Relugolix Combination Therapy To Improve Quality Of Life In Fibroid Patients
Overview
This analysis aimed to assess the impact of 52 weeks of treatment with relugolix combination therapy (consisting of relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) on symptoms of uterine fibroids (UF) and quality of life (QoL) in women experiencing heavy menstrual bleeding associated with UF and anemia (hemoglobin ≤10.5 g/dL) at baseline. The study focused on women from the LIBERTY long-term extension study who had anemia at the start of the pivotal study and had documented hemoglobin values at week 52 (referred to as the anemia-evaluable population). Treatment responders were defined as women who achieved a menstrual blood loss volume of <80 mL and a ≥50% reduction over the last 35 days of treatment. Additionally, anemia responders were those who achieved a hemoglobin increase of >2 g/dL from baseline to week 52. The analysis calculated least squares (LS) mean changes from baseline in various parameters, including uterine fibroid symptom (UFS)-QoL symptom severity, fatigue, and health-related QoL total (HR-QoL) and subscale scores.
Introduction
Uterine fibroids (UF), also termed uterine leiomyomas, represent a prevalent condition among premenopausal women, characterized by non-cancerous growths in the pelvic region that respond to estrogen and progesterone. Although not all women with UF experience symptoms, approximately 20% to 50% do, manifesting with various clinical presentations such as heavy menstrual bleeding (HMB), pelvic discomfort, and fertility issues. Notably, HMB, which affects around one-third of UF patients, can lead to iron-deficiency anemia, a condition associated with fatigue, weakness, and, in severe cases, life-threatening complications. Anemia complicates the management of UF, often necessitating more aggressive treatment strategies and resulting in poorer outcomes following surgical interventions.
Beyond the physical symptoms, UF and its associated anemia can significantly impact a patient’s health-related quality of life (HRQoL) and mental well-being. Women grappling with UF may experience emotional distress, social isolation, and heightened anxiety, alongside a diminished sense of well-being due to their chronic condition. Therefore, effective management strategies targeting UF-related symptoms and anemia are crucial not only for improving physical health but also for enhancing overall quality of life and mental health outcomes in affected individuals.
In this context, relugolix emerges as a promising therapeutic option. Relugolix is a gonadotropin-releasing hormone receptor antagonist that exerts its effects by suppressing the secretion of gonadotropins, thereby reducing ovarian hormone production, particularly estrogen and progesterone. Administered as a once-daily tablet containing relugolix, estradiol, and norethindrone acetate, this combination therapy has garnered approval for managing UF-related HMB in premenopausal women in the United States and for treating UF symptoms in adult women across the European Union. Additionally, it has received regulatory clearance in the USA for the management of moderate-to-severe pain associated with endometriosis.
Pivotal studies, such as LIBERTY 1 and LIBERTY 2, have demonstrated the efficacy and safety of relugolix combination therapy over a 24-week period, showcasing significant improvements in UF-associated symptoms compared to placebo, along with favorable tolerability profiles and preservation of bone mineral density. Furthermore, the LIBERTY long-term extension (LTE) study has provided insights into the sustained benefits of relugolix combination therapy over 52 weeks, including reductions in HMB, anemia, and overall UF symptom burden, alongside enhancements in HRQoL measures.
In light of these findings, exploring the effects of long-term relugolix combination therapy on UF symptoms and HRQoL in women presenting with HMB-associated UF and anemia at baseline is crucial for elucidating its comprehensive therapeutic potential and long-term benefits in this patient population.
Methods
Inclusion Criteria
- Premenopausal women aged 18–50 years.
- Diagnosis of uterine fibroids (UF) confirmed by transvaginal ultrasonography.
- Presence of heavy menstrual bleeding (HMB), defined as a menstrual blood loss (MBL) volume of ≥80 mL per cycle for two cycles, or ≥160 mL during one cycle.
- Hemoglobin concentration ≤10.5 g/dL at baseline.
- Participants who completed the LIBERTY 1 or LIBERTY 2 studies and were not expecting to undergo additional UF procedures within the study period.
- Women not exhibiting a BMD Z-score of <−2.
- Women who provided informed consent to participate in the study.
Exclusion Criteria
- Women with a BMD Z-score of <−2.
- Women exhibiting a decrease in BMD of 7% at the lumbar spine, total hip, or femoral neck from pivotal study baseline to week 24.
- Participants who were pregnant or breastfeeding.
- Women with contraindications to the study medication or its components.
- Women with significant medical conditions that could interfere with study participation or interpretation of results.
- Participants with a history of malignancy within the past five years, except for adequately treated non-melanoma skin cancer or in situ cervical cancer.
- Individuals with a history of bone diseases such as osteoporosis or Paget’s disease.
- Women with significant hepatic or renal impairment.
- Participants unable to comply with study procedures or follow-up visits.
- Individuals currently participating in other clinical trials or who had received investigational drugs within a specified period before study enrollment.
These inclusion and exclusion criteria were applied to ensure the enrollment of eligible participants and the integrity of the study findings. Participants meeting these criteria were included in the analysis to assess the effects of relugolix combination therapy on UF symptoms and quality of life in women with HMB-associated UF and anemia at baseline.
Analysis
The statistical analyses for the LIBERTY LTE study were conducted following previously established methodologies, as documented in prior reports. Demographic data and baseline characteristics were summarized using descriptive statistics. The analysis was performed according to the originally randomized treatment groups in the pivotal LIBERTY studies, without formal statistical comparisons between groups.
To assess the percent change from baseline in hemoglobin levels, least squares (LS) means were calculated separately for each treatment group from the parent studies. These LS means were determined using a mixed-effect model incorporating visit, region, and baseline menstrual blood loss (MBL) as fixed effects. The repeated measures for each patient were treated as random effects within the model, with a first-order autoregressive covariance structure.
For evaluating uterine fibroid symptom-quality of life (UFS-QoL) symptom severity (SS) and health-related quality of life (HRQoL) total scale and subscale scores, the items for each respective scale were aggregated and then transformed to normalized scores ranging from 0 to 100. Similar mixed-effect models with repeated measures, employing an unstructured covariance, were applied for the analysis of UFS-QoL SS and HRQoL total scale and subscale scores-related variables.
All data analyses were conducted using SAS version 9.2 or higher. The reporting of results adhered to the CONSORT (Consolidated Standards of Reporting Trials) guidelines, ensuring transparency and clarity in presenting the findings of the study.
Results
The study enrolled a total of 477 premenopausal women into the long-term extension (LTE) phase, with 115 women meeting the criteria for the anemia-evaluable population. Among these, a subset of 39 women received relugolix combination therapy for the entire 52-week duration. At the baseline of the pivotal study, demographic and baseline characteristics were generally balanced across treatment groups. Most women in the anemia-evaluable population reported concurrent use of iron products.
Regarding the primary endpoint, a high proportion of women in the relugolix combination therapy group achieved treatment response, with 87.2% meeting the criteria. Similar response rates were observed in both the placebo → relugolix combination therapy group (84.2%) and the delayed relugolix combination therapy group (92.1%).
In terms of secondary endpoints, improvements were noted in anemia responders across all treatment groups. The relugolix combination therapy group exhibited a substantial increase in hemoglobin concentration and a significant reduction in menstrual blood loss volume. Moreover, improvements in uterine fibroid symptom-quality of life (UFS-QoL) symptom severity and health-related quality of life (HRQoL) total score were observed across all treatment groups.
Regarding safety, adverse events were reported in the majority of participants across all treatment groups, with hot flush, upper respiratory tract infection, headache, and hypertension being the most common. However, the incidence of adverse events varied between treatment groups.
Overall, the findings suggest that relugolix combination therapy demonstrates efficacy in improving symptoms and quality of life in women with heavy menstrual bleeding associated with uterine fibroids and anemia.
Conclusion
In the anemia-evaluable population of women with uterine fibroids (UF) participating in the LIBERTY LTE study, relugolix combination therapy exhibited significant improvements in various parameters over the course of 52 weeks. Notably, there was a considerable increase in hemoglobin concentration, indicating an amelioration of anemia associated with UF. Additionally, there was a notable reduction in distress attributable to UF symptoms, including fatigue, suggesting an alleviation of symptom burden. Moreover, there was an overall enhancement in health-related quality of life (HRQoL) observed among participants receiving relugolix combination therapy.
Despite indications of a potentially increased disease burden in some cases, the efficacy and safety outcomes observed in the anemia-evaluable population were largely consistent with those observed in the broader LIBERTY LTE study population. These findings suggest that treatment with relugolix combination therapy may offer a viable option for longer-term management in women dealing with UF and heavy menstrual bleeding-associated anemia.
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