Efficacy and safety of Elagolix in the treatment of endometriosis associated pain: a systematic review and network meta-analysis

Background: Endometriosis commonly presents with dysmenorrhea, non-menstrual


Introduction
Endometriosis is characterized by the presence of endometrial-like tissue outside the uterus. 1,2 Ectopic tissue deposits are mainly found on the pelvic peritoneum, ovaries, and rectovaginal septum. 2 The percentage of affected females of reproductive age among the general population has been estimated to be between 2-10%. [3][4][5] The range of symptoms caused by endometriosis includes pelvic-abdominal pain, heavy menstrual bleeding, non-menstrual pelvic pain, pain at ovulation, dyschezia and dysuria. 6 Patients may additionally suffer from chronic fatigue with deleterious effects on patients' quality of life. 1 The specifics of the pathophysiology of endometriosis are still a subject of controversy. 2 One explanation --"the estrogen threshold hypothesis" --on which current medical treatments for endometriosis have been based, has shown favorable results as an alternative to surgery in selected cases. 7 Currently available medical therapies include non-steroidal anti-inflammatory drugs (NSAIDs), progestin-only oral contraceptives, combined hormonal contraceptives (CHCs), the 52mg Levonorgestrel-releasing intrauterine system and injectable gonadotropinreleasing hormone (GnRH) agonists. 8 However, the side effect profiles of these therapies still represent a gap in finding a treatment that better balances the favorable side of estrogen suppression with its unfavorable associated side effects (e.g., bone density loss, vasomotor symptoms). [8][9][10][11] Complete estrogen suppression may not be required to control endometriosis associated pain. 7 Elagolix, a novel therapy for endometriosis, is a potential solution to the issue owing to its dosedependent estrogen suppressing properties. [12][13][14] Elagolix is an oral, shortacting GnRH antagonist which can potentially induce complete estrogen suppression when given at higher doses while also being capable of causing partial estrogen suppression at lower doses. 15,16 This dose-dependent property could be the key for providing treatment with a better safety profile, as compared to current therapies, while maintaining efficacy in relieving pain experienced by endometriosis patients. There are only two doses of Elagolix approved by the FDA: 150 mg once daily for up to 24 months and 200 mg twice daily for up to 6 months. 17 However, these standards do not apply worldwide, and some of the applicable studies addressed a wider range of dosages. We performed this systematic review and meta-analysis to establish the evidence from all published randomized, controlled trials (RCTs) addressing outcomes for Elagolix in the treatment of endometriosis associated pain as compared to other available treatment options.

Materials and Methods
We followed PRISMA statement guidelines during the preparation of this systematic review and meta-analysis. 18 Additionally, we performed all steps in strict accordance with the Cochrane handbook of systematic reviews of intervention. 19 Because the study was a systematic review, it was exempt from ethical approval.

Search strategy
We performed a comprehensive search in four electronic databases: PubMed, Scopus, Cochrane Library and International Scientific Indexing (ISI), using a combination of the following MeSH terms (Elagolix OR gonadotropinreleasing hormone antagonist OR GnRH antagonist OR antigonadotropin) AND (endometriosis) AND (pelvic pain), for articles published between January 2000 and February 2020.

Eligibility criteria
We included all studies satisfying the following criteria: • Population: women diagnosed with endometriosis and suffering from associated pain, • Intervention: Elagolix, • Comparator: any other medications or placebo, • Outcomes: The main outcome measures were analgesic use at 12 weeks, the rate of dysmenorrhea at 12 and 24 weeks, the rate of non-menstrual pelvic pain at 24 weeks, quality of life at 12 weeks and side effects at 24 weeks of treatment, • Study design: randomized controlled trials.
We excluded the following: • non-randomized trials

• in vitro and animal studies
• studies whose data were unreliable for extraction and analysis • studies in non-English languages • materials from conferences, books, review articles, posters, theses and editorials.

Study selection
The three authors of this article independently conducted database searches, retrieved the results and removed duplicated studies using EndNote X7.4 software. We additionally manually searched the reference citations of included studies for additional relevant records that were not identified by the search itself.

Data extraction and analysis
We independently extracted relevant data from included studies. Disagreements were resolved through discussion and consensus among the reviewers. The extracted data included the study design, population, risk of bias domains and study outcomes. We used the "gemtc" package in R software, Supplemental File 1, to conduct our Bayesian network metaanalysis.
We calculated mean difference (MD) and confidence intervals (95% CI) for continuous outcomes including analgesic use, dysmenorrhea, non-menstrual pelvic pain and quality of life. We used odds ratios (ORs) and confidence intervals (95% CI) for dichotomous outcomes such as side effects. We assessed heterogeneity between the results using I-square test values, where I 2 >50% was used as a measure of significant heterogeneity.

Quality of included studies and risk of bias assessment
Both planned and unintentional biases can affect research outcomes. To control for this factor, two of our authors used the Cochrane risk of bias assessment tool, provided in chapter 8.5 of the Cochrane handbook of systematic reviews of interventions 5.1.0. 20 (Supplemental File 1) Risk of bias assessment included the following domains: sequence generation (selection bias), allocation sequence concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias) and other potential sources of bias. The reviewers' judgment is categorized as 'Low risk,' 'High risk' or 'Unclear risk' of bias. Any discrepancies between the two reviewers were resolved through discussion.

Search results characteristics of included studies
The search process returned a total of 124 records. We removed duplicates using Endnote software. Of the remaining 90 records screened by title/abstract, ten records seemed to be eligible. After reading the full text of the ten studies, we excluded five studies which were ineligible according to the criteria. (Figure 1) Five RCTs were finally included in the meta-analysis. 12,[21][22][23][24] Characteristics of included studies A total of five RCTs 12,21-24 with a total of 1590 patients met our inclusion criteria and were evaluated in this analysis. All women included in the studies had laparoscopically confirmed endometriosis and moderate to severe endometriosis associated pain. Elagolix was used with different doses and for different durations of treatment in the included studies. Taylor et al., compared two different doses of Elagolix (150 mg once daily and 200 mg twice daily) versus placebo for three months. 12  Reports of the same RCT n=2

Different interventions n=1
Studies included n=5

Risk of bias assessment
Using the Cochrane tool as described above, 20 we found the included studies to be of high or moderate quality, having a low risk of bias as shown in Figures 2 and 3.

Outcomes Analgesic use at 12 weeks
Our results showed no significant difference between Elagolix as compared to placebo. In the study by

Analysis of heterogeneity
Efficacy outcomes showed moderate to high heterogeneity, which we resolved using a random-effects model. The side effects showed low heterogeneity.

Discussion
To the best of our knowledge, no previous systematic reviews that investigate the efficacy and safety of Elagolix in the treatment of endometriosis-associated pain have been published. We conducted this network meta-analysis to provide evidence of the performance of Elagolix relative to these factors and in comparison with placebo and with other common treatment modalities, including LA.
Regarding efficacy, the network metaanalysis showed that both Elagolix 250 mg and LA reduced dysmenorrhea significantly when compared to placebo. However, LA was superior to Elagolix in the reduction of analgesic use and increasing quality of life after 12 weeks of treatment. Our results are consistent with another meta-analysis, which proved that LA is better in reduction of dysmenorrhea than Gestrinone in cases of endometriosis. 25  There are multiple choices for treating endometriosis-associated pain and dysmenorrhea. According to ESHRE guidelines, first-line hormonal therapies include combined-hormonal contraceptives (CHCs) or the 52mg Levonorgestrel-releasing intrauterine system. 1 Dienogest is a progestogenonly hormone preparation previously used in some trials for the treatment of endometriosis associated pain through suppression of estradiol production for the prevention of endometrial growth. 26,27 Elagolix, as a GnRH antagonist, is effective in reducing nonmenstrual pelvic pain and dysmenorrhea based on results of clinical trials only. 28 No RCT has been conducted to compare Elagolix and dienogest for treatment of endometriosis-associated pain.
Regarding side effects, Elagolix at all its dosages, as well as DMPA, did not differ from placebo in causing back pain. However, Elagolix 250 mg is the most likely drug to produce back pain after 24 weeks of treatment according to treatment ranking when compared to placebo, DMPA, and Elagolixitself in doses at 75, 150 and 200 mg. Those findings may suggest that Elagolix, as GnRH antagonist, does not affect bone density, but more research and investigations are needed to confirm this theory. Neither Elagolix nor DMPA differed from placebo in causing depression. Elagolix 200 and 250 mg showed a significant difference in causing headache.
Because this network meta-analysis depended on combined evidence from direct and indirect comparisons, it was able to provide evidence about the different doses of Elagolix. These results depended on the high-quality of RCTs according to the Cochrane assessment tool for risk of bias. We used rank order for relative efficacy to conclude that Elagolix 200mg is an effective choice in the reduction of dysmenorrhea and non-menstrual pelvic pain after 24 weeks with minimal side effects.
The results of this study are limited by the small number of studies that were evaluated and by the fact that they depended on a short duration to followup. The presence of indirect comparison gave us a small number of patients in each study arm. More and larger studies are needed to this point to provide strong evidence for the safety of Elagolix for long-term use.

Conclusion
This systematic review and metaanalysis suggests that Elagolix 200 mg could be a very effective choice to reduce dysmenorrhea and nonmenstrual pelvic pain with fewer side effects after 24 weeks of treatment in patients with endometriosis.