Key Trials

Introduction

The management of endometriosis is aimed towards alleviating the severity of symptoms including pain. The use of gonadotropin releasing hormone (GnRH) agonists is limited to short term in the absence of add back therapy since they are associated with symptoms of estrogen deprivation and bone demineralization. The adverse androgenic side effects are high with danazol. Although progestins provide effective control of the symptoms associated with endometriosis, their tolerability is dose-dependent. Recent studies have demonstrated consistent efficacy and safety of dienogest, a selective progestin, with no androgenic and estrogenic effects.

Aim

To compare the efficacy and safety of dienogest 1 mg, 2 mg and 4 mg orally once daily over 24 weeks in order to determine the lowest effective dose in the treatment of endometriosis.

Method

Study Design

• Open-label, randomized, multicenter, 24-week trial
• A total of 68 patients were randomly assigned to the 3 treatment groups
  
  • Dienogest 1 mg (n=4), 2 mg (n=29) and 4 mg (n=35)

• Statistical tests included x² and Wilcoxon signed rank tests

Inclusion Criteria

• Women between menarche and menopause
• Histologically proven endometriosis stages I-III as per revised American Society of Reproductive Medicine (r-AFS)

Endometriosis confirmed by diagnostic laparoscopy

End Points

Primary End Points

• Change in stage of endometriosis as per rAFS classification, based on laparoscopy performed within 2 weeks of study onset and repeated within 2 weeks of study end
• Proportions of women at each stage before and after treatment
• Mean change in rAFS scores before and after treatment
• Incidences of adverse events

Secondary End Points

• Patient reported symptoms like pelvic pain, dysmenorrhea and dyspareunia at weeks 6, 12 and 24
• Gynaecological examination at baseline and at week 24

Results

• Irregular menstrual bleeding led to prematurely halting of randomization in the 1 mg group
• The study was completed by 57 patients (83.8%)
• The severity of endometriosis reduced in both 2 mg and 4 mg groups

• The histological examination at 24 weeks demonstrated no endometriosis in one-third and half of the women in the 2 mg and 4 mg groups respectively
• The mean rAFS scores significantly reduced with dienogest at 24 weeks in both the groups as seen in table 1.

• There were significant improvements in symptoms such as dyspareunia, diffuse pelvic pain, dysmenorrhea and premenstrual pain in both the groups as seen in figure 2.

• Both the doses were well tolerated, with low discontinuation rates due to adverse events
• The most commonly reported adverse events were reported in more than 5% of the total cohort
• The incidence of adverse events in the 2 mg and 4 mg groups were back pain (10.3% vs 5.9%), fatigue (10.3% vs 2.9%), painful defecation (6.9% vs 5.9%), breast discomfort (3.4% vs 8.8%), breast pain (3.4% vs 11.8%) and alopecia (3.4% vs 14.7%), respectively
• Irregular bleeding was reported in 55.2% and 68.6% in 2mg and 4 mg groups respectively

Conclusion

• Dienogest 2 mg daily was the lowest effective dose for the treatment of endometriosis
• Dienogest 2 mg was associated with a slightly superior tolerability profile than 4 mg dose
• The optimal dose of 2 mg once a day has been recommended for future studies on endometriosis

Eur J Obstet Gynecol Reprod Biol. 2010 Aug;151(2):193-8. Doi:10.1016/j.ejogrb.2010.04.002.