O-305 SPIRIT long-term extension study: two-year efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain

Abstract

Study question To assess the long-term efficacy and safety of once-daily Relugolix combination therapy (Relugolix-CT) in the treatment of endometriosis-associated pain over two years. Summary answer Relugolix-CT previously demonstrated sustained improvement of endometriosis-associated pain and was generally well tolerated over 52 weeks. Research is ongoing: two-year results will be reported. What is known already SPIRIT 1&2 were international, Phase 3, replicate, randomized, double-blind, placebo-controlled studies of Relugolix-CT (relugolix 40mg, estradiol 1mg, norethisterone acetate 0.5mg) in premenopausal women with moderate-to-severe endometriosis-associated pain, which were followed by the open-label, 80-week, long-term extension. 52-week results showed sustained improvement in dysmenorrhea and non-menstrual pelvic pain (NMPP) with 84.8% and 73.3% of responders, respectively. Efficacy was evidenced by reductions in dysmenorrhea (82.8%,) NMPP (62.9%,) proportion of women using opioids, and improvements in function. Relugolix-CT was generally well tolerated. Bone mineral density (BMD) assessment showed minimal initial decline (<1%) from baseline followed by stabilization from Week 24 to 52. Study design, size, duration Women who completed the 24-week pivotal studies (SPIRIT 1&2) were eligible to enroll in an 80-week open-label, single-arm, long-term extension study of safety and efficacy, representing up to 104 weeks of treatment in total. All women enrolled in the long-term extension study received once-daily oral Relugolix-CT. Analyses were performed based on the initial randomized treatment groups in pivotal studies: Relugolix-CT, delayed Relugolix-CT (relugolix 40mg alone for 12 weeks, then Relugolix-CT for 12 weeks), or placebo. Participants/materials, setting, methods Primary endpoints are proportion of dysmenorrhea and NMPP responders at Weeks 52 and 104 based on daily Numerical Rating Scale (NRS) scores (0=no pain, 10=worst pain imaginable) and analgesic use. Responders are women who achieved a predefined, clinically meaningful reduction from baseline in NRS score and no increase in analgesic use. Secondary efficacy endpoints include change in Endometriosis Health Profile-30 pain domain scores, use of opioids/analgesics. Safety endpoints include adverse events and BMD (percent change). Main results and the role of chance Of 1251 randomized patients in SPIRIT 1&2, 1044 (83.4%) completed the pivotal studies; 802 (76.8%) enrolled in the long-term extension, and 681 (84.9%) completed 52 weeks of treatment. Baseline demographics and clinical characteristics of the long-term extension population were consistent with those of the pivotal study population. The study remains ongoing at the time of writing. Efficacy and safety data with Relugolix-CT for up to Week 104, will be presented at the scientific session of the 2022 congress. Limitations, reasons for caution The study was conducted as an open-label study without a control group over the 80 weeks of the extension period. Wider implications of the findings Through 52 weeks of treatment, Relugolix-CT demonstrated sustained improvement of dysmenorrhea, NMPP, function, and reduced need for opiates in women with endometriosis-associated pain. No new safety concerns were identified, and treatment was associated with BMD loss <1%. Data from 104 weeks of treatment will be presented at the 2022 congress. Trial registration number NCT03654274

Comparando abordagens terapêuticas no manejo da endometriose a partir de ensaios clínicos randomizados

“…O tratamento da endometriose, inicialmente, deve ter como objetivo o alívio dos sintomas, em especial da dor, além da melhora da fertilidade sempre que possível (BECKER et al, 2024;KECKSTEIN et al, 2023;LI et al, 2022). No entanto, para além dos tratamentos já existentes e aprovados para endometriose, como o manejo hormonal com intenção de reduzir níveis de estradiol e, na falha ou impossibilidade deste, a utilização de cirurgias, novas formas de tratamento são necessárias dado que mesmo após ressecções cirúrgicas bem sucedidas do tecido endometrial ectópico, sintomas podem persistir ou recorrer (BECKER et al, 2024;LI et al, 2022).…”

“…Nesse âmbito, a nível de tratamento farmacológico, é que se encontram os agonistas do hormônio liberador de gonadotrofina (GnRH). O seu uso se apoia na evidência de que, com o seu uso, há controle da síntese e secreção dos hormônios luteinizante (LH) e folículo estimulante (FSH) pela hipófise, induzindo um estado hipoestrogênico nas mulheres, fator crucial para a redução não só do crescimento do endométrio como também da inflamação e dor localizadas (BECKER et al, 2024;LI et al, 2022).…”

“…Contudo, por induzir um estado hipoestrogênico, tanto agonistas quanto antagonistas do GnRH conferem risco de diminuição da densidade mineral óssea (DMO) em mulheres que fazem o seu uso. Este fato em específico é limitador no tempo de uso do relugolix, administrado via oral em cápsulas de 200 mg, mas que apresenta tempo máximo de uso fixado em 6 meses(BECKER et al, 2024).Além das intervenções farmacológicas, recente estudo investigou o uso do HybridAPC, um sistema que combina injeção de água sem agulha e plasma de argônio, no tratamento da endometriose peritoneal. Entre os fatores que embasam uma abordagem cirúrgica em casos de endometriose peritoneal estão a proximidade com estruturas anatômicas críticas como ureteres, bexiga e intestinos, bem como a ocorrência de crescimento de uma nova lesão mais profundamente em relação àquela que foi retirada inicialmente(KECKSTEIN et al, 2023).…”

“…opção adicional no tratamento da endometriose a longo prazo(BECKER et al, 2024).Brazilian Journal of Health Review, Curitiba, v. 7, n. 2, p. 01-13, mar./apr., 2024…”

A Randomized Open-Label Study of Relugolix Alone or Relugolix Combination Therapy in Premenopausal Women

“…Additionally, no meaningful differences in mean percent change from baseline to week 24 in BMD at the lumbar spine (L1–L4) were observed between the relugolix plus E2/NETA and placebo groups, and no deleterious effects on the endometrium were observed in the active treatment group in any of the studies [ 9 , 10 ]. These effects were generally maintained for up to 2 years in extension studies for both programs [ 27 – 29 ], indicating the potential for long-term use of relugolix combination therapy.…”