1. Relugolix combination therapy significantly reduced endometriosis-associated dysmenorrhea and non-menstrual pelvic pain compared to placebo.
2. Adverse events were similar between placebo and treatment, most common being headache, nasopharyngitis and hot flashes.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Limited options currently exist for treatment of endometriosis pain. Relugolix is an oral gonadotropin-releasing hormone receptor (GnRH) antagonist that may decrease pain in combination with estradiol and a progestin. These two duplicate phase 3 trials evaluated relugolix combination therapy for endometriosis pain. Eligible participants were randomized 1:1:1 to either placebo, relugolix combination therapy or delayed relugolix combination therapy for 24 weeks. Compared to placebo, relugolix combination therapy significantly reduced dysmenorrhea and non-menstrual pelvic pain after 24 weeks. Adverse events were similar between the placebo and treatment groups, with the most common being headache, nasopharyngitis and hot flashes. Reduction in bone mineral density and hot flashes were significantly more frequent in the delayed relugolix combination therapy compared to the relugolix combination therapy group. Limitations of this study include treatment duration limited to 6 months, particularly with the need to clinically monitor adverse outcomes such as reduced bone mineral density. Nevertheless, this study provides a promising option for the treatment of endometriosis-related pain.
In-Depth [randomized controlled trial]: This study reports the results of two replicate randomized trials, SPIRIT 1 and SPIRIT 2. Eligibility criteria included premenopausal women aged 18-50 years with endometriosis with moderate-to-very severe pain rated on the Endometriosis Associated Pain Severity score and a dysmenorrhea Numerical Rating Scale (NRS) of 4.0 or higher. Exclusion criteria included low bone mineral density or any contraindication to hormonal therapy. 638 women were randomized 1:1:1 to either placebo (n=213), relugolix combination therapy (n=212) or delayed relugolix combination therapy (n=213) in SPIRIT 1 and 623 women were randomized in SPIRIT 2. Delayed combination therapy was relugolix 40 mg monotherapy for 12 weeks followed by relugolix combination therapy for 12 weeks for the purpose of measuring bone mineral density change. Treatment lasted 24 weeks in all groups. The primary endpoint was dysmenorrhea and non-menstrual pelvic pain on an NRS and analgesic usage. In SPIRIT 1, 158/212 (75%) of participants receiving relugolix combination met the dysmenorrhea responder criteria compared to 57/212 (27%) in the placebo group (treatment difference 47.6% [95% CI 39.3-56.0; p<0.0001). In SPIRIT 2, these numbers with similar (treatment difference 44.9% [36.2-53.5; p<0.0001). The most common adverse events were headache, nasopharyngitis, and hot flashes. Bone mineral density change in lumbar spine was –0.70% in placebo, 0.21% in combination therapy, and –2.0% in delayed combination group for SPIRIT 1. These were similar in SPIRIT 2.
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