Current treatments for endometriosis in South Korea: an analysis of nationwide data from 2010 to 2019.

While a wide range of treatments, including medical therapies and surgery, are used to manage endometriosis, the characteristics and treatment status of patients who received these treatments have not been investigated in Korea. This study analyzed the Korean Health Insurance Review & Assessment Service-National Patient Sample (HIRA-NPS) data from 2010 to 2019 with 7530 patients diagnosed with endometriosis. Annual trends in the types of visit and surgery, medication prescriptions and associated costs were investigated. The analysis showed that surgery slightly decreased among the types of utilized healthcare services (2010: 16.3, 2019: 12.7), dienogest prescription rapidly increased due to national health insurance coverage from 2013 (2013: 12.1, 2019: 36.0), and the use of gonadotrophin-releasing hormone analogues decreased (2010: 33.6, 2019: 16.4). There was no significant change in total and outpatient costs per person over time. Regarding endometriosis treatment, conservative treatment mainly based on prescribed medications has been gradually replacing surgery. Particularly, the listing of dienogest for national health insurance coverage might have affected the trend. However, there were no significant changes in terms of total and medication costs per person.

Cost-effectiveness Analysis of Dienogest Compared with Combined Oral Contraceptives after Surgery for Endometriosis.

STUDY OBJECTIVE: To assess the cost-effectiveness of different strategies, including the dienogest (DNG) and combined oral contraceptives (COC) therapy, for the prevention of endometriosis recurrence after surgery. DESIGN: A decision tree model was created. The analysis was based on data from a healthcare provider in China. Model inputs were derived from published data. The end points included incremental cost effectiveness ratio, net monetary benefit (NMB), and incremental NMB associated with prevention of recurrence. The uncertainty was assessed through one way and probabilistic sensitivity analysis. The Consolidated Health Economic Evaluation Reporting Standards 2022 checklist was used to assess quality of the reporting. SETTING: China healthcare system. PATIENTS: Individuals undergoing laparoscopic surgery for endometriosis. INTERVENTIONS: DNG vs COC. MEASUREMENTS AND MAIN RESULTS: The base case analysis showed that hormone supression via DNG resulted in 0.7493 quality-adjusted life years (QALYs) at a cost of $1625.49 compared with COC, which resulted in 0.7346 QALYs at a cost of $343.61. The incremental cost effectiveness ratio was $87 679.89 per additional QALY gained and the DNG treatment was associated with an incremental NMB of -$731.39. Probabilistic sensitivity analysis indicated that DNG is not cost-effective in most cases at a threshold consistent with World Health Organisation recommendations of $37 653/QALY. CONCLUSION: The result of our present analysis suggests that the DNG might not be cost-effective for the prevention of endometriosis recurrence after surgery in China.

Assessment of Two Formulations of Triptorelin in Chinese Patients with Endometriosis: A Phase 3, Randomized Controlled Trial.

INTRODUCTION: This phase 3, randomized, open-label, active-controlled, multicenter study investigated the efficacy of triptorelin pamoate prolonged-release (PR) 3-month in Chinese patients with endometriosis by demonstrating the noninferiority of the 3-month formulation to the standard of care, triptorelin acetate PR 1-month. METHODS: The trial was conducted in 24 clinical centers in China, and included 300 Chinese women (18-45 years) with endometriosis and regular menstrual cycles who required treatment with a gonadotropin-releasing hormone agonist for 6 months. One group of patients (n = 150) was treated with triptorelin pamoate PR 3-month (15 mg per injection, once every 12 weeks), and the other (n = 150) with triptorelin acetate PR 1-month (3.75 mg per injection, once every 4 weeks). The primary outcome measure was the proportion of patients with estradiol (E2) concentrations suppressed to castration levels (≤ 184 pmol/L, or 50 pg/mL) after 12 weeks of treatment. RESULTS: Triptorelin pamoate PR 3-month was noninferior to triptorelin acetate PR 1-month for the treatment of endometriosis: over 98% of patients in both groups were chemically castrated at week 12. Both formulations were also equally efficacious in reducing endometriosis-associated pelvic pain, and reducing serum concentrations of E2, luteinizing hormone, and follicle-stimulating hormone over time. No new safety concerns were identified. CONCLUSION: Triptorelin pamoate PR 3-month is a valid alternative to triptorelin acetate PR 1-month for the treatment of Chinese women with endometriosis, with fewer injections and a potentially lower burden of care. TRIAL REGISTRATION: NCT03232281.

Assessment of Quality of Life, Sexual Quality of Life, and Pain Symptoms in Deep Infiltrating Endometriosis Patients With or Without Associated Adenomyosis and the Influence of a Flexible Extended Combined Oral Contraceptive Regimen: Results of a Prospective, Observational Study.

BACKGROUND: The quality of life of women with deep infiltrating endometriosis (DIE) is impaired and may improve with combined oral contraceptives (COCs). AIM: To compare the overall and sexual quality of life of patients diagnosed with DIE with or without associated adenomyosis (AD) with that of healthy controls and determine the influence of a COC containing 2 mg dienogest/30 µg ethinyl estradiol on these aspects. METHODS: We enrolled 42 women diagnosed with DIE; 31 diagnosed with DIE + AD by transvaginal ultrasound, and 39 non-AD/DIE controls. All patients were interviewed regarding pain symptoms (dysmenorrhea, dyspareunia, dyschezia, and dysuria), heavy menstrual bleeding using the Pictorial Blood Loss Assessment Chart, quality of life using the Short Form-36 questionnaire (SF-36), and sexual quality of life using the Sexual Quality of Life-Female questionnaire (SQOL-F) and the Brief Profile of Female Sexual Function (B-PFSF) before starting COCs and after 12 months of treatment. OUTCOMES: There was significant improvement in overall and sexual quality of life after treatment in DIE and DIE + AD patients. RESULTS: Non-AD/DIE controls showed significantly higher scores in the B-PFSF, the SQOL-F and the SF-36 questionnaires (P < .05) at baseline versus the other groups. DIE + AD patients showed poorer quality of sexual life and greater intensity in pain symptoms compared with DIE patients. After 12 months of treatment, there was a significant improvement in overall and sexual quality of life in the DIE and DIE + AD groups, with improvement in sexual quality of life being slightly greater in DIE + AD patients compared with DIE patients. Pain symptoms also decreased in both groups. CLINICAL IMPLICATIONS: Patients with DIE + AD showed greater impairment in overall and sexual quality of life compared with patients with isolated DIE which seems to improve with a COC containing 2 mg dienogest/30 µg ethinyl estradiol. STRENGTHS & LIMITATIONS: Strengths include the long-term follow up, assessment of the impact of two associated conditions, and administration of the same COC in all patients. Limitations include the relatively small sample size, and the fact that we did not assess the effectiveness of a flexible extended COC regimen containing 2 mg dienogest/30 µg ethinyl estradiol since the groups were different at baseline. CONCLUSION: Patients diagnosed with DIE with or without AD have a decreased quality of life which may improve with a COC containing 2 mg dienogest/30 µg ethinyl estradiol. Further research is needed to confirm our results. Alcalde AM, Martínez-Zamora MÁ, Gracia M, et al. Assessment of Quality of Life, Sexual Quality of Life, and Pain Symptoms in Deep Infiltrating Endometriosis Patients With or Without Associated Adenomyosis and the Influence of a Flexible Extended Combined Oral Contraceptive Regimen: Results of a Prospective, Observational Study. J Sex Med 2022;19:311-318.

Surgical and Pharmacological Treatment Patterns in Women with Endometriosis: A Descriptive Analysis of Insurance Claims.

Background: Many women with endometriosis experience chronic abdominal pain. Clinical guidelines recommend treatment with analgesics, contraceptive hormones, gonadotropin-releasing hormone analogs, and surgery. Treatment patterns in women with endometriosis are not well characterized. Methods: Data from the IBM® MarketScan® Commercial Database were accessed from 2009 to 2017. One-year baseline and follow-up periods were defined around the date of the first claim with a diagnosis of endometriosis (the index date). Women 18-49 years of age on the index date with a diagnosis of endometriosis, continuous enrollment during baseline and follow-up, and pharmacy benefits were included. The following outcomes were analyzed descriptively: baseline comorbidities; medication use and surgeries; and sequence of treatment utilization in the baseline and the follow-up period. Results: A total of 190,921 women were included. The mean ± (standard deviation) age was 39.0 ± (7.3), and abdominal/pelvic pain (36.0%) and excessive or frequent menstruation (32.0%) were the most prevalent comorbidities. In the baseline period, the utilization of pharmacological treatment was: estrogen/progestin 42.5%, opioids 41.5%, and nonsteroidal anti-inflammatory drugs (NSAIDs) 37.5%. In the follow-up period, utilization of opioids and NSAIDs increased to 68.9% and 51.1%, respectively, whereas the use of estrogen/progestin dropped to 23.8%. Surgeries were infrequent in the baseline period (6.3%). However, in the follow-up period, 27.9% of women underwent laparoscopy and 29.7% had a hysterectomy, with a total of 68.1% of the study population undergoing surgical treatment. Conclusions: A diagnosis of endometriosis is accompanied by an increase in the use of analgesics and surgical procedures. The diversity of treatments suggests a lack of clarity in management guidelines.

Effect assessment of laparoscopy in combination with traditional Chinese medicine decoction in the treatment of endometriosis: A protocol for systematic review and meta-analysis.

BACKGROUND: Endometriosis (EMs) affects about 10% of women of childbearing age. It is defined as functional endometrial tissue appearing in other parts of the uterine cavity, manifested by varying degrees of pelvic pain and pelvic mass, etc. Therefore, to improve the therapeutic effect of endometriosis, we must constantly explore new ways to treat the disease. The purpose of this study is to evaluate the effectiveness and safety of the combined use of laparoscopy and traditional Chinese medicine in the treatment of patients with EMs. METHODS: A systematic literature search will be conducted at China National Knowledge Infrastructure, WanFang databases, VIP, SinoMed, PubMed, Embase, Web of Science, and the Cochrane library. The search period limit is from the time the date of database establishment to June 21, 2021. To ensure the comprehensiveness of the search, relevant references and conference literature are also included. The risk of bias in the final included studies will be evaluated based on the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. The RevMan software will be employed to perform data synthesis and statistical analysis. RESULTS: The effectiveness and safety of laparoscopic surgery combined with traditional Chinese medicine decoction in the treatment of patients with EMs will be systematically evaluated. CONCLUSION: The results of this study will provide strong evidence for judging whether laparoscopy combined with traditional Chinese medicine decoction is an effective strategy for the treatment of patients with EMs.

Cost-effectiveness Analysis of Dienogest Compared With Gonadotropin-Releasing Hormone Agonist After Conservative Surgery for Endometriosis in China.

PURPOSE: Although the clinical effect of dienogest for endometriosis after conservative surgery has been proven, the cost-effectiveness of this new pharmacotherapy remains to be determined. We aimed to assess the health economic implications of dienogest versus a gonadotropin-releasing hormone agonist (GnRH-a; goserelin in the Chinese setting. METHODS: A decision tree model was developed to evaluate the cost-effectiveness of dienogest compared with a GnRH-a (goserelin) after conservative surgery for endometriosis during a 2-year time horizon from the perspective of a health care system in China. The cost of drugs, use of outpatient care facilities, administration of medications, routine laboratory work and imaging studies, and treatment of drug-related adverse events were considered. We obtained clinical efficacy data from the peer-reviewed literature. Base case findings were further tested with 1-way and probabilistic sensitivity analyses. FINDINGS: The model projects that treatment with dienogest would result in a modest incremental 0.02 quality-adjusted life-year gains compared with a GnRH-a (goserelin) (1.48 vs 1.46) at a cost saving of ¥7274 (¥22,809 vs ¥30,164). Probabilistic sensitivity analysis found that dienogest has a 100% probability of % being considered cost-effective compared with a GnRH-a (goserelin) at the willingness-to-pay threshold of 3 times the gross domestic product per capita (¥64,644 × 3) of China in 2018 (¥1 = US$0.1454 and €0.1248). IMPLICATIONS: Dienogest is more effective and cost-saving compared with a GnRH-a (goserelin) in the treatment of patients with endometriosis after conservative surgery in China.

Short-acting and Long-acting Opioids Utilization among Women Diagnosed with Endometriosis in the United States: A Population-based Claims Study.

STUDY OBJECTIVE: To determine the prevalence and pattern of opioid use in endometriosis and the characteristics of patients prescribed an opioid using medical insurance claims data. DESIGN: We performed a retrospective cohort analysis of data from the Truven MarketScan Commercial database for the period of January 1, 2011 to December 31, 2016. SETTING: The Truven database includes inpatient, outpatient, and prescription claims covering more than 115 million unique individuals and over 36 million inpatient hospital discharges across multiple payer types and all 50 states. PATIENTS: Women with endometriosis were defined as those with 1 inpatient or 2 outpatient codes for endometriosis. INTERVENTIONS: No interventions were assigned. Women who filled an opioid prescription within 12 months of diagnosis were placed in the opioid cohort and women who did not fill an opioid prescription were placed in the nonopioid cohort. MEASUREMENTS AND MAIN RESULTS: Baseline characteristics were evaluated 12 months preindex (date of the first diagnosis) and opioid use was assessed for 12 months after the index date. The dataset included 58 472 women with endometriosis. Of these, 61.7% filled an opioid prescription during the study period. More than 95% filled prescriptions for short-acting opioids (SAOs) only, 4.1% filled prescriptions for both SAOs and extended-release/long-acting opioids (LAOs), and 0.6% filled prescriptions for LAOs only. Patients who filled an opioid prescription had higher baseline comorbidities (especially gynecologic and chronic pain comorbidities) and endometriosis-related medication use compared with patients who did not fill an opioid prescription during the study period. Patients who filled both LAO and SAO prescriptions had the highest total days' supply of opioids, the proportion of days covered by prescriptions, and morphine equivalent daily dose. These patients also had the highest proportions of opioid switching and dose augmentation. Statistical trends in data were not substantially altered when analyses excluded patients with chronic pain comorbidities or surgical opioid prescriptions. CONCLUSION: Although opioids are not a recommended treatment for endometriosis, more than half of our cohort filled an opioid prescription within 1 year after a first recorded diagnosis of endometriosis. Patients who filled an opioid prescription tended to use more endometriosis-related medications and have a higher comorbidity burden. Additional research is necessary to better understand the reasons and outcomes associated with opioid utilization in endometriosis and to determine if there is a more effective pain management treatment plan for patients taking opioids.

Effect of Elagolix Exposure on Clinical Efficacy End Points in Phase III Trials in Women With Endometriosis-Associated Pain: An Application of Markov Model.

Elagolix is an oral gonadotropin-releasing hormone antagonist approved by the US Food and Drug Administration (FDA) for the management of moderate-to-severe pain associated with endometriosis and in combination with estradiol/norethindrone acetate approved for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. The objective of this work was to characterize the relationships between elagolix exposures and clinical efficacy response rates for dysmenorrhea (DYS) and nonmenstrual pelvic pain (NMPP) in premenopausal women enrolled in the pivotal phase III studies with moderate-to-severe pain associated with endometriosis. Relationships between elagolix average concentrations (Cavg ) and efficacy responses (DYS and NMPP) were characterized using a nonlinear mixed-effects discrete-time first order Markov modeling approach. Only age was statistically significant for NMPP but not considered clinically relevant. This work indicates that the selection of elagolix dose is not determined based on tested patient demographics, baseline, or endometriosis disease severity measures in covariate analysis. In other words, the work suggests no preference of one regimen over the other to treat endometriosis-associated pain (DYS or NMPP) for any patient subpopulation based on tested covariate groups.

Healthcare Resource Use and Costs Associated with Opioid Initiation Among Patients with Newly Diagnosed Endometriosis with Commercial Insurance in the USA.

INTRODUCTION: To compare all-cause and endometriosis-related healthcare resource utilization (HCRU) and healthcare costs by service categories (outpatient, inpatient, emergency room [ER], pharmacy) among patients with newly diagnosed endometriosis using opioids compared to patients with endometriosis not using opioids. METHODS: A retrospective analysis of IBM® MarketScan® Commercial Claims data from 2009 to 2018 was performed for women aged 18-49 with newly diagnosed endometriosis (International Classification of Diseases (ICD)-9 code 617.xx; ICD-10 code N80.xx) over 24 months follow-up. Patients were stratified on the basis of opioid use within 12 months post first endometriosis diagnosis date. Patients with opioid use were 1:1 matched to patients without opioid use using propensity score matching. RESULTS: A total of 85,329 female patients with a new endometriosis diagnosis were identified and 48,470 patients (24,235 opioid and 24,235 non-opioid users) remained after inclusion-exclusion criteria and matching. Opioid patients had an estimated mean 30.33 outpatient visits, 29.59 pharmacy fills, 0.28 inpatient visits, 0.65 ER visits, and total length of stay (LOS) was 1.01 days. Non-opioid patients had an estimated mean 27.94 outpatient visits, 22.06 pharmacy fills, 0.23 inpatient visits, 0.42 ER visits, and total LOS was 0.82 days. On average, opioid patients had significantly greater all-cause HCRU compared to non-opioid patients (all p < 0.0001). Among endometriosis-related healthcare utilization, there were similar ER visits, but lower outpatient visits, inpatient visits, and total LOS and higher pharmacy fills among opioid and non-opioid patients. Estimated mean all-cause costs were higher among opioid ($26,755) vs. non-opioid ($19,302) users (p < 0.0001). A similar trend was observed for estimated mean endometriosis-related costs. CONCLUSION: This analysis observed significantly higher all-cause HCRU and costs for opioid users compared to non-opioid users among patients with newly diagnosed endometriosis. While observed endometriosis-related costs were significantly higher in opioid users compared to non-opioid users during a 24-month follow-up period, endometriosis-related HCRU varied by service categories for these two populations over this time period.

Aldo-keto reductase 1C3-Assessment as a new target for the treatment of endometriosis.

Endometriosis is a common gynecological disorder, which is treated surgically and/ or pharmacologically with an unmet clinical need for new therapeutics. A completed phase I trial and a recent phase II trial that investigated the steroidal aldo-keto reductase 1C3 (AKR1C3) inhibitor BAY1128688 in endometriosis patients prompted this critical assessment on the role of AKR1C3 in endometriosis. This review includes an introduction to endometriosis with emphasis on the roles of prostaglandins and progesterone in its pathophysiology. This is followed by an overview of the major enzymatic activities and physiological functions of AKR1C3 and of the data published to date on the expression of AKR1C3 in endometriosis at the mRNA and protein levels. The review concludes with the rationale for using AKR1C3 inhibitors, a discussion of the effects of AKR1C3 inhibition on the pathophysiology of endometriosis and a brief overview of other drugs under clinical investigation for this indication.

Healthcare utilization and cost burden among women with endometriosis by opioid prescription status in the first year after diagnosis: a retrospective claims database analysis.

Aims: Opioids do not represent standard therapy for endometriosis; however, women with endometriosis are frequently prescribed an opioid to manage related abdominal or pelvic pain. The aim of this study was to evaluate the impact of opioid use on endometriosis-related economic and healthcare burden in the United States.Materials and methods: We performed a retrospective, propensity-matched cohort analysis of the Truven MarketScan Commercial database from 1 January 2011 to 31 December 2016. Eligible women had at least 1 inpatient or 2 outpatient codes for endometriosis and 12 months of continuous enrollment before and after the index date (i.e. first recorded endometriosis diagnosis). The primary analysis examined healthcare costs and utilization for 12 months after the index date in women who filled at least 1 opioid prescription versus those who did not. The secondary analysis examined healthcare costs and utilization by the pattern of opioid use.Results: The primary analysis matched 43,516 women across 2 groups and the secondary analysis matched 13,230 women across 5 groups. In the primary analysis, total 12-month healthcare costs were significantly higher in the opioid group compared to the non-opioid group ($29,236.00 vs. $18,466.00, respectively; p < .001); the same pattern was observed for all healthcare utilization parameters. In the secondary analysis, higher morphine equivalent daily dose and proportion of days covered were associated with the highest healthcare costs and utilization compared to the non-opioid group.Limitations: Retrospective design and inability to confirm whether filled opioid prescriptions were actually taken.Conclusions: Filling an opioid prescription within 1 year after an endometriosis diagnosis was associated with significant excess healthcare burden. Patients prescribed an opioid may experience inadequate symptom management and benefit from the use of disease-specific, non-opioid therapies.

Quantitative Assessment of Elagolix Enzyme-Transporter Interplay and Drug-Drug Interactions Using Physiologically Based Pharmacokinetic Modeling.

INTRODUCTION: Elagolix is approved for the management of moderate-to-severe pain associated with endometriosis. The aim of this analysis was to develop a physiologically based pharmacokinetic (PBPK) model that describes the enzyme-transporter interplay involved in the disposition of elagolix and to predict the magnitude of drug-drug interaction (DDI) potential of elagolix as an inhibitor of P-glycoprotein (P-gp) and inducer of cytochrome P450 (CYP) 3A4. METHODS: A PBPK model (SimCYP® version 15.0.86.0) was developed using elagolix data from in vitro, clinical PK and DDI studies. Data from DDI studies were used to quantify contributions of the uptake transporter organic anion transporting polypeptide (OATP) 1B1 and CYP3A4 in the disposition of elagolix, and to quantitatively assess the perpetrator potential of elagolix as a CYP3A4 inducer and P-gp inhibitor. RESULTS: After accounting for the interplay between elagolix metabolism by CYP3A4 and uptake by OATP1B1, the model-predicted PK parameters of elagolix along with the DDI AUC∞ and Cmax ratios, were within 1.5-fold of the observed data. Based on model simulations, elagolix 200 mg administered twice daily is a moderate inducer of CYP3A4 (approximately 56% reduction in midazolam AUC∞). Simulations of elagolix 150 mg administered once daily with digoxin predicted an increase in digoxin Cmax and AUC∞ by 68% and 19%, respectively. CONCLUSIONS: A PBPK model of elagolix was developed, verified, and applied to characterize the disposition interplay between CYP3A4 and OATP1B1, and to predict the DDI potential of elagolix as a perpetrator under dosing conditions that were not tested clinically. PBPK model-based predictions were used to support labeling language for DDI recommendations of elagolix.

Cost-effectiveness of elagolix versus leuprolide acetate for treating moderate-to-severe endometriosis pain in the USA.

AIM: To assess the cost-effectiveness of elagolix versus leuprolide acetate in women with moderate to severe endometriosis pain. METHODS: A Markov model was developed. The efficacy of leuprolide acetate was derived from statistical prediction models using elagolix trial data. Model inputs were extracted from Phase III clinical trials and published literature. RESULTS: Compared with leuprolide acetate, elagolix generated positive net monetary benefit (NMB) assuming a payer's willingness-to-pay threshold of US$100,000 per quality-adjusted life year over a 1-year time horizon: US$5660 for elagolix 150 mg and US$6443 for elagolix 200 mg. The 2-year NMBs were also positive. CONCLUSION: Elagolix was cost effective versus leuprolide acetate in the management of moderate to severe endometriosis pain over 1- and 2-year time horizons. Results were robust in sensitivity analyses.

Elagolix for endometriosis: all that glitters is not gold.

Elagolix, an orally active non-peptidic GnRH antagonist, has been approved by the Food and Drug Administration for the management of moderate to severe pain associated with endometriosis. As the degree of ovarian suppression obtained with elagolix is dose-dependent, pain relief may be achieved by modulating the level of hypo-oestrogenism while limiting side effects. Elagolix may thus be considered a novelty in terms of its endocrine and pharmacological properties but not for its impact on the pathogenic mechanisms of endometriosis, as the target of this new drug is, yet again, alteration of the hormonal milieu. Given the oestrogen-dependent nature of endometriosis, a reduction of side effects may imply a proportionate decrease in pain relief. Furthermore, if low elagolix doses are used, ovulation is not consistently inhibited, and patients should use non-hormonal contraceptive systems and perform serial urine pregnancy tests to rule out unplanned conception during periods of treatment-induced amenorrhoea. If high elagolix doses are used to control severe pain for long periods of time, add-back therapies should be added, similar to that prescribed when using GnRH agonists. To date, the efficacy of elagolix has only been demonstrated in placebo-controlled explanatory trials. Pragmatic trials comparing elagolix with low-dose hormonal contraceptives and progestogens should be planned to verify the magnitude of the incremental benefit, if any, of this GnRH antagonist over currently used standard treatments. The price of elagolix may impact on patient adherence and, hence, on clinical effectiveness. In the USA, the manufacturer AbbVie Inc. priced elagolix (OrilissaTM) at around $10 000 a year, i.e. $845 per month. When faced with unaffordable treatments, some patients may choose to forego care. If national healthcare systems are funded by the tax payer, the approval and the use of a new costly drug to treat a chronic condition, such as endometriosis, means that some finite financial resources will be diverted from other areas, or that similar patients will not receive the same level of care. Thus, defining the overall 'value' of a new drug for endometriosis also has ethical implications, and trade-offs between health outcomes and costs should be carefully weighed up.

Assessment of biomarkers in women with endometriosis-associated pain using the ENG contraceptive implant or the 52 mg LNG-IUS: a non-inferiority randomised clinical trial.

OBJECTIVE: The aim of the study was to assess the serum levels of the following biomarkers in women with endometriosis-associated pelvic pain before and after six months of using the etonogestrel (ENG) contraceptive implant or the 52 mg levonorgestrel-releasing intrauterine system (LNG-IUS): cancer antigen (CA)-125, cluster of differentiation (CD) 23 and endometrial nerve fibre density. METHODS: The study was conducted at the Department of Obstetrics and Gynaecology, University of Campinas Medical School, Brazil. A total of 103 women with endometriosis-associated pain diagnosed by surgery, transvaginal ultrasound and/or magnetic resonance imaging were included. Endometrial nerve fibre density and serum levels of CA-125 and soluble CD23 were assessed before and after six months of using the allocated method and were correlated to 10 cm visual analogue scale (VAS) scores for non-cyclical pelvic pain and dysmenorrhoea. RESULTS: Both contraceptive methods significantly reduced concentrations of serum soluble CD23 and endometrial nerve fibre density (p < .001); however, CA-125 was significantly reduced only among users of the ENG implant (p < .05). No correlation was observed between reduction of biomarkers and improvement of VAS pain and dysmenorrhoea scores. No differences were observed between the ENG implant and the LNG-IUS. CONCLUSION: Both progestin-only contraceptives significantly reduced two out of the three biomarkers evaluated. These two biomarkers could, therefore, be used as surrogate markers to follow up medical treatment of endometriosis-associated pain.

Drug Development in Endometriosis and Adenomyosis: It Takes More Than Just Good Science.

The pipelines of pharmaceutical companies are filled with thousands of promising new compounds for a plethora of indications. Yet, a close review of the drugs that have recently been in clinical trials quickly reveals that only a handful of drugs under evaluation in women with endometriosis can be genuinely qualified as truly innovative and breakthrough drugs. Why is there such an industry-wide lukewarm interest in drug research and development for endometriosis/adenomyosis? Why are pharmaceutical companies so reluctant to initiate programs or invest in academic research in endometriosis/adenomyosis? It is evident that a substantial part of the novel druggable targets originate from research in academia. However, only the pharmaceutical industry has the resources and expertise to bring drugs to patients. In other words, we are fully dependent on the pharmaceutical industry to bring new therapeutics to the market. The aim of this editorial is to make scientists from academia aware of the enormous complexity of the drug development process, the drivers that propel pharmaceutical companies to initiate new programs and to prioritize their portfolios, the value of intellectual property rights, and also about the importance of scientific rigor, predictive translational models, and biomarkers. At the same time, the pharmaceutical industry must be made aware of the enormous opportunity at hand, as the current patient population with endometriosis/adenomyosis is just the tip of the iceberg. We hope that the insights presented here will enable the endometriosis/adenomyosis research community to find ways to valorize their knowledge and attract the interest of the industry.

Preventing recurrence of endometriosis by means of long-acting progestogen therapy (PRE-EMPT): report of an internal pilot, multi-arm, randomised controlled trial incorporating flexible entry design and adaption of design based on feasibility of recruitment.

BACKGROUND: Endometriosis is associated with the growth of endometrium in ectopic sites mainly within the pelvis. This results in inflammation and scarring, causing pain and impaired quality of life. Endometriotic lesions can be excised or ablated surgically, but the risk of recurrence is high. A Heath Technology Assessment commissioning call in 2011 sought applications for trials aimed at evaluating long-term effectiveness of postoperative, long-acting, reversible contraceptives (LARCs) in preventing recurrence of endometriosis. A survey of gynaecologists indicated that there was no consensus about which LARC (Levonorgestrel Intrauterine System (LNG-IUS) or depot medroxyprogesterone acetate injection (DMPA)) or comparator (combined oral contraceptive pill (COCP) or no treatment) should be evaluated. Hence, we designed a 'flexible-entry' internal pilot to assess whether a four-arm trial was feasible including a possible design adaption based on pilot findings. METHODS: In this pilot, women could be randomised to two, three or four treatment options provided that one was a LARC and one was a non-LARC. An assessment of feasibility based on recruitment to these options and a revised substantive trial design was considered by an independent oversight committee. RESULTS: The study ran for 1 year from April 2014 and 77 women were randomised. Only 5 (6%) women accepted randomisation to all groups, with 63 (82%) having a LARC preference and 55 (71%) a non-LARC preference. Four-way and three-way designs were ruled out with a two-way LARC versus COCP design, stratified by prerandomisation choice of LARC and optional subrandomisation to LNG-IUS versus DMPA considered a feasible substantive study. CONCLUSIONS: Multi-arm studies are potentially efficient as they can answer multiple questions simultaneously but are difficult to recruit to if there are strong patient or clinician preferences. A flexible approach to randomisation in a pilot phase can be used to assess feasibility of such studies and modify a trial design based on chosen recruitment options, but trialists should consider carefully any practical arrangements should groups need to be dropped during a study. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number, ISRCTN97865475 . Registered on 20 March 2014.

Long-term medical management of endometriosis with dienogest and with a gonadotropin-releasing hormone agonist and add-back hormone therapy.

Endometriosis can recur after either surgical or medical therapy. Long-term medical therapy is implemented to treat symptoms or prevent recurrence. Dienogest and gonadotropin-releasing hormone (GnRH) analogues with hormone add-back therapy seem to be equally effective for long-term treatment of pain symptoms associated with endometriosis. There is insufficient evidence to support the superiority of one therapy over the other. However, add-back hormone therapy (HT) is recommended for patients using GnRH agonists. The treatment selection depends on therapeutic effectiveness, tolerability, drug cost, the physician's experience, and expected patient compliance.

Analysis of Adherence, Persistence, and Surgery Among Endometriosis Patients Treated with Leuprolide Acetate Plus Norethindrone Acetate Add-Back Therapy.

BACKGROUND: Endometriosis affects over 10 million women in the United States. Depot leuprolide acetate (LA), a gonadotropin-releasing hormone agonist, has been used extensively for the treatment of women with endometriosis but is associated with hypoestrogenic symptoms and bone mineral density loss. The concomitant use of add-back therapies, specifically norethindrone acetate (NETA), can alleviate these adverse effects. OBJECTIVE: To compare adherence to and persistence with LA treatment and time to endometriosis-related surgery among women treated with NETA and women treated with LA plus other add-back therapies or LA only. METHODS: This retrospective analysis was conducted using Truven Health MarketScan Commercial Claims and Encounters Database. Women with a diagnosis of endometriosis (ICD-9-CM code 617.xx) who initiated LA (index date) in 2005-2011 were selected for inclusion. Additional requirements were 12 months of continuous enrollment pre- and post-index and no evidence of endometriosis-related surgeries pre-index or up to 30 days post-index; no pre-index use of estrogen or noncontraceptive hormones; and no diagnoses of uterine fibroids, malignant neoplasms, infertility, or pregnancy. Patients were characterized as using NETA; other add-back therapies (estrogens, progestins, or estrogen-progestin combinations); or no add-back therapy. Adherence to and persistence with LA were measured over the 6 months following the index date using outpatient medical and pharmacy claims. Patients were considered adherent if their proportion of days covered was greater than or equal to 0.80. Persistence was operationalized as time to discontinuation, defined as a continuous gap of > 60 days without LA on hand. Time to endometriosis-related surgery (laparotomy, laparoscopy, excision/ablation/fulguration, oophorectomy, and hysterectomy) was measured over the 12 months following the index date. Surgeries were identified from inpatient and outpatient medical claims using procedure codes. Outcomes were compared among cohorts using multivariable logistic and Cox proportional hazards regression models controlling for demographics and baseline clinical characteristics. RESULTS: The final sample included 3,114 women, with a mean age of 36.9 years. The majority of women used LA only with no add-back therapy (n = 1,963, 63.0%), while 15.1% (n = 470) used NETA, and 21.9% (N = 681) used other add-back therapies. During the 6-month follow-up, more patients in the LA plus NETA cohort were adherent to LA therapy compared with LA only (47.2% vs. 31.5%, P < 0.001), and fewer patients discontinued (37.9% vs. 59.6%, P < 0.001). Additionally, fewer patients underwent endometriosis-related surgery in the 12 months after LA initiation in the LA plus NETA cohort (12.6% vs. 16.9%, P = 0.021). In multivariable models, women who initiated LA plus NETA or LA plus other add-back therapies had a higher likelihood of being adherent to LA than LA only patients (OR = 1.91, 95% CI = 1.55-2.36 and OR = 1.95, 95% CI = 1.63-2.34) and lower likelihood of LA discontinuation (HR = 0.54, 95% CI = 0.46-0.63 and HR = 0.59, 95% CI = 0.52-0.68). NETA patients had a lower surgery rate in the 12-month post-index period compared with other add-back patients (HR = 0.68, 95% CI = 0.50-0.93) or LA only patients (HR = 0.69, 95% CI = 0.52-0.92). CONCLUSIONS: For women with endometriosis, treatment with LA and concomitant add-back therapies was associated with better adherence to and persistence with LA over the 6 months following initiation, compared with treatment with LA only. The increased adherence and persistence to LA may translate into decreased need for surgical intervention, although fewer endometriosis-related surgeries were only observed in the 12 months following LA initiation for patients using concomitant NETA add-back therapy. These results support an increased and earlier use of NETA add-back therapy among women who initiate LA. DISCLOSURES: This study was funded by AbbVie, which also markets the endometriosis drugs Lupron and Lupaneta Pack. AbbVie participated in the study design, research, data collection, analysis and interpretation, writing, review, and approval of this publication. Soliman and Castelli-Haley are employees of AbbVie and may own AbbVie stock or stock options. Bonafede and Farr are employees of Truven Health Analytics, which received a research contract to conduct this study with and on behalf of AbbVie. Winkel is a clinical professor in the Department of Obstetrics and Gynecology at Georgetown University in Washington, DC, and has served in a consulting role on research to AbbVie for this project. An earlier version of the current research was presented at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 20th Annual International Meeting; Philadelphia, PA; May 2015. All authors participated in data analysis and interpretation and contributed to the development of the manuscript.