Relugolix for oral treatment of uterine leiomyomas: a dose-finding, randomized, controlled trial

Abstract Background Uterine leiomyomas are the most common neoplasm affecting women and frequently cause heavy menstrual bleeding and pain. Gonadotropin-releasing hormone (GnRH) receptor antagonists provide fast symptom relief and show promise as a medical (non-surgical) treatment option and as a presurgical treatment to reduce leiomyoma size. The aim of this study was to evaluate the efficacy and safety of three dose levels of oral relugolix, a small molecule GnRH receptor antagonist, in Japanese women with uterine leiomyomas and heavy menstrual bleeding. Methods This phase 2, multicenter, double-blind, parallel-group study was conducted at 36 sites in Japan in women with uterine leiomyomas and heavy menstrual bleeding, defined as a pictorial blood loss assessment chart (PBAC) score of ≥ 120 in one menstrual cycle. Patients were randomized 1:1:1:1 to relugolix 10, 20, or 40 mg, or placebo, orally once daily for 12 weeks. The primary endpoint was the proportion of patients with a total PBAC score of < 10 from week 6 to 12. A sample size of 50 patients per group was estimated to provide ≥ 95% power, based on the comparison of relugolix 40 mg with placebo using a chi-square test with a significance level of 5% (two-sided). Results From November 2011 to September 2012, 216 patients were randomized and 214 patients (99.1%) were analyzed. The proportion (difference vs. placebo) of patients that achieved the primary endpoint in the placebo and 10-, 20-, and 40-mg relugolix groups were 0%, 20.8% (95% confidence interval [CI]: 9.3–32.3, P < .001), 42.6% (95% CI: 29.4–55.8, P < .001), and 83.3% (95% CI: 73.4–93.3, P < .001), respectively. Though treatment-emergent adverse events were similar between the 20- and 40-mg groups, the incidence rates were more frequent compared with the placebo group. Most of these adverse events were mild or moderate in intensity. Conclusions Relugolix decreased menstrual blood loss in women with uterine leiomyomas in a dose–response manner, and was generally well tolerated. Clinical trial registration: ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01452659, NCT01452659 (registered 17/10/2011); JAPIC Clinical Trial Information, https://www.clinicaltrials.jp, JapicCTI-111590 (registered 31/08/2011).

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Safety and efficacy of elagolix (with and without add-back therapy) for the treatment of heavy menstrual bleeding associated with uterine leiomyomas: a systematic review and meta-analysis

Middle East Fertility Society Journal ◽

10.1186/s43043-021-00064-5 ◽

2021 ◽

Vol 26 (1) ◽

Author(s):

Mustafa Ali ◽

Aruna Kumari Hira ◽

Haris Jawaid ◽

Faiza Zakaria ◽

Zehra Somjee

Keyword(s):

Clinical Trials ◽

Adverse Events ◽

Effective Treatment ◽

Meta Analysis ◽

Uterine Leiomyomas ◽

Heavy Menstrual Bleeding ◽

Menstrual Bleeding ◽

Cochrane Library ◽

Pool Data ◽

Safety And Efficacy

Abstract Background Heavy menstrual bleeding (HMB) is a common clinical finding in patients with uterine leiomyomas that can negatively impact their quality of life. Recently, a novel oral GnRH-antagonist (elagolix) has emerged as a possible therapeutic agent for this ailment. Herein data was pooled from clinical trials assessing the safety and efficacy of elagolix with and without add-back therapy. Main text PubMed and Cochrane library were systematically searched for RCTs that measured the efficacy and safety of elagolix for the treatment of uterine fibroid-associated HMB. All safety and efficacy endpoints were compared between elagolix-alone, elagolix w/add-back therapy, and placebo. The primary efficacy endpoint was defined as the number of women who achieved menstrual blood loss (MBL) < 80 ml and a reduction in MBL from baseline of > 50% at the end of treatment. Secondary outcomes assessed included change in hemoglobin levels, incidence suppression of bleeding and amenorrhea, and the incidence of adverse events. The random effects model was used to pool data, and heterogeneity was assessed using I2. Our search identified 4 clinical trials meeting our PICO criteria, with a total of 916 patients. Analysis of the primary outcome revealed that elagolix-alone was the most effective treatment compared to both placebo (LOR = 3.47, CI = 3.03–3.91, p = 0.000, I2 = 0.0%) and add-back therapy (LOR = 0.64, CI = 0.12–1.16, p = 0.016, I2 = 43.1%). Furthermore, both elagolix groups (irrespective of add-back therapy) observed a significant improvement in post-treatment hemoglobin levels as compared to the placebo group (elagolix-alone vs PBO: LOR = 1.44, CI = 0.66–2.22, I2 = 66.0%, p = 0.000; elagolix-w/add-back therapy vs PBO: LOR = 1.22, CI = 0.78–1.66, I2 = 0.0%, p = 0.000). Concerning safety, while elagolix without add-back therapy had the highest overall incidence of adverse effects (elagolix-alone vs placebo LOR = 0.84, CI = 0.48–1.20, I2 = 7.8%, p = 0.000; elagolix-alone vs elagolix-w/add-back LOR = 0.68, CI = 0.09–1.26, p = 0.024, I2 = 64.6%), the incidence of serious (life threatening) adverse events between all 3 treatment groups was not statistically different. The inclusion of add-back therapy with elagolix made the treatment noticeably safer (elagolix-w/add-back vs placebo: LOR = 0.19, CI = − 0.10 to 0.48, I2 = 0.0%, p = 0.194) without seriously compromising its efficacy. Conclusion High-quality evidence from 4 trials suggests that elagolix is an effective treatment for leiomyoma-associated HMB, with a marked improvement in all efficacy endpoints. Furthermore, the inclusion of add-back therapy in the treatment regimen should be considered as it mitigates the hypoestrogenic effects of elagolix.

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RELUGOLIX COMBINATION THERAPY SIGNIFICANTLY REDUCED MENSTRUAL BLOOD LOSS WITH FIRST TREATMENT CYCLE IN WOMEN WITH HEAVY MENSTRUAL BLEEDING ASSOCIATED WITH UTERINE FIBROIDS: LIBERTY PHASE 3 PROGRAM RESULTS

10.26226/morressier.5f5634191bffda7af85eb4b3 ◽

2020 ◽

Author(s):

Roberta Venturella

Keyword(s):

Combination Therapy ◽

Blood Loss ◽

Treatment Cycle ◽

Uterine Fibroids ◽

Heavy Menstrual Bleeding ◽

Menstrual Bleeding ◽

Menstrual Blood ◽

Menstrual Blood Loss ◽

Phase 3

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Levonorgestrel Intrauterine System Is an Effective Therapy for Fibroid-Related Heavy Menstrual Bleeding: A Secondary Analysis of a Randomized Clinical Trial

Journal of Minimally Invasive Gynecology ◽

10.1016/j.jmig.2011.08.075 ◽

2011 ◽

Vol 18 (6) ◽

pp. S19-S20

Author(s):

S.A. El-Nashar ◽

M.S. Zakherah ◽

G.H. Sayed ◽

M.M. Shaaban

Keyword(s):

Clinical Trial ◽

Randomized Clinical Trial ◽

Secondary Analysis ◽

Effective Therapy ◽

Heavy Menstrual Bleeding ◽

Menstrual Bleeding

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Is the Pictorial Blood Loss Assessment Chart (PBAC) score associated with treatment outcome after endometrial ablation for heavy menstrual bleeding? A cohort study

BJOG An International Journal of Obstetrics & Gynaecology ◽

10.1111/1471-0528.14434 ◽

2016 ◽

Vol 124 (2) ◽

pp. 277-282 ◽

Cited By ~ 8

Author(s):

MC Herman ◽

N Mak ◽

PM Geomini ◽

B Winkens ◽

BW Mol ◽

...

Keyword(s):

Cohort Study ◽

Treatment Outcome ◽

Blood Loss ◽

Endometrial Ablation ◽

Heavy Menstrual Bleeding ◽

Menstrual Bleeding ◽

Loss Assessment

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REDUCTION IN MENSTRUAL BLOOD LOSS (MBL) IN WOMEN WITH UTERINE FIBROID (UF)-ASSOCIATED HEAVY MENSTRUAL BLEEDING (HMB) TREATED WITH RELUGOLIX COMBINATION THERAPY (REL-CT): LIBERTY LONG-TERM EXTENSION (LTE) STUDY

10.26226/morressier.615c7f2662ba8657678b0a8f ◽

2021 ◽

Author(s):

Ayman Al-Hendy

Keyword(s):

Combination Therapy ◽

Blood Loss ◽

Uterine Fibroid ◽

Heavy Menstrual Bleeding ◽

Menstrual Bleeding ◽

Menstrual Blood ◽

Menstrual Blood Loss

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Management of heavy menstrual bleeding on anticoagulation

Hematology ◽

10.1182/hematology.2020000138 ◽

2020 ◽

Vol 2020 (1) ◽

pp. 533-537

Author(s):

Bethany Samuelson Bannow

Keyword(s):

Iron Deficiency ◽

Blood Loss ◽

Oral Anticoagulants ◽

Heavy Menstrual Bleeding ◽

Menstrual Bleeding ◽

School Work ◽

Medical Interventions ◽

Recurrent Venous Thromboembolism ◽

Menstruating Women ◽

Hormone Therapies

Abstract Heavy menstrual bleeding (HMB) is a common complication of anticoagulation, affecting ∼70% of menstruating women receiving oral anticoagulants. The risk of HMB is lower with apixaban and/or dabigatran than with rivaroxaban. HMB can result in iron deficiency with or without anemia, increased need for medical interventions, decreased quality of life, and missed school/work. Mainstays of treatment include hormone therapies such as the levonorgestrel intrauterine system, subdermal implant, and other progesterone-based therapies, which can result in decreased blood loss and, in some cases, amenorrhea. Combined hormone therapies can be used while patients continue receiving anticoagulation and are also highly effective for decreasing menstrual blood loss. Rarely, procedure-based interventions such as endometrial ablation may be required. Patients should be evaluated for iron deficiency and anemia and offered supportive therapies as needed. Abbreviating the course of anticoagulation or skipping doses can increase the risk of recurrent venous thromboembolism by as much as fivefold, but switching oral anticoagulants may be considered. Awareness of HMB and careful history taking at each visit are crucial to avoid a missed diagnosis.

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Daptomycin Plus Fosfomycin Versus Daptomycin Alone for Methicillin-resistant Staphylococcus aureus Bacteremia and Endocarditis: A Randomized Clinical Trial

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1081 ◽

2020 ◽

Author(s):

Miquel Pujol ◽

José-María Miró ◽

Evelyn Shaw ◽

Jose-María Aguado ◽

Rafael San-Juan ◽

...

Keyword(s):

Clinical Trial ◽

Staphylococcus Aureus ◽

Adverse Events ◽

Primary Endpoint ◽

Methicillin Resistant Staphylococcus Aureus ◽

Statistical Significance ◽

Treatment Success ◽

Open Label ◽

Methicillin Resistant ◽

Staphylococcus Aureus Bacteremia

Abstract Background We aimed to determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis. Methods A randomized (1:1) phase 3 superiority, open-label, and parallel group clinical trial of adult inpatients with MRSA bacteremia was conducted at 18 Spanish hospitals. Patients were randomly assigned to receive either 10 mg/kg of daptomycin intravenously daily plus 2 g of fosfomycin intravenously every 6 hours, or 10 mg/kg of daptomycin intravenously daily. Primary endpoint was treatment success 6 weeks after the end of therapy. Results Of 167 patients randomized, 155 completed the trial and were assessed for the primary endpoint. Treatment success at 6 weeks after the end of therapy was achieved in 40 of 74 patients who received daptomycin plus fosfomycin and in 34 of 81 patients who were given daptomycin alone (54.1% vs 42.0%; relative risk, 1.29 [95% confidence interval, .93–1.8]; P = .135). At 6 weeks, daptomycin plus fosfomycin was associated with lower microbiologic failure (0 vs 9 patients; P = .003) and lower complicated bacteremia (16.2% vs 32.1%; P = .022). Adverse events leading to treatment discontinuation occurred in 13 of 74 patients (17.6%) receiving daptomycin plus fosfomycin, and in 4 of 81 patients (4.9%) receiving daptomycin alone (P = .018). Conclusions Daptomycin plus fosfomycin provided 12% higher rate of treatment success than daptomycin alone, but this difference did not reach statistical significance. This antibiotic combination prevented microbiological failure and complicated bacteremia, but it was more often associated with adverse events. Clinical Trials Registration NCT01898338.

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