Efficacy and Safety of Elagolix Versus Dienogest for Treatment of Moderate-to-Severe Endometriosis Pain: A Phase III, Multicentric, Double-Blind, Active-Controlled, Non-Inferiority Study

Objective To compare the efficacy, safety and tolerability of elagolix with dienogest in women with moderate-to-severe endometriosis-associated pain. Design A multicentre, double-blind, double-dummy, randomised, parallel-group, active-controlled, non-inferiority phase III study. Setting Nineteen clinical centres across India. Study Population Women (18–49 years) diagnosed with endometriosis and experiencing moderate-to-severe pain.

Participants were randomised (1:1) to receive oral elagolix (150 mg once daily) or dienogest (2 mg once daily) for 24 weeks. Outcome Measures The primary outcome was change in endometriosis-related pain (Numeric Rating Scale [NRS]) from baseline to Day 85. Secondary outcomes included changes in NRS (Day 169), dysmenorrhoea, non-menstrual pelvic pain (NMPP) scores (Days 85 and 169), rescue medication use, patient global impression of change (PGIC), adverse events and bone mineral density.

Of 340 patients screened, 230 were randomised (115 per group). At Day 85, both arms showed similar reductions in NRS pain scores with a treatment difference of 0.04 (95% CI: −0.3, 0.37) [p = 0.9747] demonstrating non-inferiority as upper 95% CI was below pre-specified margin of 1.5. At Day 169, both arms showed comparable improvements in overall pain, dysmenorrhoea and NMPP from baseline (p = 0.9372, p = 0.8884, and p = 0.9616, respectively). Rescue medication use and PGIC were comparable between treatment arms. Adverse event incidence was similar (elagolix: 14.8%; dienogest: 19.1%), with no serious TEAEs or discontinuations. No significant bone mineral density changes were observed.

Elagolix demonstrated non-inferiority to dienogest with an acceptable safety and tolerability profile, supporting its use in managing endometriosis-associated pain. Trial Registration ClinicalTrials.gov identifier: CTRI/2023/01/049292 1 Introduction Endometriosis affects approximately 190 million women worldwide, corresponding to about 10% of women of reproductive age, and is marked by ectopic endometrium-like tissue leading to chronic pelvic pain, dysmenorrhoea and dyspareunia [1, 2]. The global burden of infertility due to endometriosis in 2021 showed a downward trend, with a notably higher burden in low SDI regions and the highest risk observed in the 25–29 age group [3]. The pathophysiology involves retrograde menstruation, stem cell activity, hormonal imbalance and immune dysregulation, with heightened oestrogen sensitivity and progesterone resistance sustaining inflammation and pain [4-9]. These factors limit the effectiveness of standard hormonal therapies and contribute to symptom persistence and recurrence [10, 11]. The European Society of Human Reproduction and Embryology (ESHRE) recommends a stepwise approach to managing endometriosis-associated pain, starting with NSAIDs and hormonal therapies, including combined oral contraceptives, progestins, GnRH analogues and aromatase inhibitors [12]. The Federation of Obstetric and Gynaecological Societies of India (FOGSI) recommends dienogest as the first-line hormonal treatment [13]. While dienogest is effective and generally well tolerated, its efficacy may be reduced in women with progesterone resistance and it is associated with side effects such as breakthrough bleeding and weight gain [14-16]. GnRH agonists like leuprolide provide effective oestrogen suppression but cause hypoestrogenic side effects, including bone mineral density (BMD) loss [17]. Elagolix, a short-acting, oral GnRH antagonist, provides dose-dependent oestrogen suppression with fewer long-term effects and improved reversibility [18-20]. Despite their use in clinical practice, no large-scale, prospective head-to-head comparison of elagolix and dienogest has been conducted. Hence, a large-scale, phase III, double-blind, active-controlled, non-inferiority study was planned to evaluate and compare efficacy, safety and tolerability of elagolix 150 mg and dienogest 2 mg in women with moderate-to-severe endometriosis-related pain. This study aimed to address a critical unmet need in long-term, patient-centred care [21-24]. Dienogest was selected as the comparator based on its established clinical role and recommendation by the FOGSI as a first-line therapy for endometriosis [13]. The NRS, a validated and widely used tool in endometriosis trials, was employed for pain assessment due to its simplicity, responsiveness and suitability for daily use [25]. Safety monitoring included adverse event reporting and BMD evaluation using DEXA scans to address potential long-term effects of hormonal treatments [26]. 2 Methods The study was conducted after seeking approval from the regulatory agency and ethics committees across all study sites geographically distributed across India. All patients enrolled in the study were of Indian descent. The trial was prospectively registered with the Clinical Trials Registry of India (Clinical Trial Registry, India: CTRI/2023/01/049292) on 30 January 2023, and the first participant was enrolled on 02 February 2023. 2.1 Trial Design Multicentre, double-blind, double-dummy, randomised, parallel-group, active-controlled, non-inferiority phase III clinical trial. 2.2 Interventions Participants were randomised to receive either elagolix 150 mg once daily (Egolix 150, manufactured by Sun Pharma) or dienogest 2 mg once daily as the comparator. 2.3 Participants 2.3.1 Inclusion Criteria Eligible participants for the study included premenopausal women aged 18–49 years diagnosed with endometriosis through surgery (laparoscopy or laparotomy) or ultrasound within the past 7 years. They were required to have experienced moderate-to-severe endometriosis-associated pain, with dysmenorrhea ≥ 2 and non-menstrual pelvic pain (NMPP) ≥ 2. A numeric rating scale (NRS) score ≥ 4 was required at both screening and randomisation visits. Participants should have experienced two regular menstrual cycles (28 ± 5 days) immediately prior to screening. 2.3.2 Exclusion Criteria The exclusion criteria were the presence of dyspareunia, a history of non-response to GnRH therapies or similar treatments, and a history of osteoporosis or low BMD. Participants with conditions affecting bone health, such as hyperparathyroidism or anorexia, or those with chronic pelvic pain unrelated to endometriosis, were also excluded. Additionally, individuals who had undergone recent major surgeries, including hysterectomy, gastrointestinal surgery, or endometriosis surgery, as well as those with significant gynaecologic conditions like large ovarian cysts or fibroids, were excluded. The comprehensive inclusion and exclusion criteria are provided in the Supporting Information (Supporting Information 1). 2.4 Randomisation, Blinding and Masking Eligible patients were randomised using site-wise block randomisation (block size 4) via Interactive Web Response System (IWRS) to ensure 1:1 allocation across the 15 sites. On day 1 visit, patients were randomised in a 1:1 ratio to the Test arm [Egolix 150 mg (elagolix sodium; Sun Pharma)] or Comparator arm (dienogest 2 mg OD). Double-dummy procedures ensured blinding by matching placebo tablets across treatment arms despite differences in medication forms. Emergency unblinding was outlined in the protocol for managing serious adverse events. Approved rescue medication consumption, Naproxen (max. daily dose 1250 mg for consecutive 5 days) was tracked with the help of patient diary entries and confirmed via pill count of returned blister packs of rescue medication. Rescue medications were not allowed within 12 h of study visits. All patients enrolled in the study was advised to use approved effective contraception methods for the duration of the study period. Furthermore, urine pregnancy test was performed at each study visit to ensure all participants were non-pregnant. Treatment compliance was monitored based on patient diary entries and pill counts. 2.5 Outcomes 2.5.1 Primary Outcome Measure The primary outcome measure was the mean change in the NRS score from baseline to Day 85. The NRS is an 11-point scale used to assess the severity of endometriosis-associated pain. The assessment of pain scores was based on daily diary entries by patients throughout the study [21]. 2.5.2 Secondary and Safety Outcome Measures Secondary and safety outcome measures included mean change from baseline in dysmenorrhoea and NMPP scores to Day 85 and 169, and in the NRS score at Day 169. Based on the daily diary entries, dysmenorrhoea, NMPP scores and the use of rescue medication were assessed. Patient global impression of change (PGIC) was recorded on Days 85 and 169 to capture patients' perceptions of improvement. BMD was measured at baseline and on Day 169, using a dual-energy x-ray absorptiometry (DEXA) scan. Additionally, TEAEs were documented and classified according to MedDRA preferred terms across the study period to evaluate safety outcomes [22]. 2.5.3 Sample Size Calculation The sample size was calculated to evaluate non-inferiority for NRS score change from baseline to Day 85, assuming 80% power and a 2.5% one-sided α level and setting the pre-specified non-inferiority (NI) margin at 1.5. The minimal clinically important change (MCID) in NRS score for chronic pain is 2. The pre-specified NI margin was set at 1.5, which is below the MCID [27]. Another non-inferiority trial conducted in Australia in patients with chronic pelvic pain, set the NI margin at 1.5 [28]. After accounting for a 15% dropout rate, a total of 230 patients (115 per arm) were required. 2.6 Statistical Analysis Full details of the statistical methods were prepared in the Statistical Analysis Plan (SAP). All statistical analyses were conducted by the Clinical Data Reporting and Biostatistics team following study completion. The database was unblinded on the same date. Analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina, USA). Baseline demographics, such as age and height, were summarised using descriptive statistics. Analysis populations included intent-to-treat (ITT) (all randomised patients), modified ITT (mITT) (patients with at least one post-baseline evaluation), per-protocol (PP) (patients completing treatment per protocol) and safety (patients receiving at least one dose). Safety analyses used the safety population, while primary efficacy analysis focused on the PP population, with ITT and mITT populations providing supportive evidence. Statistical significance was set at p < 0.05. Missing data was addressed via multiple imputation for MAR/MCAR data and LOCF for MNAR data. Sensitivity analysis for the primary endpoint (without imputation of missing data) was performed. Sensitivity analyses were performed using a mixed model for repeated measures (MMRM), a parametric approach assuming normality, to confirm the robustness and consistency of the results. AEs were coded using MedDRA Version 26.0 (Maintenance and Support Services Organisation, Reston, Virginia, USA) or higher, and medications were coded with WHO-DDE, version March 2023 (Uppsala Monitoring Centre, Uppsala, Sweden) or higher. 2.7 Efficacy Analyses Efficacy analyses for continuous data (like NRS, DYS, NMPP, rescue medication use and PGIC) were primarily conducted using rank analysis of covariance (ANCOVA) to account for the non-parametric distribution of pain scores, and mixed model for repeated measures (MMRM) was used for supportive analysis to confirm the robustness of the trial. Change from baseline was used for all efficacy endpoints. For the primary endpoint, non-inferiority was established if the upper bound of the two-sided 95% confidence interval (CI) for the between-group treatment difference was below the pre-specified NI margin of 1.5. The proportion of patients using rescue medication in each treatment arm was compared using a chi-square test. 2.7.1 Safety Analysis TEAEs were summarised using MedDRA terms. BMD changes were assessed for statistical significance using a two-sample t-test for comparison between groups and a paired t-test for comparison within groups (based on normality of the data). 3 Results 3.1 Participant Flow In this study, 340 patients were initially screened, of which 230 were randomised into two arms: 115 patients each in the elagolix and dienogest arms. Out of 110 excluded patients, one patient was excluded due to non-response to prior GnRH agonists or antagonists or other hormonal therapies. A total of 114 (99.1%) and 113 (98.3%) patients completed the study and were compliant with the medication in the elagolix and dienogest arms, respectively. Population distributions (ITT, mITT and PP), discontinuations and protocol deviations are detailed in Figure 1. 3.2 Demographic and Baseline Characteristics There was no significant difference in the demographic characteristics between the elagolix & dienogest arms (Table 1). | Characteristics | Test: Elagolix tablet (N = 115) mean (SD) | Comparator: Dienogest tablet (N = 115) mean (SD) | |---|---|---| | Age (years) | 31.59 (6.77) | 31.31 (7.19) | | Height (cm) | 153.9 (5.11) | 154.5 (6.56) | | Weight (kg) | 61.63 (11.12) | 60.56 (11.38) | | NRS score | 6.92 (1.63) | 7.06 (1.58) | | DYS score | 2.49 (0.50) | 2.59 (0.49) | | NMPP score | 2.37 (0.48) | 2.32 (0.47) | | Z score (femoral neck) | 0.09 (0.62) | 0.10 (0.56) | | Z score (lumbar spine) | −0.02 (0.76) | 0.10 (0.75) | | Z score (total hip) | 0.30 (0.71) | 0.31 (0.71) | | T score (femoral neck) | −0.07 (0.64) | −0.07 (0.59) | | T score (lumbar spine) | −0.05 (0.77) | 0.05 (0.78) | | T score (total hip) | 0.20 (0.67) | 0.20 (0.69) | | Prior use of GnRH agonist/antagonist [n (%)] | 3 (2.6%) | 2 (1.7%) | - Note: p value by two-sample t-test. - Abbreviations: n, number of patients with observed findings; N, total number of patients enrolled; SD, standard deviation. 3.3 Primary Endpoint By Day 85, the mean change in the NRS score was −2.43 ± 1.28 in the elagolix arm and −2.47 ± 1.26 in the dienogest arm, with a between-group p-value of 0.9747 (Figure 2). The mean difference between the two arms was 0.04 (95% CI: −0.3, 0.37). Elagolix treatment was non-inferior to Dienogest, with the upper 95% CI below the pre-defined non-inferiority margin of 1.5. Sensitivity analyses (without imputation of missing data) showed similar and consistent results across the PP, ITT and mITT populations (Table 2). | Parameters | Elagolix tablet (Test) (N = 113) | Dienogest tablet (comparator) (N = 112) | Test versus Comparator | | |---|---|---|---|---| | Treatment difference (95% CI) | p | ||| | Change from baseline in NRS score (Mean ± SD) | |||| | Day 85 | −2.43 ± 1.28 | −2.47 ± 1.26 | 0.04 (−0.3, 0.37) | 0.9747 | | Day 169 | −4.33 ± 1.46 | −4.37 ± 1.28 | 0.04 (−0.32, 0.4) | 0.9372 | | Change from baseline in DYS score (Mean ± SD) | |||| | Day 85 | −1.09 ± 0.76 | −1.08 ± 0.78 | −0.01 (−0.22, 0.19) | 0.8422 | | Day 169 | −1.56 ± 0.67 | −1.59 ± 0.64 | 0.03 (−0.14, 0.2) | 0.8884 | | Change from baseline in NMPP score (Mean ± SD) | |||| | Day 85 | −0.95 ± 0.63 | −1.03 ± 0.62 | 0.08 (−0.08, 0.25) | 0.3926 | | Day 169 | −1.53 ± 0.64 | −1.59 ± 0.71 | 0.06 (−0.12, 0.23) | 0.9616 | | Proportion of patients with use of rescue medication [n (%)] | |||| | Day 169 | 20 (17.7%) | 19 (17.0%) | 0.73 (−9.16, 10.63) | > 0.9999 | | Overall responders on PGIC scale [n (%)] | |||| | Day 85 | 71 (62.8%) | 80 (71.4%) | −8.6 (−20.8;3.6) | 0.1700 | | Day 169 | 105 (92.9%) | 106 (94.6%) | −1.7 (−8; 4.6) | 0.5928 | - Abbreviations: CI, confidence interval; DYS, dysmenorrhoea; NMPP, non-menstrual pelvic pain; NRS, numeric rating scale; PGIC, patients global impression of change; PP, per protocol; SD, standard deviation. 3.4 Secondary Endpoint The study met its secondary endpoints, with both treatment arms showing significant pain reductions. From baseline to Day 169, the mean reduction in the NRS score was −4.33 ± 1.46 (p < 0.0001) (elagolix arm) and −4.37 ± 1.28 (dienogest arm) (p < 0.0001) (Tables 2 and S1). Dysmenorrhoea scores reduced by −1.09 ± 0.76 (elagolix) and −1.08 ± 0.78 (dienogest) on Day 85 and reached −1.56 ± 0.67 (elagolix) and −1.59 ± 0.64 (dienogest) on Day 169 (p < 0.0001 for both) (Figure 3) (Table 2, Table S2). Similarly, NMPP scores reduced by −0.95 ± 0.63 (elagolix) and −1.03 ± 0.62 (dienogest) on Day 85, with further reductions observed by Day 169 to −1.53 ± 0.64 (elagolix) and −1.59 ± 0.71 (dienogest) (p 0.9999; proportion difference: 0.73; 95% CI: −9.16, 10.63) (Tables 2 and S4). The distribution of PGIC responses was comparable between the groups. On Day 85, overall responders (combined ‘much improved’ and ‘very much improved’) were reported as 62.8% in elagolix compared to 71.4% in the dienogest arm (p = 0.1700). By Day 169, overall responders were 92.9% in the elagolix arm and 94.6% in the dienogest arm (p = 0.5928) (Tables 2 and S5). 3.5 Safety Endpoints In the safety population, the incidence of TEAEs was similar between the two arms, with 17 (14.8%) in the elagolix arm and 22 (19.1%) participants in the dienogest arm. The number of drug-related TEAEs was also comparable: 2 (1.7%) and 3 (2.6%) participants in the elagolix and dienogest arm, respectively. Neither arm reported serious TEAEs; no TEAEs led to study drug interruption, discontinuation, or dose reduction. Among 64 TEAEs, 57 were of mild intensity and 7 of moderate intensity; all were reported as resolved or recovered (Table 3). | Elagolix 150 mg tablet (Test N = 115) | Dienogest 2 mg tablet (Comparator N = 115) | Overall (N = 230) | |||| |---|---|---|---|---|---|---| | n (%) | Events | n (%) | Events | n (%) | Events | | | Any AEs | 17 (14.8%) | 26 | 22 (19.1%) | 38 | 39 (17.0%) | 64 | | Any SAEs | 0 | 0 | 0 | 0 | 0 | 0 | | Any TEAEs | 17 (14.8%) | 26 | 22 (19.1%) | 38 | 39 (17.0%) | 64 | | Drug-related TEAEs | 2 (1.7%) | 2 | 3 (2.6%) | 3 | 5 (2.2%) | 5 | | Serious TEAEs | 0 | 0 | 0 | 0 | 0 | 0 | | TEAEs leading to study drug interruption | 0 | 0 | 0 | 0 | 0 | 0 | | TEAEs leading to study drug discontinuation | 0 | 0 | 0 | 0 | 0 | 0 | | TEAEs leading to dose reduction | 0 | 0 | 0 | 0 | 0 | 0 | | TEAEs leading to death | 0 | 0 | 0 | 0 | 0 | 0 | - Abbreviations: AE, adverse event; n, number of patients; TEAE, treatment-emergent adverse events. 3.6 System Organ Class Analysis Fewer gastrointestinal and general disorders were reported with elagolix (3.5% and 6.1%, respectively) compared to dienogest (6.1% and 13.0%), with lower incidences of nausea, vomiting and pyrexia, the most common TEAE, occurring in 5.2% vs. 9.6% of participants, respectively. One participant (0.9%) in the elagolix arm showed elevated LDL levels. Mild transient elevations in hepatic transaminases were observed (increase in ALT and AST each reported in one participant (0.9%)) (Table S6). No clinically relevant changes in BMD were observed in both the treatment arms. The BMD changes were comparable in both treatment arms at the end of the treatment (Figure S1). 4 Discussion This study demonstrated that elagolix 150 mg once daily was non-inferior to dienogest 2 mg in reducing moderate-to-severe endometriosis-associated pain from baseline to Day 85 and Day 169. Both treatments produced comparable improvements in overall pain, dysmenorrhoea and non-menstrual pelvic pain, with similar use of rescue medication and patient-reported global improvement from baseline to Day 169. The safety profiles were favourable, with a low incidence of treatment-emergent adverse events, no serious adverse events or treatment discontinuations, and no clinically meaningful changes in bone mineral density, supporting the tolerability of elagolix as a long-term therapeutic option. 4.1 Unmet Needs in the Medical Management of Endometriosis Despite multiple available options, the management of endometriosis-related pain remains suboptimal. Conventional therapies, including NSAIDs, hormonal agents such as GnRH agonists, and surgical approaches like ablation or excision, offer varying degrees of symptom relief but are limited by their side effect profiles, incomplete efficacy and high recurrence rates [16, 24]. GnRH agonists like leuprolide are effective in suppressing oestrogen production; however, their use is often curtailed by adverse effects, notably hypoestrogenic symptoms and bone mineral density loss [29]. Progestins such as dienogest are generally better tolerated, yet are not without limitations, including irregular bleeding, mood changes and weight gain [30]. Furthermore, the symptomatic relief achieved with these agents may be transient, with recurrence rates ranging from 6% to 67% depending on disease severity and treatment duration [16, 31]. These challenges underscore a critical unmet need for long-term, well-tolerated and efficacious medical therapies that not only alleviate pain but also improve quality of life and reduce the likelihood of recurrence [32]. Newer agents like oral GnRH antagonists, which offer dose-dependent and reversible suppression of oestrogen, represent a promising advancement in the personalised, sustained management of endometriosis. The aetiology likely involves retrograde menstruation, celomic metaplasia, stem cell involvement and potential genetic, hormonal, immune and environmental factors [1, 4]. It is suggested that heightened oestrogen sensitivity in ectopic endometrial tissue promotes lesion growth and inflammation, exacerbating symptoms like pelvic pain [4]. Overexpression of oestrogen receptor beta (ERβ) and suppression of oestrogen receptor alpha (ERα) in endometriotic stromal cells downregulate progesterone receptor B (PR-B), promoting oestrogen dominance, progesterone resistance and E2-driven inflammation and proliferation [6]. Progesterone resistance, often due to altered progesterone receptors A/B (PR-A/PR-B) ratios, impairs progesterone's anti-inflammatory effects, contributing to persistent inflammation. High expression of PR-A and low expression of PR-B are correlated with inflammation in endometrioma cases [7, 8]. Progesterone resistance poses a significant challenge, with the prevalence being 33%–67% [9, 10]. Endometriosis has severe effects on quality of life (QoL) worldwide [11]. The medical management of endometriosis primarily focuses on pain relief and suppression of hormonally active endometriotic tissue [12]. 4.2 Interpretation of Findings Previous randomised trials, such as EM-I and EM-II, have established that elagolix 150 mg significantly reduces endometriosis-associated pain, with rapid onset and sustained symptom control over 6 months [22]. These studies reported improvements in dysmenorrhoea and NMPP as early as 3 months. In alignment, the current study found that elagolix produced significant reductions in pain scores on the NRS, sustained throughout the 6-month period. The observed pain reduction was even greater than previously reported, which may be attributable to the higher baseline NRS scores in our population, indicating a more severe initial pain burden [31]. Phase 3 extension trials (EM-III and EM-IV) demonstrated that elagolix maintains efficacy in reducing dysmenorrhoea and NMPP over 12 months, with responder rates exceeding 50% [32, 33]. Consistent with these findings, our study showed sustained pain relief with both elagolix and dienogest across dysmenorrhoea and NMPP domains, supporting their long-term therapeutic value. Rescue analgesic use and PGIC scores in our study further corroborated symptom improvement and patient satisfaction over time. Elagolix has previously shown a favourable tolerability profile with relatively low rates of adverse events (AEs) and fewer gastrointestinal complaints than hormonal comparators [22]. Our study supports this, with elagolix showing a slightly lower AE incidence than dienogest and no serious treatment-emergent events. Additionally, BMD remained stable with elagolix over 6 months, consistent with EM-I and EM-II findings, where BMD loss was minimal at 150 mg daily [34]. Longer-term safety data on dienogest have raised concerns regarding skeletal health. Studies report BMD loss of up to 4.4% over 3 years, with nearly 80% of patients experiencing a decline [35]. While dienogest is typically well-tolerated, prolonged use may carry skeletal risks. By contrast, elagolix 150 mg resulted in negligible BMD changes in earlier studies and in our trial, supporting its potential as a safer option for extended use. Comparative studies have also shown elagolix provides similar efficacy to depot medroxyprogesterone acetate (DMPA-SC), with minimal BMD impact over 24 weeks [36]. Elagolix's distinct mechanism as a GnRH receptor antagonist offers an advantage over both progestins and GnRH agonists by avoiding the initial symptom flare typically seen with agonists like leuprolide [37]. This direct action may contribute to the more rapid symptom relief observed in both prior studies and our trial. 4.3 Strengths and Limitations of the Study 4.3.1 Strengths This study represents, to the best of our knowledge, the first in the world head-on, double-blind and double-dummy comparative trial of elagolix and dienogest, providing valuable efficacy and safety data specifically for the Indian population. It also marks the first study evaluating any oral GnRH antagonist therapy in the Indian population. Multiple endpoints were assessed, including the reduction in pain measured using the NRS, as well as improvements in dysmenorrhoea and NMPP scores, providing a thorough assessment of treatment efficacy. Additionally, the thorough assessment of TEAEs ensures that both the efficacy and safety profiles are well documented, making the findings highly relevant and impactful for clinical practice. 4.3.2 Limitations The study assessed outcomes over a 6-month treatment period. As progestin resistance typically emerges after 3–6 months, its assessment was not evaluated [37, 38]. Accordingly, the long-term efficacy and safety of elagolix and dienogest were not evaluated and compared. Moreover, the reliance on patient-reported outcomes for pain assessment introduces potential subjectivity, as individual perceptions of pain may vary. Furthermore, the trial did not include an evaluation of a higher dose of elagolix (Elagolix 200 mg) in endometriosis patients with dyspareunia, limiting the scope of the treatment effects and external validity. The strict selection criteria of a phase III study limit the generalisability of the results to the general population. Further, there were no patients diagnosed via histopathology enrolled in the study, nor were the patients stratified based on the grade of endometriosis. Other limitations include false positive rates of endometriosis diagnosis due to potential misclassification due to ultrasound (~8%) or unconfirmed endometriosis with histopathology (~60%) [39, 40]. High symptomatic overlap with IBD (up to 71%) may confound endometriosis pain and targeted patient screening mitigated this factor [41]. 5 Conclusion 5.1 Summary of Key Findings Current evidence and findings from the study confirm that elagolix 150 mg daily is a viable, effective and well-tolerated therapy for moderate-to-severe endometriosis-associated pain. Its comparable efficacy to dienogest, with potentially fewer long-term skeletal risks and better tolerability, supports its utility as a frontline option in clinical practice, especially in populations where treatment adherence and quality of life are key considerations. 5.2 Future Research Directions The current study on the use of elagolix in endometriosis pain management is promising and lends scope for long-term studies in real-world settings. A comparative study with the higher dose of elagolix (200 mg) in endometriosis patients with dyspareunia is required. Comparative research with treatments like dienogest, danazol, or levonorgestrel will help identify optimal treatment pathways. Additionally, investigating patient-reported outcomes and QoL will shed light on elagolix's real-world impact. Author Contributions Piyush Patel, Lalit Lakhwani, Suyog Mehta and Sadhana Joglekar contributed to the conception, design of the study and critically reviewed and approved the final manuscript. Sneha Bhoir, Jaldhara Patel, Tushar Palve, Mrinal Kanti Dash, Sweety Saigal, Gourisankar Kamilya, Shalini Srivastava, Kartikbhai Savalia, Tanusree Gupta, Deepa Choudhary, Manohar Rangaswamy, Vidya V. Bhatt, Neena Gupta, Malathi Ponnuru and Parul Shah were involved in participant recruitment, site-level execution of the study and data acquisition. Ms. Apurva Shetty, Dr. Shruti Saha, Dr. Reshma Quadros, Dr. Dipak Patil, Dr. Piyush Patel, Dr. Pravin Ghadge, Dr. Lalit Lakhwani and Dr. Suyog Mehta supported clinical data interpretation, statistical analysis, drafting of the manuscript and provided critical input during manuscript development. Dr. Sadhana Joglekar supervised the study's overall conduct, provided guidance on data interpretation and contributed to reviewing the manuscript for intellectual and scientific accuracy. All authors have read and approved the final version of the manuscript, agree to be accountable for all aspects of the work and meet the ICMJE authorship criteria.

We thank the participants who volunteered for the study and the study teams at all participating sites. We thank the clinical operations team and clinical data management team of Sun Pharma Laboratories Limited, Mumbai. We thank Dr. Gaurav Puppalwar of Sun Pharma Laboratories Limited, Mumbai, India, for reviewing the manuscript. We thank VeritasQ Research and Analytics Pvt. Ltd. for assistance in writing this manuscript. Funding This study was funded by Sun Pharmaceutical Industries Limited, which provided. Egolix, managed clinical study operations and supported data analysis/manuscript preparation. Authors from Sun Pharma declare employment and do not hold stock ownership. Disclosure Oral presentation of full study results was done at Royal College of Obstetricians and Gynaecologists (RCOG) World Congress 2024, Muscat, Oman, on 17th October 2024 and received 3rd prize as the highest-scoring abstract. In addition, subgroup and post hoc analyses were presented as e-posters in the same conference. Ethics Statement Details of Ethics Approval provided in Supporting Information. Conflicts of Interest Authors, Sneha Bohir, Jaldhara Patel, Tushar Palve, Mrinal Kanti Dash, Sweety Saigal, Gourisankar Kamilya, Shalini Srivastava, Kartikbhai Savalia, Tanusree Gupta, Deepa Choudhary, Manohar Rangaswamy, Vidya V. Bhatt, Neena Gupta, Malathi Ponnuru, Parul Shah, were the study investigators. They received a grant for conducting the study at their respective sites. Shruti Saha, Reshma Quadros, Sucheta Pandit, Dipak Patil, Pravin Ghadge and Suyog Mehta, are full-time employees of Sun Pharma Laboratories Ltd. Apurva Shetty, Piyush Patel and Lalit Lakhwani were full-time employees of Sun Pharma Laboratories Ltd. at the time of the study. Sadhna Joglekar was an employee at Sun Pharma during the conduct of this study. She is currently employed with Novartis. The views expressed in the article are the author's views and do not necessarily reflect the views or official position of Novartis. Data Availability Statement The data that support the findings of this study are available from the corresponding author upon reasonable request.