Quality of life improvements in women with uterine fibroids treated with relugolix combination therapy during the LIBERTY long‐term extension study: A descriptive subgroup analysis in women with anemia at baseline

To investigate the effects of 52 weeks of treatment with relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) on symptoms of uterine fibroids (UF) and quality of life (QoL) in women with heavy menstrual bleeding associated with UF and anemia (hemoglobin ≤10.5 g/dL) at baseline.


| INTRODUC TI ON
Uterine fibroids (UF), or uterine leiomyomas, are common estrogen and progesterone-dependent, non-cancerous pelvic tumors found in premenopausal women. 1 Approximately 20%-50% of women with UF are symptomatic, with common symptoms including heavy menstrual bleeding (HMB), pelvic pain, extrinsic compression of the bowel or bladder, and reproductive impairment. 1 Occurring in one third of patients with UF, HMB is the most common UF symptom and can result in incidence of iron-deficiency anemia. 2 HMB-associated anemia increases UF burden, potentially leading to additional symptoms of fatigue and weakness 3,4 ; in rare instances, anemia associated with UF can be life-threatening. 5Anemia can have a substantial impact on treatment approach and outcomes in women hospitalized for UF, including a higher likelihood of radical surgery, longer hospital stays and worse postoperative outcomes. 6[9] Relugolix is an orally active, non-peptide gonadotropin-releasing hormone receptor antagonist that suppresses secretion of gonadotropins, reducing follicular growth and inhibiting ovulation, causing a rapid and reversible decrease in ovarian production of estrogen and progesterone. 10,11Relugolix combination therapy is a once-daily single-tablet therapy consisting of 40 mg relugolix, 1 mg estradiol, and 0.5 mg of norethindrone acetate, that has been approved in the USA for management of HMB associated with UF in premenopausal women, and for treatment of moderate-to-severe symptoms of UF in adult women of reproductive age in the European Union. 12,13lugolix combination therapy has also been approved for treatment of moderate-to-severe pain associated with endometriosis in the USA and for symptomatic treatment of endometriosis in women with a history of previous medical or surgical treatment for their endometriosis in the European Union.12,13   Two pivotal studies (LIBERTY 1 and LIBERTY 2) investigated once daily relugolix combination therapy in premenopausal women with UF over 24 weeks.Significant improvement of UF-associated symptoms (compared with placebo) were observed, and relugolix combination therapy was well tolerated and preserved bone mineral density (BMD). 11In the LIBERTY long-term extension (LTE) study, relugolix combination therapy up to 52 weeks demonstrated sustained improvements in HMB, anemia and HRQoL, as well as reduction in overall burden of disease and distress caused by UF-associated symptoms. 11,14,15e present descriptive post hoc analyses reports the effects of 52 weeks of treatment with relugolix combination therapy during the pivotal LIBERTY studies and LTE study on symptoms of UF and HRQoL in women with HMB-associated with UF and anemia at baseline.

| Participants
Premenopausal women aged 18-50 years with a UF diagnosis (confirmed by transvaginal ultrasonography) and HMB (defined as a menstrual blood loss [MBL] volume of ≥80 mL per cycle for two cycles, or ≥160 mL during 1 cycle) were able to enroll into the replicate, 24week, phase 3, randomized, double-blind, placebo-controlled pivotal LIBERTY 1 and LIBERTY 2 studies (Clini calTr ials.gov: NCT03049735 and NCT03103087, respectively).Women with a BMD Z-score of <−2 were excluded from the studies. 11Participants who completed LIBERTY 1 or 2 and who were not expecting to undergo additional UF procedures within the study period were eligible to enroll into the 28-week LIBERTY LTE study (Clini calTr ials.gov: NCT03412890).
Women with a BMD Z-score of <−2, or with a decrease in BMD of 7% at the lumbar spine, total hip, or femoral neck from pivotal study baseline to week 24 were excluded from the LTE.Full inclusion and exclusion criteria of the LTE study have been published previously. 14e present post hoc analysis of the LIBERTY LTE was performed in the anemia-evaluable population, defined as women with anemia (hemoglobin ≤10.5 g/dL) at pivotal study baseline and with a recorded hemoglobin value at week 52.
Women who entered the LTE study on iron therapy were allowed to continue iron treatment during the study.Women who developed new microcytic iron deficiency anemia during the F I G U R E 1 Study design.In the pivotal studies (LIBERTY 1 [NCT03049735]; LIBERTY 2 [NCT03103087]), women were randomized to receive once daily relugolix combination therapy or placebo for 24 weeks, or delayed relugolix combination therapy (40 mg relugolix monotherapy for 12 weeks, followed by relugolix combination therapy for 12 weeks).Women who completed the pivotal studies could participate in the 28-week extension (LIBERTY LTE [NCT03412890]) in which all women received open-label relugolix combination therapy.LTE, long-term extension; N a , number of women in the anemia-evaluable population; N, number women in the overall trial population.study, defined as a hemoglobin concentration ≤10 g/dL, a mean corpuscular volume below the lower limit of normal, and a low serum iron and ferritin level, were required to initiate iron therapy, either oral or parenteral.

| Study design
In the pivotal LIBERTY 1 and 2 studies, women were randomized 1:1:1 into one of three treatment groups: (1) once-daily relugolix combination therapy for 24 weeks, (2) placebo for 24 weeks, or (3)   delayed relugolix combination therapy (40 mg relugolix monotherapy for 12 weeks, followed by relugolix combination therapy for 12 weeks) (Figure 1). 11All women in the multinational, open-label, single-arm, LIBERTY LTE received 28 weeks of oral relugolix combination therapy (i.e., a total of 52 weeks cumulative treatment), with patient visits occurring every 4 weeks from pivotal trial baseline to week 52. 14Data were analyzed according to the assigned treatment group at pivotal study baseline.LIBERTY 1 and LIBERTY 2 were prospectively registered trials; study protocols estimated that approximately 75% of participants would enter the planned LIBERTY LTE study. 11,14The LIBERTY LTE started in October 2017 (October

| Efficacy and safety endpoints
For this post hoc analysis, the primary endpoint was the proportion of women in the anemia-evaluable population who met treatment responder criteria: women who achieved an MBL volume of <80 mL (sub)scale scores indicate better HRQoL, whereas higher SS scores indicate a greater symptom burden (i.e., worse symptoms). 16Fatigue was assessed as part of the UFS-QoL SS scale score and evaluated post hoc for the present analysis.
Safety endpoints for this analysis included the incidence of adverse events in the anemia-evaluable population.Adverse events were categorized by the investigator based on Common Terminology Criteria for Adverse Events.

| Statistical analysis
Methodology for the LIBERTY LTE statistical analyses have been previously reported. 14Demographics and baseline characteristics were analyzed using descriptive statistics.Data were analyzed in accordance with originally randomized treatment groups in the pivotal LIBERTY studies.No formal statistical comparisons between groups were conducted.For percent change from baseline in hemoglobin, LS means were derived separately for each parent study treatment group and were based on mixed-effect model with visit, region, and baseline MBL included as fixed effects.The multiple visits for each patient were the repeated measures as random effects within each patient and a first-order autoregressive covariance.To determine UFS-QoL SS and HRQoL total scale and subscale scores, items for each (sub)scale were summed and then transformed to a normalized score (range 0-100).Similar mixed-effect models with repeated measures but an unstructured covariance were used for analyzing UFS-QoL SS and HRQoL total scale and subscale score-related variables.SAS version 9.2 or higher was used for all data analysis and CONSORT reporting guidelines were followed. 17

| Participants
In total, 477 women were enrolled into the LTE, of which 115 women met criteria for the anemia-evaluable population (Figure 2).A subset of 39 women in the anemia-evaluable population received relugolix combination therapy for 52 weeks (n = 38 in the placebo → relugolix combination therapy group; n = 38 in the delayed relugolix combination therapy group).At pivotal study baseline, demographics and baseline characteristics were generally balanced between treatment groups (Table 1).Most of the women in the anemia-evaluable population of the LTE reported use of iron products as a concomitant medication (Table 2).Approximately half of the women in the overall LIBERTY LTE population reported use of iron.

| Safety
In the anemia-evaluable population, adverse events were reported in 30/39 (76.9%), 34/38 (89.5%) and 32/38 (84.2%) women in the relugolix combination therapy group, placebo → relugolix combination therapy group and delayed relugolix combination therapy group, respectively.The most common adverse events reported by women in the anemia-evaluable population were: hot flush (reported by 2/39 women [5.1%] in the relugolix combination therapy group, a Anemia defined as women with a hemoglobin concentration of ≤10.5 g/dL at baseline.b One patient was randomized but did not receive treatment.c Anemia-evaluable population defined as women with anemia (hemoglobin concentration of ≤10.5 g/dL) at baseline and with a hemoglobin concentration value at week 52.LTE, long-term extension.group, 8/38 women [21.1%] placebo → relugolix combination therapy and 2/38 [5.3%] women in the delayed relugolix combination therapy group).These safety results were consistent with the overall study population. 14

| DISCUSS ION
In the anemia-evaluable population of the LIBERTY LTE study, oncedaily relugolix combination therapy reduced HMB through 52 weeks, with >84% treatment response observed across treatment groups.
In the relugolix combination therapy group, approximately 60% of women met criteria for anemia responders, denoting improvement in hemoglobin levels.Additionally, relugolix combination therapy led to reductions in symptom severity and fatigue, and improvement in HRQoL through 52 weeks, as measured by the UFS-QoL questionnaire.
Women included in this analysis were randomized to different treatment groups in the pivotal studies, and all women received relugolix combination therapy in the LTE.Efficacy outcomes in the placebo → relugolix combination therapy and delayed relugolix combination therapy groups were supportive of the positive treatment effect observed with the relugolix combination therapy group, with a comparable rate of responders to the primary endpoint at week 52.As expected, the percentage increase in hemoglobin concentration in the placebo → relugolix combination TA B L E 1 Demographics and baseline characteristics of the anemia-evaluable population.c UFS-QoL revised activities scale includes five of the seven most relevant items pertaining to physical and social activities. 18The summary score of the five items ranges from 0 to 100, where a lower score indicates a higher ability to do activities (i.e., lower score = good) and a higher score indicates a lower ability to do activities.Regarding difference, the anemia-evaluable women had numerically higher MBL volume (322.8 mL vs 248.7 mL in the relugolix combination therapy treatment group, for the anemia-evaluable and overall study populations, respectively), higher uterine volume (431.1 vs 386.7 cm 3 ) and lower hemoglobin levels (9.6 vs 11.4 g/dL). 14Considering occurrence of anemia is associated with HMB, 4 it was reasonable for the anemia-evaluable population to exhibit numerically higher MBL loss and lower hemoglobin levels in comparison with the overall study population.Additionally, in the relugolix combination therapy group, a numerically higher proportion of women in the anemia-evaluable women were Black or African American and from North America compared with the   ). 14Safety outcomes in anemia-evaluable women were comparable with the overall LTE population regarding overall incidence of adverse events (relugolix combination therapy group: 76.9% vs 77.9%, respectively). 14B in women with UF often leads to the development of irondeficiency anemia. 2,20[5]7 Thus, there is a need for an intervention that can reduce disease burden in this population.Although some minimally invasive surgical procedures are available to women with UF who wish to preserve their fertility (e.g., myomectomy and uterine artery embolization), many women still undergo hysterectomy to treat symptomatic disease. 1,21GnRH analogs may have a role in preoperative restoration of hematological parameters, such as correction of anemia, in women undergoing UF-related surgery. 22Improving hemoglobin levels prior to surgery may lead to improved surgical outcomes, as well as reduced blood transfusion requirements. 22,23spite experiencing symptoms of UF, patients often attempt to normalize their symptoms and do not report HMB. 24Therefore, 19, 2017), with the first patient enrolled in December 2017.The last patient was assessed for the primary endpoint in January 2020, the primary endpoint was met in January 2020, and the study completed January 2021 (January 13, 2021).All women enrolled in the LIBERTY studies provided informed consent.The studies were conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice guidelines, as well as local and national regulations.Institutional Review Board approval was also granted (Schulman Associates Institutional Review Board, Cincinnati, OH [central institutional review board]; Western Institutional Review Board, Puyallup, WA; Chesapeake Institutional Review Board, Columbia, MD).

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38 women [23.7%] placebo → relugolix combination therapy and 20/38 [52.6%] women in the delayed relugolix combination therapy group); upper respiratory tract infection (3/39 women [7.7%] in the relugolix combination therapy group, 6/38 women [15.8%] placebo → relugolix combination therapy and 5/38 [13.2%] women in the delayed relugolix combination therapy group); headache (3/39 women [7.7%] in the relugolix combination therapy group, 3/38 women [7.9%] placebo → relugolix combination therapy and 7/38 [18.4%] women in the delayed relugolix combination therapy group); and hypertension (3/39 women [7.7%] in the relugolix combination therapy F I G U R E 2 Participant flow diagram. therapy group was more pronounced after week24 when women transitioned to relugolix combination therapy.Similarly, reduction in MBL in the placebo → relugolix combination therapy group increased following transition to relugolix combination therapy after week 24 (data not shown).The findings of this subgroup analysis demonstrate that relugolix combination therapy represents an effective pharmacologic treatment for women with UF and anemia.Descriptive comparisons demonstrated some similarities and differences in demographics and clinical characteristics at baseline between the anemia-evaluable population and overall study population.The baseline characteristics of the relugolix combination therapy group in the anemia-evaluable population and the overall LTE population were comparable across several parameters, including mean age (42.4 [standard deviation 19 : 5.8] vs 42.6 [SD: 5.1] years, respectively), mean body mass index (calculated as weight in kilograms divided by the square of height in meters) (32.5 [SD: 8.4] vs 31.4 [SD: 7.0] kg/m 2 , respectively), and baseline UFS-QoL scores for symptom severity scale (59.0 [SD: 21.6] vs 56.6 [SD: 20.9]) and HRQoL (38.9 [SD: 21.6] vs 40.4 [SD: 21.4]). 14 overall LIBERTY LTE population (53.8% [n = 21] vs 42.3% [n = 69] and 76.9% [n = 30] vs 69.3% [n = 113], respectively). 14Despite these potential differences, the efficacy of relugolix combination therapy in the anemia-evaluable population was also comparable with previously published data for the overall LIBERTY LTE population, with a similar proportion of treatment responders in the relugolix combination therapy treatment group (87.2% [n = 39] vs 87.7% [n = 163], respectively). 14Additionally, by week 52 similar TA B L E 2 Summary of concomitant antianemic preparations in the anemia-evaluable population and overall LIBERTY LTE population.
reductions in LS mean percentage change in MBL volume were observed in the relugolix combination therapy treatment group across both the overall and anemia-evaluable study populations (−91.3%[n = 39] vs −89.9% [n = 163], respectively). 14Similar changes from baseline to Week 52 were observed between the anemia-evaluable population and overall study population in UFS-QoL SS scale scores (−38.5 vs −37.3, respectively), fatigue score (−31.9 vs −38.8) and HRQoL total score (41.6 vs 40.4

F I G U R E 3 F I G U R E 4 F I G U R E 6
Primary efficacy endpoint: proportion of treatment responders at week 52 in the anemia-evaluable population.Treatment responders were defined as women who achieved MBL volume of <80 mL, and ≥50% reduction in MBL volume from pivotal study baseline to the last 35 days of treatment with relugolix combination therapy, as measured by the alkaline hematin method.Error bars show 95% confidence intervals.MBL, menstrual blood loss.Proportion of anemia responders at week 52 in the anemia-evaluable population.Anemia responders were defined as women achieving hemoglobin concentration increases of >2 g/dL from baseline.Error bars show 95% confidence intervals.thediagnosis of iron-deficiency anemia in women with UF may serve as an indicator to begin active management of disease.The present analysis demonstrates that relugolix combination therapy provides a long-term, effective convenient (once-daily) and welltolerated option in women with UF and anemia that may help to alleviate symptomatic burden, such as fatigue, and improve different aspects of QoL.Over the course of the 52-week treatment period, sustained improvements in hemoglobin concentration were observed in the anemia-evaluable population, suggesting that relugolix combination therapy led to substantial improvements in HMB-associated anemia in this population.A potential limitation of this analysis is that some assessments on the anemia-evaluable population were conducted in a post hoc manner.The analysis was limited by the absence of a placebo comparator group in the LTE study and the small sample size, thus making it a descriptive comparison.Although a lack of placebo comparator in the LIBERTY LTE is a limitation of the extension, it would not be ethical to maintain a placebo group F I G U R E 5 Mean percentage change in hemoglobin concentration over 52 weeks in the anemia-evaluable population.Error bars show 95% confidence intervals.LS, least squares.Least squares (LS) mean change in UFS-QoL SS scale score from baseline to week 52.Error bars show 95% confidence intervals.SS, symptom severity; UFS-QoL, uterine fibroid symptom-quality of life.beyond24 weeks, considering the debilitating nature of a condition such as UF with HMB.Ferritin levels were not systematically measured in this study as a predefined laboratory endpoint and therefore information necessary for the type of anemia in women included in the present analysis is limited.It is possible that selection bias may have been introduced in the longitudinal assessment of patients who participated in the pivotal LIBERTY studies and then opted to enter the LTE.However, as 77% of women in the overall study population who enrolled in the pivotal studies were study completers, and 80% of the pivotal completers entered the 28-week extension, it is unlikely that interpretation of the results will be significantly affected by this potential bias.A relatively small sample size of anemia-evaluable population (n = 115) represents a subgroup of the overall study population (n = 476); therefore, direct comparisons between the two populations may be inappropriate.14