A two replicate phase 3 randomized trials (SPIRIT 1 and 2) demonstrated that Relugolix in conjunction with Estradiol and Progestin is an effective therapy for endometriosis. This study aimed to measure the efficacy and safety of 24 weeks of once-daily orally administered Relugolix combination therapy among women with endometriosis-associated pain, including dysmenorrhea and non-menstrual pelvic pain.

In this study, women (aged between 18 and 50 years) with medically or directly evident endometriosis with or without histological confirmation, or with a histological diagnosis alone were included. Women with varying severity of endometriosis-related distress and dysmenorrhea Numerical Rating Scale (NRS) scores of 4.0 or greater on two or more days during the 35-day run-in period, mean non-menstrual pelvic pain NRS scores of 2.5 or greater, mean score of 1.25 or greater that encompassed a score of 5 or greater on four or more days were chosen.

For 24 weeks, females were given once-daily oral placebo, Relugolix combination treatment (40 mg Relugolix, 1 mg Estradiol, 0.5 mg norethisterone acetate) and placebo once a day, and delayed Relugolix combination therapy (40 mg Relugolix monotherapy followed by Relugolix combination therapy, each for 12 weeks).  Responder rates at week 24 for dysmenorrhea and non-menstrual pelvic pain were the co-primary outcomes ascertained. 

Notably, 638 volunteers were recruited into SPIRIT 1 while 623 volunteers were recruited into SPIRIT 2. A total of 98 subjects in SPIRIT 1 and 115 subjects in SPIRIT 2 ceased trial participation.  In SPIRIT 1, 75% (158/212) of subjects in the Relugolix combination therapy group and 27% (57/212) of subjects  in the placebo group fulfilled the dysmenorrhoea responder criteria (treatment difference 47·6%). In SPIRIT 2, 75% (155/206) of subjects in the Relugolix combination therapy group and 30% (62/204)  in the placebo group were dysmenorrhoea responders (treatment difference 44·9%).

In SPIRIT 1, 58% (124/212) of subjects in the Relugolix combination therapy group and 40% (84 subjects) in placebo group satisfied the non-menstrual pelvic pain response criteria (treatment difference 18.9%). In SPIRIT 2, 66% (136/206) of subjects in Relugolix combination therapy group and 43% (87/204) of subjects in placebo group were non-menstrual pelvic pain responders (treatment difference 23.4%).

Nasopharyngitis, headache, and hot flushes were the most prevalent side effects. In both investigations, there were nine complaints of suicidal thoughts. No deaths were noted. In Relugolix combination medication vs placebo groups, the least squares mean percentage alteration in lumbar spine bone mineral density was -0.70 % against 0.21 % in SPIRIT 1 and -0.78 % versus 0.02 % in SPIRIT 2, while in the delayed Relugolix combination group, it was –1·9% in SPIRIT 2 and –2·0% in SPIRIT 1.

Reductions in opioid usage were reported in treated subjects when compared to placebo. Relugolix (an oral gonadotropin-releasing hormone receptor antagonist) combination oral therapy exhibits promising potential to fulfil the unmet clinical need for long-term medical therapy for endometriosis, and minimizing the requirement for opioid usage or repeated surgical therapy.