Evaluating the Efficacy and Safety of 48-Week Low-Dose Dienogest Administration in Patients With Dysmenorrhea Caused by Endometriosis: Protocol for a Randomized, Open-Label, Parallel-Group Trial (Preprint)

Kyoko Kikuno, Ryuta Asada, Takuma Ishihara, Yoshimasa Bomoto, Saki Murase, Yoko Ueda, Tomomi Shiga, Yoh Hayasaki, Tatsuro Furui, Satoko Matsuzaki, Masahiko Takemura, Kazutoshi Matsunami, Makoto Kubo, Naoki Ito, Masanori Isobe, Ken-Ichirou Morishige
2024 · doi:10.2196/preprints.66246 · W4402592308
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⚙ AI-generated summary by claude@2026-06, 2026-06-10 ⓘ

This study is evaluating the efficacy and safety of 48-week low-dose dienogest (1 mg/day vs 2 mg/day) for dysmenorrhea caused by endometriosis.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 · read from full text ⓘ

This paper describes a randomized, open-label, multicenter trial protocol in Japan evaluating the efficacy and safety of 48 weeks of low-dose dienogest at 1 mg/day versus 2 mg/day in patients with dysmenorrhea caused by endometriosis. Using a 1:1 allocation, the study will assess changes in pain on the Visual Analogue Scale as the primary endpoint, with side effects and additional evaluations including questionnaires, vital signs, MRI/ultrasound, blood tests, and bone density testing; the target sample size is 88 participants with a non-inferiority margin based on prior reports. The authors note a key context/caveat that evidence on long-term dienogest effectiveness and adverse events remains limited and that dose-comparison data beyond existing shorter-term findings are scarce, motivating the trial design. Relevance to endometriosis: the trial is explicitly designed for “dysmenorrhea caused by endometriosis,” with efficacy assessed against both pain and endometriosis-related disease activity via combined imaging and laboratory measures.

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Abstract

BACKGROUND The treatment of endometriosis includes analgesics, hormone therapy, and surgery. Even after surgical removal of endometriotic lesions, the risk of recurrence remains high once the normal menstrual cycle resumes. Therefore, long-term hormone therapy is essential to prevent recurrence. Among hormonal treatments, low-dose estrogen progestin preparations are not recommended for patients older than 40 years due to the increased risk of thrombotic side effects. In contrast, dienogest does not carry a thrombotic risk, making it a suitable option for older patients. Although dienogest requires long-term administration until menopause in patients with endometriosis, data on its long-term efficacy and potential adverse effects remain limited. In particular, comparative studies assessing the safety and effectiveness of long-term use of dienogest at different doses (1 mg/day vs 2 mg/day) have not been conducted, highlighting the need for further investigation. OBJECTIVE The purpose of this study is to investigate the efficacy and the incidence of adverse events of dienogest 1 mg/day after 48 weeks in patients with dysmenorrhea due to endometriosis, compared with dienogest 2 mg/day. METHODS This randomized, open-label, parallel-group, dose-comparison, multicenter trial follows the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 guidelines and is conducted at 6 centers in Japan. Participants are randomly assigned in a 1:1 ratio to receive either dienogest 1 mg/day or 2 mg/day. The drug is administered for 48 weeks, and its therapeutic effects and side effects are evaluated. Hospital visits include the use of questionnaires, vital sign measurements, imaging studies (magnetic resonance imaging and ultrasound), blood tests, and bone density assessments. The primary endpoint is the change in the pain visual analog scale (VAS) score from baseline to 48 weeks. The VAS is a 10 cm horizontal scale where 0 cm represents no pain and 10 cm represents the maximum imaginable pain; participants indicate their pain level on the scale, and the change is analyzed over time. The target sample size is 88, determined with a noninferiority margin based on existing literature. The protocol was approved by the Nagoya City University Hospital Clinical Research Review Board. Findings will be presented at academic conferences and published in peer-reviewed journals. RESULTS Currently, data collection is ongoing. The first participant was enrolled in August 2021. As of March 22, 2025, a total of 88 participants had been enrolled in this clinical trial. CONCLUSIONS This is the first trial to compare efficacy and safety between 1 mg/day and 2 mg/day of long-term dienogest use in patients with dysmenorrhea caused by endometriosis. Combining diagnostic imaging with patient questionnaires and blood tests allows the determination of efficacy against endometriosis itself. CLINICALTRIAL Japan Registry of Clinical Trials jRCTs041210016; https://jrct.mhlw.go.jp/en-latest-detail/jRCTs041210016 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/66246
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Abstract

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. Clinical Trial: jRCTs041210016. Citation Request queued. Please wait while the file is being generated. It may take some time. Copyright © The authors. All rights reserved. This is a privileged document currently under peer-review/community review (or an accepted/rejected manuscript). Authors have provided JMIR Publications with an exclusive license to publish this preprint on it's website for review and ahead-of-print citation purposes only. While the final peer-reviewed paper may be licensed under a cc-by license on publication, at this stage authors and publisher expressively prohibit redistribution of this draft paper other than for review purposes.

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Outcome instruments

VAS-pain

Condition tags

endometriosisdysmenorrhea

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