona Herrera F, Donnez O, Horne A, Paszkowski M, Petraglia F, Renner SP, Patel A, Boolell M, Bestel E, Dolmans MM. Linzagolix therapy versus a placebo in patients with endometriosis-associated pain: a prospective, randomized, double-blind, Phase 3 study (EDELWEISS 3). Hum Reprod. 2024 Jun 3;39(6):1208-1221. doi: 10.1093/humrep/deae076. PMID 38648863

• Study Protocol (PDF, 2020-07-27)
• Statistical Analysis Plan (PDF, 2022-06-13)

• Lecomte, Study director, ObsEva SA