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A randomized, open-label, parallel-group controlled trial investigating the efficacy and safety of long-term low-dose Dienogest in patients with dysmenorrhea due to endometriosis

The efficacy and safety of long-term low-dose Dienogest in patients with dysmenorrhea due to endometriosis.

88

Median age at consent was 42 (35-47) years in the Dienogest 1 mg group and 42 (35-47) years in the Dienogest 2 mg group. Baseline VAS was 60.0 mm (30-79.0 mm) in the Dienogest 1 mg group and 70.0 mm (39.0-80.0 mm) in the Dienogest 2 mg group.

Of the 88 patients who gave consent, 42 were randomly assigned to the Dienogest 1 mg group and 46 to the Dienogest 2 mg group. 83 of the 88 patients (excluding 3 patients who did not meet the selection criteria and 2 patients for whom no VAS data, the primary endpoint, could be obtained) were assigned to the FAS. Dienogest 1 mg group: 39 patients, Dienogest 2 mg group: 44 patients) were included in the FAS. From the FAS, 71 patients (35 in the Dienogest 1 mg group, 44 in the Dienogest 2 mg group) were included in the FAS, excluding 4 patients with at least one intolerance or deficit in the study treatment period for the primary endpoint, 4 patients who withdrew during the study, and 4 patients who were judged by the principal/partner investigator to be unable to continue the study because of adverse events, The safety analysis population included 71 patients (35 in the Dienogest 1 mg group and 36 in the Dienogest 2 mg group). The safety analysis population was 87 patients (42 in the Dienogest 1 mg group and 45 in the Dienogest 2 mg group), excluding one patient who never received the study drug.

The incidence of irregular organ bleeding was as shown in the table below. Dienogest 1mg Dienogest 2mg Week 4 13 (41.9%) 15 (45.5%) Week 12 23 (63.9%) 28 (75.7%) Week 24 21 (55.3%) 20 (54.1%) Week 36 19 (50.0%) 18 (46.2%) Week 48 19 (47.5%) 15 (39.5%) Adverse events other than low estrogen symptoms and irregular genital bleeding were observed in 3 patients, all in the Dienogest 2 mg group. They were nausea, malignant lymphoma, and genital bleeding. Serious adverse events included ovarian tumor infection in one patient, but a causal relationship was judged to be negative.

VAS change from baseline to 48 weeks post-treatment (PPS) The mean (95% confidence interval) change in VAS was 44.63 mm (35.17, 54.09) in the 1 mg Dienogest group and 54.19 mm (44.75, 63.64) in the 2 mg Dienogest group, with a difference of -9.57 mm (-22.7, 3 The lower confidence limit of the 95% confidence interval was -9.57 mm (-22.7, 3.56). The lower confidence limit of the 95% confidence interval was -22.7, which did not exceed the pre-specified non-inferiority margin of 15, so non-inferiority was not verified. The upper confidence limit for the 95% confidence interval was 15.74, which exceeded the pre-specified margin of non-inferiority of 15, thus non-inferiority was not verified. VAS change from baseline to 12, 24, and 36 weeks post-treatment (PPS) The mean (95% confidence interval) change in VAS after 12 weeks of treatment was 38.2 [28.45, 47.95] in the Dienogest 1 mg group and 51.11 [40.84, 61.39] in the Dienogest 2 mg group. The mean (95% confidence interval) change in VAS after 24 weeks of treatment was 43.66 (34.49, 52.83) in the Dienogest 1 mg group and 48.14 (36.76, 59.52) in the Dienogest 2 mg group. The mean (95% confidence interval) change in VAS after 36 weeks of treatment was 49.63 (40.63, 58.63) in the Dienogest 1 mg group and 45.53 (35.05, 56.01) in the Dienogest 2 mg group. Change in dysmenorrhea score (PPS) from baseline to 12, 24, 36, and 48 weeks post-treatment The mean (95% confidence interval) change in dysmenorrhea score from baseline to 12, 24, 36, and 48 weeks after treatment was as shown in the table below. Dienogest 1mg Dienogest 2mg Week 48 2.09 [-2.67, -1.51] -2.44 [-3.06, -1.83] Week 12 -1.86 [-2.44, -1.27] -2.28 [-2.92, -1.63] Week 24 -1.83 [-2.5, -1.15] -2.39 [-2.96, -1.82] Week 36 -2.49 [-3.11, -1.87] -2.31 [-3, -1.62] Percentage reduction in ovarian endometriotic cyst size (PPS) from baseline to 12, 24, 36, and 48 weeks post-treatment. The mean (95% confidence interval) reduction in ovarian endometriotic cyst size from baseline to 12, 24, 36, and 48 weeks after treatment was as shown in the table below. Dienogest 1mg Dienogest 2mg Week 48 -0.37 [-0.62, -0.12] -0.5 [-0.81, -0.18] Week 12 -0.35 [-0.59, -0.12] 0.17 [-1.02, 1.35] Week 24 0.18 [-0.65, 1.01] -0.04 [-1.02, 0.94] Week 36 -0.46 [-0.64, -0.27] -0.41 [-0.73, -0.1] Incidence of low estrogen symptoms during the study treatment period (safety analysis population) Dienogest 1mg Dienogest 2mg Week 4 30 (71.4%) 33 (73.3%) Week 12 32 (76.2%) 33 (73.3%) Week 24 31 (75.6%) 34 (81.0%) Week 36 31 (77.5%) 34 (85.0%) Week 48 32 (80.0%) 30 (78.9%) Change in Menopausal Score from Baseline to Weeks 12, 24, 36, and 48 (safety analysis population) The mean (95% confidence interval) change in menopausal score from baseline to 12, 24, 36, and 48 weeks after treatment was as shown in the table below. Dienogest 1mg Dienogest 2mg Week 48 -4.95 [-7.09, -2.82] -4.93 [-7.45, -2.42] Week 12 -4.12 [-6.12, -2.12] -5.11 [-7.59, -2.63] Week 24 -3.52 [-5.83, -1.21] -5 [-7.51, -2.49] Week 36 -3.26 [-5.08, -1.44] -4.38 [-6.7, -2.06] Change in bone mineral density (g/cm2) from baseline to 12, 24, 36, and 48 weeks after treatment (safety analysis population) The mean (95% confidence interval) change in femur bone mineral density from baseline to 12, 24, 36, and 48 weeks after treatment was as shown in the table below. Dienogest 1mg Dienogest 2mg Week 48 -0.003 [-0.015, 0.008] -0.012 [-0.033, 0.008] Week 12 0.001 [-0.001, 0.003] 0.003 [-0.003, 0.009] Week 24 -0.001 [-0.005, 0.002] 0.003 [-0.007, 0.014] Week 36 -0.001 [-0.005, 0.003] 0.004 [-0.007, 0.014] The mean (95% confidence interval) change in vertebral bone density from baseline to 12, 24, 36, and 48 weeks after treatment was as shown in the table below. Dienogest 1mg Dienogest 2mg Week 48 -0.005 [-0.02, 0.011] -0.024 [-0.045, -0.003] Week 12 -0.001 [-0.003, 0.001] 0 [-0.001, 0] Week 24 -0.001 [-0.002, 0.001] 0 [-0.001, 0] Week 36 -0.001 [-0.002, 0.001] 0.001 [-0.003, 0.004] Change in blood estradiol concentration from baseline at 12, 24, 36, and 48 weeks (safety analysis population) The mean (95% confidence interval) change in blood estradiol concentration from baseline to 12, 24, 36, and 48 weeks after treatment was as shown in the table below. Dienogest 1mg Dienogest 2mg Week 48 -90.45 [-152.51, -28.39] -104.73 [-150.6, -58.86] Week 12 -94.93 [-157.65, -32.21] -101.38 [-144.6, -58.16] Week 24 -47.76 [-121.46, 25.94] -79.89 [-133.43, -26.35] Week 36 -98.55 [-159.11, -37.99] -104.91 [-151.12, -58.7]

The "dose" was 44.63 mm (35.17, 54.09) in the Dienogest 1 mg group and 54.19 mm (44.75, 63.64) in the Dienogest 2 mg group, suggesting that the 2 mg group may be more effective for pain, for which non-inferiority was not tested. The change in bone mineral density from baseline to 48 weeks after treatment was lower in the Dienogest 2 mg group than in the Dienogest 1 mg group, suggesting that Dienogest 1 mg/day may be safer during long-term treatment.

Oct. 31, 2025

Yes

Undecided. We are currently evaluating the feasibility of IPD sharing in compliance with ethical guidelines and patient consent.

https://jrct.mhlw.go.jp/latest-detail/jRCTs041210016

Kikuno Kyoko

Gifu University Hospital

1-1 Yanagido Gifu,Gifu

kikuno.kyoko.f0@f.gifu-u.ac.jp

Kikuno Kyoko

Gifu University Hospital

1-1 Yanagido Gifu,Gifu

+81-58-230-6000

kikuno.kyoko.f0@f.gifu-u.ac.jp

Complete

May. 11, 2021

Interventional

randomized controlled trial

open(masking not used)

dose comparison control

parallel assignment

treatment purpose

1.Patients who have been diagnosed with endometriosis (ovarian endometriotic cyst) and do not plan to undergo surgery
2. Patients with dysmenorrhea
3. Patients who plan to continue using Dienogest for more than 48 weeks.
4.Patients over 20years old to premenopausal at the time of consent
5.Patients who have written consent to participate in this study

1.Patients who have been diagnosed with endometriosis (ovarian endometriotic cyst) and do not plan to undergo surgery
2. Patients with dysmenorrhea
3. Patients who plan to continue using Dienogest for more than 48 weeks.
4.Patients over 20years old to premenopausal at the time of consent
5.Patients who have written consent to participate in this study

Female

dysmenorrhea due to endometriosis

0.5 mg group: Dienogest 0.5 mg twice daily, 1 tablet at a time for 48 weeks.
1 mg group: Dienogest 1 mg twice daily, 1 tablet at a time for 48 weeks.

endometriosis dysmenorrhea

Changes in VAS 48 weeks after baseline administration

1. Incidence of low estrogen symptoms during reserch treatment(quantified using menopausal score)
2. Changes in dysmenorrhea score 48 weeks after dosing from baseline
3. Changes in menopausal score 48 weeks after dosing from baseline
4. Rate of reduction in ovarian endometriotic cyst size 48 weeks after baseline administration
5. Change in bone mineral density 48 weeks after administration from baseline
6. Primary endopoints and secondary endopoints above at 12,24,and 36 weeks.

+81-52-858-7215

Feb. 24, 2021

none