{"paper_id":"6ffd82eb-e507-4a21-86b6-8b40d98812f2","body_text":"Vol.:(0123456789)\nThe Patient - Patient-Centered Outcomes Research (2019) 12:651–660 \nhttps://doi.org/10.1007/s40271-019-00394-7\nORIGINAL RESEARCH ARTICLE\nImpact of Elagolix on Workplace and Household Productivity Among \nWomen with Moderate to Severe Pain Associated with Endometriosis: \nA Pooled Analysis of Two Phase III Trials\nEric S. Surrey1 · Ahmed M. Soliman2 · Hannah L. Palac2 · Sanjay K. Agarwal3\nPublished online: 25 October 2019 \n© The Author(s) 2019\nAbstract\nBackground Endometriosis profoundly impairs women’s workplace and household productivity.\nObjective The aim of this study was to evaluate the impact of elagolix on endometriosis-related workplace and household \nproductivity losses.\nMethods Data were pooled from two phase III trials of women aged 18–49 years with moderate to severe endometriosis-associated \npain treated for 6 months with elagolix 150 mg daily (QD), 200 mg twice daily (BID), or placebo. The Health-Related Productiv-\nity Questionnaire was administered at baseline, Month 3, and Month 6 to determine workplace and household absenteeism and \npresenteeism. Productivity changes from baseline were compared between placebo and elagolix doses via analysis of covariance.\nResults Workplace analyses included 1270 employed women and household analyses included 1565 women. At baseline, women \nreported average weekly losses of 16 workplace hours, 8.3 household work hours, 45% of scheduled work, and 64% of planned \nhousehold chores. At Month 6, treatment with elagolix 150 mg QD or 200 mg BID increased productive workplace hours by \n1.7 (95% CI 0.1–3.4; p = 0.041) and 5.4 h (95% CI 3.7–7.1; p < 0.001) relative to placebo, corresponding to gains of 5.2% (95% \nCI 0.7–9.7; p = 0.022) and 14.6% (95% CI 10.0–19.1; p < 0.001) of scheduled work, respectively. Both elagolix doses improved \nhousehold productivity at Month 6 by 1.7 (95% CI 0.7–2.7) and 3.1 (95% CI 2.1–4.0) hours relative to placebo (both p < 0.001), \nwith increases of 8.8% (95% CI 3.5–14.1; p = 0.001) and 20.4% (95% CI 15.1–25.6; p < 0.001) of planned household work.\nConclusions Treatment with elagolix improved endometriosis-related workplace and household productivity impairments.\nTrial Registration ELARIS EM-I (NCT01620528) and ELARIS EM-II (NCT01931670)\nData presented in this communication were reported in part at \nthe International Society for Pharmacoeconomics and Outcomes \nResearch Annual Conference, May 18–22, 2019, New Orleans, \nLA, USA.\n * Eric S. Surrey \n ESurrey@colocrm.com\n1 Colorado Center for Reproductive Medicine, 10290 \nRidgeGate Circle, Lone Tree, CO 80124, USA\n2 AbbVie Inc., North Chicago, IL, USA\n3 Center for Endometriosis Research and Treatment, University \nof California, San Diego, CA, USA\nKey Points for Decision Makers \nEndometriosis and its associated pain symptoms have been \nshown to profoundly reduce women’s health-related quality \nof life as well as impair employment-based and household \nproductivity.\nThis is the first pooled analysis of data from randomized, \nplacebo-controlled studies investigating the impact of \ntreatment on workplace and household productivity \nimpairment in a large cohort of women with moderate to \nsevere endometriosis-associated pain.\nWomen with moderate to severe endometriosis-associ-\nated pain treated with elagolix 150 mg daily or 200 mg \ntwice daily reported significant improvements in work-\nplace and household productivity after 3 and 6 months of \ntreatment compared with productivity prior to treatment \nand compared with women given placebo.\n\n652 E. S. Surrey et al.\n1 Introduction\nEndometriosis is a common gynecological disease in \nwhich endometrial-like tissue grows outside of the uterus \nin an estrogen-dependent manner [1 ]. Ectopic endometrial \ngrowths are associated with a chronic inflammatory state \nthat promotes disease progression [2 ]. The condition is \nfound in women of reproductive age, with the highest prev-\nalence in women aged 35–44 years [3 ]. It is estimated that \nendometriosis affects approximately 10% of women world-\nwide [4], with a recent survey reporting a 6.1% prevalence \namong women aged 18–49 years in the United States of \nAmerica (USA) [2]. The most prominent symptom of endo-\nmetriosis is pain, which can include dysmenorrhea, chronic \npelvic pain, lower back pain, dyspareunia, pain at ovula-\ntion, dyschezia, and dysuria; women with endometriosis also \nexperience menorrhagia, fatigue, and infertility [5 –7].\nMany studies have found that endometriosis has a sub-\nstantial negative impact on women’s health-related quality \nof life (HRQOL) [7 –11]. The chronic nature of endome-\ntriosis and the prominence of pain symptoms consider -\nably affect all aspects of women’s social, emotional, and \nphysical well-being [7 –9, 11]. Women with endometrio-\nsis report physical limitations such as impaired mobility, \nreduced energy, and difficulties performing daily activi-\nties and self-care [11, 12]. Furthermore, women com-\nmonly report experiencing anxiety/stress, depression, and \nnegative impacts on intimate relationships and reproduc-\ntive planning [8 , 11–13]. A large, cross-sectional study \nof women with endometriosis in the USA found that the \nseverity and number of symptoms was inversely correlated \nwith HRQOL [2 ]. In particular, pelvic pain/cramping dur -\ning menstrual periods, general abdominal pain, irregular \nperiods, and dyspareunia had the most significant negative \nimpacts on HRQOL [2 ].\nIn addition to the established negative effects of endo-\nmetriosis on mental and physical well-being, several stud-\nies have documented the profound impact of endometrio -\nsis-associated symptoms on both employment-based and \nhousehold productivity [9 –11, 13, 14]. Missed time from \nwork (absenteeism) and reduced effectiveness while at work \n(presenteeism) comprise overall workplace productivity \nloss. Women with endometriosis reportedly miss, on aver -\nage, 3–13% of work time owing to absenteeism and lose \n14–65% of productive work time owing to endometriosis \nsymptoms, especially pain [10, 11, 14]. Reduced productiv-\nity in the household has also been reported; in one study, \nup to 79% of women reported significant impairments in \nperforming household chores [13]. Moreover, a population-\nbased survey of women with endometriosis demonstrated a \ncorrelation between symptom severity and loss of productiv-\nity in the workplace and the household. Loss of workplace \nproductivity in women with endometriosis carries a sub-\nstantial societal economic burden. In the USA, the indirect \ncost of workplace absenteeism and short- and long-term \ndisability in women with endometriosis was estimated to \nbe US$2132 per patient per year, which does not factor in \nlosses due to presenteeism [15]. A 2011 study in the USA \nestimated that monetary losses due to presenteeism were \nfivefold higher than those due to absenteeism, with approxi-\nmately US$250 lost per week per patient from presenteeism \nand US$50 lost per week per patient from absenteeism [10].\nGiven the substantial burden that endometriosis symp-\ntoms place on women’s HRQOL and the high indirect costs \nto society, management strategies are needed to mitigate \nproductivity loss associated with endometriosis. Estrogen is \ncentral to the pathophysiology of endometriosis, promoting \nendometrial tissue growth and inflammation [1]. Therefore, \nreduced estrogen can alleviate endometriosis-related symp-\ntoms, including pain [16]. Elagolix is an oral gonadotropin-\nreleasing hormone receptor antagonist that results in dose-\ndependent suppression of gonadotropins and ovarian sex \nsteroids [17 , 18]. Two phase III trials (ELARIS EM-I and \nELARIS EM-II) have demonstrated that elagolix 150 mg \nonce daily (QD) and 200 mg twice daily (BID) improves \ndysmenorrhea and nonmenstrual pelvic pain in women with \nmoderate to severe pain associated with endometriosis after \n3 and 6 months of treatment [18]. This post hoc analysis \nwas conducted on data pooled from the ELARIS EM-I and \nEM-II trials to evaluate the impact of elagolix on workplace \nand household productivity in a large population of women \nwith moderate to severe endometriosis-associated pain.\n2  Methods\n2.1  Study Design and Participants\nThe data for these analyses were pooled from two inter -\nnational phase III trials (ELARIS EM-I [NCT01620528] \nand ELARIS EM-II [NCT01931670]) for which the study \ndesigns and participant recruitment have been previ-\nously described [18]. Briefly, both were randomized, \ndouble-blind, multicenter, placebo-controlled studies that \nevaluated the efficacy and safety of two doses of elago-\nlix (150 mg QD or 200 mg BID) versus placebo in pre-\nmenopausal women with moderate to severe endometri -\nosis-associated pain [18]. Women aged 18–49 years who \nreceived a surgical diagnosis of endometriosis in the previ-\nous 10 years and who had moderate to severe endometrio-\nsis-associated pain were included in these studies. Women \nwith a clinically significant gynecologic or chronic pain \ncondition unrelated to endometriosis were excluded.\nWomen were randomly assigned 2:2:3 to receive elago -\nlix 150 mg QD, 200 mg BID, or placebo for 6 months, \n\n653\nElagolix and Endometriosis-Associated Productivity Loss\nwith a 12-month follow-up period, or optional enrollment \nin a 6-month open-label extension period. The primary \nendpoints in both studies were the proportion of women \nwith a clinical response (clinically meaningful reduction \nin pain score and decreased or stable use of analgesics) for \ndysmenorrhea and nonmenstrual pelvic pain at 3 months \n[18]. Patient-reported outcomes were measured as second-\nary outcomes in these studies. The present study evalu-\nated change from baseline to each visit during the 6-month \ntreatment period (Months 3 and 6) in workplace and \nhousehold productivity per the Health-Related Productiv -\nity Questionnaire (HRPQ) [19]. Outcomes of patients in \nthe extension period were not evaluated in this analysis.\n2.2  Health‑Related Productivity Questionnaire \n(HRPQ)\nThis post hoc analysis was performed to evaluate data from \nthe administered HRPQ at baseline and during Months 3 \nand 6 of treatment. The HRPQ is a 9-item questionnaire \nthat assesses a patient’s ability to perform employment-\nbased work and daily activities in the home, measur -\ning absenteeism (work time missed) and presenteeism \n(reduced work effectiveness) because of endometriosis in \nthe workplace and in the household [19]. Patients who \nwere employed part- or full-time and had scheduled work \nhours in the week prior to survey completion were eligible \nto respond to questions regarding workplace productiv -\nity. All patients with planned household work hours in \nthe week prior to taking the survey, regardless of employ -\nment status, could answer questions related to household \nproductivity. Respondents were asked to report scheduled \nemployment-based work hours and planned household \nwork hours in the previous week, which included house-\nhold activities such as cooking, cleaning, gardening, and \nrepairs.\nThe HRPQ was modified to be specific to endometrio-\nsis, asking study participants, “Did endometriosis-associ-\nated pain or its treatment(s) keep you from working any of \nyour scheduled hours during the last week?” If the answer \nwas “Yes,” respondents gave the number of hours missed. \nTo assess workplace presenteeism, study participants \nwere asked, “For the hours that you did work during the \npast week, how did endometriosis-associated pain or its \ntreatment(s) impact your work output?” Response options \nwere on a 0–100% scale in which 0% indicated that endo-\nmetriosis-associated pain/treatment had no impact on how \nmuch was accomplished and 100% indicated that endome-\ntriosis-associated pain/treatment prevented the respondent \nfrom accomplishing anything. The hours lost to presentee-\nism were then calculated as:\nThe same questions were asked regarding the impact of \nendometriosis-associated pain or treatment on household \nproductivity due to absenteeism and presenteeism. Patient \nresponses were used to calculate the number of employment-\nbased and household work hours spent away from workplace/\nhousehold work (absenteeism), productive hours lost while \nworking in the workplace/household (presenteeism), and total \nhours lost owing to absenteeism and presenteeism in the work-\nplace/household. The percentages of scheduled employment-\nbased work hours and planned household work hours lost due \nto absenteeism, presenteeism, and in total, were calculated.\n2.3  Statistical Analyses\nAnalyses were performed with SAS version 9.3 (SAS \nInstitute, Cary, NC, USA) using the UNIX operating sys-\ntem. The data were analyzed as observed, without imputa-\ntion for missing responses. The patients included in these \nanalyses were those who were randomized and received at \nleast one dose of placebo or elagolix (modified intent-to-\ntreat population). Patients who responded to the question \nof absent and worked hours in the workplace at baseline \nwere included in workplace productivity analyses. Patients \nwho reported having planned household work hours in the \nweek prior to taking the survey were included in house-\nhold productivity analyses. Least squares (LS) means \nwere calculated for the number and percentage of hours \nlost to absenteeism, presenteeism, and in total at base-\nline. Productivity gains at Months 3 and 6 of treatment \nwere calculated as − 1 × LS mean change from baseline \nin productive hours or the percentage of planned/sched-\nuled productive hours. Differences between elagolix dose \ngroups and placebo at baseline were assessed using an \nanalysis of variance (ANOVA) model with treatment as the \nmain effect. At Months 3 and 6 of treatment, differences \nbetween elagolix dose groups and placebo were assessed \nusing an analysis of covariance (ANCOVA) model with \ntreatment as the main effect and baseline productivity \nloss as a covariate. The corresponding 95% confidence \nintervals (CIs) and p  values were calculated. P  < 0.05 was \nconsidered statistically significant.\n3  Results\n3.1  Baseline Characteristics\nA total of 1270 women with moderate to severe endometri-\nosis-associated pain responded to workplace productivity \nPresenteeism = actual hours worked\n× (% impact on work output ∕100).\n\n654 E. S. Surrey et al.\nquestions in this analysis, including 556 treated with pla-\ncebo, 359 treated with elagolix 150 mg QD, and 355 treated \nwith elagolix 200 mg BID, representing 75% of all rand-\nomized patients. The baseline demographics and clinical \ncharacteristics for these patients were similar between treat-\nment groups (Table 1). The average patient age was approxi-\nmately 32 years in all treatment arms, and scores were very \nsimilar or the same among groups for dysmenorrhea (2.1 \n[SD 0.5]), nonmenstrual pelvic pain (1.5–1.6 [SD 0.5]), and \ndyspareunia (1.5 [SD 0.8–0.9]).\nAt baseline, mean total hours of workplace productivity \nlost in the previous week (16 h) was similar among groups, \nwith 3 h lost owing to absenteeism and 13 h lost owing to \npresenteeism. Across treatment arms, women reported an \naverage loss of 45% of scheduled workplace productivity, \nwith fourfold greater loss due to presenteeism than the loss \ndue to absenteeism. Household productivity data were avail-\nable for 1565 women who reported having planned house -\nhold work hours in the week prior to taking the survey, rep-\nresenting approximately 93% of all randomized patients (681 \nreceived placebo, 437 received elagolix 150 mg QD, and \n447 received elagolix 200 mg BID; Table  1). On average, \n8.3 h of household productivity were lost at baseline across \ntreatment groups, with 4.7 h lost due to absenteeism and \n3.6 h lost due to presenteeism. Women lost 64% of planned \nhousehold productivity hours at baseline, with 38% loss due \nto absenteeism and 26% loss due to presenteeism. Therefore, \nabsenteeism accounted for 60% of the total planned house-\nhold productivity lost, whereas presenteeism accounted for \n40% of planned household productivity lost.\nTable 1  Baseline characteristics of patients in analysis (modified intent-to-treat)a\na Women employed full- or part-time with scheduled work hours in the week prior to taking the survey were included in workplace productivity \nanalyses (n = 1270); women with planned household work hours in the week prior to taking the survey, regardless of employment status, were \nincluded in household productivity analyses (n = 1565)\nb Pain responses were none = 0, mild = 1, moderate = 2, and severe = 3; group mean is based on the daily average score over the 35-day interval\nc Pain responses were none = 0, mild = 1, moderate = 2, severe = 3, and not applicable; group mean is based on the daily average score over the \n35-day interval. Subjects responding ‘not applicable’ for the entire 35-day interval are excluded for a total of 1384 subjects with baseline dys-\npareunia pain responses\nBID twice daily, BMI body mass index, LS least squares, N/A not applicable, QD once daily, SD standard deviation, SE standard error\nCharacteristic N Placebo N Elagolix 150 mg QD N Elagolix 200 mg BID\nAge, years, mean ± SD 556 32.7 ± 6.5 359 32.4 ± 6.4 355 32.4 ± 6.6\nBMI, kg/m2, mean ± SD 553 27.5 ± 6.1 358 27.7 ± 6.6 351 27.3 ± 6.4\nDysmenorrhea score, mean ± SD\n(scale 0–3)b\n556 2.1 ± 0.5 359 2.1 ± 0.5 355 2.1 ± 0.5\nNonmenstrual pelvic pain score, mean ± SD (scale 0–3)b 556 1.6 ± 0.5 359 1.6 ± 0.5 355 1.5 ± 0.5\nDyspareunia score, mean ± SD (scale 0–3, or N/A)c 456 1.5 ± 0.8 294 1.5 ± 0.9 289 1.5 ± 0.9\nHours of scheduled employment-based work in previous week, LS \nmean ± SE\n556 33.0 ± 0.5 359 34.2 ± 0.7 355 33.0 ± 0.7\nHours of workplace productivity lost, LS mean ± SE\n Total hours lost 556 15.7 ± 0.5 359 16.2 ± 0.6 355 16.0 ± 0.6\n Absenteeism 556 3.2 ± 0.2 359 3.0 ± 0.3 355 3.0 ± 0.3\n Presenteeism 552 12.6 ± 0.4 356 13.4 ± 0.5 350 13.2 ± 0.5\nPercentage of workplace productivity lost, LS mean ± SE\n Total percentage of hours lost 556 44.0 ± 1.2 359 44.5 ± 1.4 355 45.3 ± 1.5\n Absenteeism 556 9.8 ± 0.7 359 8.3 ± 0.9 355 9.6 ± 0.9\n Presenteeism 552 34.4 ± 1.0 356 36.6 ± 1.2 350 36.3 ± 1.3\nHours of planned household work in previous week, LS mean ± SE 681 7.7 ± 0.3 437 8.1 ± 0.4 447 7.9 ± 0.4\nHours of household productivity lost, LS mean ± SE\n Total hours lost 681 8.3 ± 0.3 437 8.6 ± 0.4 447 8.1 ± 0.4\n Absenteeism 681 4.7 ± 0.2 437 4.8 ± 0.3 447 4.7 ± 0.3\n Presenteeism 679 3.6 ± 0.2 435 3.8 ± 0.2 443 3.4 ± 0.2\nPercentage of household productivity lost, LS mean ± SE\n Total percentage of hours lost 681 65.6 ± 1.1 437 63.4 ± 1.4 447 64.4 ± 1.4\n Absenteeism 681 39.1 ± 1.1 437 37.4 ± 1.4 447 38.7 ± 1.4\n Presenteeism 679 26.6 ± 0.7 435 26.2 ± 0.9 443 25.9 ± 0.9\n\n655\nElagolix and Endometriosis-Associated Productivity Loss\n3.2  Impact of Elagolix on Employment‑Based \nProductivity\nWomen given placebo gained a total of 5.9 productive work-\nplace hours per week by Month 3 and 6.9 h by Month 6 \n(Fig.  1). Both doses of elagolix were associated with sig-\nnificantly greater improvements than placebo in productive \nworkplace hours per week at Months 3 and 6 of treatment \n(Fig.  1). At Month 3, women gained 2.4 productive work -\nplace hours (95% CI 0.9–3.9; p = 0.002) and 4.7 productive \nworkplace hours (95% CI 3.6–6.2; p < 0.001) per week rela-\ntive to placebo with elagolix 150 mg QD and 200 mg BID, \nrespectively. At Month 6, workplace productivity increased \nby 1.7 h (95% CI 0.1–3.4; p  = 0.041) and 5.4 h (95% CI \n3.7–7.1; p < 0.001) per week relative to placebo with elago-\nlix 150 mg QD and 200 mg BID, respectively. Gains in pro-\nductive workplace hours owing to reduced absenteeism were \nsignificantly higher than placebo for both doses at Month 3 \nand only the 200-mg dose at Month 6. Reduced presenteeism \naccounted for 63–71% of total gains relative to placebo in \nproductive workplace hours. At Month 3, elagolix 150 mg \nQD and 200 mg BID were associated with 1.5-h (95% CI \n0.2–2.8; p = 0.022) and 3.1-h (95% CI 1.8–4.3; p  < 0.001) \ngains, respectively, relative to placebo in weekly productive \nworkplace hours due to reduced presenteeism. By Month 6, \nwomen treated with elagolix 200 mg BID reported a 3.8-h \n(95% CI 2.4–5.2; p < 0.001) increase relative to placebo in \nproductive workplace hours due to reduced presenteeism.\nTreatment with elagolix 150 mg QD or 200 mg BID was \nassociated with significant gains over placebo in the per -\ncentage of scheduled employment-based work hours actually \nworked (Fig.  2). At Month 3, women treated with elagolix \n150 mg QD and 200 mg BID had gains of 6.6% (95% CI \n2.7–10.4) and 11.6% (95% CI 7.7–15.5), respectively (both \np < 0.001), of scheduled employment-based work relative to \nplacebo. At Month 6, elagolix 200 mg BID was associated \nwith a gain of 14.6% of scheduled work relative to placebo \n(95% CI 10.0–19.1; p  < 0.001), versus a 5.2% gain with \nelagolix 150 mg QD (95% CI 0.7–9.7; p  = 0.022). Reduced \nabsenteeism significantly contributed to productivity gains \nper scheduled work with both doses of elagolix at Month \n3 and with elagolix 200 mg BID at Month 6. Decreased \npresenteeism accounted for 59–66% of total workplace gains \nrelative to placebo in scheduled work at Months 3 and 6 \nof elagolix treatment. Gains in the percentage of scheduled \nworkplace hours from decreased presenteeism were signifi-\ncant with elagolix 150 mg QD and 200 mg BID at Month 3 \n(p = 0.021 and p < 0.001, respectively) and elagolix 200 mg \nBID at Month 6 (p < 0.001).\n3.3  Impact of Elagolix on Household Productivity\nIn addition to improved workplace productivity, women \ngiven placebo also gained a total of 3.0 productive household \nhours per week by Month 3 and 3.1 h by Month 6 (Fig.  3). \nBoth elagolix doses were associated with improvements \nFig. 1  Gains in productive workplace hours per week at Months \n3 and 6 of treatment. Mean hours gained in workplace productivity \nfrom baseline, defined as −  1 × LS mean change from baseline in \nhours of workplace productivity lost due to absenteeism, presentee-\nism, and total hours lost (absenteeism + presenteeism). ***p < 0.001; \n**p < 0.01; *p < 0.05. BID twice daily, CI confidence interval, LS  \nleast squares, PBO placebo, QD once daily\n\n656 E. S. Surrey et al.\nin household productivity beyond the gains observed with \nplacebo. Relative to placebo, patients treated for 3 months \nwith elagolix 150 mg QD gained 1.4 productive household \nhours per week (95% CI 0.5–2.3; p  = 0.004), and patients \ntreated with elagolix 200 mg BID gained 2.0 productive \nhousehold hours per week (95% CI 1.1–3.0; p  < 0.001). At \nMonth 6, household productivity gains with elagolix 150 mg \nQD and 200 mg BID were 1.5- and twofold higher than \nplacebo, respectively. A total of 1.7 (95% CI 0.7–2.7) and \n3.1 (95% CI 2.1–4.0) productive household hours per week \nwere gained relative to placebo with elagolix 150 mg QD \nand 200 mg BID, respectively (both p  < 0.001). Women \ntreated for 3 months with both elagolix doses had signifi-\ncant increases in productive household hours from reduced \nabsenteeism (p < 0.001). At Month 6, productive household \nhours increased by 1.0 (95% CI 0.4–1.7) and 2.0 (95% CI \n1.4–2.7) hours relative to placebo due to reduced absentee-\nism with elagolix 150 mg QD (p  = 0.003) and 200 mg BID \n(p < 0.001), respectively. Gains in household productivity \ndue to reduced presenteeism were less pronounced but still \nsignificant for women treated with elagolix 200 mg BID at \nMonth 3 (p = 0.049) and both doses at Month 6 (150 mg QD, \np = 0.016; 200 mg BID, p < 0.001).\nThere were also large gains in the percentage of house-\nhold productivity per planned household work at both \ntimepoints with both elagolix doses (Fig.  4). At Month 6, \nelagolix 150 mg QD was associated with a gain of 8.8% \nof planned household productivity relative to placebo (95% \nCI 3.5–14.1; p  = 0.001), while elagolix 200 mg BID was \nassociated with a gain of 20.4% relative to placebo (95% \nCI 15.1–25.6; p < 0.001). Reduced absenteeism at Month 6 \ncorresponded to a gain of 4.7% (95% CI 0.6–8.8; p = 0.024) \nof planned household productivity relative to placebo \nwith elagolix 150 mg QD and 13.0% (95% CI 8.9–17.0; \np < 0.001) with elagolix 200 mg BID. Decreased presentee-\nism accounted for a gain of 4.7% of planned household pro-\nductivity relative to placebo (95% CI 1.7–7.6; p  = 0.002) in \nwomen treated with elagolix 150 mg QD and 7.5% (95% CI \n4.6–10.4; p < 0.001) in women treated with elagolix 200 mg \nBID at Month 6.\n4  Discussion\nThis analysis of pooled data from two large, placebo-con-\ntrolled trials [18] demonstrates that treatment with elagolix \nsignificantly improves productivity in both the workplace \nand household among women with moderate to severe endo-\nmetriosis-associated pain. Previous research has established \na clear negative impact of endometriosis-associated pain on \nwomen’s HRQOL and productivity [7 –11]. Importantly, \nthis study is among the first to demonstrate that a treatment \nwhich effectively manages endometriosis pain also posi-\ntively impacts patients’ ability to productively participate \nin the workforce and perform household tasks.\nFig. 2  Gains in percentage of scheduled workplace productivity per \nweek at Months 3 and 6 of treatment. Mean gains in the percentage of \nscheduled workplace hours worked, defined as − 1 × LS mean change \nfrom baseline in percentage of scheduled workplace hours lost due to \nabsenteeism, presenteeism, and total (absenteeism + presenteeism). \n***p < 0.001; **p < 0.01; *p < 0.05. BID twice daily, CI confidence \ninterval, LS least squares, PBO placebo, QD once daily\n\n657\nElagolix and Endometriosis-Associated Productivity Loss\nIn the current study, women with moderate to severe \nendometriosis-associated pain experienced a signifi-\ncant loss in workplace and household productivity prior \nto treatment that approached a total of 45% of scheduled \nemployment-based work and 64% of planned household \nwork. The impact of endometriosis on women’s daily lives is \nunderscored by the 20% greater loss in household productiv-\nity than workplace productivity. These results are generally \nFig. 3  Gains in hours of household productivity per week at Months \n3 and 6 of treatment. Mean hours gained in household productivity, \ndefined as − 1 × LS mean change from baseline in hours of household \nproductivity lost due to absenteeism, presenteeism, and total (absen-\nteeism + presenteeism). ***p < 0.001; **p < 0.01; *p < 0.05. BID \ntwice daily, CI confidence interval, LS least squares, PBO placebo, \nQD once daily\nFig. 4  Gains in percentage of planned household productivity per \nweek at Months 3 and 6 of treatment. Mean gains in the percentage \nof planned household work hours worked, defined as − 1 × LS mean \nchange from baseline in percentage of planned household work hours \nlost due to absenteeism, presenteeism, and total (absenteeism + pres-\nenteeism). ***p < 0.001; **p < 0.01; *p < 0.05. BID twice daily, CI \nconfidence interval, LS least squares, PBO placebo, QD once daily\n\n658 E. S. Surrey et al.\nconsistent with previous studies that found substantial pro-\nductivity impairments in women with endometriosis [10, \n11, 13, 14]. At baseline, women in this study lost an aver -\nage of 16 h of workplace productivity and 8 h of household \nproductivity per week. The magnitude of productivity losses \nreported here by women with endometriosis are greater than \nthose reported by patients with other chronic pain condi-\ntions. Patients with rheumatoid arthritis reported a total of \n29% workplace productivity loss and 41% impairment of \ndaily activities, and patients with inflammatory bowel dis-\nease reported an overall 21% work productivity loss and 30% \nactivity impairment [20]. At baseline, common pain condi-\ntions, such as headache and back pain, were associated with \n3.5 and 5.3 h of productive work time lost per week, respec-\ntively [21], significantly less work time lost than reported \nhere. Impaired productivity not only stems from pain-related \nendometriosis symptoms, but also from moderate/severe \nsymptoms such as fatigue, heavy menstrual bleeding, spot-\nting/bleeding during periods, irregular periods, and bloating. \nMoreover, women with endometriosis have a significantly \nhigher incidence of comorbid conditions [22]. The pres-\nence of comorbid ovarian cysts, depression, and hyperten-\nsion were found to be strong predictors for workplace and \nhousehold productivity losses, suggesting that comorbid \nconditions may increase productivity loss.\nTreatment with elagolix was associated with significant \ngains in productive workplace hours, equivalent to restor -\ning 1–1.5 work days per week, versus 0.75 work days per \nweek with placebo. The impact of endometriosis on women’s \nparticipation in the workforce may be underappreciated if \nbased solely on time absent from work. Decreased efficiency \nand productivity while at work due to endometriosis-related \nsymptoms (presenteeism) heavily contributes to productivity \nlosses. In the current study, workplace productivity losses \nat baseline due to presenteeism were approximately 4–4.5 \ntimes as large as losses due to absenteeism. Previous studies \nin women with endometriosis have documented 2.3 [10], 2.7 \n[11], and 4.8 [14] times greater work productivity losses from \npresenteeism. These findings suggest that women with endo-\nmetriosis are present at work despite experiencing symptoms \nthat limit their ability to effectively perform work [10, 11, \n14]. Symptoms that predict poor performance at work include \ndysmenorrhea, nonmenstrual pelvic pain, dyspareunia, \nirregular periods, abdominal pain, incapacitating pain, and \ndepression [13, 14]. Unlike workplace productivity losses, \nhousehold productivity losses at baseline due to absenteeism \nand presenteeism were similar, with approximately 1.4 times \ngreater productivity loss due to absenteeism than presentee-\nism. The ratio of household absenteeism to presenteeism \nreported in the current study is similar to that reported pre-\nviously (ratio 1.1) in women in the USA with endometriosis.\nImportantly, women treated with elagolix 150 mg QD \nand 200 mg BID reported substantial improvements in \nworkplace and household productivity, including produc-\ntivity gains due to reduced absenteeism and presenteeism, \ncompared with women given placebo. Significant gains in \nboth workplace and household productivity were reported \nby Month 3 of treatment with elagolix and persisted or \nwere greater by Month 6. Generally, elagolix 200 mg BID \nwas associated with greater improvements in productiv -\nity than elagolix 150 mg QD. By Month 6, treatment with \nelagolix 200 mg BID was associated with a 15% increase \nin workplace productivity per scheduled work hours and a \n20% increase in household productivity per planned house-\nhold work hours, relative to placebo. Taken together, these \npatient-reported results suggest that elagolix 150 mg QD \nand 200 mg BID effectively mitigate the negative impact of \nendometriosis symptoms on employment-based and house-\nhold productivity.\nElagolix 150 mg QD and 200 mg BID reduce dysmenor -\nrhea and nonmenstrual pelvic pain [18], symptoms which, \nwhen moderate or severe, are strongly correlated with \ngreater productivity losses [14]. In ELARIS EM-I and EM-II \nstudies, 42.1–46.4% of women taking elagolix 150 mg QD \nand 72.4–76.9% of women taking elagolix 200 mg BID \nexperienced clinically meaningful pain reduction and \ndecreased or stable use of rescue analgesics for dysmenor -\nrhea over 6 months of treatment, compared with 19.6–25.4% \nof women receiving placebo [18]. Women receiving both \nelagolix doses also experienced pain reduction and reduced \nanalgesic use for nonmenstrual pelvic pain (45.7–51.6% \nwith elagolix 150 mg QD; 54.5–62.2% with elagolix 200 mg \nBID; 34.9–40.6% with placebo) [18]. The current analysis \nwas not designed to correlate pain improvement scores \nwith productivity improvements, and it is therefore possi-\nble that the impact of elagolix on non-pain symptoms may \nalso contribute to improvements in productivity. Beyond \npain, fatigue is a highly prevalent symptom of endometrio-\nsis, which may be intense and bothersome [ 8, 23, 24] and \nhas been associated with impairments in workplace, house-\nhold, and social activities [14, 25]. Treatment with elagolix \n150 mg QD and 200 mg BID significantly improves fatigue \nat both 3 and 6 months of treatment in women with mod-\nerate to severe endometriosis-associated pain [24]. Fatigue \nand endometriosis-associated pain symptoms are inter -\nrelated, with individual pain symptoms (dysmenorrhea, \nnonmenstrual pelvic pain, dyspareunia) increasing fatigue \n[24]. Thus, improvements in endometriosis-associated pain \nand fatigue from elagolix treatment may both play a role in \nimproving productivity.\nThe present study is the first to assess whether an endo-\nmetriosis treatment can address the substantial productiv -\nity impairments women experience, but the study has some \nlimitations. As previously discussed, the HRPQ is a self-\nreported instrument and therefore results may suffer from \nrecall bias and reporting errors. For example, reporting on \n\n659\nElagolix and Endometriosis-Associated Productivity Loss\nplanned household chore hours for the previous week relied \non a priori prediction of the number of hours respondents \nintended to spend on household chores, whereas scheduled \nwork hours for the previous week was based on empirical \nknowledge. The bias may be mitigated given that the recall \nperiod was only 1 week. The HRPQ has good construct and \ncriterion validity but requires further research and reliabil-\nity testing [19]. The productivity outcomes reported here \nwere from a large cohort of patients in a randomized, well-\ncontrolled clinical trial, and therefore may not be representa-\ntive of the general population of women with endometriosis. \nFurthermore, the study was not designed to compare out-\ncomes between the two doses of elagolix, only to compare \noutcomes against placebo. While many sociodemographic \nand health characteristics can influence a person’s participa-\ntion in the workforce, this study did not evaluate the impact \nof these factors on productivity outcomes. Although women \ntreated with placebo reported higher-than-expected produc-\ntivity improvements, the productivity gains associated with \nelagolix treatment remained significantly higher than pla-\ncebo (1.2- to 2-fold higher). It is possible that the effects \nobserved with placebo were related to use of analgesic res-\ncue medication during the trial.\nDespite these limitations, the results reported herein pro-\nvide needed insight as to the management of workplace and \nhousehold productivity impairment in women with moder -\nate to severe endometriosis-associated pain. Moreover, these \ndata are important to dispel negative perceptions of women \nwith endometriosis, such as exaggeration of symptoms [26] \nand using endometriosis as an excuse to avoid work. The \ndata in this study argue against the idea that women with \nendometriosis are simply avoiding work and further rein-\nforce the pervasive and debilitating nature of endometriosis. \nOverall, elagolix appears to reverse endometriosis-related \nproductivity losses, enhancing women’s HRQOL and reduc-\ning the indirect costs of endometriosis.\n5  Conclusion\nWomen with moderate to severe endometriosis-associated \npain experience substantial impairments in workplace and \nhousehold productivity, both in work hours missed and \nreduced work effectiveness due to symptoms. Treatment \nwith elagolix 150 mg QD or 200 mg BID significantly \nimproves workplace and household productivity among \nwomen with moderate to severe endometriosis-associated \npain. Further research is needed to assess long-term treat-\nment with elagolix as a management strategy for endome-\ntriosis-associated pain and concomitant productivity loss.\nData Sharing Statement AbbVie is committed to respon-\nsible data sharing regarding the clinical trials we sponsor. \nAccess is provided to anonymized, patient- and trial-level \ndata (analysis data sets), as well as other information (e.g., \nprotocols and Clinical Study Reports) from AbbVie-spon-\nsored phase II–IV global interventional clinical trials con-\nducted in patients (completed as of May 2004, for products \nand indications approved in either the United States or the \nEuropean Union), as long as the trials are not part of an \nongoing or planned regulatory submission). This includes \nrequests for clinical trial data for unlicensed products and \nindications.\nAccess to this clinical trial data can be requested by any \nqualified researchers who engage in rigorous, independent \nscientific research, and will be provided following review \nand approval of a research proposal and Statistical Analy -\nsis Plan (SAP) and execution of a Data Sharing Agreement \n(DSA). Data requests can be submitted at any time and the \ndata will be accessible for 12 months, with possible exten-\nsions considered. For more information on the process, or \nto submit a request, visit the following link: https ://www.\nabbvi e.com/our-scien ce/clini cal-trial s/clini cal-trial s-data-\nand-infor  matio n-shari  ng/data-and-infor  matio n-shari  ng-\nwith-quali fied-resea rcher s.html.\nAcknowledgements This study was funded by AbbVie, Inc. AbbVie \nsponsored the study; contributed to the design; participated in collec-\ntion, analysis, and interpretation of data; and in writing, reviewing, and \napproval of the final version. Medical writing assistance was provided \nby Emily Mercadante, PhD, of JK Associates, Inc., a member of the \nFishawack Group of Companies, Conshohocken, PA, USA, and was \nfunded by AbbVie, Inc., North Chicago, IL, USA.\nAuthors’ contributions All authors were responsible for the study’s \ndesign and conception and for interpretation of data, drafting of the \nmanuscript, and critical revision of the manuscript for important intel-\nlectual content. Statistical analyses were performed by A.M. Soliman \nand H.L. Palac. All authors read and approved the final manuscript.\nCompliance with Ethical Standards \nFunding This study was funded by AbbVie, North Chicago, IL, USA. \nAbbVie was involved in developing the study concept and participated \nin the analysis and interpretation of the data; preparation, review, and \napproval of the article; and decision to submit the article for publica-\ntion.\nConflict of interest Eric S. Surrey is Medical Director at Colorado \nCenter for Reproductive Medicine, has served in a consulting role for \nAbbVie and DOT Laboratories, received research grants from AbbVie, \nand served on the speaker bureau for AbbVie and Ferring Laborato-\nries. Ahmed M. Soliman is an employee of, owns stock/stock options, \nand holds patents for AbbVie. Hannah L. Palac was an employee of \nAbbVie Inc. at the time the research was conducted. Sanjay K. Agar -\nwal is Director of Fertility Services in the UC San Diego Department \nof Reproductive Medicine, Director of the UC San Diego Center for \nEndometriosis Research and Treatment, and has served in a consulting \nrole on research for AbbVie Inc. and has received research support \nfrom AbbVie Inc.\n\n660 E. S. Surrey et al.\nEthical approval Shulman Associates Institutional Review Board (IRB) \nconducted the majority of the IRB approvals at each study center. The \ntrial was conducted in accordance with the Declaration of Helsinki and \nInternational Conference on Harmonisation guidelines.\nInformed consent Informed consent was obtained from all individuals \nparticipating in the study.\nOpen Access This article is distributed under the terms of the Crea-\ntive Commons Attribution-NonCommercial 4.0 International License \n(http://creat iveco mmons .org/licen ses/by-nc/4.0/), which permits any \nnoncommercial use, distribution, and reproduction in any medium, \nprovided you give appropriate credit to the original author(s) and the \nsource, provide a link to the Creative Commons license, and indicate \nif changes were made.\nReferences\n 1. Reis FM, Petraglia F, Taylor RN. Endometriosis: hormone regu-\nlation and clinical consequences of chemotaxis and apoptosis. \nHum Reprod Update. 2013;19(4):406–18. https ://doi.org/10.1093/\nhumup d/dmt01 0.\n 2. Fuldeore MJ, Soliman AM. Prevalence and symptomatic burden of \ndiagnosed endometriosis in the United States: national estimates \nfrom a cross-sectional survey of 59,411 women. Gynecol Obstet \nInvest. 2017;82(5):453–61. https ://doi.org/10.1159/00045 2660.\n 3. Abbas S, Ihle P, Koster I, Schubert I. Prevalence and incidence \nof diagnosed endometriosis and risk of endometriosis in patients \nwith endometriosis-related symptoms: findings from a statutory \nhealth insurance-based cohort in Germany. Eur J Obstet Gynecol \nReprod Biol. 2012;160(1):79–83. https ://doi.org/10.1016/j.ejogr \nb.2011.09.041.\n 4. Wheeler JM. Epidemiology of endometriosis-associated infertility. \nJ Reprod Med. 1989;34(1):41–6.\n 5. Kennedy S, Bergqvist A, Chapron C, D’Hooghe T, Dunselman \nG, Greb R, et al. ESHRE guideline for the diagnosis and treat-\nment of endometriosis. Hum Reprod. 2005;20(10):2698–704. \nhttps ://doi.org/10.1093/humre p/dei13 5.\n 6. Johnson NP, Hummelshoj L, World Endometriosis Society \nMontpellier Consortium. Consensus on current management \nof endometriosis. Hum Reprod. 2013;28(6):1552–68. https ://\ndoi.org/10.1093/humre p/det05 0.\n 7. De Graaff AA, D’Hooghe TM, Dunselman GA, Dirksen CD, \nHummelshoj L, WERF EndoCost Consortium, et al. The sig-\nnificant effect of endometriosis on physical, mental and social \nwellbeing: results from an international cross-sectional survey. \nHum Reprod. 2013;28(10):2677–85. https ://doi.org/10.1093/\nhumre p/det28 4.\n 8. Soliman AM, Coyne KS, Zaiser E, Castelli-Haley J, Fuldeore \nMJ. The burden of endometriosis symptoms on health-related \nquality of life in women in the United States: a cross-sectional \nstudy. J Psychosom Obstet Gynaecol. 2017;38(4):238–48. https  \n://doi.org/10.1080/01674 82X.2017.12895 12.\n 9. Culley L, Law C, Hudson N, Denny E, Mitchell H, Baumgarten \nM, et al. The social and psychological impact of endometrio-\nsis on women’s lives: a critical narrative review. Hum Reprod \nUpdate. 2013;19(6):625–39. https ://doi.org/10.1093/humup d/\ndmt02 7.\n 10. Nnoaham KE, Hummelshoj L, Webster P, d’Hooghe T, de Cicco \nNardone F, de Cicco Nardone C et al. Impact of endometriosis on \nquality of life and work productivity: a multicenter study across \nten countries. Fertil Steril. 2011;96(2):366–73 e8. https ://doi.\norg/10.1016/j.fertn stert .2011.05.090.\n 11. Fourquet J, Baez L, Figueroa M, Iriarte RI, Flores I. Quantification \nof the impact of endometriosis symptoms on health-related quality \nof life and work productivity. Fertil Steril. 2011;96(1):107–12. \nhttps ://doi.org/10.1016/j.fertn stert .2011.04.095.\n 12. Simoens S, Dunselman G, Dirksen C, Hummelshoj L, Bokor A, \nBrandes I, et al. The burden of endometriosis: costs and quality of \nlife of women with endometriosis and treated in referral centres. \nHum Reprod. 2012;27(5):1292–9. https ://doi.org/10.1093/humre \np/des07 3.\n 13. Fourquet J, Gao X, Zavala D, Orengo JC, Abac S, Ruiz A, et al. \nPatients’ report on how endometriosis affects health, work, \nand daily life. Fertil Steril. 2010;93(7):2424–8. https ://doi.\norg/10.1016/j.fertn stert .2009.09.017.\n 14. Soliman AM, Coyne KS, Gries KS, Castelli-Haley J, Snabes MC, \nSurrey ES. The effect of endometriosis symptoms on absentee-\nism and presenteeism in the workplace and at home. J Manag \nCare Spec Pharm. 2017;23(7):745–54. https ://doi.org/10.18553  \n/jmcp.2017.23.7.745.\n 15. Soliman AM, Surrey E, Bonafede M, Nelson JK, Castelli-Haley \nJ. Real-world evaluation of direct and indirect economic burden \namong endometriosis patients in the United States. Adv Ther. \n2018;35(3):408–23. https ://doi.org/10.1007/s1232 5-018-0667-3.\n 16. Barbieri RL. Hormone treatment of endometriosis: the estrogen \nthreshold hypothesis. Am J Obstet Gynecol. 1992;166(2):740–5. \nhttps ://doi.org/10.1016/0002-9378(92)91706 -g.\n 17. Ng J, Chwalisz K, Carter DC, Klein CE. Dose-dependent sup-\npression of gonadotropins and ovarian hormones by elagolix \nin healthy premenopausal women. J Clin Endocrinol Metab. \n2017;102(5):1683–91. https ://doi.org/10.1210/jc.2016-3845.\n 18. Taylor HS, Giudice LC, Lessey BA, Abrao MS, Kotarski J, Archer \nDF, et al. Treatment of endometriosis-associated pain with elago-\nlix, an oral GnRH antagonist. N Engl J Med. 2017;377(1):28–40. \nhttps ://doi.org/10.1056/NEJMo a1700 089.\n 19. Tundia N, Hass S, Fuldeore MJ, Wang L, Cavanaugh T, Boone \nJ, et al. Validation and U.S. population norms of health-related \nproductivity questionnaire. Value Health. 2014;18(3):A24.\n 20. Buono JL, Carson RT, Flores NM. Health-related quality of life, \nwork productivity, and indirect costs among patients with irrita-\nble bowel syndrome with diarrhea. Health Qual Life Outcomes. \n2017;15(1):35. https ://doi.org/10.1186/s1295 5-017-0611-2.\n 21. Stewart WF, Ricci JA, Chee E, Morganstein D, Lipton R. Lost \nproductive time and cost due to common pain conditions in \nthe US workforce. JAMA. 2003;290(18):2443–54. https  ://doi.\norg/10.1001/jama.290.18.2443.\n 22. Surrey ES, Soliman AM, Johnson SJ, Davis M, Castelli-Haley J, \nSnabes MC. Risk of developing comorbidities among women with \nendometriosis: a retrospective matched cohort study. J Womens \nHealth (Larchmt). 2018;27(9):1114–23. https ://doi.org/10.1089/\njwh.2017.6432.\n 23. Touboul C, Amate P, Ballester M, Bazot M, Fauconnier A, \nDarai E. Quality of life assessment using EuroQOL EQ-5D \nquestionnaire in patients with deep infiltrating endometriosis: \nthe relation with symptoms and locations. Int J Chronic Dis. \n2013;2013:452134. https ://doi.org/10.1155/2013/45213 4.\n 24. Surrey ES, Soliman AM, Agarwal SK, Snabes MC, Diamond MP. \nImpact of elagolix treatment on fatigue experienced by women \nwith moderate to severe pain associated with endometriosis. Fertil \nSteril. 2019. https ://doi.org/10.1016/j.fertn stert .2019.02.031.\n 25. Moradi M, Parker M, Sneddon A, Lopez V, Ellwood D. \nImpact of endometriosis on women’s lives: a qualita-\ntive study. BMC Womens Health. 2014;14:123. https ://doi.\norg/10.1186/1472-6874-14-123.\n 26. Whelan E. ‘No one agrees except for those of us who have \nit’: endometriosis patients as an epistemological community. \nSociol Health Illn. 2007;29(7):957–82. https ://doi.org/10.111\n1/j.1467-9566.2007.01024 .x.","source_license":"CC0","license_restricted":false}