Impact of Elagolix on Workplace and Household Productivity Among Women with Moderate to Severe Pain Associated with Endometriosis: A Pooled Analysis of Two Phase III Trials

Background Endometriosis profoundly impairs women’s workplace and household productivity.

The aim of this study was to evaluate the impact of elagolix on endometriosis-related workplace and household productivity losses.

Data were pooled from two phase III trials of women aged 18–49 years with moderate to severe endometriosis-associated pain treated for 6 months with elagolix 150 mg daily (QD), 200 mg twice daily (BID), or placebo. The Health-Related Productiv- ity Questionnaire was administered at baseline, Month 3, and Month 6 to determine workplace and household absenteeism and presenteeism. Productivity changes from baseline were compared between placebo and elagolix doses via analysis of covariance.

Workplace analyses included 1270 employed women and household analyses included 1565 women. At baseline, women reported average weekly losses of 16 workplace hours, 8.3 household work hours, 45% of scheduled work, and 64% of planned household chores. At Month 6, treatment with elagolix 150 mg QD or 200 mg BID increased productive workplace hours by 1.7 (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% CI 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 household 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), with 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.

Treatment with elagolix improved endometriosis-related workplace and household productivity impairments. Trial Registration ELARIS EM-I (NCT01620528) and ELARIS EM-II (NCT01931670) Data presented in this communication were reported in part at the International Society for Pharmacoeconomics and Outcomes Research Annual Conference, May 18–22, 2019, New Orleans, LA, USA. * Eric S. Surrey [email protected] 1 Colorado Center for Reproductive Medicine, 10290 RidgeGate Circle, Lone Tree, CO 80124, USA 2 AbbVie Inc., North Chicago, IL, USA 3 Center for Endometriosis Research and Treatment, University of California, San Diego, CA, USA Key Points for Decision Makers Endometriosis and its associated pain symptoms have been shown to profoundly reduce women’s health-related quality of life as well as impair employment-based and household productivity. This is the first pooled analysis of data from randomized, placebo-controlled studies investigating the impact of treatment on workplace and household productivity impairment in a large cohort of women with moderate to severe endometriosis-associated pain. Women with moderate to severe endometriosis-associ- ated pain treated with elagolix 150 mg daily or 200 mg twice daily reported significant improvements in work- place and household productivity after 3 and 6 months of treatment compared with productivity prior to treatment and compared with women given placebo. 652 E. S. Surrey et al. 1 Introduction Endometriosis is a common gynecological disease in which endometrial-like tissue grows outside of the uterus in an estrogen-dependent manner [1 ]. Ectopic endometrial growths are associated with a chronic inflammatory state that promotes disease progression [2 ]. The condition is found in women of reproductive age, with the highest prev- alence in women aged 35–44 years [3 ]. It is estimated that endometriosis affects approximately 10% of women world- wide [4], with a recent survey reporting a 6.1% prevalence among women aged 18–49 years in the United States of America (USA) [2]. The most prominent symptom of endo- metriosis is pain, which can include dysmenorrhea, chronic pelvic pain, lower back pain, dyspareunia, pain at ovula- tion, dyschezia, and dysuria; women with endometriosis also experience menorrhagia, fatigue, and infertility [5 –7]. Many studies have found that endometriosis has a sub- stantial negative impact on women’s health-related quality of life (HRQOL) [7 –11]. The chronic nature of endome- triosis and the prominence of pain symptoms consider - ably affect all aspects of women’s social, emotional, and physical well-being [7 –9, 11]. Women with endometrio- sis report physical limitations such as impaired mobility, reduced energy, and difficulties performing daily activi- ties and self-care [11, 12]. Furthermore, women com- monly report experiencing anxiety/stress, depression, and negative impacts on intimate relationships and reproduc- tive planning [8 , 11–13]. A large, cross-sectional study of women with endometriosis in the USA found that the severity and number of symptoms was inversely correlated with HRQOL [2 ]. In particular, pelvic pain/cramping dur - ing menstrual periods, general abdominal pain, irregular periods, and dyspareunia had the most significant negative impacts on HRQOL [2 ]. In addition to the established negative effects of endo- metriosis on mental and physical well-being, several stud- ies have documented the profound impact of endometrio - sis-associated symptoms on both employment-based and household productivity [9 –11, 13, 14]. Missed time from work (absenteeism) and reduced effectiveness while at work (presenteeism) comprise overall workplace productivity loss. Women with endometriosis reportedly miss, on aver - age, 3–13% of work time owing to absenteeism and lose 14–65% of productive work time owing to endometriosis symptoms, especially pain [10, 11, 14]. Reduced productiv- ity in the household has also been reported; in one study, up to 79% of women reported significant impairments in performing household chores [13]. Moreover, a population- based survey of women with endometriosis demonstrated a correlation between symptom severity and loss of productiv- ity in the workplace and the household. Loss of workplace productivity in women with endometriosis carries a sub- stantial societal economic burden. In the USA, the indirect cost of workplace absenteeism and short- and long-term disability in women with endometriosis was estimated to be US$2132 per patient per year, which does not factor in losses due to presenteeism [15]. A 2011 study in the USA estimated that monetary losses due to presenteeism were fivefold higher than those due to absenteeism, with approxi- mately US$250 lost per week per patient from presenteeism and US$50 lost per week per patient from absenteeism [10]. Given the substantial burden that endometriosis symp- toms place on women’s HRQOL and the high indirect costs to society, management strategies are needed to mitigate productivity loss associated with endometriosis. Estrogen is central to the pathophysiology of endometriosis, promoting endometrial tissue growth and inflammation [1]. Therefore, reduced estrogen can alleviate endometriosis-related symp- toms, including pain [16]. Elagolix is an oral gonadotropin- releasing hormone receptor antagonist that results in dose- dependent suppression of gonadotropins and ovarian sex steroids [17 , 18]. Two phase III trials (ELARIS EM-I and ELARIS EM-II) have demonstrated that elagolix 150 mg once daily (QD) and 200 mg twice daily (BID) improves dysmenorrhea and nonmenstrual pelvic pain in women with moderate to severe pain associated with endometriosis after 3 and 6 months of treatment [18]. This post hoc analysis was conducted on data pooled from the ELARIS EM-I and EM-II trials to evaluate the impact of elagolix on workplace and household productivity in a large population of women with moderate to severe endometriosis-associated pain. 2 Methods 2.1 Study Design and Participants The data for these analyses were pooled from two inter - national phase III trials (ELARIS EM-I [NCT01620528] and ELARIS EM-II [NCT01931670]) for which the study designs and participant recruitment have been previ- ously described [18]. Briefly, both were randomized, double-blind, multicenter, placebo-controlled studies that evaluated the efficacy and safety of two doses of elago- lix (150 mg QD or 200 mg BID) versus placebo in pre- menopausal women with moderate to severe endometri - osis-associated pain [18]. Women aged 18–49 years who received a surgical diagnosis of endometriosis in the previ- ous 10 years and who had moderate to severe endometrio- sis-associated pain were included in these studies. Women with a clinically significant gynecologic or chronic pain condition unrelated to endometriosis were excluded. Women were randomly assigned 2:2:3 to receive elago - lix 150 mg QD, 200 mg BID, or placebo for 6 months, 653 Elagolix and Endometriosis-Associated Productivity Loss with a 12-month follow-up period, or optional enrollment in a 6-month open-label extension period. The primary endpoints in both studies were the proportion of women with a clinical response (clinically meaningful reduction in pain score and decreased or stable use of analgesics) for dysmenorrhea and nonmenstrual pelvic pain at 3 months [18]. Patient-reported outcomes were measured as second- ary outcomes in these studies. The present study evalu- ated change from baseline to each visit during the 6-month treatment period (Months 3 and 6) in workplace and household productivity per the Health-Related Productiv - ity Questionnaire (HRPQ) [19]. Outcomes of patients in the extension period were not evaluated in this analysis. 2.2 Health‑Related Productivity Questionnaire (HRPQ) This post hoc analysis was performed to evaluate data from the administered HRPQ at baseline and during Months 3 and 6 of treatment. The HRPQ is a 9-item questionnaire that assesses a patient’s ability to perform employment- based work and daily activities in the home, measur - ing absenteeism (work time missed) and presenteeism (reduced work effectiveness) because of endometriosis in the workplace and in the household [19]. Patients who were employed part- or full-time and had scheduled work hours in the week prior to survey completion were eligible to respond to questions regarding workplace productiv - ity. All patients with planned household work hours in the week prior to taking the survey, regardless of employ - ment status, could answer questions related to household productivity. Respondents were asked to report scheduled employment-based work hours and planned household work hours in the previous week, which included house- hold activities such as cooking, cleaning, gardening, and repairs. The HRPQ was modified to be specific to endometrio- sis, asking study participants, “Did endometriosis-associ- ated pain or its treatment(s) keep you from working any of your scheduled hours during the last week?” If the answer was “Yes,” respondents gave the number of hours missed. To assess workplace presenteeism, study participants were asked, “For the hours that you did work during the past week, how did endometriosis-associated pain or its treatment(s) impact your work output?” Response options were on a 0–100% scale in which 0% indicated that endo- metriosis-associated pain/treatment had no impact on how much was accomplished and 100% indicated that endome- triosis-associated pain/treatment prevented the respondent from accomplishing anything. The hours lost to presentee- ism were then calculated as: The same questions were asked regarding the impact of endometriosis-associated pain or treatment on household productivity due to absenteeism and presenteeism. Patient responses were used to calculate the number of employment- based and household work hours spent away from workplace/ household work (absenteeism), productive hours lost while working in the workplace/household (presenteeism), and total hours lost owing to absenteeism and presenteeism in the work- place/household. The percentages of scheduled employment- based work hours and planned household work hours lost due to absenteeism, presenteeism, and in total, were calculated. 2.3 Statistical Analyses Analyses were performed with SAS version 9.3 (SAS Institute, Cary, NC, USA) using the UNIX operating sys- tem. The data were analyzed as observed, without imputa- tion for missing responses. The patients included in these analyses were those who were randomized and received at least one dose of placebo or elagolix (modified intent-to- treat population). Patients who responded to the question of absent and worked hours in the workplace at baseline were included in workplace productivity analyses. Patients who reported having planned household work hours in the week prior to taking the survey were included in house- hold productivity analyses. Least squares (LS) means were calculated for the number and percentage of hours lost to absenteeism, presenteeism, and in total at base- line. Productivity gains at Months 3 and 6 of treatment were calculated as − 1 × LS mean change from baseline in productive hours or the percentage of planned/sched- uled productive hours. Differences between elagolix dose groups and placebo at baseline were assessed using an analysis of variance (ANOVA) model with treatment as the main effect. At Months 3 and 6 of treatment, differences between elagolix dose groups and placebo were assessed using an analysis of covariance (ANCOVA) model with treatment as the main effect and baseline productivity loss as a covariate. The corresponding 95% confidence intervals (CIs) and p values were calculated. P < 0.05 was considered statistically significant. 3 Results 3.1 Baseline Characteristics A total of 1270 women with moderate to severe endometri- osis-associated pain responded to workplace productivity Presenteeism = actual hours worked × (% impact on work output ∕100). 654 E. S. Surrey et al. questions in this analysis, including 556 treated with pla- cebo, 359 treated with elagolix 150 mg QD, and 355 treated with elagolix 200 mg BID, representing 75% of all rand- omized patients. The baseline demographics and clinical characteristics for these patients were similar between treat- ment groups (Table 1). The average patient age was approxi- mately 32 years in all treatment arms, and scores were very similar or the same among groups for dysmenorrhea (2.1 [SD 0.5]), nonmenstrual pelvic pain (1.5–1.6 [SD 0.5]), and dyspareunia (1.5 [SD 0.8–0.9]). At baseline, mean total hours of workplace productivity lost in the previous week (16 h) was similar among groups, with 3 h lost owing to absenteeism and 13 h lost owing to presenteeism. Across treatment arms, women reported an average loss of 45% of scheduled workplace productivity, with fourfold greater loss due to presenteeism than the loss due to absenteeism. Household productivity data were avail- able for 1565 women who reported having planned house - hold work hours in the week prior to taking the survey, rep- resenting approximately 93% of all randomized patients (681 received placebo, 437 received elagolix 150 mg QD, and 447 received elagolix 200 mg BID; Table  1). On average, 8.3 h of household productivity were lost at baseline across treatment groups, with 4.7 h lost due to absenteeism and 3.6 h lost due to presenteeism. Women lost 64% of planned household productivity hours at baseline, with 38% loss due to absenteeism and 26% loss due to presenteeism. Therefore, absenteeism accounted for 60% of the total planned house- hold productivity lost, whereas presenteeism accounted for 40% of planned household productivity lost. Table 1 Baseline characteristics of patients in analysis (modified intent-to-treat)a a Women employed full- or part-time with scheduled work hours in the week prior to taking the survey were included in workplace productivity analyses (n = 1270); women with planned household work hours in the week prior to taking the survey, regardless of employment status, were included in household productivity analyses (n = 1565) b 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 c 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 35-day interval. Subjects responding ‘not applicable’ for the entire 35-day interval are excluded for a total of 1384 subjects with baseline dys- pareunia pain responses BID twice daily, BMI body mass index, LS least squares, N/A not applicable, QD once daily, SD standard deviation, SE standard error Characteristic N Placebo N Elagolix 150 mg QD N Elagolix 200 mg BID Age, years, mean ± SD 556 32.7 ± 6.5 359 32.4 ± 6.4 355 32.4 ± 6.6 BMI, kg/m2, mean ± SD 553 27.5 ± 6.1 358 27.7 ± 6.6 351 27.3 ± 6.4 Dysmenorrhea score, mean ± SD (scale 0–3)b 556 2.1 ± 0.5 359 2.1 ± 0.5 355 2.1 ± 0.5 Nonmenstrual pelvic pain score, mean ± SD (scale 0–3)b 556 1.6 ± 0.5 359 1.6 ± 0.5 355 1.5 ± 0.5 Dyspareunia 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 Hours of scheduled employment-based work in previous week, LS mean ± SE 556 33.0 ± 0.5 359 34.2 ± 0.7 355 33.0 ± 0.7 Hours of workplace productivity lost, LS mean ± SE  Total hours lost 556 15.7 ± 0.5 359 16.2 ± 0.6 355 16.0 ± 0.6  Absenteeism 556 3.2 ± 0.2 359 3.0 ± 0.3 355 3.0 ± 0.3  Presenteeism 552 12.6 ± 0.4 356 13.4 ± 0.5 350 13.2 ± 0.5 Percentage of workplace productivity lost, LS mean ± SE  Total percentage of hours lost 556 44.0 ± 1.2 359 44.5 ± 1.4 355 45.3 ± 1.5  Absenteeism 556 9.8 ± 0.7 359 8.3 ± 0.9 355 9.6 ± 0.9  Presenteeism 552 34.4 ± 1.0 356 36.6 ± 1.2 350 36.3 ± 1.3 Hours 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 Hours of household productivity lost, LS mean ± SE  Total hours lost 681 8.3 ± 0.3 437 8.6 ± 0.4 447 8.1 ± 0.4  Absenteeism 681 4.7 ± 0.2 437 4.8 ± 0.3 447 4.7 ± 0.3  Presenteeism 679 3.6 ± 0.2 435 3.8 ± 0.2 443 3.4 ± 0.2 Percentage of household productivity lost, LS mean ± SE  Total percentage of hours lost 681 65.6 ± 1.1 437 63.4 ± 1.4 447 64.4 ± 1.4  Absenteeism 681 39.1 ± 1.1 437 37.4 ± 1.4 447 38.7 ± 1.4  Presenteeism 679 26.6 ± 0.7 435 26.2 ± 0.9 443 25.9 ± 0.9 655 Elagolix and Endometriosis-Associated Productivity Loss 3.2 Impact of Elagolix on Employment‑Based Productivity Women given placebo gained a total of 5.9 productive work- place hours per week by Month 3 and 6.9 h by Month 6 (Fig.  1). Both doses of elagolix were associated with sig- nificantly greater improvements than placebo in productive workplace hours per week at Months 3 and 6 of treatment (Fig.  1). At Month 3, women gained 2.4 productive work - place hours (95% CI 0.9–3.9; p = 0.002) and 4.7 productive workplace hours (95% CI 3.6–6.2; p < 0.001) per week rela- tive to placebo with elagolix 150 mg QD and 200 mg BID, respectively. At Month 6, workplace productivity increased by 1.7 h (95% CI 0.1–3.4; p = 0.041) and 5.4 h (95% CI 3.7–7.1; p < 0.001) per week relative to placebo with elago- lix 150 mg QD and 200 mg BID, respectively. Gains in pro- ductive workplace hours owing to reduced absenteeism were significantly higher than placebo for both doses at Month 3 and only the 200-mg dose at Month 6. Reduced presenteeism accounted for 63–71% of total gains relative to placebo in productive workplace hours. At Month 3, elagolix 150 mg QD and 200 mg BID were associated with 1.5-h (95% CI 0.2–2.8; p = 0.022) and 3.1-h (95% CI 1.8–4.3; p < 0.001) gains, respectively, relative to placebo in weekly productive workplace hours due to reduced presenteeism. By Month 6, women treated with elagolix 200 mg BID reported a 3.8-h (95% CI 2.4–5.2; p < 0.001) increase relative to placebo in productive workplace hours due to reduced presenteeism. Treatment with elagolix 150 mg QD or 200 mg BID was associated with significant gains over placebo in the per - centage of scheduled employment-based work hours actually worked (Fig.  2). At Month 3, women treated with elagolix 150 mg QD and 200 mg BID had gains of 6.6% (95% CI 2.7–10.4) and 11.6% (95% CI 7.7–15.5), respectively (both p < 0.001), of scheduled employment-based work relative to placebo. At Month 6, elagolix 200 mg BID was associated with a gain of 14.6% of scheduled work relative to placebo (95% CI 10.0–19.1; p < 0.001), versus a 5.2% gain with elagolix 150 mg QD (95% CI 0.7–9.7; p = 0.022). Reduced absenteeism significantly contributed to productivity gains per scheduled work with both doses of elagolix at Month 3 and with elagolix 200 mg BID at Month 6. Decreased presenteeism accounted for 59–66% of total workplace gains relative to placebo in scheduled work at Months 3 and 6 of elagolix treatment. Gains in the percentage of scheduled workplace hours from decreased presenteeism were signifi- cant with elagolix 150 mg QD and 200 mg BID at Month 3 (p = 0.021 and p < 0.001, respectively) and elagolix 200 mg BID at Month 6 (p < 0.001). 3.3 Impact of Elagolix on Household Productivity In addition to improved workplace productivity, women given placebo also gained a total of 3.0 productive household hours per week by Month 3 and 3.1 h by Month 6 (Fig.  3). Both elagolix doses were associated with improvements Fig. 1 Gains in productive workplace hours per week at Months 3 and 6 of treatment. Mean hours gained in workplace productivity from baseline, defined as −  1 × LS mean change from baseline in hours of workplace productivity lost due to absenteeism, presentee- ism, and total hours lost (absenteeism + presenteeism). ***p < 0.001; **p < 0.01; *p < 0.05. BID twice daily, CI confidence interval, LS least squares, PBO placebo, QD once daily 656 E. S. Surrey et al. in household productivity beyond the gains observed with placebo. Relative to placebo, patients treated for 3 months with elagolix 150 mg QD gained 1.4 productive household hours per week (95% CI 0.5–2.3; p = 0.004), and patients treated with elagolix 200 mg BID gained 2.0 productive household hours per week (95% CI 1.1–3.0; p < 0.001). At Month 6, household productivity gains with elagolix 150 mg QD and 200 mg BID were 1.5- and twofold higher than placebo, respectively. A total of 1.7 (95% CI 0.7–2.7) and 3.1 (95% CI 2.1–4.0) productive household hours per week were gained relative to placebo with elagolix 150 mg QD and 200 mg BID, respectively (both p < 0.001). Women treated for 3 months with both elagolix doses had signifi- cant increases in productive household hours from reduced absenteeism (p < 0.001). At Month 6, productive household hours increased by 1.0 (95% CI 0.4–1.7) and 2.0 (95% CI 1.4–2.7) hours relative to placebo due to reduced absentee- ism with elagolix 150 mg QD (p = 0.003) and 200 mg BID (p < 0.001), respectively. Gains in household productivity due to reduced presenteeism were less pronounced but still significant for women treated with elagolix 200 mg BID at Month 3 (p = 0.049) and both doses at Month 6 (150 mg QD, p = 0.016; 200 mg BID, p < 0.001). There were also large gains in the percentage of house- hold productivity per planned household work at both timepoints with both elagolix doses (Fig.  4). At Month 6, elagolix 150 mg QD was associated with a gain of 8.8% of planned household productivity relative to placebo (95% CI 3.5–14.1; p = 0.001), while elagolix 200 mg BID was associated with a gain of 20.4% relative to placebo (95% CI 15.1–25.6; p < 0.001). Reduced absenteeism at Month 6 corresponded to a gain of 4.7% (95% CI 0.6–8.8; p = 0.024) of planned household productivity relative to placebo with elagolix 150 mg QD and 13.0% (95% CI 8.9–17.0; p < 0.001) with elagolix 200 mg BID. Decreased presentee- ism accounted for a gain of 4.7% of planned household pro- ductivity relative to placebo (95% CI 1.7–7.6; p = 0.002) in women treated with elagolix 150 mg QD and 7.5% (95% CI 4.6–10.4; p < 0.001) in women treated with elagolix 200 mg BID at Month 6. 4 Discussion This analysis of pooled data from two large, placebo-con- trolled trials [18] demonstrates that treatment with elagolix significantly improves productivity in both the workplace and household among women with moderate to severe endo- metriosis-associated pain. Previous research has established a clear negative impact of endometriosis-associated pain on women’s HRQOL and productivity [7 –11]. Importantly, this study is among the first to demonstrate that a treatment which effectively manages endometriosis pain also posi- tively impacts patients’ ability to productively participate in the workforce and perform household tasks. Fig. 2 Gains in percentage of scheduled workplace productivity per week at Months 3 and 6 of treatment. Mean gains in the percentage of scheduled workplace hours worked, defined as − 1 × LS mean change from baseline in percentage of scheduled workplace hours lost due to absenteeism, presenteeism, and total (absenteeism + presenteeism). ***p < 0.001; **p < 0.01; *p < 0.05. BID twice daily, CI confidence interval, LS least squares, PBO placebo, QD once daily 657 Elagolix and Endometriosis-Associated Productivity Loss In the current study, women with moderate to severe endometriosis-associated pain experienced a signifi- cant loss in workplace and household productivity prior to treatment that approached a total of 45% of scheduled employment-based work and 64% of planned household work. The impact of endometriosis on women’s daily lives is underscored by the 20% greater loss in household productiv- ity than workplace productivity. These results are generally Fig. 3 Gains in hours of household productivity per week at Months 3 and 6 of treatment. Mean hours gained in household productivity, defined as − 1 × LS mean change from baseline in hours of household productivity lost due to absenteeism, presenteeism, and total (absen- teeism + presenteeism). ***p < 0.001; **p < 0.01; *p < 0.05. BID twice daily, CI confidence interval, LS least squares, PBO placebo, QD once daily Fig. 4 Gains in percentage of planned household productivity per week at Months 3 and 6 of treatment. Mean gains in the percentage of planned household work hours worked, defined as − 1 × LS mean change from baseline in percentage of planned household work hours lost due to absenteeism, presenteeism, and total (absenteeism + pres- enteeism). ***p < 0.001; **p < 0.01; *p < 0.05. BID twice daily, CI confidence interval, LS least squares, PBO placebo, QD once daily 658 E. S. Surrey et al. consistent with previous studies that found substantial pro- ductivity impairments in women with endometriosis [10, 11, 13, 14]. At baseline, women in this study lost an aver - age of 16 h of workplace productivity and 8 h of household productivity per week. The magnitude of productivity losses reported here by women with endometriosis are greater than those reported by patients with other chronic pain condi- tions. Patients with rheumatoid arthritis reported a total of 29% workplace productivity loss and 41% impairment of daily activities, and patients with inflammatory bowel dis- ease reported an overall 21% work productivity loss and 30% activity impairment [20]. At baseline, common pain condi- tions, such as headache and back pain, were associated with 3.5 and 5.3 h of productive work time lost per week, respec- tively [21], significantly less work time lost than reported here. Impaired productivity not only stems from pain-related endometriosis symptoms, but also from moderate/severe symptoms such as fatigue, heavy menstrual bleeding, spot- ting/bleeding during periods, irregular periods, and bloating. Moreover, women with endometriosis have a significantly higher incidence of comorbid conditions [22]. The pres- ence of comorbid ovarian cysts, depression, and hyperten- sion were found to be strong predictors for workplace and household productivity losses, suggesting that comorbid conditions may increase productivity loss. Treatment with elagolix was associated with significant gains in productive workplace hours, equivalent to restor - ing 1–1.5 work days per week, versus 0.75 work days per week with placebo. The impact of endometriosis on women’s participation in the workforce may be underappreciated if based solely on time absent from work. Decreased efficiency and productivity while at work due to endometriosis-related symptoms (presenteeism) heavily contributes to productivity losses. In the current study, workplace productivity losses at baseline due to presenteeism were approximately 4–4.5 times as large as losses due to absenteeism. Previous studies in women with endometriosis have documented 2.3 [10], 2.7 [11], and 4.8 [14] times greater work productivity losses from presenteeism. These findings suggest that women with endo- metriosis are present at work despite experiencing symptoms that limit their ability to effectively perform work [10, 11, 14]. Symptoms that predict poor performance at work include dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, irregular periods, abdominal pain, incapacitating pain, and depression [13, 14]. Unlike workplace productivity losses, household productivity losses at baseline due to absenteeism and presenteeism were similar, with approximately 1.4 times greater productivity loss due to absenteeism than presentee- ism. The ratio of household absenteeism to presenteeism reported in the current study is similar to that reported pre- viously (ratio 1.1) in women in the USA with endometriosis. Importantly, women treated with elagolix 150 mg QD and 200 mg BID reported substantial improvements in workplace and household productivity, including produc- tivity gains due to reduced absenteeism and presenteeism, compared with women given placebo. Significant gains in both workplace and household productivity were reported by Month 3 of treatment with elagolix and persisted or were greater by Month 6. Generally, elagolix 200 mg BID was associated with greater improvements in productiv - ity than elagolix 150 mg QD. By Month 6, treatment with elagolix 200 mg BID was associated with a 15% increase in workplace productivity per scheduled work hours and a 20% increase in household productivity per planned house- hold work hours, relative to placebo. Taken together, these patient-reported results suggest that elagolix 150 mg QD and 200 mg BID effectively mitigate the negative impact of endometriosis symptoms on employment-based and house- hold productivity. Elagolix 150 mg QD and 200 mg BID reduce dysmenor - rhea and nonmenstrual pelvic pain [18], symptoms which, when moderate or severe, are strongly correlated with greater productivity losses [14]. In ELARIS EM-I and EM-II studies, 42.1–46.4% of women taking elagolix 150 mg QD and 72.4–76.9% of women taking elagolix 200 mg BID experienced clinically meaningful pain reduction and decreased or stable use of rescue analgesics for dysmenor - rhea over 6 months of treatment, compared with 19.6–25.4% of women receiving placebo [18]. Women receiving both elagolix doses also experienced pain reduction and reduced analgesic use for nonmenstrual pelvic pain (45.7–51.6% with elagolix 150 mg QD; 54.5–62.2% with elagolix 200 mg BID; 34.9–40.6% with placebo) [18]. The current analysis was not designed to correlate pain improvement scores with productivity improvements, and it is therefore possi- ble that the impact of elagolix on non-pain symptoms may also contribute to improvements in productivity. Beyond pain, fatigue is a highly prevalent symptom of endometrio- sis, which may be intense and bothersome [ 8, 23, 24] and has been associated with impairments in workplace, house- hold, and social activities [14, 25]. Treatment with elagolix 150 mg QD and 200 mg BID significantly improves fatigue at both 3 and 6 months of treatment in women with mod- erate to severe endometriosis-associated pain [24]. Fatigue and endometriosis-associated pain symptoms are inter - related, with individual pain symptoms (dysmenorrhea, nonmenstrual pelvic pain, dyspareunia) increasing fatigue [24]. Thus, improvements in endometriosis-associated pain and fatigue from elagolix treatment may both play a role in improving productivity. The present study is the first to assess whether an endo- metriosis treatment can address the substantial productiv - ity impairments women experience, but the study has some limitations. As previously discussed, the HRPQ is a self- reported instrument and therefore results may suffer from recall bias and reporting errors. For example, reporting on 659 Elagolix and Endometriosis-Associated Productivity Loss planned household chore hours for the previous week relied on a priori prediction of the number of hours respondents intended to spend on household chores, whereas scheduled work hours for the previous week was based on empirical knowledge. The bias may be mitigated given that the recall period was only 1 week. The HRPQ has good construct and criterion validity but requires further research and reliabil- ity testing [19]. The productivity outcomes reported here were from a large cohort of patients in a randomized, well- controlled clinical trial, and therefore may not be representa- tive of the general population of women with endometriosis. Furthermore, the study was not designed to compare out- comes between the two doses of elagolix, only to compare outcomes against placebo. While many sociodemographic and health characteristics can influence a person’s participa- tion in the workforce, this study did not evaluate the impact of these factors on productivity outcomes. Although women treated with placebo reported higher-than-expected produc- tivity improvements, the productivity gains associated with elagolix treatment remained significantly higher than pla- cebo (1.2- to 2-fold higher). It is possible that the effects observed with placebo were related to use of analgesic res- cue medication during the trial. Despite these limitations, the results reported herein pro- vide needed insight as to the management of workplace and household productivity impairment in women with moder - ate to severe endometriosis-associated pain. Moreover, these data are important to dispel negative perceptions of women with endometriosis, such as exaggeration of symptoms [26] and using endometriosis as an excuse to avoid work. The data in this study argue against the idea that women with endometriosis are simply avoiding work and further rein- force the pervasive and debilitating nature of endometriosis. Overall, elagolix appears to reverse endometriosis-related productivity losses, enhancing women’s HRQOL and reduc- ing the indirect costs of endometriosis. 5 Conclusion Women with moderate to severe endometriosis-associated pain experience substantial impairments in workplace and household productivity, both in work hours missed and reduced work effectiveness due to symptoms. Treatment with elagolix 150 mg QD or 200 mg BID significantly improves workplace and household productivity among women with moderate to severe endometriosis-associated pain. Further research is needed to assess long-term treat- ment with elagolix as a management strategy for endome- triosis-associated pain and concomitant productivity loss. Data Sharing Statement AbbVie is committed to respon- sible data sharing regarding the clinical trials we sponsor. Access is provided to anonymized, patient- and trial-level data (analysis data sets), as well as other information (e.g., protocols and Clinical Study Reports) from AbbVie-spon- sored phase II–IV global interventional clinical trials con- ducted in patients (completed as of May 2004, for products and indications approved in either the United States or the European Union), as long as the trials are not part of an ongoing or planned regulatory submission). This includes requests for clinical trial data for unlicensed products and indications. Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analy - sis Plan (SAP) and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time and the data will be accessible for 12 months, with possible exten- sions considered. For more information on the process, or to submit a request, visit the following link: https ://www. abbvi e.com/our-scien ce/clini cal-trial s/clini cal-trial s-data- and-infor matio n-shari ng/data-and-infor matio n-shari ng- with-quali fied-resea rcher s.html.

This study was funded by AbbVie, Inc. AbbVie sponsored the study; contributed to the design; participated in collec- tion, analysis, and interpretation of data; and in writing, reviewing, and approval of the final version. Medical writing assistance was provided by Emily Mercadante, PhD, of JK Associates, Inc., a member of the Fishawack Group of Companies, Conshohocken, PA, USA, and was funded by AbbVie, Inc., North Chicago, IL, USA. Authors’ contributions All authors were responsible for the study’s design and conception and for interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intel- lectual content. Statistical analyses were performed by A.M. Soliman and H.L. Palac. All authors read and approved the final manuscript. Compliance with Ethical Standards Funding This study was funded by AbbVie, North Chicago, IL, USA. AbbVie was involved in developing the study concept and participated in the analysis and interpretation of the data; preparation, review, and approval of the article; and decision to submit the article for publica- tion. Conflict of interest Eric S. Surrey is Medical Director at Colorado Center for Reproductive Medicine, has served in a consulting role for AbbVie and DOT Laboratories, received research grants from AbbVie, and served on the speaker bureau for AbbVie and Ferring Laborato- ries. Ahmed M. Soliman is an employee of, owns stock/stock options, and holds patents for AbbVie. Hannah L. Palac was an employee of AbbVie Inc. at the time the research was conducted. Sanjay K. Agar - wal is Director of Fertility Services in the UC San Diego Department of Reproductive Medicine, Director of the UC San Diego Center for Endometriosis Research and Treatment, and has served in a consulting role on research for AbbVie Inc. and has received research support from AbbVie Inc. 660 E. S. Surrey et al. Ethical approval Shulman Associates Institutional Review Board (IRB) conducted the majority of the IRB approvals at each study center. The trial was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation guidelines. Informed consent Informed consent was obtained from all individuals participating in the study. Open Access This article is distributed under the terms of the Crea- tive Commons Attribution-NonCommercial 4.0 International License (http://creat iveco mmons .org/licen ses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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