Self-Reported Experiences of Women Taking Hormonal Treatments for Their Endometriosis and Uterine Fibroids Symptoms: Results from a Real-World Study in the US (MyEndoUF)

Of 411 participants, 185 had an EM and 226 had a UF diagnosis. Mean age (standard deviation [SD]) was 34.9 (7.4) and 37.5 (7.7) years in the EM and UF cohorts, respectively. Participants with EM and UF reported first heavy menstrual bleeding at 14.0 (interquartile range [IQR] 13.0, 18.0) and 19.5 (IQR 13.0, 32.0) years of age, respectively, and first pelvic pain during menses at 15.0 years of age (IQR: EM 13.0, 18.0; UF 13.0, 23.3). During the study period, 17.7% of observed days were bleeding days, most commonly spotting. Pelvic pain was rated as mild, with a median score of 3.4 (1.0, 5.0) and 2.7 (1.3, 4.4) for dysmenorrhea and 1.3 (0.4, 2.7) and 1.5 (0.3, 3.8) for non-menstrual pelvic pain for EM and UF, respectively. In both cohorts, the most frequently used hormonal treatments were combined contraceptive pills and levonorgestrel intrauterine devices, with most participants having received their current treatments for > 2 years. Hormonal treatment switching or discontinuation during the study was low. Pain medication use, most frequently over-the-counter medications, was higher on bleeding days. Absenteeism, presenteeism, and work impairment scores were higher during bleeding versus non-bleeding weeks.

In this observational study of individuals with EM and UF using hormonal therapy, participants reported mild symptoms, with increased pain medication use and work impairment during periods. Bleeding abnormalities and period pain appeared early in life, which could represent potential indicators for EM and UF, warranting further investigation.

endometriosis, hormonal treatments, patient experience, prospective observational study, real-world, uterine fibroids

Endometriosis (EM) and uterine fibroids (UF) are common gynecological conditions that can significantly affect women’s health, often leading to a high symptom burden adversely affecting quality of life.1–3 EM is a chronic, inflammatory condition defined as having endometrial-like tissue external to the uterus that often leads to dysmenorrhea, non-menstrual pelvic pain (NMPP) and chronic pelvic pain, and reproductive issues including complications with fertility and pregnancy.2,4,5 EM affects approximately 10% of women of reproductive age, although prevalence varies across differing patient populations and diagnostic procedures.5–9 Prevalence estimates as high as 75% have been reported in symptomatic adolescents with pelvic pain unresponsive to medical treatment.5,7,8 UF are estrogen- and progesterone-dependent non-cancerous pelvic tumors associated with heavy menstrual bleeding, pelvic pressure, back pain, and fatigue.10,11 UF prevalence similarly differs by population and diagnostic procedures, ranging between 5% and 77% of women of reproductive age, 20–50% of whom are symptomatic.10,12 EM and UF may present together, although the level of comorbidity reported varies from 19.6% to up to 87% of patients.13–16 Although there is some therapeutic overlap between EM and UF treatments, approaches remain disease-specific, and need to consider the type and duration of hormonal treatment, and need for surgical intervention.17,18 Treatments guidelines for EM and UF in both the US and Europe include recommendations for both pharmacological treatments for symptom management as well as surgical interventions.16,18,19 Because the conditions are both hormone-driven pathologies, hormonal therapies are key for the management of symptoms. A limited number of pharmacological therapies are specifically approved for EM and/or UF: the progestins depot medroxyprogesterone acetate and norethindrone acetate are approved for EM, and gonadotropin-releasing hormone (GnRH) agonists and GnRH antagonists such as elagolix and relugolix are both also approved for use for EM or UF (additional treatments are also approved in Europe; for example, the GnRH antagonist linzagolix, which is not approved in the US).20–26 Oral hormonal contraceptives are commonly used off-label to treat EM and UF symptoms;20,22 however, evidence from clinical studies supporting their use is lacking and the efficacy data for treating pain are limited.20,22,27 Surgical interventions are widely used for both EM and UF, with myomectomy and hysterectomies being common for UF and lesion excision for EM.3,4,28 These surgeries all come with inherent risks, and, with the exception of hysterectomy in women with UF, they are not curative and symptoms may persist or recur post-surgery.3,29–31 In females with EM, persistent or recurring symptoms led to reoperation in 27–58% of cases after surgery.29 For UF, symptoms were found to recur in 12–32% of people following myomectomy.17,32 Despite the widespread use of hormonal therapies, real-world evidence for females with EM or UF who are taking these treatments to manage their symptoms remains limited. In particular, there is a lack of prospective real-world data focused on longitudinal patient-reported outcomes to capture the patient experience. Reported here are the results of a prospective, observational study, which assessed the characteristics and self-reported experiences of females with EM and UF taking hormonal therapies to manage the symptoms of their estrogen-driven condition.

Study Design The MyEndoUF prospective 16-week observational study enrolled participants across the US who self-reported that they had received a physician diagnosis of EM and/or UF. This was a descriptive study, aiming to assess self-reported patient experiences. As part of the recruitment process, targeted emails and postings were directed at members of “Evidation”, an online platform developed by Evidation Health. When individuals created an Evidation account previously, they agreed to be contacted with study opportunities such as the MyEndoUF study. Additional recruitment methods were utilized for non-Evidation members via the distribution of information to advocacy groups and physician offices as well as targeted advertisements on social media and forums. Individuals without an Evidation account, who expressed an interest in the study, were required to create an account. Interested former and new Evidation members had to provide informed consent for the MyEndoUF study and subsequently completed a screener to determine their eligibility (Figure 1). Participant eligibility criteria are detailed in Table 1. | Table 1 Participant Eligibility Criteria | Eligible participants were assigned to either the EM or UF cohort based on their self-reported diagnosis. If participants had both EM and UF, they were asked additional questions such as “Which of the following symptoms is most bothersome to you?” to identify the most appropriate cohort assignment. Once enrolled, after completing the baseline survey, participants were required to respond to daily, weekly, and monthly surveys. Participants who did not complete surveys as scheduled received reminders via email, text message, or phone call. The study was approved by the WCG Institutional Review Board. Study Endpoints Study endpoints were assessed based on information collected across the baseline, daily, weekly, and monthly surveys. Baseline Survey Participants self-reported their demographics, medical history (including bleeding and pelvic pain history), clinical and physical features, any comorbidities (no formal diagnosis required), and their current use of hormonal therapies. Daily Survey The daily survey included questions regarding menstrual status, bleeding severity, pelvic pain, sexual activity, pain before/during/after intercourse, and pain medication usage. Bleeding severity was assessed based on four categories—no spotting or bleeding, spotting, bleeding, and heavy bleeding—which were transformed into an ordinal variable for analysis. Dysmenorrhea and NMPP were evaluated daily using an 11-point Numeric Rating Scale (NRS), in which participants rated their worst pelvic pain from 0 (“no pain”) to 10 (“pain as bad as you can imagine”). Dysmenorrhea was assessed during bleeding days, whereas NMPP was determined on non-bleeding days. Participants reported whether they had been sexually active. If so, participants rated their worst pain before, during, or after sexual intercourse (dyspareunia). Participants also reported their use of pain medication for EM and UF from the day prior, categorized into over-the-counter (OTC) medications, non-opioid, and opioid prescription medications. For OTC medications, participants reported the specific type taken, while for both non-opioid and opioid prescriptions, participants selected from a list of non-opioid and opioid prescriptions available. Weekly Survey The weekly surveys asked about changes in hormonal therapy, reasons for these changes, whether participants had ceased taking the therapy entirely, or had stopped and then started a new hormonal regimen. Weekly surveys also included questions on whether participants underwent procedures or surgeries to treat their symptoms and if they used other treatment strategies such as massage or yoga to manage symptoms. For menstrual bleeding, a bleeding week was defined as a week in which at least 2 of the 7 days of that week were associated with self-reports of bleeding. Work productivity and activity impairment (WPAI) was measured weekly with the WPAI-Special Health Problem instrument, tailored for EM and UF.33 This tool is used to assess absenteeism (percentage of work time missed due to EM or UF), presenteeism (percent impairment due to EM or UF while working), overall work impairment (percent overall work impairment due to EM or UF), and non-work impairment (percent non-work activity impairment due to EM or UF) over a 7-day period. Monthly Survey Symptom burden was assessed monthly using specific domains from two validated questionnaires: the Endometriosis Health Profile-30 (EHP-30, scored 0–100) pain domain for the EM cohort, which addresses the impact of EM-associated pain on daily activities and functioning, and the UF Symptom and Quality of Life Symptom Severity (UFS-QoL-SS, scored 0–100) scale for the UF cohort, which focuses on the level of distress due to specific UF-associated symptoms. Statistical Considerations The study was conducted over a 16-week observational period designed to capture three full menstrual cycles or treatment periods. Data for each disease cohort (EM, UF) were summarized using descriptive statistics. Between-cohort statistical comparisons were not planned for outcomes or any other variables. Categorical variables were reported with counts and frequencies, while continuous variables included the mean and standard deviation (SD). The analysis population consisted of enrolled, eligible participants who completed the study and met both the data quality requirements and data density criteria (see Supplementary Appendix for details). Data censoring occurred when participants switched medications, resulting in a change in hormonal drug therapy class as indicated in weekly surveys. Data were also censored when participants stopped their treatments or underwent surgeries or minimally invasive procedures. In these cases, data were censored from the study week, in which the stopping of hormonal therapy, change in hormonal therapy class, or procedures/surgeries was reported. Both observed (non-missing) and missing values were reported for each characteristic or endpoint across all participants. An “observed day” was defined as any uncensored day that was utilized in the analysis and had data available. In contrast, an “unobserved day” was one that fell within the observation period but lacked data provided by the participant for that specific day.

Participant Baseline and Demographics Of the 499 participants enrolled in the MyEndoUF study, 88 were excluded from the analysis population because they did not meet the data density requirements (9.6%), data quality requirements (1%), or had no available data after censoring (7%; Figure 2). As such, data for 411 participants, in total, were analyzed, with 185 participants in the EM cohort and 226 participants in the UF cohort. | Figure 2 Total analysis population. | In the EM cohort, mean age was 34.9 (SD±7.4) years old, with a mean body mass index (BMI) of 29.2 (±7.3; Table 2) kg/m2; 75.7% of participants were White and 12.4% were Black or African American (Table 2). | Table 2 Baseline Characteristics | In the UF cohort, mean age was 37.5 (±7.7) years, with a mean BMI of 26.8 (±9.9) kg/m2 (Table 2); 67.7% of participants were White and 27.4% were Black or African American (Table 2). In terms of data completeness, in the EM cohort, 80.2% of days were observed and 6.0% were unobserved (missing). In the UF cohort, 77.1% of days were observed and 5.1% were unobserved. Education Level, Employment, and Health Insurance Status The majority (99.0%) of participants in both cohorts were educated beyond high school, with 33.5% and 46.5% of participants in the EM and UF cohorts, respectively, having obtained a master’s degree or higher (Table 2). Most participants were employed, with 83.8% and 80.5% of those in the EM and UF cohorts, respectively, working full- or part-time (Table 2). The majority of participants across both cohorts had private health insurance (Table 2). Bleeding and Pelvic Pain History Participants in the EM cohort reported they first had heavy menstrual bleeding when 14.0 (interquartile range [IQR] 13.0, 18.0) years old, and first experienced pelvic pain during menses at 15.0 (IQR 13.0, 18.0) years of age (Table 3). Participants in the UF cohort reported that they first had heavy menstrual bleeding when 19.5 (IQR 13.0, 32.0) years old and first had pelvic pain during menses at 15.0 (IQR 13.0, 23.3) years of age. | Table 3 Baseline Medical History | Comorbidities Anxiety and depression were the most common comorbidities in both cohorts, reported in 31.4% and 23.2% of the EM cohort and 16.8% and 14.6% of the UF cohort, respectively (Table 3). Adenomyosis was present in 4.9% of participants with EM and 1.8% of those with UF (Table 3). Self-Reported Difficulties in Getting Pregnant In the EM cohort, 26.5% of participants reported difficulties getting pregnant. In the UF cohort, 15.5% of participants indicated these difficulties (Table 3). Treatment at Baseline The most frequently used hormonal treatments in the EM cohort were combined contraceptive pills (33.5%) and levonorgestrel intrauterine devices (15.7%). The use of recently approved GnRH receptor antagonists was reported by 14.6% of participants with EM (Table 3). Similarly, the most frequently used hormonal treatments in the UF cohort were combined contraceptive pills (35.4%) and levonorgestrel intrauterine devices (16.8%). GnRH receptor antagonist use was reported by 15.9% of participants with UF (Table 3). In terms of the length of time participants had spent on their current hormonal therapies, 31.4% in the EM cohort had received the current treatment for between 2 and 5 years, and 39.5% for over 5 years; 18.6% in the UF cohort had received the current treatment for between 2 and 5 years, and 25.2% for over 5 years (Table 3). Prior Surgeries For participants in the EM cohort, 42.7% did not report any prior gynecological procedures (Table 3), while 16.2% had an endometrial ablation, 14.6% an excision or resection of endometrial lesions, and 16.8% a removal of ovarian cysts. In the UF cohort, 69.5% of participants with UF did not report any prior gynecological procedures (Table 3), while 12.4% had undergone a myomectomy. Study Outcomes Daily Survey Bleeding Days and Bleeding Severity In the EM cohort over the 16-week study period, 17.7% (±16.2) of observed days were bleeding days, of which 1.9% (±5.3) were reported to be heavy bleeding, 7.1% (±9.1) bleeding, and 8.6% (±9.2) spotting (Table 4). | Table 4 Bleeding Severity | In the UF cohort, 17.7% (±18.9) of observed days were bleeding days, of which 2.0% (±4.4) were reported to be heavy bleeding, 7.2% (±10.9) bleeding, and 8.5% (±10.4) spotting (Table 4). Pelvic Pain from Dysmenorrhea, NMPP and Dyspareunia Outcomes Participants reported mild levels of EM- or UF-related pain across both cohorts. Females in the EM cohort rated their pelvic pain on bleeding days (dysmenorrhea) as mild with a median NRS score of 3.4 (IQR 1.0, 5.0). Additionally, they reported low levels of NMPP with a median NRS score of 1.3 (IQR 0.4, 2.7; Table 5). | Table 5 Pelvic Pain and Dyspareunia | Similarly, in the UF cohort, participants reported mild levels of dysmenorrhea with a median NRS score of 2.7 (IQR 1.3, 4.4) and low levels of NMPP with a median score of 1.5 (IQR 0.3, 3.8; Table 5). In participants who reported sexual activity the previous day, participants with EM rated their pain during sexual activity (dyspareunia) as mild with a median NRS score of 2.0 (IQR 0.8, 3.3), while participants with UF reported a median NRS score of 1.2 (IQR 0.4, 3.0; Table 5). Pain Medication Use Across both the EM and UF cohorts, there was a noticeable trend of increased pain medication use on bleeding days than on non-bleeding days. Among participants with EM, pain medication was used on 30.8% of bleeding days, and only on 8.6% of non-bleeding days. On bleeding days, OTCs were most commonly used (22.5% of bleeding days), followed by non-opioid prescription medicines (8.1%) and opioid prescription medicines (1.6%). Similarly, these participants most commonly used OTC pain medications on non-bleeding days (5.6% of non-bleeding days), followed by non-opioid prescription medicines (2.5%) and opioid prescription medicines (0.1%) (Table 6). | Table 6 Daily Pain Medication Use | A similar pattern was observed among participants with UF. Pain medication was used on 25.1% of bleeding days versus 5.2% of non-bleeding days. On bleeding days, OTC medications were most commonly used (19.2% of bleeding days), followed by non-opioid prescription medicines (5.4%) and opioid prescription medicines (2.8%). On non-bleeding days, participants most commonly reported use of OTC pain medications (4.1% of non-bleeding days), followed by non-opioid prescription medicines (1.0%), and opioid prescription medicines (0.6%) (Table 6). Weekly Survey Hormonal Therapy Changes, Procedures, and Surgeries During Observation Period There was a low percentage of participants overall who switched or discontinued hormonal medication use, with 2.8% of participant-weeks reported as including a switch for any reason in the EM cohort and 2.5% in the UF cohort. Furthermore, few surgeries or procedures for EM or UF were reported during the study, with only 1.2% of participant-weeks in the EM cohort and 3.8% in UF-cohort. Non-Hormonal Approaches for Symptom Management Overall, study participants reported using non-hormonal approaches to manage their EM and UF symptoms in 49.4% of participant weeks. The most common approaches were yoga (24.9%), massage (19.9%), and meditation (17.0%). WPAI Outcomes In both the EM and UF cohorts, WPAI scores were higher during bleeding versus non-bleeding weeks. For the EM cohort, using WPAI-EM, mean scores for absenteeism were 3.7% (SD ±6.6) versus 2.9% (±11.1), presenteeism 26.3% (±22.3) versus 14.7% (±16.5), work impairment 28.1% (±23.4) versus 16.0% (±18.3), and non-work impairment 31.7% (±24.5) versus 20.4% (±21.2) for bleeding versus non-bleeding weeks. For the UF cohort, using WPAI-UF, mean scores for absenteeism were 5.3% (±13.0) versus 2.5% (±5.7), presenteeism 20.1% (±21.8) versus 13.0% (±16.7), work impairment 22.0% (±23.2) versus 14.3% (±17.6), and non-work impairment 24.5% (±23.8) versus 25.1% (±25.3) for bleeding versus non-bleeding weeks (Figure 3a and b). Monthly Survey EHP-30 Pain Domain Score, UFS-QoL-SS Score The mean EHP-30 pain scale for participants with EM overall was 28.4 (SD±21.7), ranging from 25.6 (±22.2) in those receiving combined hormonal therapy to 43.9 (±24.8) in those with no hormonal therapy. The mean UFS-QoL-SS score for participants with UF was 35.7 (±21.0), ranging from 32.1 (±18.6) in those receiving combined hormonal therapy to 48.5 (±29.7) in those with no hormonal therapy (Figures 4a and b).

This is the first observational, longitudinal study to include participants with EM and with UF who are taking hormonal therapies to treat their symptoms. The aim of this study was to describe the characteristics and self-reported experiences of these populations in a real-world, non-clinical setting. The latter are relevant for the assessment of treatment success, yet real-world data on this aspect are limited. As this was an observational, real-world study, baseline characteristics differed in some aspects versus those of participants enrolled in randomized clinical trials for hormonal treatments for EM or UF.6,34–37 For example, the BMI of the participants with UF in this study was lower than what has typically been reported in clinical studies, particularly in the US.36,37 This aligns with US-based cross-sectional data suggesting that hormonal contraceptive use is reduced in women in higher BMI categories.38 Conversely, the BMI of participants with EM in this study was higher than observed in clinical studies, potentially due to the high proportion of women from Europe enrolled in clinical EM trials, with generally a lower BMI than those in the US.6,34 The age of the UF population (37.5 [SD±7.7]) in this study was younger than reported previously in clinical studies (with UF more commonly reported in individuals over 40 years old),10,39 which could be due to healthcare professionals being hesitant to prescribe hormonal products to older women due to perceived health risks with increasing age.40 However, the age of the EM population was similar to those seen in clinical studies.6,34 Participants in this study first experienced symptoms on average during adolescence. This is not surprising for EM, as it has been established that symptoms can manifest in teenage years.5 UF is often asymptomatic, and even in females in their early twenties, presentation and diagnosis have been reported to be very rare.39 Diagnosis of UF relies on imaging techniques to detect structural changes associated with UF, which are often not detectable at earlier life stages.41,42 However, in this study, participants with UF experienced heavy menstrual bleeding at on average 19.5 years old; this finding may indicate that heavy menstrual bleeding at an earlier age may be an important indicator for the development of UF in later life. A monitoring of potential early indicators may help to address the extended gap often seen between symptom onset and diagnosis in UF, shown previously to be over 9 years.42 EM has also been reported to be associated with potentially long diagnostic delays of up to 12 years.43 Understanding early signs and determining diagnostic indicators could potentially aid in better diagnosis, monitoring and management strategies for women who may be at risk of estrogen-driven conditions, and as such further investigation would be of value.42,43 Dysmenorrhea and NMPP were reported as mild or close to minimal by participants in both cohorts, and the proportion of days with heavy menstrual bleeding was minimal for both EM and UF cohorts, with the majority of bleeding days reported as spotting. The treatments utilized by women with EM and UF in this study, including hormonal products, may be associated with the average mild or low symptomatic burden observed; however, these data should be interpreted with caution given the study design, which only allows for hypothesis-generation rather than an evaluation of treatment efficacy. The combined oral contraceptive pill and the hormonal intrauterine device were identified as the most common hormonal treatments used across both cohorts to treat symptoms. The low proportion of study participants who reported use of GnRH receptor antagonists demonstrates a low utilization of modern approved treatment options in daily clinical practice.21–25 Pain medication use was highest during bleeding days in both EM and UF cohorts, potentially indicating that further reduction of bleeding days in women with estrogen-driven conditions may not only lead to fewer bleeding symptoms, but potentially also reduce the utilization of pain medications. Additionally, the low proportion of participants switching or discontinuing their hormonal treatments during the study, coupled with a high proportion of participants in both cohorts receiving their current hormonal therapy for ≥2 years, may indicate an overall high satisfaction with the medications being received. However, this is speculative, and the low proportion of switching treatment could alternatively be due to a lack of treatment options or therapeutic inertia. Further investigation into treatment satisfaction and treatment utilization may provide additional insights for this population. The proportion of patients reporting to have received surgeries or procedures for EM or UF during the study was also very low. The levels of self-reported impact of EM-associated pain on daily activities and functioning in the EM cohort (EHP-30 pain domain) were substantially lower in this study compared with untreated individuals entering into clinical studies.6,34 Similarly, participants in the UF cohort had lower self-reported symptom severity based on the UFS-QoL-SS scale compared with untreated participants in prior UF in clinical studies.36 Taken together with the data on bleeding, pain, and treatments, these results could potentially indicate that effective management of EM and UF symptoms may be achieved with hormonal and pain medications, although further investigation is required. WPAI data from the current study indicate that there is a moderate impact of EM and UF on workplace impairment. However, the impairment reported in this study (through WPAI responses on absenteeism, presenteeism, and work and non-work impairment) was lower compared with those reported in previous studies of EM and UF, which did not require participants who receive hormonal treatments to be included.44,45 This highlights the societal and economic impact of unmanaged symptoms of EM and UF, and the associated potential benefits of effective management. The main limitation of this study is the reliance on self-reported data, which may introduce potential bias due to inaccuracies in the participant’s recollection or understanding of their medical history. Diagnosis of EM or UF was also self-reported, without clinical validation, which may introduce a misclassification bias. Without verification from healthcare practitioners for diagnoses, the reliability of the findings may be impacted. The current sample may not be representative of the broader population, as most participants had health insurance (97.3%, slightly higher than the reported by the US Census Bureau in 2023 of 92.0%),46 participant selection was based on receipt of hormonal treatment, and participants who had undergone an hysterectomy were excluded. Exclusion of data following changes in treatment, discontinuation or surgery may potentially introduce survivorship bias for those participants who remained on study and receiving hormonal treatments. Furthermore, the recruitment strategy via the Evidation platform, social media and patient advocacy groups could potentially introduce a selection bias and result in a sample of individuals who were particularly engaged and attentive to their own health to monitoring their conditions. This may impact the symptom burden of the sample and limit the generalizability of the results to the overall population of those with EM or UF. The participants in this study were generally well-educated and employed, potentially contributing to their access to various prescription treatments. This may have influenced results, as educational and employment status can impact health literacy and the ability to navigate healthcare systems.47 These socioeconomic factors may affect the generalizability of the findings to broader, more diverse populations.47 This study did not include a control group or comparisons to pre-intervention data, and as such conclusions drawn from the data based on treatment received are limited and should be interpreted with caution. The data are descriptive only, and as such any findings are exploratory, for the purposes of generating hypotheses for further investigation. Finally, missing data in the study may also have had an impact on the robustness and completeness of the study results.

As the first observational, longitudinal study to include both participants with EM and UF on hormonal therapies, the MyEndoUF study provides important descriptive insights into individuals’ experiences with EM and UF while on hormonal treatment. The exploratory findings of the study provide potential avenues for further investigation of EM and UF; future studies should cover a larger population with broader, more representative demographics, and further investigate patient-reported outcomes to best expand knowledge on the experiences of individuals with these conditions and address the symptoms associated with them. Data Sharing Statement The data presented in this study are available on reasonable request to the corresponding author. Ethics Approval and Informed Consent All study materials, including the survey, recruitment materials, and informed consent forms were approved by the Western Institutional Review Board (WIRB; now WIRB-Copernicus Group IRB [WCG IRB]; 20234253) in Cary, NC, USA. The study was conducted in accordance with the approved protocol (project ID: 1361284) and with consensus ethical principles derived from international guidelines, including the Declaration of Helsinki.48 All participants, or their parents or legal guardians, provided written informed consent. Acknowledgments The authors would like to thank the individuals who participated in this study. The authors would also like to acknowledge editorial support and medical writing from AXON Communications (London, UK), which was sponsored by Sumitomo Pharma America, Inc, in accordance with Good Publication Practice guidelines. Funding Funded by Sumitomo Pharma America, Inc. Disclosure E.H. and V.R. are previous employees of Sumitomo Pharma Switzerland GmbH. J.C. is a previous employee of Sumitomo Pharma America Inc. S.A. has no conflicts of interest to report. Sumitomo Pharma Switzerland GmbH, Basel, Switzerland was the affiliations of Elke Hunsche and Viatcheslav G Rakov at the time of study conduct; and Sumitomo Pharma America Inc., Cambridge, MA, USA was the affiliation of Jennifer Coppola at the time of study conduct.

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