{"paper_id":"cc338cbf-9bda-49d1-a90c-e61a706c0d61","body_text":"Endometriosis is a chronic, debilitating, gynaecological condition affecting\napproximately 6–10% of women of reproductive age. 1 , 2  The disease is characterized by\nthe presence of endometrial tissue outside the uterine cavity where the implanted\ncells secrete prostaglandin E2 and multiple cytokines that elicit an inflammatory\nresponse. 2 , 3 \nThe most common clinical symptoms/sequelae of endometriosis are chronic pelvic pain\n(i.e. dysmenorrhoea, non-menstrual pelvic pain, dyspareunia) and\ninfertility. 2 , 3 \nHowever, endometriosis is also increasingly recognized as a systemic condition with\nmany non-pain-related manifestations that extend beyond the pelvis and peritoneum\ninto multiple organ systems. 4 , 5 \nThese systemic effects are characterized by altered inflammatory, immunologic and\nmetabolic functions that can produce non-pain-related symptoms such as fatigue,\nbowel dysfunction, weight loss, allergies and systemic inflammation. 4  As reviewed by Alderman and colleagues, 4  several comorbidities have been associated with endometriosis, including\ncardiovascular disease, allergy, autoimmune disease and cancers. Although the\nmechanism of these non-pelvic systemic manifestations is not well understood,\nincreased circulating inflammatory cytokines, growth factors, micro-RNAs and\nexcreted endometrial cells may be involved. 4  The pathogenesis of endometriosis is complex involving multiple processes and\nis currently an active area of research. 6 – 8  A complete understanding of the\npathophysiology of endometriosis may lead to the development of novel therapies for\nthis disabling condition.\nThe non-pelvic effects of endometriosis result in numerous non-pain outcomes that can\nimpact patients’ lives. Fatigue is a common symptom in patients with\nendometriosis, 9 – 13  and patients experience many\nadverse psychological, emotional, social, familial, sexual, educational and\nworkplace effects, all of which can result in decreased health-related\nquality-of-life (HRQoL). 14 – 19\nIn addition, endometriosis is associated with a substantial economic burden,\nincluding reduced workplace and household productivity. 14 , 20 – 22  Thus, it is important that\nendometriosis be considered more than just a disease of the pelvis and that a more\nholistic approach to disease management should be considered.\nEndometriosis-related pelvic pain can be treated with medical therapy or\nsurgery. 23 – 28  First-line medical treatments\ninclude non-steroidal anti-inflammatory drugs and hormonal contraceptives. 23 – 26  Over time, women may progress\nto second-line therapy, which includes progestogens and anti-progestogens,\ngonadotropin-releasing hormone receptor agonists and antagonists, and aromatase\ninhibitors. 23 – 26  Because of the complex nature\nof endometriosis, treatment is often individualized and based on the impact of the\ndisease and the effect of the treatment on HRQoL. Elagolix, an oral\ngonadotropin-releasing hormone receptor antagonist, was approved in July 2018 by the\nUnited States Food and Drug Administration (FDA) for management of moderate to\nsevere pain associated with endometriosis. This article reviews the benefits of this\nnew therapy on non-pain outcomes, including HRQoL, fatigue and productivity in women\nwith moderate to severe endometriosis.\nElagolix is a novel, non-peptide, orally active gonadotropin-releasing hormone\nreceptor antagonist that produces dose-dependent suppression of the\npituitary-ovarian axis. 16  The safety and efficacy of elagolix in the treatment of endometriosis\nhave been evaluated in four phase 2 trials, 16 , 29 – 31  two phase 3 trials and two\nphase 3 extension studies. 32 , 33  The initial phase 2 trials\nsuggested that elagolix was effective for endometriosis-related pain and\nassociated with an adequate safety profile. 16 , 29 – 31  Based on the positive\nresults obtained in the phase 2 studies, two phase 3 trials (Elaris\nEndometriosis I and II (EM-I and EM-II)) were conducted to further evaluate the\nefficacy and safety of elagolix in women with moderate to severe\nendometriosis-associated pain. 33\nEM-I ( N  = 872) and EM-II ( N  = 817) were of a\nvery similar design, evaluating the effects of two doses of elagolix (150 mg\nonce daily or 200 mg twice daily)  versus  placebo over 6 months. 33  The studies included premenopausal women aged 18 to 49 years with a\nsurgical diagnosis of endometriosis within the previous 10 years who were\nexperiencing moderate to severe endometriosis-related pain. 33  Baseline demographic and clinical characteristics of these patients are\nsummarized in  Table\n1 . 33  There were two primary efficacy endpoints in these studies: (1) the\nproportion of women who had clinical response to dysmenorrhoea, and (2) the\nproportion who had clinical response with respect to non-menstrual pelvic pain\nat 3 months, as assessed by a reduction in pain scores and decreased/stable use\nof rescue analgesic agents. 33  In both EM-I and EM-II, elagolix treatment was associated with\nsignificantly lower scores for dysmenorrhoea and non-menstrual pelvic pain\ncompared with placebo in each dosage group at 3 and 6 months. 33  In addition, elagolix (200 mg twice daily group) was also superior to\nplacebo with respect to the use of rescue analgesic use, dyspareunia score and\nrescue opioid use. The most common adverse events were hot flushes, headache and\nnausea, with 25–30%, 20–22% and 12–18% of patients in the 150 mg once daily\ngroup and 52–55%, 25–29% and 15–25% of patients in the 200 mg twice daily group\nexperiencing these symptoms, respectively. 32  The majority of hot flushes were mild to moderate with discontinuation\nrates for hot flushes ranging from <1% for the lower dose group to <3% for\nthe higher dose. 33  Positive efficacy results obtained in the pivotal trials led to the\napproval of elagolix for the management of moderate to severe pain associated\nwith endometriosis. 34\nDemographic and clinical characteristics of patients in EM-I and EM-II. 33\nBMI, body mass index; EM-I, Elaris Endometriosis I; EM-II, Elaris\nEndometriosis II; SD, standard deviation.\nOther includes Asian, multiracial, American Indian or Alaskan native,\nand native Hawaiian or other Pacific Islander.\nIn addition to the primary endpoints of dysmenorrhoea and non-menstrual pelvic\npain, several non-pain outcomes were evaluated in EM-I and EM-II, either as\nsecondary endpoints or in post hoc analyses. These include elagolix effects on\nHRQoL and fatigue as well as the economic impact of elagolix therapy,\nparticularly on workplace and household productivity. These effects are reviewed\nin detail in the following sections.\nHRQoL was assessed in the EM-I and EM-II trials using the self-administered\n30-item Endometriosis Health Profile (EHP-30) with assessments at 1, 3 and 6 months. 33  The EHP-30 is an endometriosis-specific instrument that assesses five\ncore domains: pain (11 questions), control and powerlessness (six\nquestions), emotional well-being (six questions), social support (four\nquestions) and self-image (three questions). The EHP-30 is the most\nextensively validated HRQoL instrument for women with endometriosis. 35  A modular questionnaire assessing sexual intercourse (five questions)\nwas also included, making a total of six domains assessing HRQoL. Responses\nto the EHP-30 and sexual intercourse questionnaires were coded as 0\n( never ), 1 ( rarely ), 2\n( sometimes ), 3 ( often ) and 4\n( always ), and were normalized to a scale of 0\n( best health ) to 100 ( worst health )\nfor each domain. Lower scores indicate better HRQoL. 33\nBaseline EHP-30 scores for patients in EM-I and EM-II are summarized in  Table 2 . 36  While all domains showed impairment, the control and powerlessness\nand sexual relationship domains showed the greatest impairment. Treatment\nwith elagolix in these studies was associated with dose-dependent\nimprovements in all six domains of the EHP-30 for the elagolix 150 mg once\ndaily and 200 mg twice daily doses  versus  placebo in both\nEM-I and EM-II ( Figure\n1 ) with significant differences from placebo evident as early as\n1 month. For elagolix 150 mg/day, significant differences from placebo were\nseen at 3 and 6 months in three of six domains in EM-I (pain, control and\npowerlessness, social support) and in four of six domains in EM-II (pain,\ncontrol and powerlessness, emotional well-being, social support).\nImprovements in the elagolix 200 mg twice daily group were significantly\ngreater than for placebo in all six EHP-30 domains at months 1, 3 and 6 in\nboth EM-I and EM-II with one exception (social support at month 1 in EM-II).\nFor all domains, improvements in the elagolix 200 mg twice daily group were\nprogressively greater at each assessment time point (i.e. 1, 3 and\n6 months). Furthermore, improvements in EHP-30 scores were greater for the\nelagolix 200 mg twice daily group than for the lower dose group at all time\npoints.\nMean baseline EHP-30 scores among patients with endometriosis in the\nEM-I and EM-II trials. 36\nEHP-30, 30-item Endometriosis Health Profile; EM-I, Elaris\nEndometriosis I; EM-II, Elaris Endometriosis II; SD, standard\ndeviation.\nMean change from baseline to month 6 in the EHP-30 scores in patients\nreceiving elagolix 150 mg once daily or 200 mg twice daily or\nplacebo in (a) EM-I and (b) EM-II. 33  Each domain had multiple questions. Each question was scored\nfrom 0 ( never ) to 4 ( always ) and\nnormalized to a scale of 0–100 for each domain. Lower scores\nindicate better quality of life. Statistical significance was based\non contrasts within a one-way ANCOVA with treatment as the main\neffect and baseline value as a covariate. The mean difference from\nplacebo is indicated for two-sided  p  value;\n p  < 0.05 (*),  p  < 0.01\n(**),  p  < 0.001 (***). Error bars respresent\nstandard error and month 0 refers to baseline.\nSource: From Taylor and colleagues, 33  Copyright © 2017 Massachusetts Medical Society. Reprinted\nwith permission from Massachusetts Medical Society. 33\nANCOVA, analysis of covariance; BID, twice daily; EHP-30, 30-item\nEndometriosis Health Profile; LS, least squares; QD, once daily.\nA post hoc analysis used pooled data from the EM-I and EM-II trials to apply\nresponder definitions for EHP-30 subscales in order to determine whether\nEHP-30 improvements were clinically meaningful. 37  Responders in the various domains of the EHP-30 were defined as\nfollows: a 35-point reduction in control and powerlessness, a 30-point\nreduction in pain and 30-point reductions in emotional well-being, social\nsupport, self-image and sexual intercourse. At month 6, patients receiving\nelagolix 200 mg twice daily were significantly more likely to meet the\nEHP-30 definition of response for all six domains compared with placebo with\nresponder rates of 65%  versus  24% for pain, 66%\n versus  28% for control and powerlessness, 62%\n versus  36% for emotional well-being, 59%\n versus  33% for social support, 53%\n versus  30% for self-image and 62%\n versus  38% for sexual intercourse, respectively, for\nthe elagolix and placebo groups ( p  < 0.0001 for all\ncomparisons). For patients receiving elagolix 150 mg/day, response rates\nwere somewhat lower than for the higher dose group, but these patients were\nsignificantly more likely than placebo-treated patients to meet the\ndefinition of responder for all domains except sexual intercourse.\nAnother post hoc analysis of the EM-I and EM-II trials evaluated the\nrelationship between endometriosis pain symptoms and improvements in HRQoL\nproduced by elagolix, as measured by the EHP-30. 38  Patients who were characterized as achieving a clinical response for\ndysmenorrhoea or non-menstrual pelvic pain were found to achieve\nimprovements in all domains of the EHP-30. Mean changes in EHP-30 domain\nscores were above the thresholds of clinical meaningfulness among patients\nwho were categorized as being either a dysmenorrhoea responder or a\nnon-menstrual pelvic pain responder at 3 months following treatment\ninitiation. Among dysmenorrhoea responders, mean decreases in EHP-30 domain\nscores ranged from 24 points (self-image) to 48 points (control and\npowerlessness) in EM-I and from 21 points (self-image) to 40 points (control\nand powerlessness) in EM-II. The proportions of dysmenorrhoea responders who\nmet the EHP-30 domain threshold for a clinically meaningful EHP-30 response\nranged from 53% (self-image) to 70% (control and powerlessness) in EM-I and\nfrom 48% (self-image) to 60% (pain) for patients in EM-II. Similar\nimprovements in EHP-30 domains were also seen among non-menstrual pelvic\npain responders. In contrast, patients who did not achieve a pain response\n(either dysmenorrhoea or non-menstrual pelvic pain) had smaller improvements\nin EHP-30 domains. The EHP-30 domain response ranged from 19% for the pain\ndomain in EM-I to 37% for the sexual relationship domain for both\ndysmenorrhoea non-responders and non-menstrual pelvic pain non-responders. 36\nFatigue was measured in the EM-I trial using the Patient-Reported Outcomes\nMeasurement Information System (PROMIS) Fatigue Short Form 6a questionnaire. 39  This instrument is composed of six questions related to the severity\nof fatigue within the last 7 days with patients answering the question as\n‘not at all’, ‘a little bit’, ‘somewhat’, ‘quite a bit’ or ‘very much’, with\nthe responses assigned a raw score of 1 through 5, respectively. Raw scores\nwere converted to a standardized  T -score with a mean of 50\nthat represents the average for the US general population. 39 , 40  Higher\n T -scores indicate worse fatigue.\nAmong the 860 patients included in the fatigue analysis in EM-I, the mean\nbaseline  T -score ranged from 62 to 64 among the three\ntreatment groups. 39  More than 54% of respondents reported having fatigue-related issues\n‘quite a bit’ or ‘very much’. All three primary symptoms associated with\nendometriosis (non-menstrual pelvic pain, dyspareunia, dysmenorrhoea) were\nindependently associated with an increased fatigue score at baseline.\nTreatment with elagolix was associated with significant dose-dependent\nimprovements in fatigue scores  versus  placebo in this\nanalysis with improvements evident as early as 1 month and maintained over\n6 months ( Figure 2 ).\nDifferences between elagolix groups and placebo continued to increase over\ntime, particularly in the elagolix 200 mg twice daily group. At 1 month, the\nmean changes from baseline in  T -score were −3.27, −4.28 and\n−5.54, respectively, in the placebo, elagolix 150 mg/day and elagolix 200 mg\ntwice daily groups with the difference  versus  placebo\nreaching statistical significance in the elagolix high-dose group\n( p  < 0.001). By month 6, mean changes from baseline\nincreased to −4.53, −6.73 and −10.42, respectively\n( p  = 0.008 and  p  < 0.001\n versus  placebo, respectively). The proportion of\npatients who had responses of ‘quite a bit’ or ‘very much’ in the six\nindividual items on PROMIS decreased from 58–79% to 29–43% at 6 months in\nthe elagolix 150 mg/day group and from 56–79% to 14–29% in the elagolix\n200 mg twice daily group. By comparison, the percentage of patients in the\nplacebo group with responses of ‘quite a bit’ or ‘very much’ in the six\nindividual items decreased from 49–68% at baseline to 35–50% at 6 months. 39  The reductions in fatigue scores were maintained through 12 months.\nThere was a strong relationship between the achievement of clinical\nresponses and fatigue improvement in patients who achieved a clinically\nmeaningful response in dysmenorrhoea and non-menstrual pelvic pain compared\nwith non-responders. 39\nMean change from baseline to month 6 in the PROMIS Fatigue\nQuestionnaire  T -scores in patients receiving\nelagolix 150 mg once daily or 200 mg twice daily or placebo in EM-I. 39 \n N  values (placebo/elagolix 150 mg once\ndaily/elagolix 200 mg twice daily): month 1: 348/224/219; month 3:\n314/216/198; month 6: 246/170/161. The mean difference from placebo\nis indicated for  p  < 0.05 (*),\n p  < 0.01 (**),  p  < 0.001\n(***).\nSource: Reprinted from Surrey and colleagues, 39  Copyright © 2019, with permission from Elsevier.\nBID, twice daily; LS, least squares; PROMIS, Patient-Reported\nOutcomes Measurement Information System, QD, once daily; SE,\nstandard error.\nEM-II and EM-IV (Elaris Endometriosis IV) were extension studies 32  that enrolled women who completed the EM-I or EM-II studies. Women\nwere excluded if after the first 6 months of elagolix treatment in\nEM-I/EM-II they had a bone mineral density decrease from baseline of 8% or\ngreater in the spine, femoral neck or total hip or if they had a clinically\nsignificant condition detected in EM-I or EM-II. EM-III (Elaris\nEndometriosis III) and EM-IV consisted of two periods: a 6-month treatment\nperiod and a post-treatment follow-up period of up to 12 months. Women who\nenrolled in the extension studies received the same elagolix dose that was\ntaken in EM-I and EM-II for an additional 6 months. Of 952 women who\ninitiated treatment with elagolix in EM-I and EM-II, 33  569 participated in the extension studies. Patients discontinued the\noriginal studies for a variety of reasons, including adverse events,\nnon-compliance and withdrawal of consent, and the percentage of patients who\ndiscontinued for each reason was similar across the placebo and elagolix groups. 33  Treatment with elagolix for 12 months resulted in sustained\nreductions in dysmenorrhoea, non-menstrual pelvic pain and dyspareunia. 32\nLong-term elagolix treatment also had anticipated changes as a result of\ndecreased oestradiol levels, including hot flushes, reduced bone mineral\ndensity and increased lipid levels. 32  The incidence of hot flush over 12 months of treatment was 30–55%\n(across EM-III/EM-IV and both doses). Bone mineral density loss was dose\ndependent and increased with duration of treatment. After 6 months of\ntreatment, 2–4%, 16–21% and 1–2% of patients experienced more than 5% loss\nin bone mineral density in the 150 mg once daily, 200 mg twice daily and\nplacebo groups, respectively. 33  In the extension studies, 1 patient in the 150 mg once daily group\nand 10 patients in the 200 mg twice daily group discontinued treatment (as\nrequired by the study protocol) because they experienced a greater than 8%\ndecrease in bone mineral density from baseline. 32  The observed decreases in bone mineral density may not be completely\nreversible, and the impact of these losses on long-term bone health and risk\nof future fractures is unknown. 34  Phase 3 trials ( NCT03213457 ,  NCT03343067 ) are currently being\nconducted to assess the efficacy and safety of elagolix in combination with\nlow-dose, add-back hormonal therapy in women with endometriosis-related\npain.\nFrom baseline to 6 months (EM-I and EM-II), significantly greater increases\nin total cholesterol, low-density lipoprotein, high-density lipoprotein and\ntriglycerides were observed in both elagolix dose groups compared with placebo. 33  No further increases in lipid levels were observed during the\nextension studies (EM-III and EM-IV), and the lipid levels returned to\npretreatment levels within the first month of the post-treatment follow-up period. 32  The impact of these changes in lipid levels on long-term\ncardiovascular risk is unknown.\nThe FDA prescribing information instructs physicians to counsel patients on\nsigns and symptoms of liver injury, advise patients to seek immediate\nmedical attention if they experience depression, warn patients that use of\nelagolix may reduce their ability to recognize pregnancy and use the lowest\neffective dose of elagolix, considering the severity of symptoms and\ntreatment objectives of individual patients. 34\nWorkplace and household productivity in the populations of the EM-I and EM-II\ntrials were assessed in a post hoc analysis. 41 , 42  The analysis of\nworkplace productivity included 1270 women who were employed full- or\npart-time, while the household analysis included 1565 women. Productivity\nwas assessed using the Health-Related Productivity Questionnaire, a\nnine-item instrument that assesses the ability to perform employment- and\nhousehold-related activities. Captured outcomes included absenteeism (work\ntime missed) and presenteeism (reduced work effectiveness) due to\nendometriosis in the workplace and household. 43  The changes from baseline over 6 months in workplace and household\nproductivity are illustrated in  Figures 3  and  4 , respectively. 42  Both doses of elagolix were associated with significant improvements\nin productive workplace hours, but the effect was greatest for the 200 mg\ntwice daily group. Relative to placebo, women treated with elagolix\n150 mg/day gained 2.4 productive workplace hours per week at 3 months\n( p  = 0.002) and 1.7 workplace hours per week at\n6 months ( p  = 0.041). Even greater improvements in\nworkplace productivity  versus  placebo were seen among women\nreceiving elagolix 200 mg twice daily with gains of 4.7 hours per week at\n3 months ( p  < 0.001) and 5.4 hours per week at 6 months\n( p  < 0.001). Reduced presenteeism accounted for\napproximately two-thirds of the gains relative to placebo. Elagolix\n150 mg/day and 200 mg twice daily were also associated with significantly\ngreater gains than placebo for scheduled employment-based hours actually\nworked with increases of 6.6% and 11.6%, respectively, at 3 months and 5.2%\nand 14.6%, respectively, at 6 months relative to placebo.\nGains in productive workplace hours per week over time in pooled data\nfrom EM-I and EM-II. 42  Mean hours gained in workplace productivity, defined as\n−1 × LS mean change from baseline in hours of workplace productivity\nlost due to absenteeism, presenteeism and total hours lost\n(absenteeism + presenteeism).  p  < 0.05 (*),\n p  < 0.01 (**),  p  < 0.001\n(***).\nSource: With kind permission from Springer Science + Business Media:\nSurrey and colleagues, 42  Copyright © 2019, Springer Nature.\nBID, twice daily; CI, confidence interval; EM-I, Elaris Endometriosis\nI; EM-II, Elaris Endometriosis II; LS, least squares; PBO, placebo;\nQD, once daily.\nGains in household productivity per week over time in pooled data\nfrom EM-I and EM-II. 42  Mean hours gained in household productivity, defined as\n−1 × LS mean change from baseline in hours of household productivity\nlost due to absenteeism, presenteeism and total hours lost\n(absenteeism + presenteeism).  p  < 0.05 (*),\n p  < 0.01 (**),  p  < 0.001\n(***).\nSource: With kind permission from Springer Science + Business Media:\nSurrey and colleagues, 42  Copyright © 2019, Springer Nature.\nBID, twice daily; CI, confidence interval; EM-I, Elaris Endometriosis\nI; EM-II, Elaris Endometriosis II; LS, least squares; PBO, placebo;\nQD, once daily.\nHousehold productivity was also significantly increased in both elagolix\ndosage groups at months 3 and 6. Gains of 1.4 and 2.0 hours per week,\nrespectively, were reported for the elagolix 150 mg/day and 200 mg twice\ndaily groups at 3 months relative to placebo ( p  = 0.004 and\n p  < 0.001, respectively). These gains in productive\nhousehold hours increased to 1.7 and 3.1 hours per week at 6 months in the\ntwo elagolix dosage groups ( p  < 0.001 for both).\nCost savings associated with the improvements in absenteeism and presenteeism\nwere calculated by multiplying the number of hours gained with treatment by\nthe average hourly employer cost in the United States in 2018. 41  For the 150 mg/day dose, the average cost savings were >US$1500 at\n6 months, >US$3100 after 12 months of treatment and >US$6200 for\n24 months of treatment. For the 200 mg twice daily dose, the cost savings\nwere >US$3300 over 6 months of treatment. 41\nIn another study, a Markov model was developed using data from the EM-I and\nEM-II clinical trials to assess the cost-effectiveness of elagolix\n versus  leuprolide acetate for the management of\nmoderate to severe endometriosis pain over 1- and 2-year time frames. 44  Both doses of elagolix were associated with a positive net monetary\nbenefit (NMB; i.e. more quality-adjusted life years for less costs) relative\nto leuprolide acetate over both 1- and 2-year time frames. Over a 1-year\nhorizon, elagolix 150 mg/day was associated with an NMB of US$5660 while\nelagolix 200 mg twice daily was associated with an NMB of US$6443. Over\n2 years, both doses were also associated with a positive NMB relative to\nleuprolide acetate (US$2374 and US$1342, respectively). 44  The results were robust to sensitivity analyses.\n\nPain is the most common manifestation of endometriosis; however, the disease is\ncomplex with multiple systemic manifestations. 4 , 5  As noted previously,\nendometriosis is associated with several comorbidities such as autoimmune disease,\nallergy, cancers and cardiovascular disease, suggesting that the disease affects\ninflammatory, immunologic and metabolic functions. 4  Given that endometriosis has such widespread effects, a selective focus on\npain-related outcomes will underestimate the full disease burden on women with\nendometriosis. A more complete assessment of disease burden should include non-pain\nsymptoms as well as the impact on HRQoL and economic outcomes. Indeed, the\nimportance of patient-reported outcomes such as the EHP-30 is increasingly\nrecognized and included in interventional clinical trials in endometriosis. 35\nNumerous studies have demonstrated that endometriosis is associated with negative\nphysical, psychological, emotional, social, familial, sexual and educational\nworkplace effects that adversely impact HRQoL. 14 , 15 , 17 – 19 , 21 , 45 , 46  In particular, women with\nendometriosis often report experiencing a sense of powerlessness, a loss of control\nover one’s life and increases in anxiety and depression. 18 , 45 – 48  The EHP-30 is a reliable and\nvalid HRQoL instrument that was designed as a disease-specific tool for the\nevaluation of HRQoL in women with endometriosis 47 , 49  and has been shown to perform\nwell in the assessment of HRQoL of endometriosis. 35  A meta-analysis of studies assessing the impact of endometriosis found that\nthe disease has a moderate to high negative effect on all core domains of the EHP-30\nwith the domains of control and powerlessness, emotional well-being and social\nsupport having the most negative effects on HRQoL. 50\nAn analysis of data from the EM-I and EM-II trials showed that elagolix was\nassociated with dose-dependent improvements in all six domains of the EHP-30 with\nsignificant differences from placebo evident as early as 1 month. 33  This indicates that elagolix produces improvements in all aspects of HRQoL\nthat are clinically meaningful to patients. A detailed analysis of HRQoL data from\nEM-I and EM-II allowed a determination of EHP-30 thresholds for clinically\nmeaningful change. 38  Using these thresholds, it was shown that elagolix-treated patients who\ndemonstrated a clinical response in dysmenorrhoea or non-menstrual pelvic pain also\nachieved clinically meaningful improvements in all EHP-30 domains. 36  This suggests that the EHP-30 may be useful in the clinic, providing a way to\nevaluate and monitor outcomes and treatment progress in areas that are important to\nindividual patients. Such a focus on patient-centred outcomes is likely to be well\nreceived by patients and can allow clinicians to tailor treatment toward achieving\neach individual’s goals. 38\nFatigue is a well-recognized symptom of endometriosis that is associated with\nsignificant physical, psychological and HRQoL impacts. 9 , 11 , 13  In the EM-I and EM-II trials,\nfatigue was commonly reported at baseline, with 17% of patients having a severe\nlevel of fatigue and 57% having a moderate level of fatigue at baseline. 39  When patients were asked how fatigued they were, how bothersome the fatigue\nwas and how rundown they felt, more than 60% of patients responded ‘quite a bit’ or\n‘very much’. Fatigue was associated with a difficulty in initiating activities and\nan interference in physical functioning in more than half of patients. 39  Data from the EM-I trial demonstrated that fatigue was improved with\nelagolix, beginning as early as 1 month and maintained throughout the 6-month study period. 39  The benefit was dose dependent with improvements greatest for the elagolix\ntwice daily regimen although both doses produced significantly greater improvements\n versus  placebo. Given the high prevalence of fatigue in the\nwomen with endometriosis, these benefits are likely to be clinically important.\nFinally, the economic burden of endometriosis is also substantial. It has been\nestimated that the annual costs associated with endometriosis are similar to that of\ndiabetes mellitus, Crohn’s disease and rheumatoid arthritis. 21  The lost work and reduced productivity associated with endometriosis is a\nvery important concern for women with endometriosis. 14 , 45  For example, a survey of women\nwith endometriosis found that work productivity was extremely affected in 48% of respondents. 39  Pelvic pain and disease severity appear to be the major factors that drive\nlosses of productivity. 14 , 43\nResults from EM-I and EM-II demonstrated that elagolix 150 mg/day and 200 mg twice\ndaily were associated with significant improvements in workplace and household\nproductivity relative to placebo after 3 and 6 months of treatment. 42  The estimated economic benefits of these improvements in productivity were\nsubstantial, with cost savings ranging from >US$1500 to >US$3300 over 6 months\nof treatment. 41  Furthermore, a cost-effectiveness analysis found that elagolix was dominant\nover leuprolide acetate in the treatment of moderate to severe endometriosis (i.e.\nclinically superior and cost saving). These economic benefits were robust to\nextensive sensitivity analyses.\nGiven the systemic nature of endometriosis and the negative effect that\nendometriosis-related symptoms have on physical, psychological, emotional and social\nwell-being; familial and sexual relationships; and workplace productivity, it seems\nreasonable to take a holistic approach to relieve the burden of endometriosis. Such\nan approach would include not only pain management but also emotional and social\nsupport, and services to assist with work issues. Future clinical trials evaluating\nendometriosis treatments need to include outcomes that assess the effect of\ntreatment regimens on fatigue, depression, anxiety, emotional distress and various\naspects of HRQoL in order to address the individual needs of women suffering from\nendometriosis.\n\nIn summary, it is increasingly recognized that the clinical impact of endometriosis\nextends beyond pelvic pain with multiple systemic effects that can produce non-pain\nsymptoms and adversely impact psychological and social function, workplace and\nhousehold productivity, and ultimately HRQoL. Thus, it is important to assess the\neffect of treatment regimens on these non-pain outcomes that are very meaningful to\nthe lives of women with endometriosis. Elagolix is a gonadotropin-releasing hormone\nreceptor antagonist that is not only effective for the treatment of dysmenorrhoea\nand non-menstrual pelvic pain but also positively impacts HRQoL, reduces fatigue and\nimproves work/household productivity.","source_license":"CC0","license_restricted":false}