Study protocol for a randomized, open-label, parallel-group dose comparison investigating the efficacy and safety of long-term low-dose dienogest in patients with dysmenorrhea caused by endometriosis; Randomized Controlled Trial (Preprint)

BACKGROUND The treatment of endometriosis includes analgesics and hormone therapy and surgery. Even with surgical removal of endometriotic lesions, there is high risk of recurrence of endometriosis once the normal menstrual cycle is restored. Therefore, long-term hormone treatment is required to prevent recurrence. Among drug therapies, low-dose estrogen progestin (LEP) preparations are difficult to use in patients over 40 years of age because of the risk of thrombotic side effects. Dienogest (DNG) is a drug without the side effect of thrombosis and can be used by patients over 40 years old. Although DNG must be used for a long time, until menopause, in patients with endometriosis, there are few reports on its effectiveness and occurrence of side effects during long-term administration, and these need to be examined and evaluated. Furthermore, in recent years, the efficacy and tolerability of DNG at 1 mg/day has been recognized in studies by Osuga et al., but there are no reports of long-term comparison of doses of 1 mg/day versus 2 mg/day. OBJECTIVE The purpose of this study is to investigate the efficacy and the incidence of adverse events of DNG 1 mg/day after 48 weeks administration in patients with dysmenorrhea due to endometriosis in comparison with DNG 2 mg/day administration. METHODS This study is a randomized, open-label, parallel-group, dose-comparison, multicenter trial performed at six centers in Japan. Subjects are randomly assigned at a 1:1 ratio to DNG 1 mg/day and 2 mg/day groups, the drug is administered for 48 weeks, and the subsequent therapeutic effect and side effects are investigated. At the subjects’ hospital visits, a questionnaire survey, vital signs measurements, and imaging (MRI, ultrasound), blood, and bone density tests are performed. The primary endpoint is the change in the pain Visual Analogue Scale from baseline to 48 weeks after administration. The target number of cases was set to 88 cases by setting a non-inferiority margin based on existing reports. The study protocol was approved by an accredited clinical research review committee (Nagoya City University Hospital Clinical Research Review Board). Data will be presented at academic conferences and published in peer-reviewed journals. RESULTS This is a first trial to compare efficacy and safety between 1 mg/day and 2 mg/day of long-term DNG use in patients with dysmenorrhea caused by endometriosis. By combining diagnostic imaging with patient questionnaires and blood tests, efficacy against endometriosis itself can also be determined. CONCLUSIONS Currently, data collection is ongoing. The first participant was enrolled in August 2021, marking the official start of the experiment. As of the submission of the paper, there are 88 participants. As of August 12, 2024, a total of up to 88 participants have been enrolled in this clinical trial. CLINICALTRIAL jRCTs041210016.