Non-inferiority study to compare the efficacy of relugolix with dienogest for endometriosis-associated pain and usefulness of administering relugolix prior to dienogest (READY study): study protocol for a multicenter randomized controlled study

Abstract

Background

Endometriosis presents as endometrial tissue growths outside the uterine cavity with its major symptoms including dysmenorrhea and infertility. Progestin preparations, such as dienogest, are the first-line therapy for endometriosis symptoms, but may cause abnormal uterine bleeding. A gonadotropin-releasing hormone (GnRH) agonist may also be used to ease symptoms, but may induce flare-ups. Relugolix is a non-peptide GnRH antagonist that does not induce flare-ups. This study aims to compare the efficacy of relugolix with that of dienogest for reducing endometriosis-associated pain, and to evaluate if relugolix, administered prior to dienogest, decreases abnormal uterine bleeding.

Methods

A multicenter, open-label, active-controlled, non-inferiority randomized study will be conducted at 11 sites in Japan. A total of 100 premenopausal patients aged ≥ 18 years with endometriosis, a maximum visual analog scale (VAS) score > 30 for endometriosis-associated pain, and dysmenorrhea or pelvic pain of at least moderate severity on the Biberoglu & Behrman (B&B) scale will be randomized in a 1:1 ratio to either a relugolix group or dienogest group. Patients in the relugolix group will receive 40 mg oral relugolix once daily for 16 weeks, followed by 1 mg oral dienogest twice daily for 24 weeks. Patients in the dienogest group will receive oral dienogest 1 mg twice daily for 24 weeks. The primary outcome will be change in maximum VAS score for endometriosis-associated pain from baseline to 13–16 weeks after start of treatment. The secondary outcomes will include VAS score for dyspareunia, B&B score for dysmenorrhea, severity of induration in the pouch of Douglas, restricted uterine mobility, pelvic tenderness, quality of life, analgesic use, and ovarian endometrioma diameter. The safety outcomes will include treatment-emergent adverse events, bone density, bone markers, menstrual status, genital bleeding, and endometrial thickness.

Discussion

This study will determine the efficacy of relugolix for improving endometriosis-associated pain and dienogest-induced abnormal uterine bleeding. The results will support treatment decisions regarding endometriosis-associated pain, and the introduction of new treatments to reduce dienogest-induced abnormal uterine bleeding.

Trial registration

Japan Registry of Clinical Trials ID jRCTs061230064. Registered on 29 September 2023.

Background

Endometriosis is a benign estrogen-dependent disease, in which tissue that is morphologically and functionally similar to the endometrium grows outside the uterine cavity. Its main clinical symptoms are pain, including menstrual pain (dysmenorrhea) and infertility. Patients with endometriosis frequently experience endometriosis-associated pain, as well as pain during sexual intercourse (dyspareunia), even at times other than during menstruation, which significantly impair their quality of life (QOL) [1, 2].

One treatment option for managing endometriosis symptoms involves lowering the blood concentration of sex hormones by suppressing the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) [3]. Gonadotropin-releasing hormone (GnRH) agonists have been administered to patients to suppress GnRH secretion by desensitization of GnRH receptors in the pituitary gland. However, this treatment may temporarily worsen symptoms caused by stimulated LH and FSH secretion (flare-up) at the beginning of treatments and, then, hypoestrogenic side effects such as accelerated bone loss [3,4,5,6].

Relugolix is a non-peptide oral GnRH antagonist that directly antagonizes GnRH receptor and suppresses LH and FSH secretion and therefore does not induce flare-ups like GnRH agonists, and rapidly lowers the concentrations of estradiol (E₂) and progesterone [7, 8]. Relugolix was approved in Japan in January 2019 for the indications of uterine fibroid-related symptoms, menorrhagia, lower abdominal pain, lower back pain, and anemia, with addition of the further indication of endometriosis-associated pain in December 2021 [1, 4].

A phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled study comparing the efficacy and safety of relugolix with the GnRH agonist leuprorelin was carried out in 335 Japanese patients with endometriosis-associated pain [1]. The primary endpoint, defined as change in maximum visual analog scale (VAS) score for pelvic pain from baseline until 28 days before the end of treatment in patients treated with 40 mg oral relugolix once daily for 24 weeks, was non-inferior to that in patients treated with subcutaneous leuprorelin administered every 4 weeks for 24 weeks (between-group difference, 4.9). The results demonstrated that the incidence of treatment-emergent adverse events (TEAEs) in the relugolix group was similar to that in the leuprorelin group. Drug-related TEAEs were reported in 79.5% of patients treated with relugolix, including hot flushes in 42.7% (73 patients), metrorrhagia in 31.0% (53 patients), and headache in 10.5% (18 patients) of patients [1]. However, a decrease in E₂ concentration is known to cause TEAEs and, therefore, GnRH analog preparations cannot be administered for > 6 months because of the risk of bone density reduction [6, 9, 10].

Progestin is another hormonal treatment option for endometriosis. Dienogest is a progestin preparation that acts selectively on progesterone receptors and suppresses ovarian function and endometrial cell proliferation. It improves endometriosis symptoms and can be administered for long periods of time, and has thus been the first-line hormone therapy for endometriosis [3].

A previous randomized parallel group study compared the efficacy and safety of dienogest with the GnRH agonist buserelin acetate in 255 patients with endometriosis, who were treated with 1 mg oral dienogest twice daily for 24 weeks or 300 μg buserelin acetate intranasally three times a day for 24 weeks [11]. The results demonstrated non-inferiority of dienogest to buserelin acetate in terms of the primary endpoint, changes in scores of the five subjective symptoms during non-menstruation and two objective findings (between-group difference, − 2.7 [95% confidence interval [CI], − 12.6%, 7.3%]). Drug-related TEAEs were reported in 100% (129/129 patients) of patients treated with dienogest, with genital bleeding (94.6%, 122/129), hot flushes (49.6%, 64/129), and headache (24.8%, 32/129) being the most frequent events.

Furthermore, dienogest frequently causes abnormal uterine bleeding by prompting decidualization of the endometrium due to the action of progesterone [2]. Although a GnRH agonist has been administered prior to dienogest to thin the endometrium to reduce this abnormal uterine bleeding [4], there is currently no high-level evidence for the effectiveness of pretreatment with a GnRH antagonist in randomized controlled studies.

This Relugolix and Dienogest for Endometriosis: Randomized Controlled (READY) study therefore aims to compare the efficacy of relugolix with that of dienogest for improving endometriosis-associated pain in patients with endometriosis, and to compare the incidence rate of genital bleeding in patients treated with dienogest with or without prior relugolix treatment.

Methods/design

This multicenter, open-label, active-controlled, non-inferiority randomized study will be carried out in two parallel groups at 11 obstetrics and gynecology hospitals and clinics in Japan. Investigators will enroll and assign eligible patients in a 1:1 ratio to either a relugolix group or dienogest group by stratified randomization with minimization (stratification factors: presence of uterine fibroids, submucosal fibroids, and adenomyosis), using an electronic data capture (EDC) system (Viedoc version 4, Viedoc Technologies AB, Uppsala, Sweden).

The study design is summarized in Fig. 1. Patients in the relugolix group will receive a 40 mg relugolix tablet orally once daily before meals for 16 weeks, with the first dose on days 2–5 of the menstrual cycle. Starting the day after the last dose of relugolix, a 1 mg dienogest tablet will be administered orally twice daily for 24 weeks. Before the first dose of dienogest, patients will take a urine human chorionic gonadotropin test to exclude pregnancy. Patients in the dienogest group will receive an oral dienogest tablet 1 mg twice daily for 24 weeks, with the first dose on days 2–5 of the menstrual cycle.

Fig. 1

Study design

Patients will record their intakes of relugolix and/or dienogest in their patient diary from the first through to the last dose, to monitor and improve adherence to treatment with relugolix and dienogest.

Concomitant treatments

During the study, patients will be allowed to take the following concomitant treatments: nonsteroidal anti-inflammatory drugs for unbearable endometriosis-associated pain, Chinese herbal medicines and supplements to ease the symptoms of endometriosis and relugolix/dienogest-related TEAEs, and drugs for diseases other than endometriosis. During the study period, patients will use contraceptives other than oral contraceptives and intrauterine devices. From visit 1 to the end of the study period or study withdrawal, patients will be prohibited from taking GnRH agonists or antagonists (except relugolix), sex hormones (except dienogest), antihormones, anticoagulants, and hemostatic agents.

Ethical considerations

This study protocol has been approved by the Certified Review Board (CRB) of Tottori University Hospital (version 1.3, approval number: 23C004, 30 January 2024), and the study is registered in Japan Registry of Clinical Trials (JRCT) ID (registration number: jRCTs061230064, 29 September 2023). Any changes and/or revision to the study protocol, informed consent form (see Additional file 1 for an approved informed consent form), or other study-related documents will need to be approved by the CRB. Upon approval of these changes, the principal investigator will notify investigators, who will then notify each study site and explain the protocol changes to the patients after the study site has approved them. Data collected in this study may be used for future studies without identifiable personal information; if new studies are carried out using the data, new study protocols and consent forms will be prepared and approved. No patients’ samples or specimens will be stored. This study will be conducted following ethical committee guidelines, the Declaration of Helsinki, Clinical Trials Act (Act No. 16, 2017), and Act on the Protection of Personal Information (Act No. 57, 2003). The study protocol is reported following the SPIRIT reporting guidelines [12] (Additional file 2: SPIRIT checklist).

Participants and eligibility criteria

Inclusion criteria

• 1. Premenopausal Japanese patients aged ≥ 18 years at the time of informed consent

• 2. Patients with endometriosis, diagnosed by one of the following methods, and, in the case of recurrence after surgical treatment of endometriosis, patients re-diagnosed with one of the following methods:

  • Laparotomy or laparoscopy performed within 5 years prior to visit 1

  • Ovarian endometrioma diagnosed using magnetic resonance imaging within 1 year prior to visit 1 or ultrasound (transvaginal, transabdominal, or transrectal) at visit 1 or visit 2

  • Diagnosed with clinical endometriosis and with either induration in the pouch of Douglas, restricted uterine mobility, or pelvic tenderness by internal or rectal examination performed at visit 1 or visit 2 [1, 13]

Reason: This study will include patients with clinical endometriosis, because drug treatment may be initiated following a comprehensive diagnosis based on subjective symptoms, examinations, and test findings in a real clinical setting.

• 3. Maximum VAS score > 30 for endometriosis-associated pain during the screening period, including more than one menstrual period

Reason: The threshold VAS > 30 is based on a previous report demonstrating that a VAS ≤ 30 indicated a pain level that did not interfere with the patient’s daily life [1]

• 1. Dysmenorrhea or pelvic pain of moderate or greater severity on the Biberoglu & Behrman (B&B) scale at visit 2

• 2. Cyclic menstruation

• 3. Agreed appropriate contraception on a daily basis from the time of informed consent and throughout the study

Exclusion criteria

• 1. Use of sex hormones within 4 weeks prior to obtaining consent

• 2. Use of GnRH analogs within 12 weeks prior to obtaining consent

• 3. Ovarian endometrioma ≥ 10 cm and age ≥ 40 years at the time of image inspection

• 4. History of total hysterectomy or bilateral oophorectomy

• 5. Complications of undiagnosed abnormal genital bleeding

• 6. Lower abdominal pain due to irritable bowel syndrome or severe interstitial cystitis

• 7. Complications of pelvic infection

• 8. Malignant tumors

• 9. History or complications of severe hypersensitivity or severe adverse reactions to relugolix or dienogest

• 10. Pregnant, lactating, planning to become pregnant between the time of informed consent and 1 month after completion of the study, or planning to donate eggs during this period

• 11. Deemed by the principal investigators to be unsuitable to participate in this study

Study discontinuation criteria

The investigators will discontinue participation by patients who meet any of the following discontinuation criteria before final assessments.

• 1. Investigator determines that a patient experiences TEAEs that make the study difficult to continue

• 2. Patients who do not meet the inclusion criteria or who meet the exclusion criteria

• 3. Pregnancy

• 4. Patients request to withdraw from the study

• 5. Inability to continue the study because a patient fails to visit the study site

• 6. Serious study deviation as determined by an investigator

• 7. Other reasons identified by an investigator

Data for patients who discontinue the study will still be included in the analyses, except for patients who request to withdraw their consent.

Outcomes

The schedules of enrollment, intervention, and assessment are reported according to the SPIRIT statement for the relugolix group (Fig. 2) and the dienogest group (Fig. 3).

Fig. 2

Schedule of enrollment, interventions, and assessments in SPIRIT format in the relugolix group. B&B Biberoglu & Behrman, EHP-30 Endometriosis Health Profile 30, WHO-HPQ WHO Health and Work Performance Questionnaire, EQ-5D EuroQol 5 Dimension, VAS visual analog scale, PBAC pictorial blood loss assessment chart, TEAE treatment-emergent adverse event. ^aAfter visit 1, each patient will visit the study site on days 2–5 of the second or subsequent menstrual period (visit 2). During visit 2, patients will register, receive a prescription for the study drug(s), and start taking the study drug. ^bPatients will take relugolix until 1 day before visit 5, and start dienogest treatment after all tests have been completed and negative pregnancy test results are confirmed. ^cTest results carried out during the screening period can be used as baseline data. ^dFor lumbar spine dual-energy X-ray absorptiometry data up to 4 weeks before informed consent may be used as baseline data

Fig. 3

Schedule of enrollment, interventions, and assessments in SPIRIT format in the dienogest group. B&B Biberoglu & Behrman, EHP-30 Endometriosis Health Profile 30, WHO-HPQ WHO Health and Work Performance Questionnaire, EQ-5D EuroQol 5 Dimension, VAS visual analog scale, PBAC pictorial blood loss assessment chart, TEAE treatment-emergent adverse event. ^aAfter visit 1, each patient will visit the study site on days 2–5 of the second or subsequent menstrual period (visit 2). During visit 2, patients will register, receive a prescription for the study drug, and start taking the study drug. ^bTest results carried out during the screening period can be used as baseline data. ^cFor lumbar spine dual-energy X-ray absorptiometry data up to 4 weeks before informed consent may be used as baseline data

The primary outcome will be change from baseline in maximum VAS score for endometriosis-associated pain during the primary evaluation period (last 28 days of the relugolix treatment period in the relugolix group, and 28 days from 13 to 16 weeks during the dienogest treatment period in the dienogest group). Endometriosis-associated pain is defined as pelvic pain associated with endometriosis occurring throughout the menstrual cycle (during and outside the menstrual period). The maximum VAS score is the highest VAS score observed during the evaluation period among the maximum patient-recorded pain within each 24 h.

The secondary outcomes will be:

• 1. Change from baseline in mean VAS score for endometriosis-associated pain during the primary evaluation period.

• 2. Maximum VAS score for endometriosis-associated pain every 28 days after administration and each change from baseline.

• 3. Mean VAS score for endometriosis-associated pain every 28 days after administration and each change from baseline.

• 4. Maximum VAS score for dysmenorrhea every 28 days after administration and each change from baseline.

• 5. Mean VAS score for dysmenorrhea every 28 days after administration and each change from baseline.

• 6. Maximum VAS score for nonmenstrual pelvic pain every 28 days after administration and each change from baseline.

• 7. Mean VAS score for nonmenstrual pelvic pain every 28 days after administration and each change from baseline.

• 8. VAS score for dyspareunia and changes from baseline at each visit.

• 9. B&B scores for dysmenorrhea, pelvic pain (outside the menstrual period), dyspareunia and each change from baseline.

• 10. Severity of induration in the pouch of Douglas, restricted uterine mobility, and pelvic tenderness and changes from baseline.

• 11. Disease-specific QOL (Endometriosis Health Profile 30 [EHP-30]) score.

• 12. Health-related QOL (EuroQol 5 Dimension [EQ-5D]) score.

• 13. Work Productivity (WHO Health and Work Performance Questionnaire [WHO-HPQ] short form, Japanese edition) score.

• 14. Number of days and rate of analgesic medication use every 28 days after administration and change from baseline.

• 15. Maximum ovarian endometrioma diameter and change from baseline. For multiple ovarian endometriomas, record up to three largest diameters of cysts in the EDC [14].

The safety outcome measures will be TEAEs and drug-related TEAEs, hemoglobin level, alanine transaminase, aspartate aminotransferase, E₂, bone density (lumbar spine using dual-energy X-ray absorptiometry), bone markers (tartrate-resistant acid phosphatase 5b, bone-specific alkaline phosphatase), menstrual status, genital bleeding (pictorial blood loss assessment chart [PBAC] and score bleeding from 0 [none] to 5 [heavy]), and endometrial thickness, measured as a double layer in medio-sagittal sections by ultrasound (transvaginal or transrectal).

Pelvic pain on VAS, genital bleeding (PBAC and score bleeding from 0 [none] to 5 [heavy]), and analgesic and other concomitant drug use will be recorded by patients in a patient diary.

Treatment-emergent adverse events

TEAEs in this study refer to any undesirable or unintended injury, illness, or symptom experienced by patients, irrespective of the causal relationship to the study. If a patient experiences a TEAE, an investigator will take appropriate measures for the patient and enter the name of the TEAE, date of occurrence, severity, seriousness, predictability, outcome/date of outcome, and causal relationship with the study drug(s) in the EDC. An investigator must report the occurrence of a TEAE that is suspected to be caused by the study drugs to the study site and the principal investigator. The principal investigator then must notify the CRB of the TEAE occurrence and discontinue the study or take other necessary measures.

Although no serious harm is expected, any patients harmed as a direct result of taking part in this study will receive appropriate examinations and treatments within the scope of medical insurance, as for regular medical treatment. After completion of this study, the investigators will provide patients with the best possible treatment.

Data collection and management

The original data source is the EDC, which is retained at each study site. The following baseline information will be collected by an investigator: date of birth, height, body weight, body mass index, pregnancy/past childbirth, endometriosis diagnosis method, date of endometriosis diagnosis, presence or absence of endometriosis surgery (if yes, date of surgery), presence or absence of hormone therapy for endometriosis, medical history, and complications, presence or absence of and uterine fibroids, submucosal fibroids, and adenomyosis by ultrasound (visit 1 and/or 2).

No data monitoring committee or audit has been formally planned for this study because there are low risks to patient safety. However, the data will be monitored. As an on-site monitoring strategy, we plan to monitor until the end of the study period the first patient registered at each study site. We will also monitor if the patient provided written consent and met eligibility criteria. If no issue is found with the patient, monitoring will cease. In addition, patients with study-related serious adverse events or major deviations from the study protocol will be monitored irrespective of the order of registration.

Patient data will be coded and kept confidential by the investigators, and managed by an outsourced subcontractor that will be in charge of collecting case report forms, data fix, quality control, and analyses. The following procedures will be implemented and monitored to ensure that this study is conducted safely and in accordance with the study protocol and applicable guidelines and that the data are collected accurately.

• 1. The human rights of participants will be protected and their safety ensured.

• 2. The study will be carried out in compliance with the latest study plan, protocol, and Clinical Research Act.

• 3. Written consent will be obtained from all patients.

• 4. The accuracy of records will be verified by checking the source documents.

All data related to this study will be stored by the principal investigators and investigators for 5 years after the completion of this study in accordance with the guidelines.

The clinical research organization provides administrative support and is responsible for data management and statistical analyses. The clinical research coordinators establish the clinical research center at each facility and assist principal investigators on day-to-day organizational work.

Data analyses

Sample size estimation

For evaluating the change in maximum VAS score for endometriosis-associated pain from baseline after 16 weeks of treatment, the standard deviation was estimated to be 25, based on previous studies of relugolix or dienogest, with an assumption of no difference between the two treatment groups [1, 15]. The non-inferiority margin was set at 15.0, based on the results of a previous comparative study of leuprorelin and dienogest in patients with endometriosis [15]. Based on our estimates, 45 patients will be needed in each treatment group to verify the non-inferiority of relugolix to dienogest using t-tests with a power of 80% and a type I error of 2.5% (one-sided). Considering approximately 10% unevaluable patients, a sample size of 50 patients in each treatment group has been set. To achieve adequate participant enrollment to reach the target sample size, we selected study sites that could secure eight to nine patients within 12 months.

Statistical analyses

Efficacy outcomes will be evaluated in the full analysis set, consisting of all patients except those not treated with any study drug, without efficacy data, or those who did not provide consent. In addition, the efficacy outcomes will be evaluated in the per protocol set, excluding patients from the full analysis set who did not meet the inclusion criteria or who met the exclusion criteria, with adherence to the study drug < 80%, or with serious violation of the study protocol. Safety outcomes will be evaluated in the safety analysis set, including all patients who received the study drug at least once. All data will be used and missing values will not be imputed, unless otherwise specified.

All statistical analyses will be performed using SAS version 9.4 (SAS Institute, Tokyo, Japan) software. Regarding baseline patient characteristics, continuous variables will be described as mean (standard deviation) or median (25% and 75% percentiles), and categorical variables will be described as frequency or percentage. The primary outcome will be analyzed by presenting summary statistics at each time point, followed by t-tests at a significance level of 2.5% (one-sided), and 95%CIs will be also calculated. Secondary outcomes will be analyzed by the same procedures, except t-tests. For the safety analyses, TEAEs and drug-related TEAEs will be summarized by system organ class and preferred term based on the Medical Dictionary for Regulatory Activities, and the number of patients and incidence rate will be obtained for each event. In the relugolix group, separate analyses will be carried out for the relugolix treatment period (up to 16 weeks) and the dienogest treatment period (after 17 weeks). Other safety outcomes will be analyzed as for the secondary outcomes.

A preliminary analysis will be carried using data recorded from visit 1 to day 113 (treatment period), excluding genital bleeding in the patient diary, and data obtained from visit 1 to visit 5.

Participant retention

At the time of consent, patients will be given a full explanation of the content and significance of the study. At each visit, an appointment for the next visit will be made, and the date of the visit will be written on the cover page of the patient diary.

Discussion

Management options for endometriosis-associated symptoms, including control of hormone levels, are still suboptimal. Currently available treatments for endometriosis symptoms, such as the progestin preparation dienogest, and the GnRH agonists leuprorelin and buserelin, are known to cause unfavorable side effects [2,3,4,5,6]. This READY study will investigate the efficacy of the GnRH antagonist relugolix in patients with endometriosis, with the expectation that pretreatment with relugolix will reduce the incidence rate of abnormal uterine bleeding caused by dienogest. The first aim of the READY study is to compare the efficacy of relugolix with that of dienogest for reducing endometriosis-associated pain. To achieve this, the study is designed to test the non-inferiority of relugolix to dienogest for reducing the VAS score for assessing endometriosis-associated pain in patients treated for 16 weeks with either 40 mg relugolix once daily or 1 mg dienogest twice daily. This study will also investigate if prior treatment with relugolix can reduce the incidence rate of dienogest-induced abnormal uterine bleeding, by treating patients with 1 mg dienogest twice daily for 24 weeks with or without prior treatment with 40 mg relugolix once daily for 16 weeks.

Although estroprogestins and progestins are the first-line therapies for managing endometriosis-associated symptoms, they are only effective in two-thirds of patients [16]. Among several alternative therapies, GnRH agonists and antagonists might provide promising clinical outcomes, if their hypoestrogenic side effects can be better managed. Relugolix in combination with E₂ and norethisterone acetate demonstrated efficacy and safety in a recent study [17], with improved endometriosis symptoms and reduced hypoestrogenic side effects. Accordingly, we expect that the current study will demonstrate the non-inferiority of relugolix to dienogest in alleviating endometriosis-associated pain, with a reduced incidence rate of dienogest-induced bleeding.

The strengths of this study are its multicenter, randomized, controlled design, including sufficient patients to evaluate the non-inferiority of relugolix to dienogest. Furthermore, the dosing regimen will be similar to that used in actual clinical practice. Relugolix was administered for 6 months in the previous study [1], but will be administered for 4 months in this study because administration for 6 months increases the number of patients likely to withdraw treatment due to hypoestrogenic side effects. We will therefore obtain results relevant to real clinical settings.

A limitation of this study is that it is not double-blinded; however, it is not ethical to treat patients in the dienogest group with placebo for 16 weeks while patients in the relugolix group are treated with relugolix, and the study was therefore designed as an open-label study.

In conclusion, the READY study will investigate the efficacy of relugolix for improving endometriosis-associated pain and dienogest-induced abnormal uterine bleeding in patients with endometriosis. Upon completion of this randomized, controlled study, we expect to be able to suggest treatment options for endometriosis-associated pain, and to recommend new treatment regimens to reduce dienogest-induced abnormal uterine bleeding in line with evidence-based results.

Trial status

The current protocol is version 1.3 dated 30 January 2024. Recruitment began on 29 September 2023 and is open until 30 September 2024. The study is anticipated to be completed by 31 May 2026.